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MDedge conference coverage features onsite reporting of the latest study results and expert perspectives from leading researchers.
New Drug Combo Boosts PFS
At a median follow-up of 4 years, progression-free survival for the new treatment, known as BrECADD, was 94.3% vs. 90.9% for BEACOPP (hazard ratio, 0.66, 95% CI, P = .035), researchers led by Peter Borchmann, MD, assistant medical director of hematology and oncology at the University Hospital of Cologne, Germany, reported at the annual meeting of the American Society of Clinical Oncology (ASCO).
“These results are really striking,” said hematologist-oncologist Oreofe O. Odejide, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, who was not involved in the study and commented on it during an ASCO news briefing. “This is really poised to impact the standard-of-care treatment for patients with advanced-stage classical Hodgkin lymphoma.”
As Dr. Borchmann explained at the briefing, Hodgkin lymphoma is the most common cancer among young adults. “The median age at onset is around 30 years, and it can be primarily cured with chemotherapy. Intensified chemotherapy probably is better primary lymphoma control than less intensive treatment, but this comes at the cost of treatment-related adverse events.”
Dr. Borchmann and colleagues developed the existing treatment known as BEACOPP, a combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. “It’s our standard of care due to its high primary cure rate, which is reflected by compelling progression-free survival,” he said.
However, he said, “it’s a high burden of treatment.” The investigational treatment, BrECADD, includes six drugs instead of seven: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone. Two of the additions — brentuximab vedotin and dacarbazine — are cancer drugs, and dexamethasone is a steroid. There is one fewer cancer drug in the new formulation.
In the international HD21 trial (9 countries, 233 sites), researchers recruited patients aged 18-60 who received four or six cycles of either BEACOPP or BrECADD. The doses were guided by PET2 findings.
In the intention-to-treat cohort of 1,482 subjects (median age 31.1, 44% female), 742 were assigned to BrECADD and 740 to BEACOPP.
There were few early treatment failures in the BrECADD group vs. BEACOPP. The numbers who had primary progression within the first 3 months were 5 vs. 15, respectively, and the numbers reaching early relapse between months 3 and 12 were 11 vs. 23, respectively.
Four-year overall survival rates in the groups were nearly identical at 98.5% for BrECADD and 98.2% for BEACOPP. In regard to fertility, follicle-stimulating hormone recovery rates after 1 year were higher in the BrECADD group in both men (67% vs. 24%, respectively) and women (89% vs. 68%, respectively). Birth rates were also higher in the BrECADD group (n = 60 vs. n = 43 in the BEACOPP group).
Nearly two-thirds of those in BrECADD group (64%) required 12 weeks of therapy — four cycles. As for treatment-related morbidity toxicities, they were less common in the BrECADD group vs. the BEACOPP group (42% vs. 59%, respectively, P < .0001), and 1% of BrECADD-treated had them at 1 year.
Oncologist Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, welcomed the findings at the ACO news briefing. “By replacing some pretty toxic chemo with an antibody-drug conjugate [brentuximab vedotin], and changing the regimen a bit, and using PET scan to determine the number of cycles received, the long-term outcomes were maintained, if not even improved upon,” said Dr. Dr. Gralow, who was not involved in the study.
In addition, she said, the findings about fertility are good news because “these are young people who probably haven’t started a family yet, and we’re increasing the odds that they will be able to do so after survival.”
Moving forward, she said, “we will need to have some discussion on how this relates to ABVD, which is a more commonly used regimen in the United States right now.” ABVD refers to a combination of doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine.
Takeda funded the study. Dr. Borchmann reported ties with BMS, GmbH & Co, Incyte, MSD/Merck, Roche, Takeda/Millennium, Miltenyi, Amgen, and Novartis. Some of the other study authors reported various disclosures. Dr. Odejide and Dr. Gralow have no disclosures.
At a median follow-up of 4 years, progression-free survival for the new treatment, known as BrECADD, was 94.3% vs. 90.9% for BEACOPP (hazard ratio, 0.66, 95% CI, P = .035), researchers led by Peter Borchmann, MD, assistant medical director of hematology and oncology at the University Hospital of Cologne, Germany, reported at the annual meeting of the American Society of Clinical Oncology (ASCO).
