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Adjuvant nivo+ipilimumab fails in kidney cancer, in contrast to pembro
PARIS – contrast with those from a previous trial that showed benefit with another agent.
The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.
The finding was presented at the annual meeting of the European Society for Medical Oncology.
CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.
The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.
Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.
However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.
There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.
In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
Differences between trials
When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”
However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”
Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”
In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”
“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.
Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.
“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.
Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.
He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”
In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.
Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.
“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
Details of the new results
Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.
So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.
Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.
They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.
Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.
The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.
After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.
Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.
Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.
While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.
During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.
In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.
The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.
Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.
Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.
Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”
As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.
He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.
Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”
There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.
The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.
A version of this article first appeared on Medscape.com.
PARIS – contrast with those from a previous trial that showed benefit with another agent.
The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.
The finding was presented at the annual meeting of the European Society for Medical Oncology.
CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.
The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.
Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.
However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.
There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.
In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
Differences between trials
When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”
However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”
Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”
In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”
“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.
Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.
“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.
Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.
He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”
In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.
Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.
“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
Details of the new results
Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.
So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.
Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.
They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.
Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.
The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.
After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.
Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.
Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.
While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.
During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.
In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.
The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.
Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.
Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.
Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”
As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.
He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.
Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”
There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.
The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.
A version of this article first appeared on Medscape.com.
PARIS – contrast with those from a previous trial that showed benefit with another agent.
The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.
The finding was presented at the annual meeting of the European Society for Medical Oncology.
CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.
The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.
Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.
However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.
There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.
In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
Differences between trials
When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”
However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”
Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”
In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”
“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.
Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.
“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.
Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.
He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”
In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.
Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.
“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
Details of the new results
Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.
So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.
Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.
They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.
Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.
The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.
After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.
Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.
Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.
While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.
During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.
In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.
The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.
Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.
Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.
Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”
As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.
He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.
Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”
There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.
The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.
A version of this article first appeared on Medscape.com.
Complete endoscopic healing key when stopping anti-TNFs in IBD
The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.
Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.
“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.
De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.
However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.
Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
Study details
To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.
The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.
The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.
Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.
Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.
All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.
After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.
Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
Better healing, better outcomes
However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.
At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.
Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.
Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.
Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
Reluctance remains
Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.
The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.
“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.
Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”
The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.
“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.
Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.
Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.
“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.
“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.
The study received support from the Dutch Health Insurance Innovation Fund.
Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.
Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.
A version of this article first appeared on Medscape.com.
The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.
Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.
“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.
De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.
However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.
Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
Study details
To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.
The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.
The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.
Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.
Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.
All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.
After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.
Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
Better healing, better outcomes
However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.
At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.
Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.
Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.
Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
Reluctance remains
Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.
The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.
“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.
Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”
The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.
“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.
Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.
Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.
“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.
“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.
The study received support from the Dutch Health Insurance Innovation Fund.
Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.
Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.
A version of this article first appeared on Medscape.com.
The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.
Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.
“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.
De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.
However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.
Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
Study details
To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.
The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.
The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.
Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.
Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.
All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.
After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.
Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
Better healing, better outcomes
However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.
At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.
Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.
Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.
Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
Reluctance remains
Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.
The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.
“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.
Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”
The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.
“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.
Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.
Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.
“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.
“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.
The study received support from the Dutch Health Insurance Innovation Fund.
Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.
Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.
A version of this article first appeared on Medscape.com.
Complete endoscopic healing key when stopping anti-TNFs in IBD
The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.
Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.
“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.
De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.
However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.
Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
Study details
To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.
The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.
The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.
Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.
Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.
All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.
After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.
Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
Better healing, better outcomes
However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.
At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.
Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.
Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.
Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
Reluctance remains
Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.
The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.
“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.
Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”
The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.
“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.
Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.
Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.
“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.
“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.
The study received support from the Dutch Health Insurance Innovation Fund.
Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.
A version of this article first appeared on Medscape.com.
The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.
Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.
“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.
De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.
However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.
Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
Study details
To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.
The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.
The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.
Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.
Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.
All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.
After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.
Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
Better healing, better outcomes
However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.
At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.
Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.
Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.
Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
Reluctance remains
Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.
The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.
“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.
Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”
The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.
“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.
Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.
Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.
“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.
“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.
The study received support from the Dutch Health Insurance Innovation Fund.
Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.
A version of this article first appeared on Medscape.com.
The level of remission in patients with remitting inflammatory bowel disease (IBD) appears to play a major role in whether they will relapse after treatment when biologic therapies are discontinued, according to a new prospective study.
Patients with complete endoscopic healing have half the rate of relapse after withdrawal of anti-tumor necrosis factor alpha (anti-TNF) treatment than those with only partial healing, according to a study published online in Clinical Gastroenterology and Hepatology.
“Applying strict criteria for endoscopic healing and mesalamine treatment ... may lower the risk of relapse after withdrawal of anti-TNF treatment,” write Bas Oldenburg, MD, PhD, a professor at University Medical Center Utrecht, the Netherlands, and colleagues in their analysis of 81 patients.
De-escalation of anti-TNF treatment in IBD patients in remission has the potential to “reduce side effects, including risks of serious infections and malignancies, decrease health care expenditures, and meet patients’ preferences,” they note.
However, withdrawal of the drugs increases the risk of relapse by 30%-45% at 12 months. When patients relapse, reintroduction of anti-TNF therapy returns over 80% to remission.
Although no consensus exists on how to select patients for therapy de-escalation, evidence suggests that persistent inflammation affects outcomes and that the “depth” of endoscopic healing is a key indicator, the authors note.
Study details
To further the knowledge base, they conducted a prospective study of patients in remission to determine the relapse rate following de-escalation of anti-TNF therapy; evaluate relapse factors, including degree of endoscopic healing; and assess outcomes after reintroduction of anti-TNF therapy.
The study was limited to adult patients with IBD with at least 6 months of corticosteroid-free clinical remission, confirmed baseline clinical remission and endoscopic healing, no current hospitalization, and no pregnancy.
The patients underwent elective discontinuation of anti-TNF therapy between 2018 and 2020. The recommended protocol was to measure C-reactive protein (CRP) and fecal calprotectin at 3, 6, 12, and 24 months and to perform endoscopy at 12 months.
Patients also completed questionnaires at baseline and at 3, 6, 12, and 24 months. The authors selected the patient–Harvey-Bradshaw Index for patients with Crohn’s disease and the patient–Simple Clinical Colitis Activity Index for patients with ulcerative colitis and unclassified IBD, as well as the short IBD Quality of Life measure.
Of the 81 patients from 13 centers who took part, 51% had Crohn’s disease. The median duration of remission at baseline was 3.5 years, and the median disease duration was 9.1 years.
All patients had evidence of endoscopic healing, and 88% met the strict criteria for complete endoscopic healing. In 34%, trough levels of anti-TNF treatments were judged to be subtherapeutic.
After withdrawal of the drugs, 25.9% of patients continued on immunomodulators.
Over a median follow-up of 2 years, 49% of patients relapsed, which was confirmed via endoscopy, fecal calprotectin, or CRP in 83% of cases and inferred from treatment escalation for clinical flare in 17%. Rates of relapse were comparable between patients with Crohn’s disease and ulcerative colitis or unclassified IBD and between those discontinuing adalimumab and those stopping infliximab.
Better healing, better outcomes
However, analysis showed that partial endoscopic healing was independently associated with a higher risk of relapse, at an adjusted hazard ratio versus complete endoscopic healing of 3.28.
At 12 months, 70% of patients with partial endoscopic healing had relapsed versus 35% of those with complete endoscopic healing.
Treatment with the anti-inflammatory agent mesalamine (multiple brands) was independently associated with a reduced risk of relapse, at an adjusted hazard ratio of 0.08. No other potential predictors of relapse were identified.
Of the patients who relapsed, 75% restarted anti-TNF treatment, and the majority (87%) were restarted on the same agent at a median of 0.9 years since its withdrawal and a median of 24 days since the onset of relapse.
Clinical remission was achieved at 3 months in 73% of patients who restarted anti-TNF therapy, which was found to restore quality of life and well-being in relapsed patients, the authors report.
Reluctance remains
Stephen B. Hanauer, MD, professor of medicine (gastroenterology and hepatology) at Northwestern University Feinberg School of Medicine, Chicago, said the findings “reinforce the benefits of the maintenance versus the withdrawal of therapy” and “the deeper the remission” the more likely it is to be sustained.
The 35% relapse rate at 12 months, even in patients with compete endoscopic healing, indicates that treatment should be maintained, Dr. Hanauer said.
“What is also relevant, but was not evaluated, is the additional endpoint of histologic healing, which is likely to sustain remissions even longer,” he added.
Nevertheless, Dr. Hanauer said, the “observed relapse rate is important to discuss in shared decision-making with patients.”
The findings are interesting, but the study didn’t follow the patients for long enough to understand why 35% of those with complete endoscopic healing relapsed, Miguel Regueiro, MD, chair of the Cleveland Clinic’s Digestive Disease & Surgery Institute, told this news organization.
“Are there predictors, factors, or other treatments that could be used to reduce that 35% risk of relapse further?” he questioned.
Although the study didn’t clear up that question for Dr. Regueiro, he found it compelling that mesalamine continuation resulted in higher rates of sustained remission after anti-TNF withdrawal among patients with ulcerative colitis.
Dr. Regueiro said that he will not begin recommending withdrawal of advanced therapies, including anti-TNF drugs, in patients who have achieved a stable remission.
“We have not yet found the cure for IBD, and my concern is that patients may relapse with more severe disease than previously and that recurrence of inflammation could have potential risks for complications,” he said.
“Nonetheless, this study is intriguing and important, and at least prompts the discussion of withdrawing therapy in those who have achieved a deep endoscopic remission for a sustained period of time,” Dr. Regueiro added.
The study received support from the Dutch Health Insurance Innovation Fund.
Dr. Oldenburg declares relationships with AbbVie, Celltrion, Ferring, Takeda, Galapagos, Pfizer, Cablon, PBMS, Janssen, and MSD. Other authors also declare numerous relationships. The full list can be found with the original article. Dr. Hanauer declares relationships with AbbVie, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Regueiro declares relationships with AbbVie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., BMS, CME Outfitters, Imedex, GI Health Foundation, Cornerstones, Remedy, MJH Life Sciences, Medscape, MDEducation, WebMD, and HMPGlobal.
A version of this article first appeared on Medscape.com.
Could nivolumab prevent oral cancer in high-risk patients?
(PL), a high-risk precancerous disease, into oral cancer, suggest the results from a phase 2 study.
“We think that immunotherapy as a preventative strategy, either as first-line or even secondary prevention, should be further explored,” said lead researcher Glenn J. Hanna, MD, director, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston.
The research was presented at the European Society for Medical Oncology Annual Congress in Paris.
Oral leukoplakia refers to a white plaque of “questionable cancer risk” that affects about 4% of the global population, Dr. Hanna explained. However, about 5% of leukoplakia cases develop into oral proliferative leukoplakia, an aggressive form of the disease characterized by multifocal lesions. It has a high risk of transformation to oral squamous cell carcinoma (OSCC), at approaching 10% per year, and the 5-year cancer-free survival rate is estimated to be 47%.
While there are no effective therapies to prevent progression to oral cancer, the condition does have a “rich immune microenvironment,” potentially making it amenable to programmed death (PD)-1 blockade, Dr. Hanna said.
His team conducted a single-arm, phase 2 trial involving 33 patients with proliferative leukoplakia with greater than or equal to 2 multifocal lesions, or contiguous lesions of greater than or equal to 3 cm, or a single lesion greater than or equal to 4 cm with any degree of epithelial dysplasia. The median age was 63.2 years, and 55% were women. Just over half (52%) were never smokers.
The main disease subsite was the oral tongue in 39% of participants, followed by the buccal gingiva in 30%, and 24% of patients had a prior diagnosis of OSCC.
Following a pretreatment biopsy at one to three sites, the patients received four doses of nivolumab every 28 days, followed by rebiopsy. At each visit, the patients had intraoral photographs taken of the lesions and measurements taken.
The median time from study registration to the first dose of nivolumab was 9 days. The majority (88%) of patients completed all four doses of nivolumab.
The median time from the first dose of nivolumab to the posttreatment biopsy was 115 days and ranged from 29 to 171 days.
The overall response rate, defined as a greater than or equal to 40% decrease in a composite score combining the size and degree of dysplasia between the pre- and posttreatment assessments, was observed in 36.4% of patients.
After a median follow-up of 14.7 months, the median cancer-free survival was not reached, with cancer events recorded in 21.2% of patients. The median time from the last dose of nivolumab to the first OSCC event was 3.7 months.
Cancer-free survival at 1 year was calculated to be 77.7%, which was unchanged at 2 years. At the final follow-up, all patients were still alive.
Additional analysis of the biopsies revealed that the lesions had programmed death ligand 1 (PD-L1) combined positive scores that ranged from 0 to 80, with 66.7% of patients having a score of greater than or equal to 1. A cutoff score of greater than or equal to 20 did not reveal any significant differences in cancer-free survival rates.
Turning to safety, Dr. Hanna said that nivolumab was associated with “acceptable toxicity” in this “non-cancer population,” with 21.2% of patients experiencing a grade 3-4 adverse event.
The most common adverse events of any grade were fatigue (55%), diarrhea (27%), elevated alanine transaminase levels (18%), elevated aspartate transaminase levels (18%), and other skin disorders (18%).
With a relatively low rate of adverse events and a “clinical benefit” in up to a third of patients, Dr. Hanna said that this was the “first study to our knowledge to demonstrate the potential efficacy of anti–PD-L1 blockade among patients with a high-risk oral precancerous disease.”
Discussing this study at the meeting, Amanda Psyrri, MD, PhD, professor of medical oncology, Attikon University Hospital, Athens, who was not involved in the research, said these data were “very interesting,” but she expressed some reservations over the way the study was conducted.
She said that the composite score to measure response rates was “defined arbitrarily,” its prognostic value “has not been demonstrated,” and also pointed out that mixed responses by lesions within the same patient led to changes in scores.
In addition, the time interval between the end of treatment and lesion rebiopsy was “highly variable,” and the follow-up period was short.
Consequently, Dr. Psyrri believes the importance of the findings is “unclear,” especially as several patients who responded to nivolumab went on to develop cancer anyway, a finding that needs further investigation.
The study was funded by Bristol Myers Squibb.
Dr. Hanna declared relationships with BMS, Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme, Maverick, and Merck.
A version of this article first appeared on Medscape.com.
(PL), a high-risk precancerous disease, into oral cancer, suggest the results from a phase 2 study.
“We think that immunotherapy as a preventative strategy, either as first-line or even secondary prevention, should be further explored,” said lead researcher Glenn J. Hanna, MD, director, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston.
The research was presented at the European Society for Medical Oncology Annual Congress in Paris.
Oral leukoplakia refers to a white plaque of “questionable cancer risk” that affects about 4% of the global population, Dr. Hanna explained. However, about 5% of leukoplakia cases develop into oral proliferative leukoplakia, an aggressive form of the disease characterized by multifocal lesions. It has a high risk of transformation to oral squamous cell carcinoma (OSCC), at approaching 10% per year, and the 5-year cancer-free survival rate is estimated to be 47%.
While there are no effective therapies to prevent progression to oral cancer, the condition does have a “rich immune microenvironment,” potentially making it amenable to programmed death (PD)-1 blockade, Dr. Hanna said.
His team conducted a single-arm, phase 2 trial involving 33 patients with proliferative leukoplakia with greater than or equal to 2 multifocal lesions, or contiguous lesions of greater than or equal to 3 cm, or a single lesion greater than or equal to 4 cm with any degree of epithelial dysplasia. The median age was 63.2 years, and 55% were women. Just over half (52%) were never smokers.
The main disease subsite was the oral tongue in 39% of participants, followed by the buccal gingiva in 30%, and 24% of patients had a prior diagnosis of OSCC.
Following a pretreatment biopsy at one to three sites, the patients received four doses of nivolumab every 28 days, followed by rebiopsy. At each visit, the patients had intraoral photographs taken of the lesions and measurements taken.
The median time from study registration to the first dose of nivolumab was 9 days. The majority (88%) of patients completed all four doses of nivolumab.
The median time from the first dose of nivolumab to the posttreatment biopsy was 115 days and ranged from 29 to 171 days.
The overall response rate, defined as a greater than or equal to 40% decrease in a composite score combining the size and degree of dysplasia between the pre- and posttreatment assessments, was observed in 36.4% of patients.
After a median follow-up of 14.7 months, the median cancer-free survival was not reached, with cancer events recorded in 21.2% of patients. The median time from the last dose of nivolumab to the first OSCC event was 3.7 months.
Cancer-free survival at 1 year was calculated to be 77.7%, which was unchanged at 2 years. At the final follow-up, all patients were still alive.
Additional analysis of the biopsies revealed that the lesions had programmed death ligand 1 (PD-L1) combined positive scores that ranged from 0 to 80, with 66.7% of patients having a score of greater than or equal to 1. A cutoff score of greater than or equal to 20 did not reveal any significant differences in cancer-free survival rates.
Turning to safety, Dr. Hanna said that nivolumab was associated with “acceptable toxicity” in this “non-cancer population,” with 21.2% of patients experiencing a grade 3-4 adverse event.
The most common adverse events of any grade were fatigue (55%), diarrhea (27%), elevated alanine transaminase levels (18%), elevated aspartate transaminase levels (18%), and other skin disorders (18%).
With a relatively low rate of adverse events and a “clinical benefit” in up to a third of patients, Dr. Hanna said that this was the “first study to our knowledge to demonstrate the potential efficacy of anti–PD-L1 blockade among patients with a high-risk oral precancerous disease.”
Discussing this study at the meeting, Amanda Psyrri, MD, PhD, professor of medical oncology, Attikon University Hospital, Athens, who was not involved in the research, said these data were “very interesting,” but she expressed some reservations over the way the study was conducted.
She said that the composite score to measure response rates was “defined arbitrarily,” its prognostic value “has not been demonstrated,” and also pointed out that mixed responses by lesions within the same patient led to changes in scores.
In addition, the time interval between the end of treatment and lesion rebiopsy was “highly variable,” and the follow-up period was short.
Consequently, Dr. Psyrri believes the importance of the findings is “unclear,” especially as several patients who responded to nivolumab went on to develop cancer anyway, a finding that needs further investigation.
The study was funded by Bristol Myers Squibb.
Dr. Hanna declared relationships with BMS, Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme, Maverick, and Merck.
A version of this article first appeared on Medscape.com.
(PL), a high-risk precancerous disease, into oral cancer, suggest the results from a phase 2 study.
“We think that immunotherapy as a preventative strategy, either as first-line or even secondary prevention, should be further explored,” said lead researcher Glenn J. Hanna, MD, director, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston.
The research was presented at the European Society for Medical Oncology Annual Congress in Paris.
Oral leukoplakia refers to a white plaque of “questionable cancer risk” that affects about 4% of the global population, Dr. Hanna explained. However, about 5% of leukoplakia cases develop into oral proliferative leukoplakia, an aggressive form of the disease characterized by multifocal lesions. It has a high risk of transformation to oral squamous cell carcinoma (OSCC), at approaching 10% per year, and the 5-year cancer-free survival rate is estimated to be 47%.
While there are no effective therapies to prevent progression to oral cancer, the condition does have a “rich immune microenvironment,” potentially making it amenable to programmed death (PD)-1 blockade, Dr. Hanna said.
His team conducted a single-arm, phase 2 trial involving 33 patients with proliferative leukoplakia with greater than or equal to 2 multifocal lesions, or contiguous lesions of greater than or equal to 3 cm, or a single lesion greater than or equal to 4 cm with any degree of epithelial dysplasia. The median age was 63.2 years, and 55% were women. Just over half (52%) were never smokers.
The main disease subsite was the oral tongue in 39% of participants, followed by the buccal gingiva in 30%, and 24% of patients had a prior diagnosis of OSCC.
Following a pretreatment biopsy at one to three sites, the patients received four doses of nivolumab every 28 days, followed by rebiopsy. At each visit, the patients had intraoral photographs taken of the lesions and measurements taken.
The median time from study registration to the first dose of nivolumab was 9 days. The majority (88%) of patients completed all four doses of nivolumab.
The median time from the first dose of nivolumab to the posttreatment biopsy was 115 days and ranged from 29 to 171 days.
The overall response rate, defined as a greater than or equal to 40% decrease in a composite score combining the size and degree of dysplasia between the pre- and posttreatment assessments, was observed in 36.4% of patients.
After a median follow-up of 14.7 months, the median cancer-free survival was not reached, with cancer events recorded in 21.2% of patients. The median time from the last dose of nivolumab to the first OSCC event was 3.7 months.
Cancer-free survival at 1 year was calculated to be 77.7%, which was unchanged at 2 years. At the final follow-up, all patients were still alive.
Additional analysis of the biopsies revealed that the lesions had programmed death ligand 1 (PD-L1) combined positive scores that ranged from 0 to 80, with 66.7% of patients having a score of greater than or equal to 1. A cutoff score of greater than or equal to 20 did not reveal any significant differences in cancer-free survival rates.
Turning to safety, Dr. Hanna said that nivolumab was associated with “acceptable toxicity” in this “non-cancer population,” with 21.2% of patients experiencing a grade 3-4 adverse event.
The most common adverse events of any grade were fatigue (55%), diarrhea (27%), elevated alanine transaminase levels (18%), elevated aspartate transaminase levels (18%), and other skin disorders (18%).
With a relatively low rate of adverse events and a “clinical benefit” in up to a third of patients, Dr. Hanna said that this was the “first study to our knowledge to demonstrate the potential efficacy of anti–PD-L1 blockade among patients with a high-risk oral precancerous disease.”
Discussing this study at the meeting, Amanda Psyrri, MD, PhD, professor of medical oncology, Attikon University Hospital, Athens, who was not involved in the research, said these data were “very interesting,” but she expressed some reservations over the way the study was conducted.
She said that the composite score to measure response rates was “defined arbitrarily,” its prognostic value “has not been demonstrated,” and also pointed out that mixed responses by lesions within the same patient led to changes in scores.
In addition, the time interval between the end of treatment and lesion rebiopsy was “highly variable,” and the follow-up period was short.
Consequently, Dr. Psyrri believes the importance of the findings is “unclear,” especially as several patients who responded to nivolumab went on to develop cancer anyway, a finding that needs further investigation.
The study was funded by Bristol Myers Squibb.
Dr. Hanna declared relationships with BMS, Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme, Maverick, and Merck.
A version of this article first appeared on Medscape.com.
‘Unprecedented’ responses to neoadjuvant treatment in dMMR colon cancer
PARIS – was given before surgery to patients with DNA mismatch repair deficient (dMMR) colon cancer, say researchers reporting new results from the NICHE-2 trial.
The trial involved 112 patients with dMMR colon cancer who were given one cycle of low-dose ipilimumab and two cycles of nivolumab followed by surgery.
The results show that 95% of patients had a major pathologic response (MPR), and 67% had a pathologic complete response (pCR) to immunotherapy.
To date, none of these patients have had disease recurrence after a median follow-up of 13.1 months.
Study presenter Myriam Chalabi, MD, an oncologist at the Netherlands Cancer Institute, Amsterdam, described the findings as “unprecedented,” especially as many of the patients had stage 3 and high-risk disease, and the expected disease recurrence rate with standard-of-care adjuvant chemotherapy in these patients would usually have been around 15%.
“Importantly, this treatment was very well-tolerated,” she added.
Dr. Chalabi presented the new results during a presidential session at the European Society for Medical Oncology Congress 2022, held in Paris.
Neoadjuvant immunotherapy “has the potential to become standard of care” in these patients, she said, adding that the “future has never been brighter” for dMMR colon cancer.