“These results are really striking,” said hematologist-oncologist Oreofe O. Odejide, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, who was not involved in the study and commented on it during an ASCO news briefing. “This is really poised to impact the standard-of-care treatment for patients with advanced-stage classical Hodgkin lymphoma.”
As Dr. Borchmann explained at the briefing, Hodgkin lymphoma is the most common cancer among young adults. “The median age at onset is around 30 years, and it can be primarily cured with chemotherapy. Intensified chemotherapy probably is better primary lymphoma control than less intensive treatment, but this comes at the cost of treatment-related adverse events.”
Dr. Borchmann and colleagues developed the existing treatment known as BEACOPP, a combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. “It’s our standard of care due to its high primary cure rate, which is reflected by compelling progression-free survival,” he said.
However, he said, “it’s a high burden of treatment.” The investigational treatment, BrECADD, includes six drugs instead of seven: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone. Two of the additions — brentuximab vedotin and dacarbazine — are cancer drugs, and dexamethasone is a steroid. There is one fewer cancer drug in the new formulation.
In the international HD21 trial (9 countries, 233 sites), researchers recruited patients aged 18-60 who received four or six cycles of either BEACOPP or BrECADD. The doses were guided by PET2 findings.
In the intention-to-treat cohort of 1,482 subjects (median age 31.1, 44% female), 742 were assigned to BrECADD and 740 to BEACOPP.
There were few early treatment failures in the BrECADD group vs. BEACOPP. The numbers who had primary progression within the first 3 months were 5 vs. 15, respectively, and the numbers reaching early relapse between months 3 and 12 were 11 vs. 23, respectively.
Four-year overall survival rates in the groups were nearly identical at 98.5% for BrECADD and 98.2% for BEACOPP. In regard to fertility, follicle-stimulating hormone recovery rates after 1 year were higher in the BrECADD group in both men (67% vs. 24%, respectively) and women (89% vs. 68%, respectively). Birth rates were also higher in the BrECADD group (n = 60 vs. n = 43 in the BEACOPP group).
Nearly two-thirds of those in BrECADD group (64%) required 12 weeks of therapy — four cycles. As for treatment-related morbidity toxicities, they were less common in the BrECADD group vs. the BEACOPP group (42% vs. 59%, respectively, P < .0001), and 1% of BrECADD-treated had them at 1 year.
Oncologist Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, welcomed the findings at the ACO news briefing. “By replacing some pretty toxic chemo with an antibody-drug conjugate [brentuximab vedotin], and changing the regimen a bit, and using PET scan to determine the number of cycles received, the long-term outcomes were maintained, if not even improved upon,” said Dr. Dr. Gralow, who was not involved in the study.
In addition, she said, the findings about fertility are good news because “these are young people who probably haven’t started a family yet, and we’re increasing the odds that they will be able to do so after survival.”
Moving forward, she said, “we will need to have some discussion on how this relates to ABVD, which is a more commonly used regimen in the United States right now.” ABVD refers to a combination of doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine.
Takeda funded the study. Dr. Borchmann reported ties with BMS, GmbH & Co, Incyte, MSD/Merck, Roche, Takeda/Millennium, Miltenyi, Amgen, and Novartis. Some of the other study authors reported various disclosures. Dr. Odejide and Dr. Gralow have no disclosures.
At a median follow-up of 4 years, progression-free survival for the new treatment, known as BrECADD, was 94.3% vs. 90.9% for BEACOPP (hazard ratio, 0.66, 95% CI, P = .035), researchers led by Peter Borchmann, MD, assistant medical director of hematology and oncology at the University Hospital of Cologne, Germany, reported at the annual meeting of the American Society of Clinical Oncology (ASCO).
“These results are really striking,” said hematologist-oncologist Oreofe O. Odejide, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, who was not involved in the study and commented on it during an ASCO news briefing. “This is really poised to impact the standard-of-care treatment for patients with advanced-stage classical Hodgkin lymphoma.”
As Dr. Borchmann explained at the briefing, Hodgkin lymphoma is the most common cancer among young adults. “The median age at onset is around 30 years, and it can be primarily cured with chemotherapy. Intensified chemotherapy probably is better primary lymphoma control than less intensive treatment, but this comes at the cost of treatment-related adverse events.”
Dr. Borchmann and colleagues developed the existing treatment known as BEACOPP, a combination of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. “It’s our standard of care due to its high primary cure rate, which is reflected by compelling progression-free survival,” he said.