Around 10%-15% of colon cancers are dMMR, and around 33% of these are associated with Lynch syndrome, she noted.
She also urged pharmaceutical companies to seek approval for immunotherapy in this patient population, to warm applause from the audience.
Commenting on the results, Andrés Cervantes, MD, PhD, professor of medicine at the University of Valencia, Spain, said in an ESMO press release that the “innovative” study “questions the need for surgery and postoperative chemotherapy in all patients in whom the primary tumor has disappeared.”
He observed that adjuvant chemotherapy has remained standard of care, “despite the fact that chemotherapy is not so active, and a complete disappearance of the tumor in the surgical specimen is not observed.”
Overall, Dr. Cervantes said that dMMR status is a “strong predictor of the positive effect observed with this short-course immunotherapy,” adding that “determining dMMR can be easily done by immunohistochemistry in the conventional pathology lab, without the need for complex molecular testing.”
The “minimal toxicity” seen in the study “may also facilitate the implementation of this strategy, potentially sparing patients from surgery.”
Details of the new results
For the NICHE-2 study, patients with stage cT3 dMMR colon cancer and/or nodal involvement but without metastases and no signs of obstruction received one dose of ipilimumab 1 mg/kg and two doses of nivolumab 3 mg/kg before undergoing surgery within 6 weeks of enrollment.
The 112 participants were a median age of 60 years, and just over half were women. High-risk stage 3 disease was present in 74% of patients, which included 64% of patients with clinical T4a or T4b tumors and 62% with radiologic N2 stage cancer.
Median time from the first immunotherapy dose to surgery was 5.4 weeks.
Immune-related adverse events were seen in 61% of patients, but just 4% of patients experienced grade 3-4 immune-related adverse events, and 2% consequently had a delay in surgery, meaning the study met its primary safety endpoint.
In the end, all patients underwent surgery, with 100% having R0 resections.
A pathologic response was seen in 99% of patients, with 95% having an MPR, defined as less than or equal to 10% residual viable tumor, and 4% a partial response, defined as 10% to less than or equal to 50% residual viable tumor. A pCR, which included both the tumor bed and lymph nodes, was seen in 67% of participants.
There was a borderline significant difference in pCR patients between the 66 patients with sporadic tumors and the 32 with Lynch syndrome, at 58% versus 78% (P = .056).
At the meeting, discussant James Larkin, MD, PhD, consultant medical oncologist, The Royal Marsden, London, who was not involved with the study, agreed that the results were “striking,” with “brief treatment ... [showing] a major effect.”
However, he emphasized that it will be “important” to see the prespecified 3-year disease-free survival data, and he questioned whether the single low dose of ipilimumab was, in fact, necessary.
Dr. Larkin also emphasized that organ-sparing strategies in colon cancer are less “clear cut” than they are in rectal cancer and would require ongoing follow-up with colonoscopies and, potentially, biopsies. He also said it is “critical” to get patients’ views on the desirability of organ sparing.
The study was funded by Bristol Myers Squibb. Dr. Chalabi has reported no financial interests. Disclosures for the other authors are listed with the abstract. Dr. Larkin has declared relationships with Eisai, Novartis, Merck, Pfizer, BMS, iOnctura, Debiopharm, Incyte, MSD, Pierre Fabre, Ibsen, Roche, EUSA Pharma, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, and Nektar Therapeutics.
A version of this article first appeared on Medscape.com.
PARIS – was given before surgery to patients with DNA mismatch repair deficient (dMMR) colon cancer, say researchers reporting new results from the NICHE-2 trial.
The trial involved 112 patients with dMMR colon cancer who were given one cycle of low-dose ipilimumab and two cycles of nivolumab followed by surgery.
The results show that 95% of patients had a major pathologic response (MPR), and 67% had a pathologic complete response (pCR) to immunotherapy.
To date, none of these patients have had disease recurrence after a median follow-up of 13.1 months.
Study presenter Myriam Chalabi, MD, an oncologist at the Netherlands Cancer Institute, Amsterdam, described the findings as “unprecedented,” especially as many of the patients had stage 3 and high-risk disease, and the expected disease recurrence rate with standard-of-care adjuvant chemotherapy in these patients would usually have been around 15%.
“Importantly, this treatment was very well-tolerated,” she added.
Dr. Chalabi presented the new results during a presidential session at the European Society for Medical Oncology Congress 2022, held in Paris.
Neoadjuvant immunotherapy “has the potential to become standard of care” in these patients, she said, adding that the “future has never been brighter” for dMMR colon cancer.
Around 10%-15% of colon cancers are dMMR, and around 33% of these are associated with Lynch syndrome, she noted.
She also urged pharmaceutical companies to seek approval for immunotherapy in this patient population, to warm applause from the audience.
Commenting on the results, Andrés Cervantes, MD, PhD, professor of medicine at the University of Valencia, Spain, said in an ESMO press release that the “innovative” study “questions the need for surgery and postoperative chemotherapy in all patients in whom the primary tumor has disappeared.”
He observed that adjuvant chemotherapy has remained standard of care, “despite the fact that chemotherapy is not so active, and a complete disappearance of the tumor in the surgical specimen is not observed.”
Overall, Dr. Cervantes said that dMMR status is a “strong predictor of the positive effect observed with this short-course immunotherapy,” adding that “determining dMMR can be easily done by immunohistochemistry in the conventional pathology lab, without the need for complex molecular testing.”
The “minimal toxicity” seen in the study “may also facilitate the implementation of this strategy, potentially sparing patients from surgery.”
Details of the new results
For the NICHE-2 study, patients with stage cT3 dMMR colon cancer and/or nodal involvement but without metastases and no signs of obstruction received one dose of ipilimumab 1 mg/kg and two doses of nivolumab 3 mg/kg before undergoing surgery within 6 weeks of enrollment.
The 112 participants were a median age of 60 years, and just over half were women. High-risk stage 3 disease was present in 74% of patients, which included 64% of patients with clinical T4a or T4b tumors and 62% with radiologic N2 stage cancer.
Median time from the first immunotherapy dose to surgery was 5.4 weeks.
Immune-related adverse events were seen in 61% of patients, but just 4% of patients experienced grade 3-4 immune-related adverse events, and 2% consequently had a delay in surgery, meaning the study met its primary safety endpoint.
In the end, all patients underwent surgery, with 100% having R0 resections.
A pathologic response was seen in 99% of patients, with 95% having an MPR, defined as less than or equal to 10% residual viable tumor, and 4% a partial response, defined as 10% to less than or equal to 50% residual viable tumor. A pCR, which included both the tumor bed and lymph nodes, was seen in 67% of participants.
There was a borderline significant difference in pCR patients between the 66 patients with sporadic tumors and the 32 with Lynch syndrome, at 58% versus 78% (P = .056).
At the meeting, discussant James Larkin, MD, PhD, consultant medical oncologist, The Royal Marsden, London, who was not involved with the study, agreed that the results were “striking,” with “brief treatment ... [showing] a major effect.”
However, he emphasized that it will be “important” to see the prespecified 3-year disease-free survival data, and he questioned whether the single low dose of ipilimumab was, in fact, necessary.
Dr. Larkin also emphasized that organ-sparing strategies in colon cancer are less “clear cut” than they are in rectal cancer and would require ongoing follow-up with colonoscopies and, potentially, biopsies. He also said it is “critical” to get patients’ views on the desirability of organ sparing.
The study was funded by Bristol Myers Squibb. Dr. Chalabi has reported no financial interests. Disclosures for the other authors are listed with the abstract. Dr. Larkin has declared relationships with Eisai, Novartis, Merck, Pfizer, BMS, iOnctura, Debiopharm, Incyte, MSD, Pierre Fabre, Ibsen, Roche, EUSA Pharma, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, and Nektar Therapeutics.
A version of this article first appeared on Medscape.com.
PARIS – was given before surgery to patients with DNA mismatch repair deficient (dMMR) colon cancer, say researchers reporting new results from the NICHE-2 trial.
The trial involved 112 patients with dMMR colon cancer who were given one cycle of low-dose ipilimumab and two cycles of nivolumab followed by surgery.
The results show that 95% of patients had a major pathologic response (MPR), and 67% had a pathologic complete response (pCR) to immunotherapy.
To date, none of these patients have had disease recurrence after a median follow-up of 13.1 months.
Study presenter Myriam Chalabi, MD, an oncologist at the Netherlands Cancer Institute, Amsterdam, described the findings as “unprecedented,” especially as many of the patients had stage 3 and high-risk disease, and the expected disease recurrence rate with standard-of-care adjuvant chemotherapy in these patients would usually have been around 15%.
“Importantly, this treatment was very well-tolerated,” she added.
Dr. Chalabi presented the new results during a presidential session at the European Society for Medical Oncology Congress 2022, held in Paris.
Neoadjuvant immunotherapy “has the potential to become standard of care” in these patients, she said, adding that the “future has never been brighter” for dMMR colon cancer.
Around 10%-15% of colon cancers are dMMR, and around 33% of these are associated with Lynch syndrome, she noted.
She also urged pharmaceutical companies to seek approval for immunotherapy in this patient population, to warm applause from the audience.
Commenting on the results, Andrés Cervantes, MD, PhD, professor of medicine at the University of Valencia, Spain, said in an ESMO press release that the “innovative” study “questions the need for surgery and postoperative chemotherapy in all patients in whom the primary tumor has disappeared.”
He observed that adjuvant chemotherapy has remained standard of care, “despite the fact that chemotherapy is not so active, and a complete disappearance of the tumor in the surgical specimen is not observed.”
Overall, Dr. Cervantes said that dMMR status is a “strong predictor of the positive effect observed with this short-course immunotherapy,” adding that “determining dMMR can be easily done by immunohistochemistry in the conventional pathology lab, without the need for complex molecular testing.”
The “minimal toxicity” seen in the study “may also facilitate the implementation of this strategy, potentially sparing patients from surgery.”
Details of the new results
For the NICHE-2 study, patients with stage cT3 dMMR colon cancer and/or nodal involvement but without metastases and no signs of obstruction received one dose of ipilimumab 1 mg/kg and two doses of nivolumab 3 mg/kg before undergoing surgery within 6 weeks of enrollment.
The 112 participants were a median age of 60 years, and just over half were women. High-risk stage 3 disease was present in 74% of patients, which included 64% of patients with clinical T4a or T4b tumors and 62% with radiologic N2 stage cancer.
Median time from the first immunotherapy dose to surgery was 5.4 weeks.
Immune-related adverse events were seen in 61% of patients, but just 4% of patients experienced grade 3-4 immune-related adverse events, and 2% consequently had a delay in surgery, meaning the study met its primary safety endpoint.
In the end, all patients underwent surgery, with 100% having R0 resections.
A pathologic response was seen in 99% of patients, with 95% having an MPR, defined as less than or equal to 10% residual viable tumor, and 4% a partial response, defined as 10% to less than or equal to 50% residual viable tumor. A pCR, which included both the tumor bed and lymph nodes, was seen in 67% of participants.
There was a borderline significant difference in pCR patients between the 66 patients with sporadic tumors and the 32 with Lynch syndrome, at 58% versus 78% (P = .056).
At the meeting, discussant James Larkin, MD, PhD, consultant medical oncologist, The Royal Marsden, London, who was not involved with the study, agreed that the results were “striking,” with “brief treatment ... [showing] a major effect.”
However, he emphasized that it will be “important” to see the prespecified 3-year disease-free survival data, and he questioned whether the single low dose of ipilimumab was, in fact, necessary.
Dr. Larkin also emphasized that organ-sparing strategies in colon cancer are less “clear cut” than they are in rectal cancer and would require ongoing follow-up with colonoscopies and, potentially, biopsies. He also said it is “critical” to get patients’ views on the desirability of organ sparing.