However, he said, “it’s a high burden of treatment.” The investigational treatment, BrECADD, includes six drugs instead of seven: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone. Two of the additions — brentuximab vedotin and dacarbazine — are cancer drugs, and dexamethasone is a steroid. There is one fewer cancer drug in the new formulation.
In the international HD21 trial (9 countries, 233 sites), researchers recruited patients aged 18-60 who received four or six cycles of either BEACOPP or BrECADD. The doses were guided by PET2 findings.
In the intention-to-treat cohort of 1,482 subjects (median age 31.1, 44% female), 742 were assigned to BrECADD and 740 to BEACOPP.
There were few early treatment failures in the BrECADD group vs. BEACOPP. The numbers who had primary progression within the first 3 months were 5 vs. 15, respectively, and the numbers reaching early relapse between months 3 and 12 were 11 vs. 23, respectively.
Four-year overall survival rates in the groups were nearly identical at 98.5% for BrECADD and 98.2% for BEACOPP. In regard to fertility, follicle-stimulating hormone recovery rates after 1 year were higher in the BrECADD group in both men (67% vs. 24%, respectively) and women (89% vs. 68%, respectively). Birth rates were also higher in the BrECADD group (n = 60 vs. n = 43 in the BEACOPP group).
Nearly two-thirds of those in BrECADD group (64%) required 12 weeks of therapy — four cycles. As for treatment-related morbidity toxicities, they were less common in the BrECADD group vs. the BEACOPP group (42% vs. 59%, respectively, P < .0001), and 1% of BrECADD-treated had them at 1 year.
Oncologist Julie R. Gralow, MD, chief medical officer and executive vice president of ASCO, welcomed the findings at the ACO news briefing. “By replacing some pretty toxic chemo with an antibody-drug conjugate [brentuximab vedotin], and changing the regimen a bit, and using PET scan to determine the number of cycles received, the long-term outcomes were maintained, if not even improved upon,” said Dr. Dr. Gralow, who was not involved in the study.
In addition, she said, the findings about fertility are good news because “these are young people who probably haven’t started a family yet, and we’re increasing the odds that they will be able to do so after survival.”
Moving forward, she said, “we will need to have some discussion on how this relates to ABVD, which is a more commonly used regimen in the United States right now.” ABVD refers to a combination of doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine.
Takeda funded the study. Dr. Borchmann reported ties with BMS, GmbH & Co, Incyte, MSD/Merck, Roche, Takeda/Millennium, Miltenyi, Amgen, and Novartis. Some of the other study authors reported various disclosures. Dr. Odejide and Dr. Gralow have no disclosures.
FROM ASCO 2024
CML: Asciminib Bests Standard TKIs as Frontline Therapy
“In the ASC4FIRST trial, asciminib is the first and only agent to demonstrate statistically significant efficacy versus standard-of-care frontline TKIs in newly diagnosed CML patients,” said senior author Jorge E. Cortes, MD, director of the Georgia Cancer Center at Augusta University in Georgia, in presenting the findings at a press briefing for the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
”Asciminib’s strong benefit-risk profile may transform the CML treatment paradigm,” Dr. Cortes said.
The study was published concurrently in The New England Journal of Medicine.
While TKIs have transformed the treatment of CML, improving the 5-year survival rates from 22% in the 1970s to 70% in recent years, nearly half of patients do not achieve a major molecular response within a year, due to either resistance or intolerance, causing the common switching of drugs.
Long-term use is further associated with common side effects, including gastrointestinal and cardiovascular events, due to off-target effects.
Asciminib is a potent and highly specific agent is an allosteric inhibitor targeting ABL myristoyl pocket, which is important in avoiding off-target effects that cause the common side effects.
The drug already has approval from the US Food and Drug Administration (FDA) for the treatment of patients with chronic phase CML who are resistant or intolerant to at least 2 prior TKIs or those with T315I mutation.
For the current pivotal phase 3 ASC4FIRST trial to evaluate the drug as a frontline therapy in recently diagnosed patients with chronic phase CML, 405 patients from cancer centers in 29 countries were enrolled.
The participants were randomized to treatment either with asciminib 80 mg once daily (n = 201) or to an investigator-selected TKI (n = 204), determined based on factors including patient age, preference, and overall health.