The study was funded by Bristol Myers Squibb. Dr. Chalabi has reported no financial interests. Disclosures for the other authors are listed with the abstract. Dr. Larkin has declared relationships with Eisai, Novartis, Merck, Pfizer, BMS, iOnctura, Debiopharm, Incyte, MSD, Pierre Fabre, Ibsen, Roche, EUSA Pharma, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, and Nektar Therapeutics.
A version of this article first appeared on Medscape.com.
Cabozantinib boosts dual immunotherapy in advanced RCC
PARIS – (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.
At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.
Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.
The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.
The research was presented at the European Society for Medical Oncology Congress in Paris.
The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.
Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.
The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.
However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.
In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.
The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.
He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”
“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.
He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”
Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”
“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.
“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”
Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.
He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.
Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”
So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”
Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”
However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.
Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.
“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.
“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
Details of the new results
The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.
They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.
Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.
The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).
At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.
Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.
Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.
However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.
But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.
Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.
Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.
Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.
However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.
Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.
He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”
In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.
He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.
The study was funded by Exelixis.
Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.
A version of this article first appeared on Medscape.com.
PARIS – (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.
At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.
Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.
The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.
The research was presented at the European Society for Medical Oncology Congress in Paris.
The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.
Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.
The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.
However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.
In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.
The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.
He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”
“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.
He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”
Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”
“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.
“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”
Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.
He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.
Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”
So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”
Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”
However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.
Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.
“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.
“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
Details of the new results
The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.
They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.
Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.
The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).
At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.
Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.
Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.
However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.
But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.
Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.
Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.
Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.
However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.
Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.
He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”
In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.
He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.
The study was funded by Exelixis.
Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.
A version of this article first appeared on Medscape.com.
PARIS – (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.
At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.
Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.
The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.
The research was presented at the European Society for Medical Oncology Congress in Paris.
The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.
Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.
The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.
However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.
In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.
The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.
He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”
“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.
He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”
Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”
“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.
“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”
Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.
He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.
Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”
So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”
Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”
However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.
Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.
“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.
“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
Details of the new results
The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.
They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.
Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.
The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).
At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.
Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.
Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.
However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.
But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.
Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.
Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.
Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.
However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.
Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.
He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”
In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.
He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.
The study was funded by Exelixis.
Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.
A version of this article first appeared on Medscape.com.
First drug for desmoid tumors: ‘Impressive’ data for nirogacestat
PARIS –
Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.
Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.
The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.
Trial results were presented at the annual meeting of the European Society for Medical Oncology.
Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.
There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.
Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”
With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”
Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.
“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”
However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”
Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
Large trial in rare cancer
DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.
“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”
Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”
“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.
Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.
Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
Details of the results
Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”
Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.
Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.
Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.
The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.
Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”
He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.
In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.
The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.
At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).
This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.
The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.
The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.
Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).
There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.
After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.
The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.
Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.
The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.
A version of this article first appeared on Medscape.com.
PARIS –
Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.
Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.
The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.
Trial results were presented at the annual meeting of the European Society for Medical Oncology.
Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.
There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.
Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”
With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”
Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.
“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”
However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”
Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
Large trial in rare cancer
DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.
“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”
Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”
“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.
Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.
Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
Details of the results
Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”
Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.
Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.
Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.
The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.
Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”
He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.
In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.
The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.
At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).
This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.
The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.
The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.
Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).
There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.
After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.
The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.
Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.
The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.
A version of this article first appeared on Medscape.com.
PARIS –
Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.
Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.
The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.
Trial results were presented at the annual meeting of the European Society for Medical Oncology.
Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.
There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.
Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”
With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”
Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.
“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”
However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”
Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
Large trial in rare cancer
DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.
“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”
Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”
“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.
Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.
Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
Details of the results
Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”
Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.
Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.
Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.
The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.
Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”
He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.
In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.
The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.
At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).
This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.
The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.
The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.
Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).
There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.
After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.
The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.
Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.
The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.
A version of this article first appeared on Medscape.com.
FROM ESMO 2022
Dupilumab offers ‘clinically meaningful’ improvements in prurigo nodularis
(Dupixent), indicate results from the phase 2 LIBERTY-PN PRIME trial.
The research was presented at the annual Congress of the European Academy of Dermatology and Venereology.
More than 150 patients with severe PN whose quality of life was impaired were randomly assigned to receive dupilumab (Dupixent) or placebo for 24 weeks. Use of the monoclonal antibody was associated with significant improvements in itch scores.
The researchers also found that the percentage of patients who had no or few PN lesions increased substantially with use of dupilumab, and there were no new safety signals, confirming results from previous studies. Dupilumab, an interleukin-4 receptor alpha antagonist administered by injection, was initially approved by the U.S. Food and Drug Administration for treating atopic dermatitis in 2022.
Study presenter Gil Yosipovitch, MD, professor of dermatology at the University of Miami, emphasized that the improvements in itch and skin lesions seen in these patients were “clinically meaningful.”
In the discussion after the presentation, Dr. Yosipovitch was asked whether the presence or absence of atopy had any bearing on the results.
He replied that although there were too few patients with atopy in the current study to answer that question, other data indicate that there is no overall difference between patients with atopy and those without atopy.
Asked whether dupilumab should be used for only 24 weeks, Dr. Yosipovitch said his that “impression” is that there can be a “honeymoon period” during which the medication is stopped and the treating clinician sees “what happens.”
“It would be interesting in the future” to find out, he added, but he noted that whatever the result, patients would need treatment “for the rest of their life.”
Dr. Yosipovitch, director of the Miami Itch Center and the study’s principal investigator, began his presentation by noting that currently, no systemic therapies have been approved by the FDA or the European Medicines Agency for PN.
Although treatments such as topical medications, ultraviolet light therapy, immunosuppressive agents, and systemic neuromodulators are used off label, for many patients with moderate to severe PN, disease control is inadequate, and the patients are “miserable.”
Recently, the phase 3 LIBERTY-PN PRIME2 trial showed that dupilumab significantly reduced itch and skin lesions for patients with PN, and the safety profile was consistent with that seen in approved indications for the drug.
Dr. Yosipovitch explained that LIBERTY-PN PRIME was a phase 2 study in which, after a screening period, patients with PN were randomly assigned in a 1:1 ratio to receive dupilumab as a 600-mg loading dose followed by 300 mg twice weekly or a matched placebo. Treatment was given for 24 weeks, after which there was a post treatment 12-week follow-up period.
Participants were aged 18-80 years and had been diagnosed with PN for a period of at least 3 months. To be included in the trial, patients had to have an average Worst Itch Numerical Rating Scale (WI-NRS) score of at least 7 and at least 20 lesions, among other criteria. (Patients were allowed to continue treatment with mid- to low-potency topical steroids or topical calcineurin inhibitors if they had been taking them at baseline.)
Among 151 patients in the study, the mean age was 50.1 years, and 66.2% were women. The majority (53.0%) were White; 7.3% were Black; and 35.8% were Asian; 40.4% of patients had a history of atopy. The mean WI-NRS was 8.5, and the mean skin pain score on a 10-point scale was 7.2.
The Investigator’s Global Assessment for PN stage of disease (IGA PN-S) was also employed in the trial. That measure uses a 5-point scale to assess disease severity, with 0 indicating no lesions and 4 indicating more than 100 lesions. At baseline, 28.7% of patients had a score of 4, and the remainder had a score of 3, indicating the presence of 20-100 PN lesions.
Dr. Yosipovitch said that quality of life for these patients was “low” and that scores on the Hospital Anxiety and Depression scale indicated that the participants, many of whom had previously received topical and systemic medications for their PN, indicated they were depressed.
He showed that at week 24, the proportion of patients who had experienced an improvement in the WI-NRS score of greater than or equal to 4 (the study’s primary endpoint) was significantly greater with dupilumab, at 60.0% versus 18.4% among patients given placebo (P < .0001).
Moreover, the proportion of patients at week 24 with an IGA PN-S score of 0 or 1 (the secondary endpoint) was 48.0% in the active treatment group, versus 18.4% with placebo (P =.0004).
With regard to safety, rates of any treatment-emergent adverse events were similar between the groups, at 70.7% for dupilumab and 62.7% for placebo, as were rates for severe treatment-emergent adverse events, at 6.7% and 10.7%, respectively.
Rates of treatment-emergent adverse events of interest, such as skin infections, conjunctivitis, herpes viral infections, and injection site reactions, also suggested that there was no increased risk with active treatment.
Dupilumab is currently under review at the FDA and in Europe for the treatment of PN, according to dupilumab manufacturers Regeneron and Sanofi.
The study was sponsored by Sanofi in collaboration with Regeneron Pharmaceuticals. Dr. Yosipovitch has relationships with Arcutis Biotherapeutics, Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, and Trevi Therapeutics.
A version of this article first appeared on Medscape.com.
(Dupixent), indicate results from the phase 2 LIBERTY-PN PRIME trial.
The research was presented at the annual Congress of the European Academy of Dermatology and Venereology.
More than 150 patients with severe PN whose quality of life was impaired were randomly assigned to receive dupilumab (Dupixent) or placebo for 24 weeks. Use of the monoclonal antibody was associated with significant improvements in itch scores.
The researchers also found that the percentage of patients who had no or few PN lesions increased substantially with use of dupilumab, and there were no new safety signals, confirming results from previous studies. Dupilumab, an interleukin-4 receptor alpha antagonist administered by injection, was initially approved by the U.S. Food and Drug Administration for treating atopic dermatitis in 2022.
Study presenter Gil Yosipovitch, MD, professor of dermatology at the University of Miami, emphasized that the improvements in itch and skin lesions seen in these patients were “clinically meaningful.”
In the discussion after the presentation, Dr. Yosipovitch was asked whether the presence or absence of atopy had any bearing on the results.
He replied that although there were too few patients with atopy in the current study to answer that question, other data indicate that there is no overall difference between patients with atopy and those without atopy.
Asked whether dupilumab should be used for only 24 weeks, Dr. Yosipovitch said his that “impression” is that there can be a “honeymoon period” during which the medication is stopped and the treating clinician sees “what happens.”
“It would be interesting in the future” to find out, he added, but he noted that whatever the result, patients would need treatment “for the rest of their life.”
Dr. Yosipovitch, director of the Miami Itch Center and the study’s principal investigator, began his presentation by noting that currently, no systemic therapies have been approved by the FDA or the European Medicines Agency for PN.
Although treatments such as topical medications, ultraviolet light therapy, immunosuppressive agents, and systemic neuromodulators are used off label, for many patients with moderate to severe PN, disease control is inadequate, and the patients are “miserable.”
Recently, the phase 3 LIBERTY-PN PRIME2 trial showed that dupilumab significantly reduced itch and skin lesions for patients with PN, and the safety profile was consistent with that seen in approved indications for the drug.
Dr. Yosipovitch explained that LIBERTY-PN PRIME was a phase 2 study in which, after a screening period, patients with PN were randomly assigned in a 1:1 ratio to receive dupilumab as a 600-mg loading dose followed by 300 mg twice weekly or a matched placebo. Treatment was given for 24 weeks, after which there was a post treatment 12-week follow-up period.
Participants were aged 18-80 years and had been diagnosed with PN for a period of at least 3 months. To be included in the trial, patients had to have an average Worst Itch Numerical Rating Scale (WI-NRS) score of at least 7 and at least 20 lesions, among other criteria. (Patients were allowed to continue treatment with mid- to low-potency topical steroids or topical calcineurin inhibitors if they had been taking them at baseline.)
Among 151 patients in the study, the mean age was 50.1 years, and 66.2% were women. The majority (53.0%) were White; 7.3% were Black; and 35.8% were Asian; 40.4% of patients had a history of atopy. The mean WI-NRS was 8.5, and the mean skin pain score on a 10-point scale was 7.2.
The Investigator’s Global Assessment for PN stage of disease (IGA PN-S) was also employed in the trial. That measure uses a 5-point scale to assess disease severity, with 0 indicating no lesions and 4 indicating more than 100 lesions. At baseline, 28.7% of patients had a score of 4, and the remainder had a score of 3, indicating the presence of 20-100 PN lesions.