In the latter group, 102 patients were receiving imatinib and an equal number receive a stronger, second-generation TKI.
Overall, the patients had a median age of 52 and 65% were male. About 54% were White and 44% were Asian. Those receiving second-generation TKIs were more likely to be younger and without additional health concerns, allowing them to tolerate the more potent drugs.
The median follow-up was 16.3 months in the asciminib group and 15.7 months in the other TKIs group.
For the primary outcome, a major molecular response occurred at week 48 among 67.7% of patients in the asciminib group, compared with 49% in the combined TKI arm of imatinib and second-generation TKI groups (P < .001).
In a subanalysis of patients who were randomized to receive imatinib, a major molecular response occurred at week 48 in 69.3% in the asciminib group versus 40.2% of patients in the imatinib arm (P < .001).
The corresponding rates in the comparison of patients on second-generation TKIs were 66.0% and 57.8%, which was not a statistically significant difference.
Furthermore, a deep molecular response, which may lead to remission and discontinuation of treatment, occurred at week 48 in among 38.8% in the asciminib arm compared with the 20.6% in the combined investigator-selected TKI arm.
In the imatinib comparison analysis, the deep molecular response occurred in 42.6% of patients in the asciminib arm versus 17.8% in the imatinib arm, and in the second-generation TKI arm, the deep molecular response occurred in 35% versus 26.5%, respectively.
Importantly, in the TKI-treated group, significantly more patients in the asciminib group — 86%, remained on therapy at the data cut-off, compared with 62% of those receiving imatinib and 75% of those receiving a second generation TKI.
Adverse events of grade 3 or higher that led to discontinuation were lower with asciminib versus imatinib and second-generation TKIs (38% vs 44.4% and 54.9%, respectively), as were events leading to discontinuation (4.5% versus 11.1% and 9.8%, respectively).
The most common adverse events occurring with asciminib were low platelet count (13%) and low neutrophil count (10%). In terms of severe side effects, blood clots, a known severe side effect of TKIs, occurred in only 1% of patients.
In addition, dose adjustments and treatment interruptions were also more significantly less common in the asciminib group.
Overall, the results indicate that “asciminib has the potential to become a therapy of choice for patients with newly diagnosed chronic phase CML,” said first author Timothy P. Hughes, MD, of South Australian Health and Medical Research Institute and University of Adelaide, Australia, in presenting the findings.
Commenting on the study in an interview, Dr. Cortes underscored the importance of molecular responses as indicators of longer-term responses.
“Early responses correlate with better long-term outcomes,” he said. “Most importantly, they are associated with better probabilities of having a deep molecular response, a requirement for considerations of treatment discontinuation,” which is a highly desirable goal for many patients, he noted.
“If we can get more patients to be eligible for treatment discontinuation and to discontinue successfully, this could be a major advance,” Dr. Cortes emphasized.
“Also, for the patients who do have to stay on therapy for the rest of their lives, a treatment option that has fewer adverse events would be very desirable,” he said.
“We need to see that longer follow-up confirms the current trends, but we are very encouraged by what we see so far.”
Impressive Results; Financial Toxicity Concerns
In discussing the significance of the findings at the meeting, Pankit Vachhani, MD, assistant professor of medicine at the University of Alabama at Birmingham, said the efficacy and toxicity profiles with asciminib were impressive.
“The nearly 70% major molecular response is one of the highest rates that we have seen in clinical trials at week 48,” he said. “That’s great and maybe we will see deeper responses with time.”
He added that the toxicity profile “was better than imagined — frankly I did not expect that, so that’s a welcome surprise, but we do need longer-term data especially on arterial occlusive events not to mention some other adverse events as well.”
“The question to ask ourselves, though, is whether the use of lower dose first- or second-generation TKIs leads to comparable amounts of toxicities.”
Dr. Vachhani raised the concern of cost: “There is the issue of financial toxicity,” he noted. “At current prices, treatment using asciminib would come to approximately $260,000 per year in terms of the cost to the healthcare system,” he said.
“Meanwhile, imatinib right now, in the US, can be obtained for $500 per year, and additional TKIs are going generic [soon],” he said, noting that survival differences remain unclear.