Dr. Yosipovitch said that quality of life for these patients was “low” and that scores on the Hospital Anxiety and Depression scale indicated that the participants, many of whom had previously received topical and systemic medications for their PN, indicated they were depressed.
He showed that at week 24, the proportion of patients who had experienced an improvement in the WI-NRS score of greater than or equal to 4 (the study’s primary endpoint) was significantly greater with dupilumab, at 60.0% versus 18.4% among patients given placebo (P < .0001).
Moreover, the proportion of patients at week 24 with an IGA PN-S score of 0 or 1 (the secondary endpoint) was 48.0% in the active treatment group, versus 18.4% with placebo (P =.0004).
With regard to safety, rates of any treatment-emergent adverse events were similar between the groups, at 70.7% for dupilumab and 62.7% for placebo, as were rates for severe treatment-emergent adverse events, at 6.7% and 10.7%, respectively.
Rates of treatment-emergent adverse events of interest, such as skin infections, conjunctivitis, herpes viral infections, and injection site reactions, also suggested that there was no increased risk with active treatment.
Dupilumab is currently under review at the FDA and in Europe for the treatment of PN, according to dupilumab manufacturers Regeneron and Sanofi.
The study was sponsored by Sanofi in collaboration with Regeneron Pharmaceuticals. Dr. Yosipovitch has relationships with Arcutis Biotherapeutics, Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, and Trevi Therapeutics.
A version of this article first appeared on Medscape.com.
(Dupixent), indicate results from the phase 2 LIBERTY-PN PRIME trial.
The research was presented at the annual Congress of the European Academy of Dermatology and Venereology.
More than 150 patients with severe PN whose quality of life was impaired were randomly assigned to receive dupilumab (Dupixent) or placebo for 24 weeks. Use of the monoclonal antibody was associated with significant improvements in itch scores.
The researchers also found that the percentage of patients who had no or few PN lesions increased substantially with use of dupilumab, and there were no new safety signals, confirming results from previous studies. Dupilumab, an interleukin-4 receptor alpha antagonist administered by injection, was initially approved by the U.S. Food and Drug Administration for treating atopic dermatitis in 2022.
Study presenter Gil Yosipovitch, MD, professor of dermatology at the University of Miami, emphasized that the improvements in itch and skin lesions seen in these patients were “clinically meaningful.”
In the discussion after the presentation, Dr. Yosipovitch was asked whether the presence or absence of atopy had any bearing on the results.
He replied that although there were too few patients with atopy in the current study to answer that question, other data indicate that there is no overall difference between patients with atopy and those without atopy.
Asked whether dupilumab should be used for only 24 weeks, Dr. Yosipovitch said his that “impression” is that there can be a “honeymoon period” during which the medication is stopped and the treating clinician sees “what happens.”
“It would be interesting in the future” to find out, he added, but he noted that whatever the result, patients would need treatment “for the rest of their life.”
Dr. Yosipovitch, director of the Miami Itch Center and the study’s principal investigator, began his presentation by noting that currently, no systemic therapies have been approved by the FDA or the European Medicines Agency for PN.
Although treatments such as topical medications, ultraviolet light therapy, immunosuppressive agents, and systemic neuromodulators are used off label, for many patients with moderate to severe PN, disease control is inadequate, and the patients are “miserable.”
Recently, the phase 3 LIBERTY-PN PRIME2 trial showed that dupilumab significantly reduced itch and skin lesions for patients with PN, and the safety profile was consistent with that seen in approved indications for the drug.
Dr. Yosipovitch explained that LIBERTY-PN PRIME was a phase 2 study in which, after a screening period, patients with PN were randomly assigned in a 1:1 ratio to receive dupilumab as a 600-mg loading dose followed by 300 mg twice weekly or a matched placebo. Treatment was given for 24 weeks, after which there was a post treatment 12-week follow-up period.
Participants were aged 18-80 years and had been diagnosed with PN for a period of at least 3 months. To be included in the trial, patients had to have an average Worst Itch Numerical Rating Scale (WI-NRS) score of at least 7 and at least 20 lesions, among other criteria. (Patients were allowed to continue treatment with mid- to low-potency topical steroids or topical calcineurin inhibitors if they had been taking them at baseline.)
Among 151 patients in the study, the mean age was 50.1 years, and 66.2% were women. The majority (53.0%) were White; 7.3% were Black; and 35.8% were Asian; 40.4% of patients had a history of atopy. The mean WI-NRS was 8.5, and the mean skin pain score on a 10-point scale was 7.2.
The Investigator’s Global Assessment for PN stage of disease (IGA PN-S) was also employed in the trial. That measure uses a 5-point scale to assess disease severity, with 0 indicating no lesions and 4 indicating more than 100 lesions. At baseline, 28.7% of patients had a score of 4, and the remainder had a score of 3, indicating the presence of 20-100 PN lesions.
Dr. Yosipovitch said that quality of life for these patients was “low” and that scores on the Hospital Anxiety and Depression scale indicated that the participants, many of whom had previously received topical and systemic medications for their PN, indicated they were depressed.
He showed that at week 24, the proportion of patients who had experienced an improvement in the WI-NRS score of greater than or equal to 4 (the study’s primary endpoint) was significantly greater with dupilumab, at 60.0% versus 18.4% among patients given placebo (P < .0001).
Moreover, the proportion of patients at week 24 with an IGA PN-S score of 0 or 1 (the secondary endpoint) was 48.0% in the active treatment group, versus 18.4% with placebo (P =.0004).
With regard to safety, rates of any treatment-emergent adverse events were similar between the groups, at 70.7% for dupilumab and 62.7% for placebo, as were rates for severe treatment-emergent adverse events, at 6.7% and 10.7%, respectively.
Rates of treatment-emergent adverse events of interest, such as skin infections, conjunctivitis, herpes viral infections, and injection site reactions, also suggested that there was no increased risk with active treatment.
Dupilumab is currently under review at the FDA and in Europe for the treatment of PN, according to dupilumab manufacturers Regeneron and Sanofi.
The study was sponsored by Sanofi in collaboration with Regeneron Pharmaceuticals. Dr. Yosipovitch has relationships with Arcutis Biotherapeutics, Bellus Health, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi, and Trevi Therapeutics.
A version of this article first appeared on Medscape.com.
FROM THE EADV CONGRESS
Test Lp(a) levels to inform ASCVD management: NLA statement
Lipoprotein(a) (Lp[a]) levels should be measured in clinical practice to refine risk prediction for atherosclerotic cardiovascular disease (ASCVD) and inform treatment decisions, even if they cannot yet be lowered directly, recommends the National Lipid Association (NLA) in a scientific statement.
The statement was published in the Journal of Clinical Lipidology.
Don P. Wilson, MD, department of pediatric endocrinology and diabetes, Cook Children’s Medical Center, Fort Worth, Tex., told this news organization that lipoprotein(a) is a “very timely subject.”
“The question in the scientific community is: What role does that particular biomarker play in terms of causing serious heart disease, stroke, and calcification of the aortic valve?”
“It’s pretty clear that, in and of itself, it actually can contribute and or cause any of those conditions,” he added. “The thing that’s then sort of problematic is that we don’t have a specific treatment to lower” Lp(a).
However, Dr. Wilson said that the statement underlines it is “still worth knowing” an individual’s Lp(a) concentrations because the risk with increased levels is “even higher for those people who have other conditions, such as metabolic disease or diabetes or high cholesterol.”
There are nevertheless several drugs in phase 2 and 3 clinical trials that appear to have the potential to significantly lower Lp(a) levels.
“I’m very excited,” said Dr. Wilson, noting that, so far, the drugs seem to be “quite safe,” and the currently available data suggest that they can “reduce Lp(a) levels by about 90%, which is huge.”
“That’s better than any drug we’ve got on the market.”
He cautioned, however, that it is going to take time after the drugs are approved to see the real benefits and risks once they start being used in very large populations, given that raised Lp(a) concentrations are present in about 20% of the world population.
The publication of the NLA statement coincides with a similar one from the European Atherosclerosis Society presented at the European Society of Cardiology Congress 2022 on Aug. 29, and published simultaneously in the European Heart Journal.
Coauthor of the EAS statement, Alberico L. Catapano, MD, PhD, professor of pharmacology at the University of Milan, and past president of the EAS, said that there are many areas in which the two statements are “in complete agreement.”
“However, the spirit of the documents is different,” he continued, chief among them being that the EAS statement focuses on the “global risk” of ASCVD and provides a risk calculator to help balance the risk increase with Lp(a) with that from other factors.
Another is that increased Lp(a) levels are recognized as being on a continuum in terms of their risk, such that there is no level at which raised concentrations can be deemed safe.
Dr. Wilson agreed with Dr. Capatano’s assessment, saying that the EAS statement takes current scientific observations “a step further,” in part by emphasizing that Lp(a) is “only one piece of the puzzle” for determining an individuals’ cardiovascular risk.
This will have huge implications for the conversations clinicians have with patients over shared decision-making, Dr. Wilson added.
Nevertheless, Dr. Catapano underlined to this news organization that “both documents are very important” in terms of the need to “raise awareness about a causal risk factor” for cardiovascular disease as well as that modifying Lp(a) concentrations “will probably reduce the risk.”
The statement from the NLA builds on the association’s prior Recommendations for the Patient-Centered Management of Dyslipidemia, published in two parts in 2014 and 2015, and comes to many of the same conclusions as the EAS statement.
It explains that apolipoprotein A, a component of Lp(a) attached to apolipoprotein B, has “unique” properties that promote the “initiation and progression of atherosclerosis and calcific valvular aortic stenosis, through endothelial dysfunction and proinflammatory responses, and pro-osteogenic effects promoting calcification.”
This, in turn, has the potential to cause myocardial infarction and ischemic stroke, the authors note.
This has been confirmed in meta-analyses of prospective, population-based studies showing a high risk for MI, coronary heart disease, and ischemic stroke with high Lp(a) levels, the statement adds.
Moreover, large genetic studies have confirmed that Lp(a) is a causal factor, independent of low-density lipoprotein cholesterol levels, for MI, ischemic stroke, valvular aortic stenosis, coronary artery stenosis, carotid stenosis, femoral artery stenosis, heart failure, cardiovascular mortality, and all-cause mortality.
Like the authors of the EAS statement, the NLA statement authors underline that the measurement of Lp(a) is “currently not standardized or harmonized,” and there is insufficient evidence on the utility of different cut-offs for risk based on age, gender, ethnicity, or the presence of comorbid conditions.
However, they do suggest that Lp(a) levels greater than 50 mg/dL (> 100 nmol/L) may be considered as a risk-enhancing factor favoring the initiation of statin therapy, although they note that the threshold could be threefold higher in African American individuals.
Despite these reservations, the authors say that Lp(a) testing “is reasonable” for refining the risk assessment of ASCVD in the first-degree relatives of people with premature ASCVD and those with a personal history of premature disease as well as in individuals with primary severe hypercholesterolemia.
Testing also “may be reasonable” to “aid in the clinician-patient discussion about whether to prescribe a statin” in people aged 40-75 years with borderline 10-year ASCVD risk, defined as 5%-7.4%, as well as in other equivocal clinical situations.
In terms of what to do in an individual with raised Lp(a) levels, the statement notes that lifestyle therapy and statins do not decrease Lp(a).
Although lomitapide (Juxtapid) and proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors both lower levels of the lipoprotein, the former is “not recommended for ASCVD risk reduction,” whereas the impact of the latter on ASCVD risk reduction via Lp(a) reduction “remains undetermined.”
Several experimental agents are currently under investigation to reduce Lp(a) levels, including SLN360 (Silence Therapeutics), and AKCEA-APO(a)-LRX (Akcea Therapeutics/Ionis Pharmaceuticals).
In the meantime, the authors say it is reasonable to use Lp(a) as a “risk-enhancing factor” for the initiation of moderate- or high-intensity statins in the primary prevention of ASCVD and to consider the addition of ezetimibe and/or PCSK9 inhibitors in high- and very high–risk patients already on maximally tolerated statin therapy.
Finally, the authors recognize the need for “additional evidence” to support clinical practice. In the absence of a randomized clinical trial of Lp(a) lowering in those who are at risk for ASCVD, they note that “several important unanswered questions remain.”
These include: “Is it reasonable to recommend universal testing of Lp(a) in everyone regardless of family history or health status at least once to help encourage healthy habits and inform clinical decision-making?” “Will earlier testing and effective interventions help to improve outcomes?”
Alongside more evidence in children, the authors also emphasize that “additional data are urgently needed in Blacks, South Asians, and those of Hispanic descent.”
No funding declared. Dr. Wilson declares relationships with Osler Institute, Merck Sharp & Dohm, Novo Nordisk, and Alexion Pharmaceuticals. Other authors also declare numerous relationships. Dr. Catapano declares a relationship with Novartis.
A version of this article first appeared on Medscape.com.
Lipoprotein(a) (Lp[a]) levels should be measured in clinical practice to refine risk prediction for atherosclerotic cardiovascular disease (ASCVD) and inform treatment decisions, even if they cannot yet be lowered directly, recommends the National Lipid Association (NLA) in a scientific statement.
The statement was published in the Journal of Clinical Lipidology.
Don P. Wilson, MD, department of pediatric endocrinology and diabetes, Cook Children’s Medical Center, Fort Worth, Tex., told this news organization that lipoprotein(a) is a “very timely subject.”
“The question in the scientific community is: What role does that particular biomarker play in terms of causing serious heart disease, stroke, and calcification of the aortic valve?”
“It’s pretty clear that, in and of itself, it actually can contribute and or cause any of those conditions,” he added. “The thing that’s then sort of problematic is that we don’t have a specific treatment to lower” Lp(a).
However, Dr. Wilson said that the statement underlines it is “still worth knowing” an individual’s Lp(a) concentrations because the risk with increased levels is “even higher for those people who have other conditions, such as metabolic disease or diabetes or high cholesterol.”
There are nevertheless several drugs in phase 2 and 3 clinical trials that appear to have the potential to significantly lower Lp(a) levels.
“I’m very excited,” said Dr. Wilson, noting that, so far, the drugs seem to be “quite safe,” and the currently available data suggest that they can “reduce Lp(a) levels by about 90%, which is huge.”
“That’s better than any drug we’ve got on the market.”
He cautioned, however, that it is going to take time after the drugs are approved to see the real benefits and risks once they start being used in very large populations, given that raised Lp(a) concentrations are present in about 20% of the world population.
The publication of the NLA statement coincides with a similar one from the European Atherosclerosis Society presented at the European Society of Cardiology Congress 2022 on Aug. 29, and published simultaneously in the European Heart Journal.
Coauthor of the EAS statement, Alberico L. Catapano, MD, PhD, professor of pharmacology at the University of Milan, and past president of the EAS, said that there are many areas in which the two statements are “in complete agreement.”
“However, the spirit of the documents is different,” he continued, chief among them being that the EAS statement focuses on the “global risk” of ASCVD and provides a risk calculator to help balance the risk increase with Lp(a) with that from other factors.
Another is that increased Lp(a) levels are recognized as being on a continuum in terms of their risk, such that there is no level at which raised concentrations can be deemed safe.
Dr. Wilson agreed with Dr. Capatano’s assessment, saying that the EAS statement takes current scientific observations “a step further,” in part by emphasizing that Lp(a) is “only one piece of the puzzle” for determining an individuals’ cardiovascular risk.
This will have huge implications for the conversations clinicians have with patients over shared decision-making, Dr. Wilson added.
Nevertheless, Dr. Catapano underlined to this news organization that “both documents are very important” in terms of the need to “raise awareness about a causal risk factor” for cardiovascular disease as well as that modifying Lp(a) concentrations “will probably reduce the risk.”
The statement from the NLA builds on the association’s prior Recommendations for the Patient-Centered Management of Dyslipidemia, published in two parts in 2014 and 2015, and comes to many of the same conclusions as the EAS statement.
It explains that apolipoprotein A, a component of Lp(a) attached to apolipoprotein B, has “unique” properties that promote the “initiation and progression of atherosclerosis and calcific valvular aortic stenosis, through endothelial dysfunction and proinflammatory responses, and pro-osteogenic effects promoting calcification.”
This, in turn, has the potential to cause myocardial infarction and ischemic stroke, the authors note.
This has been confirmed in meta-analyses of prospective, population-based studies showing a high risk for MI, coronary heart disease, and ischemic stroke with high Lp(a) levels, the statement adds.
Moreover, large genetic studies have confirmed that Lp(a) is a causal factor, independent of low-density lipoprotein cholesterol levels, for MI, ischemic stroke, valvular aortic stenosis, coronary artery stenosis, carotid stenosis, femoral artery stenosis, heart failure, cardiovascular mortality, and all-cause mortality.
Like the authors of the EAS statement, the NLA statement authors underline that the measurement of Lp(a) is “currently not standardized or harmonized,” and there is insufficient evidence on the utility of different cut-offs for risk based on age, gender, ethnicity, or the presence of comorbid conditions.
However, they do suggest that Lp(a) levels greater than 50 mg/dL (> 100 nmol/L) may be considered as a risk-enhancing factor favoring the initiation of statin therapy, although they note that the threshold could be threefold higher in African American individuals.
Despite these reservations, the authors say that Lp(a) testing “is reasonable” for refining the risk assessment of ASCVD in the first-degree relatives of people with premature ASCVD and those with a personal history of premature disease as well as in individuals with primary severe hypercholesterolemia.
Testing also “may be reasonable” to “aid in the clinician-patient discussion about whether to prescribe a statin” in people aged 40-75 years with borderline 10-year ASCVD risk, defined as 5%-7.4%, as well as in other equivocal clinical situations.
In terms of what to do in an individual with raised Lp(a) levels, the statement notes that lifestyle therapy and statins do not decrease Lp(a).
Although lomitapide (Juxtapid) and proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors both lower levels of the lipoprotein, the former is “not recommended for ASCVD risk reduction,” whereas the impact of the latter on ASCVD risk reduction via Lp(a) reduction “remains undetermined.”
Several experimental agents are currently under investigation to reduce Lp(a) levels, including SLN360 (Silence Therapeutics), and AKCEA-APO(a)-LRX (Akcea Therapeutics/Ionis Pharmaceuticals).
In the meantime, the authors say it is reasonable to use Lp(a) as a “risk-enhancing factor” for the initiation of moderate- or high-intensity statins in the primary prevention of ASCVD and to consider the addition of ezetimibe and/or PCSK9 inhibitors in high- and very high–risk patients already on maximally tolerated statin therapy.
Finally, the authors recognize the need for “additional evidence” to support clinical practice. In the absence of a randomized clinical trial of Lp(a) lowering in those who are at risk for ASCVD, they note that “several important unanswered questions remain.”
These include: “Is it reasonable to recommend universal testing of Lp(a) in everyone regardless of family history or health status at least once to help encourage healthy habits and inform clinical decision-making?” “Will earlier testing and effective interventions help to improve outcomes?”
Alongside more evidence in children, the authors also emphasize that “additional data are urgently needed in Blacks, South Asians, and those of Hispanic descent.”
No funding declared. Dr. Wilson declares relationships with Osler Institute, Merck Sharp & Dohm, Novo Nordisk, and Alexion Pharmaceuticals. Other authors also declare numerous relationships. Dr. Catapano declares a relationship with Novartis.
A version of this article first appeared on Medscape.com.
Lipoprotein(a) (Lp[a]) levels should be measured in clinical practice to refine risk prediction for atherosclerotic cardiovascular disease (ASCVD) and inform treatment decisions, even if they cannot yet be lowered directly, recommends the National Lipid Association (NLA) in a scientific statement.
The statement was published in the Journal of Clinical Lipidology.
Don P. Wilson, MD, department of pediatric endocrinology and diabetes, Cook Children’s Medical Center, Fort Worth, Tex., told this news organization that lipoprotein(a) is a “very timely subject.”
“The question in the scientific community is: What role does that particular biomarker play in terms of causing serious heart disease, stroke, and calcification of the aortic valve?”
“It’s pretty clear that, in and of itself, it actually can contribute and or cause any of those conditions,” he added. “The thing that’s then sort of problematic is that we don’t have a specific treatment to lower” Lp(a).
However, Dr. Wilson said that the statement underlines it is “still worth knowing” an individual’s Lp(a) concentrations because the risk with increased levels is “even higher for those people who have other conditions, such as metabolic disease or diabetes or high cholesterol.”
There are nevertheless several drugs in phase 2 and 3 clinical trials that appear to have the potential to significantly lower Lp(a) levels.
“I’m very excited,” said Dr. Wilson, noting that, so far, the drugs seem to be “quite safe,” and the currently available data suggest that they can “reduce Lp(a) levels by about 90%, which is huge.”
“That’s better than any drug we’ve got on the market.”
He cautioned, however, that it is going to take time after the drugs are approved to see the real benefits and risks once they start being used in very large populations, given that raised Lp(a) concentrations are present in about 20% of the world population.
The publication of the NLA statement coincides with a similar one from the European Atherosclerosis Society presented at the European Society of Cardiology Congress 2022 on Aug. 29, and published simultaneously in the European Heart Journal.
Coauthor of the EAS statement, Alberico L. Catapano, MD, PhD, professor of pharmacology at the University of Milan, and past president of the EAS, said that there are many areas in which the two statements are “in complete agreement.”
“However, the spirit of the documents is different,” he continued, chief among them being that the EAS statement focuses on the “global risk” of ASCVD and provides a risk calculator to help balance the risk increase with Lp(a) with that from other factors.
Another is that increased Lp(a) levels are recognized as being on a continuum in terms of their risk, such that there is no level at which raised concentrations can be deemed safe.
Dr. Wilson agreed with Dr. Capatano’s assessment, saying that the EAS statement takes current scientific observations “a step further,” in part by emphasizing that Lp(a) is “only one piece of the puzzle” for determining an individuals’ cardiovascular risk.
This will have huge implications for the conversations clinicians have with patients over shared decision-making, Dr. Wilson added.
Nevertheless, Dr. Catapano underlined to this news organization that “both documents are very important” in terms of the need to “raise awareness about a causal risk factor” for cardiovascular disease as well as that modifying Lp(a) concentrations “will probably reduce the risk.”
The statement from the NLA builds on the association’s prior Recommendations for the Patient-Centered Management of Dyslipidemia, published in two parts in 2014 and 2015, and comes to many of the same conclusions as the EAS statement.
It explains that apolipoprotein A, a component of Lp(a) attached to apolipoprotein B, has “unique” properties that promote the “initiation and progression of atherosclerosis and calcific valvular aortic stenosis, through endothelial dysfunction and proinflammatory responses, and pro-osteogenic effects promoting calcification.”
This, in turn, has the potential to cause myocardial infarction and ischemic stroke, the authors note.
This has been confirmed in meta-analyses of prospective, population-based studies showing a high risk for MI, coronary heart disease, and ischemic stroke with high Lp(a) levels, the statement adds.
Moreover, large genetic studies have confirmed that Lp(a) is a causal factor, independent of low-density lipoprotein cholesterol levels, for MI, ischemic stroke, valvular aortic stenosis, coronary artery stenosis, carotid stenosis, femoral artery stenosis, heart failure, cardiovascular mortality, and all-cause mortality.
Like the authors of the EAS statement, the NLA statement authors underline that the measurement of Lp(a) is “currently not standardized or harmonized,” and there is insufficient evidence on the utility of different cut-offs for risk based on age, gender, ethnicity, or the presence of comorbid conditions.
However, they do suggest that Lp(a) levels greater than 50 mg/dL (> 100 nmol/L) may be considered as a risk-enhancing factor favoring the initiation of statin therapy, although they note that the threshold could be threefold higher in African American individuals.
Despite these reservations, the authors say that Lp(a) testing “is reasonable” for refining the risk assessment of ASCVD in the first-degree relatives of people with premature ASCVD and those with a personal history of premature disease as well as in individuals with primary severe hypercholesterolemia.
Testing also “may be reasonable” to “aid in the clinician-patient discussion about whether to prescribe a statin” in people aged 40-75 years with borderline 10-year ASCVD risk, defined as 5%-7.4%, as well as in other equivocal clinical situations.
In terms of what to do in an individual with raised Lp(a) levels, the statement notes that lifestyle therapy and statins do not decrease Lp(a).
Although lomitapide (Juxtapid) and proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors both lower levels of the lipoprotein, the former is “not recommended for ASCVD risk reduction,” whereas the impact of the latter on ASCVD risk reduction via Lp(a) reduction “remains undetermined.”
Several experimental agents are currently under investigation to reduce Lp(a) levels, including SLN360 (Silence Therapeutics), and AKCEA-APO(a)-LRX (Akcea Therapeutics/Ionis Pharmaceuticals).
In the meantime, the authors say it is reasonable to use Lp(a) as a “risk-enhancing factor” for the initiation of moderate- or high-intensity statins in the primary prevention of ASCVD and to consider the addition of ezetimibe and/or PCSK9 inhibitors in high- and very high–risk patients already on maximally tolerated statin therapy.
Finally, the authors recognize the need for “additional evidence” to support clinical practice. In the absence of a randomized clinical trial of Lp(a) lowering in those who are at risk for ASCVD, they note that “several important unanswered questions remain.”
These include: “Is it reasonable to recommend universal testing of Lp(a) in everyone regardless of family history or health status at least once to help encourage healthy habits and inform clinical decision-making?” “Will earlier testing and effective interventions help to improve outcomes?”
Alongside more evidence in children, the authors also emphasize that “additional data are urgently needed in Blacks, South Asians, and those of Hispanic descent.”
No funding declared. Dr. Wilson declares relationships with Osler Institute, Merck Sharp & Dohm, Novo Nordisk, and Alexion Pharmaceuticals. Other authors also declare numerous relationships. Dr. Catapano declares a relationship with Novartis.
A version of this article first appeared on Medscape.com.
New ESC cardio-oncology guideline aims to reduce cardiotoxicity
BARCELONA – Cardiovascular disease risk factors, as well as established disease, in patients undergoing cancer therapy can be safely managed to minimize cancer therapy–related cardiovascular toxicity (CVR-CVT), conclude the first cardio-oncology guidelines from the European Society of Cardiology.
The guidelines were presented at the annual congress of the European Society of Cardiology and published simultaneously in the European Heart Journal.
Guideline cochair Alexander R. Lyon, MD, PhD, told this news organization that the aim of the guideline was to “personalize the decision-making of a patient with cancer who has cardiovascular disease or is at risk of developing it from their treatment ... because it’s not one size fits all.”
because how you manage someone who’s at high risk is going to be different” than managing someone who is at moderate or low risk, he said.
“We’re doing a lot of surveillance because one of the big advantages of cardio-oncology is we know when someone is about to get treated,” Dr. Lyon, from the National Heart and Lung Institute, Imperial College London, and Cardio-Oncology Service, Royal Brompton Hospital, London, said.
“You don’t know in nature when someone’s going to have an acute myocardial infarction or acute viral myocarditis, but we do know when they’re coming into an oncology clinic to get an infusion of chemotherapy or tablets,” he noted.
The guidelines offer recommendations so that patients can “have their treatment safely and minimize interruptions.”
“We know these cancer therapies work; we’re here to get the best of both worlds” by minimizing cardiotoxicity, Dr. Lyon said.
Steady decline in cancer-related mortality
The guidelines note that since the 1990s there has been a “steady decline in cancer-related mortality, mirrored by a steady increase in cancer survival,” and the result is that “treatment-related side effects have gained more significance.”
Dr. Lyon said that between 2011 and 2021, there was a fivefold increase in the number of new referrals of cancer patients with cardiological consequences to his institution.
He said that one of main drivers is modifiable factors, such as smoking, obesity, and inactivity, which increase the risk for both cancer and cardiovascular disease.
“Allied to that, there’s been an improvement in treating cardiovascular diseases in people in their 40s, 50s, and 60s, so they’re surviving their heart failure, myocardial infarction, atrial fibrillation to develop cancers in later life.”
Combined with the aging population, the result is that “not only are many more people being diagnosed with cancer, because they’re living longer, but they have all these pre-existing heart risk factors, whether as confirmed disease or just the risk factors associated with that,” he said.
Another aspect is that many of the newer, targeted cancer therapies confer a cardiovascular risk.
Dr. Lyon said that the “most famous one” is trastuzumab, a monoclonal antibody that is used to treat HER2-positive breast cancer but that also causes left ventricular impairment “in about 15%-20% of the women taking it and can cause severe heart failure if it is missed.”
That, he continued, was the “forerunner of designer, targeted therapies,” and the subsequent “explosion” in the availability of modern cancer therapies has included many that confer cardiac issues.
The final reason for the greater interest in cardio-oncology, Dr. Lyon added, is the increasing awareness in oncology and hematology teams of the potential for cardiac problems among their patients.
“We have been reaching out to our oncology and hematology colleagues over the last 5-10 years to explain we’re here to help. We’re not here to stop their treatments, we’re here to support them.”
Presenting the guidelines, cochair Teresa López-Fernández, MD, cardiology department, La Paz University Hospital, IdiPAZ Research Institute, Madrid, said that the “spectrum of CVR-CVT presentations” includes arterial hypertension, cardiac arrhythmias, coronary artery disease, heart failure, and myocarditis.
She explained that cytotoxic cancer therapies are associated with an increased risk for cardiac toxicity that is most acute during the treatment phase but is not entirely diminished once it is over, then typically accumulates during long-term follow-up.
Crucially, the impact of cancer therapy on cardiovascular risk is dependent on several factors, such as patient age, cancer history, pre-existing cardiovascular risk factors or cardiovascular disease, and previous cardiotoxic cancer therapy.
There are nevertheless a number of potential strategies to reduce the risk for cardiac toxicity, including primary and secondary prevention prior to the start of cancer therapy and early CVR-CVT management during treatment, as well as cardiovascular risk assessment in the first year after treatment completion and cancer-survivorship programs.
To those ends, Dr. López-Fernández said the guidelines incorporate 272 new recommendations that cover the entire cardio-oncology care pathway, beginning with cardiovascular risk stratification before anticancer therapy.
They offer a risk-assessment checklist and make a series of recommendations for patients to be treated with potentially cardiotoxic drugs, such as anthracyclines, as well as recommendations on cardiac imaging.
The guidelines provide a range of recommendations for primary and secondary cancer therapy–related cardiovascular toxicity prevention, including minimization of the use of cardiotoxic drugs and the use of angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta blockers, and statins for primary prevention.
They establish CVR-CVT monitoring protocols across the gamut of cancer therapies, from HER-targeted therapies, through immune checkpoint inhibitors, Bruton tyrosine kinase, CDK4/6, EGFR, VEGF, and ALK inhibitors, and androgen-deprivation and endocrine therapies, to the more novel CAR-T-cell therapies.
A section on radiotherapy-induced cardiovascular toxicity has its own protocol for the establishment of an individual’s mean heart dose of radiation or the amount of radiation exposure to the heart during treatment.
Next, Dr. Lyon looked at recommendations for the management of cardiovascular disease and cancer therapy–related cardiovascular toxicity in patients receiving anticancer treatment.
He underlined that treatment decisions should consider the cancer and cardiovascular symptom burden, the cancer prognosis, the requirements for cancer treatment, including alternative options, drug-drug interactions, and patient preferences.
Dr. Lyon highlighted the algorithms designed to aid the management of cardiac dysfunction related to anthracycline chemotherapy, HER2-targeted therapy, and immune checkpoint inhibitors, as well as QTc-prolonging anticancer drugs.
In the first 12 months after the completions of therapy, there are a number of risk factors for future cardiovascular disease, he continued.
These include high and very high baseline cardiovascular toxicity risk, anticancer treatments known to have a high risk for long-term cardiovascular complications, such as doxorubicin and radiotherapy, and moderate or severe CTR-CVT during anticancer treatment.
Over the long term, the guidelines recommend that surveillance in asymptomatic cancer survivors range from an annual cardiovascular risk assessment in low-risk patients to patient education and cardiovascular risk factor optimization, alongside regular transthoracic echocardiography in high-risk groups.
Finally, Dr. Lyon said the guidelines turn their attention to special populations, such as patients with cardiac masses and tumors, those with carcinoid heart disease, pregnant women receiving cancer therapy, as well as those with cardiac implantable electronic devices undergoing radiotherapy.
The guidelines were developed by the task force on cardio-oncology of the ESC, in collaboration with the European Hematology Association, the European Society for Therapeutic Radiology and Oncology, and the International Cardio-Oncology Society. Dr. Lyon declares relationships with Akcea, Takeda Pharmaceuticals, Pfizer, GlaxoSmithKline, AstraZeneca, Novartis, Ferring Pharmaceuticals, Heartfelt Technologies, Brainstorm, and Myocardial Solutions. Dr. López-Fernández declares relationships with Daiichi Sankyo, Almirall Spain, Janssen-Cilag, Bayer, Roche, Philips, and Incyte.
A version of this article first appeared on Medscape.com.
BARCELONA – Cardiovascular disease risk factors, as well as established disease, in patients undergoing cancer therapy can be safely managed to minimize cancer therapy–related cardiovascular toxicity (CVR-CVT), conclude the first cardio-oncology guidelines from the European Society of Cardiology.
The guidelines were presented at the annual congress of the European Society of Cardiology and published simultaneously in the European Heart Journal.
Guideline cochair Alexander R. Lyon, MD, PhD, told this news organization that the aim of the guideline was to “personalize the decision-making of a patient with cancer who has cardiovascular disease or is at risk of developing it from their treatment ... because it’s not one size fits all.”
because how you manage someone who’s at high risk is going to be different” than managing someone who is at moderate or low risk, he said.
“We’re doing a lot of surveillance because one of the big advantages of cardio-oncology is we know when someone is about to get treated,” Dr. Lyon, from the National Heart and Lung Institute, Imperial College London, and Cardio-Oncology Service, Royal Brompton Hospital, London, said.
“You don’t know in nature when someone’s going to have an acute myocardial infarction or acute viral myocarditis, but we do know when they’re coming into an oncology clinic to get an infusion of chemotherapy or tablets,” he noted.
The guidelines offer recommendations so that patients can “have their treatment safely and minimize interruptions.”
“We know these cancer therapies work; we’re here to get the best of both worlds” by minimizing cardiotoxicity, Dr. Lyon said.
Steady decline in cancer-related mortality
The guidelines note that since the 1990s there has been a “steady decline in cancer-related mortality, mirrored by a steady increase in cancer survival,” and the result is that “treatment-related side effects have gained more significance.”
Dr. Lyon said that between 2011 and 2021, there was a fivefold increase in the number of new referrals of cancer patients with cardiological consequences to his institution.
He said that one of main drivers is modifiable factors, such as smoking, obesity, and inactivity, which increase the risk for both cancer and cardiovascular disease.
“Allied to that, there’s been an improvement in treating cardiovascular diseases in people in their 40s, 50s, and 60s, so they’re surviving their heart failure, myocardial infarction, atrial fibrillation to develop cancers in later life.”
Combined with the aging population, the result is that “not only are many more people being diagnosed with cancer, because they’re living longer, but they have all these pre-existing heart risk factors, whether as confirmed disease or just the risk factors associated with that,” he said.
Another aspect is that many of the newer, targeted cancer therapies confer a cardiovascular risk.
Dr. Lyon said that the “most famous one” is trastuzumab, a monoclonal antibody that is used to treat HER2-positive breast cancer but that also causes left ventricular impairment “in about 15%-20% of the women taking it and can cause severe heart failure if it is missed.”
That, he continued, was the “forerunner of designer, targeted therapies,” and the subsequent “explosion” in the availability of modern cancer therapies has included many that confer cardiac issues.
The final reason for the greater interest in cardio-oncology, Dr. Lyon added, is the increasing awareness in oncology and hematology teams of the potential for cardiac problems among their patients.
“We have been reaching out to our oncology and hematology colleagues over the last 5-10 years to explain we’re here to help. We’re not here to stop their treatments, we’re here to support them.”
Presenting the guidelines, cochair Teresa López-Fernández, MD, cardiology department, La Paz University Hospital, IdiPAZ Research Institute, Madrid, said that the “spectrum of CVR-CVT presentations” includes arterial hypertension, cardiac arrhythmias, coronary artery disease, heart failure, and myocarditis.
She explained that cytotoxic cancer therapies are associated with an increased risk for cardiac toxicity that is most acute during the treatment phase but is not entirely diminished once it is over, then typically accumulates during long-term follow-up.
Crucially, the impact of cancer therapy on cardiovascular risk is dependent on several factors, such as patient age, cancer history, pre-existing cardiovascular risk factors or cardiovascular disease, and previous cardiotoxic cancer therapy.
There are nevertheless a number of potential strategies to reduce the risk for cardiac toxicity, including primary and secondary prevention prior to the start of cancer therapy and early CVR-CVT management during treatment, as well as cardiovascular risk assessment in the first year after treatment completion and cancer-survivorship programs.
To those ends, Dr. López-Fernández said the guidelines incorporate 272 new recommendations that cover the entire cardio-oncology care pathway, beginning with cardiovascular risk stratification before anticancer therapy.
They offer a risk-assessment checklist and make a series of recommendations for patients to be treated with potentially cardiotoxic drugs, such as anthracyclines, as well as recommendations on cardiac imaging.
The guidelines provide a range of recommendations for primary and secondary cancer therapy–related cardiovascular toxicity prevention, including minimization of the use of cardiotoxic drugs and the use of angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta blockers, and statins for primary prevention.
They establish CVR-CVT monitoring protocols across the gamut of cancer therapies, from HER-targeted therapies, through immune checkpoint inhibitors, Bruton tyrosine kinase, CDK4/6, EGFR, VEGF, and ALK inhibitors, and androgen-deprivation and endocrine therapies, to the more novel CAR-T-cell therapies.
A section on radiotherapy-induced cardiovascular toxicity has its own protocol for the establishment of an individual’s mean heart dose of radiation or the amount of radiation exposure to the heart during treatment.
Next, Dr. Lyon looked at recommendations for the management of cardiovascular disease and cancer therapy–related cardiovascular toxicity in patients receiving anticancer treatment.
He underlined that treatment decisions should consider the cancer and cardiovascular symptom burden, the cancer prognosis, the requirements for cancer treatment, including alternative options, drug-drug interactions, and patient preferences.
Dr. Lyon highlighted the algorithms designed to aid the management of cardiac dysfunction related to anthracycline chemotherapy, HER2-targeted therapy, and immune checkpoint inhibitors, as well as QTc-prolonging anticancer drugs.
In the first 12 months after the completions of therapy, there are a number of risk factors for future cardiovascular disease, he continued.
These include high and very high baseline cardiovascular toxicity risk, anticancer treatments known to have a high risk for long-term cardiovascular complications, such as doxorubicin and radiotherapy, and moderate or severe CTR-CVT during anticancer treatment.
Over the long term, the guidelines recommend that surveillance in asymptomatic cancer survivors range from an annual cardiovascular risk assessment in low-risk patients to patient education and cardiovascular risk factor optimization, alongside regular transthoracic echocardiography in high-risk groups.
Finally, Dr. Lyon said the guidelines turn their attention to special populations, such as patients with cardiac masses and tumors, those with carcinoid heart disease, pregnant women receiving cancer therapy, as well as those with cardiac implantable electronic devices undergoing radiotherapy.
The guidelines were developed by the task force on cardio-oncology of the ESC, in collaboration with the European Hematology Association, the European Society for Therapeutic Radiology and Oncology, and the International Cardio-Oncology Society. Dr. Lyon declares relationships with Akcea, Takeda Pharmaceuticals, Pfizer, GlaxoSmithKline, AstraZeneca, Novartis, Ferring Pharmaceuticals, Heartfelt Technologies, Brainstorm, and Myocardial Solutions. Dr. López-Fernández declares relationships with Daiichi Sankyo, Almirall Spain, Janssen-Cilag, Bayer, Roche, Philips, and Incyte.
A version of this article first appeared on Medscape.com.
BARCELONA – Cardiovascular disease risk factors, as well as established disease, in patients undergoing cancer therapy can be safely managed to minimize cancer therapy–related cardiovascular toxicity (CVR-CVT), conclude the first cardio-oncology guidelines from the European Society of Cardiology.
The guidelines were presented at the annual congress of the European Society of Cardiology and published simultaneously in the European Heart Journal.
Guideline cochair Alexander R. Lyon, MD, PhD, told this news organization that the aim of the guideline was to “personalize the decision-making of a patient with cancer who has cardiovascular disease or is at risk of developing it from their treatment ... because it’s not one size fits all.”
because how you manage someone who’s at high risk is going to be different” than managing someone who is at moderate or low risk, he said.
“We’re doing a lot of surveillance because one of the big advantages of cardio-oncology is we know when someone is about to get treated,” Dr. Lyon, from the National Heart and Lung Institute, Imperial College London, and Cardio-Oncology Service, Royal Brompton Hospital, London, said.
“You don’t know in nature when someone’s going to have an acute myocardial infarction or acute viral myocarditis, but we do know when they’re coming into an oncology clinic to get an infusion of chemotherapy or tablets,” he noted.
The guidelines offer recommendations so that patients can “have their treatment safely and minimize interruptions.”
“We know these cancer therapies work; we’re here to get the best of both worlds” by minimizing cardiotoxicity, Dr. Lyon said.
Steady decline in cancer-related mortality
The guidelines note that since the 1990s there has been a “steady decline in cancer-related mortality, mirrored by a steady increase in cancer survival,” and the result is that “treatment-related side effects have gained more significance.”
Dr. Lyon said that between 2011 and 2021, there was a fivefold increase in the number of new referrals of cancer patients with cardiological consequences to his institution.
He said that one of main drivers is modifiable factors, such as smoking, obesity, and inactivity, which increase the risk for both cancer and cardiovascular disease.
“Allied to that, there’s been an improvement in treating cardiovascular diseases in people in their 40s, 50s, and 60s, so they’re surviving their heart failure, myocardial infarction, atrial fibrillation to develop cancers in later life.”
Combined with the aging population, the result is that “not only are many more people being diagnosed with cancer, because they’re living longer, but they have all these pre-existing heart risk factors, whether as confirmed disease or just the risk factors associated with that,” he said.
Another aspect is that many of the newer, targeted cancer therapies confer a cardiovascular risk.
Dr. Lyon said that the “most famous one” is trastuzumab, a monoclonal antibody that is used to treat HER2-positive breast cancer but that also causes left ventricular impairment “in about 15%-20% of the women taking it and can cause severe heart failure if it is missed.”
That, he continued, was the “forerunner of designer, targeted therapies,” and the subsequent “explosion” in the availability of modern cancer therapies has included many that confer cardiac issues.
The final reason for the greater interest in cardio-oncology, Dr. Lyon added, is the increasing awareness in oncology and hematology teams of the potential for cardiac problems among their patients.
“We have been reaching out to our oncology and hematology colleagues over the last 5-10 years to explain we’re here to help. We’re not here to stop their treatments, we’re here to support them.”
Presenting the guidelines, cochair Teresa López-Fernández, MD, cardiology department, La Paz University Hospital, IdiPAZ Research Institute, Madrid, said that the “spectrum of CVR-CVT presentations” includes arterial hypertension, cardiac arrhythmias, coronary artery disease, heart failure, and myocarditis.
She explained that cytotoxic cancer therapies are associated with an increased risk for cardiac toxicity that is most acute during the treatment phase but is not entirely diminished once it is over, then typically accumulates during long-term follow-up.
Crucially, the impact of cancer therapy on cardiovascular risk is dependent on several factors, such as patient age, cancer history, pre-existing cardiovascular risk factors or cardiovascular disease, and previous cardiotoxic cancer therapy.
There are nevertheless a number of potential strategies to reduce the risk for cardiac toxicity, including primary and secondary prevention prior to the start of cancer therapy and early CVR-CVT management during treatment, as well as cardiovascular risk assessment in the first year after treatment completion and cancer-survivorship programs.
To those ends, Dr. López-Fernández said the guidelines incorporate 272 new recommendations that cover the entire cardio-oncology care pathway, beginning with cardiovascular risk stratification before anticancer therapy.
They offer a risk-assessment checklist and make a series of recommendations for patients to be treated with potentially cardiotoxic drugs, such as anthracyclines, as well as recommendations on cardiac imaging.
The guidelines provide a range of recommendations for primary and secondary cancer therapy–related cardiovascular toxicity prevention, including minimization of the use of cardiotoxic drugs and the use of angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta blockers, and statins for primary prevention.
They establish CVR-CVT monitoring protocols across the gamut of cancer therapies, from HER-targeted therapies, through immune checkpoint inhibitors, Bruton tyrosine kinase, CDK4/6, EGFR, VEGF, and ALK inhibitors, and androgen-deprivation and endocrine therapies, to the more novel CAR-T-cell therapies.
A section on radiotherapy-induced cardiovascular toxicity has its own protocol for the establishment of an individual’s mean heart dose of radiation or the amount of radiation exposure to the heart during treatment.
Next, Dr. Lyon looked at recommendations for the management of cardiovascular disease and cancer therapy–related cardiovascular toxicity in patients receiving anticancer treatment.
He underlined that treatment decisions should consider the cancer and cardiovascular symptom burden, the cancer prognosis, the requirements for cancer treatment, including alternative options, drug-drug interactions, and patient preferences.
Dr. Lyon highlighted the algorithms designed to aid the management of cardiac dysfunction related to anthracycline chemotherapy, HER2-targeted therapy, and immune checkpoint inhibitors, as well as QTc-prolonging anticancer drugs.
In the first 12 months after the completions of therapy, there are a number of risk factors for future cardiovascular disease, he continued.
These include high and very high baseline cardiovascular toxicity risk, anticancer treatments known to have a high risk for long-term cardiovascular complications, such as doxorubicin and radiotherapy, and moderate or severe CTR-CVT during anticancer treatment.
Over the long term, the guidelines recommend that surveillance in asymptomatic cancer survivors range from an annual cardiovascular risk assessment in low-risk patients to patient education and cardiovascular risk factor optimization, alongside regular transthoracic echocardiography in high-risk groups.
Finally, Dr. Lyon said the guidelines turn their attention to special populations, such as patients with cardiac masses and tumors, those with carcinoid heart disease, pregnant women receiving cancer therapy, as well as those with cardiac implantable electronic devices undergoing radiotherapy.
The guidelines were developed by the task force on cardio-oncology of the ESC, in collaboration with the European Hematology Association, the European Society for Therapeutic Radiology and Oncology, and the International Cardio-Oncology Society. Dr. Lyon declares relationships with Akcea, Takeda Pharmaceuticals, Pfizer, GlaxoSmithKline, AstraZeneca, Novartis, Ferring Pharmaceuticals, Heartfelt Technologies, Brainstorm, and Myocardial Solutions. Dr. López-Fernández declares relationships with Daiichi Sankyo, Almirall Spain, Janssen-Cilag, Bayer, Roche, Philips, and Incyte.
A version of this article first appeared on Medscape.com.