Further commenting, Eunice Wang, MD, associate professor of medicine at the Roswell Park Cancer Institute in Buffalo, New York, agreed that the results are impressive, saying the trial supports asciminib as “the new standard of care of first line therapy of newly diagnosed CML based on both efficacy.”
Dr. Wang, who moderated the ASCO session, noted the caveat that “given the chronicity of this disease, it is important to continue to follow the patients enrolled on this study for longevity and durability of these efficacy endpoints.”
Nevertheless, “given the lower discontinuation rates versus other TKIs and the fact that, in my opinion, most patients who stop drug will do so in the first 6-12 months if not tolerated, these results are highly promising,” she said.
Dr. Wang also agreed, however, that the rising costs of the TKIs are an important concern.
“All of the BCR-ABL TKIs except imatinib already cost several thousand dollars per month, but there is a trend that newer agents are priced higher than prior,” she said. “This needs to be addressed as $10-$20K per month is not reasonable, and the pharmaceutical companies need to be aware.
“Yes, the data with asciminib is better, but if many patients who respond to imatinib just take longer and there is no difference in overall or disease-free survival long-term, the financial costs are a serious topic of discussion,” Dr. Wang noted.
The study was funded by Novartis. Dr. Cortes disclosed ties with Ascentage Pharma, Bio-Path Holdings, BMS, Novartis, Pfizer, Rigel Pharmeuticals, Sun Pharmaceutical Industries, and Takeda Oncology. Dr. Vachhani and Dr. Wang reported various disclosures.
“In the ASC4FIRST trial, asciminib is the first and only agent to demonstrate statistically significant efficacy versus standard-of-care frontline TKIs in newly diagnosed CML patients,” said senior author Jorge E. Cortes, MD, director of the Georgia Cancer Center at Augusta University in Georgia, in presenting the findings at a press briefing for the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
”Asciminib’s strong benefit-risk profile may transform the CML treatment paradigm,” Dr. Cortes said.
The study was published concurrently in The New England Journal of Medicine.
While TKIs have transformed the treatment of CML, improving the 5-year survival rates from 22% in the 1970s to 70% in recent years, nearly half of patients do not achieve a major molecular response within a year, due to either resistance or intolerance, causing the common switching of drugs.
Long-term use is further associated with common side effects, including gastrointestinal and cardiovascular events, due to off-target effects.
Asciminib is a potent and highly specific agent is an allosteric inhibitor targeting ABL myristoyl pocket, which is important in avoiding off-target effects that cause the common side effects.
The drug already has approval from the US Food and Drug Administration (FDA) for the treatment of patients with chronic phase CML who are resistant or intolerant to at least 2 prior TKIs or those with T315I mutation.
For the current pivotal phase 3 ASC4FIRST trial to evaluate the drug as a frontline therapy in recently diagnosed patients with chronic phase CML, 405 patients from cancer centers in 29 countries were enrolled.
The participants were randomized to treatment either with asciminib 80 mg once daily (n = 201) or to an investigator-selected TKI (n = 204), determined based on factors including patient age, preference, and overall health.
In the latter group, 102 patients were receiving imatinib and an equal number receive a stronger, second-generation TKI.
Overall, the patients had a median age of 52 and 65% were male. About 54% were White and 44% were Asian. Those receiving second-generation TKIs were more likely to be younger and without additional health concerns, allowing them to tolerate the more potent drugs.
The median follow-up was 16.3 months in the asciminib group and 15.7 months in the other TKIs group.
For the primary outcome, a major molecular response occurred at week 48 among 67.7% of patients in the asciminib group, compared with 49% in the combined TKI arm of imatinib and second-generation TKI groups (P < .001).
In a subanalysis of patients who were randomized to receive imatinib, a major molecular response occurred at week 48 in 69.3% in the asciminib group versus 40.2% of patients in the imatinib arm (P < .001).
The corresponding rates in the comparison of patients on second-generation TKIs were 66.0% and 57.8%, which was not a statistically significant difference.
Furthermore, a deep molecular response, which may lead to remission and discontinuation of treatment, occurred at week 48 in among 38.8% in the asciminib arm compared with the 20.6% in the combined investigator-selected TKI arm.
In the imatinib comparison analysis, the deep molecular response occurred in 42.6% of patients in the asciminib arm versus 17.8% in the imatinib arm, and in the second-generation TKI arm, the deep molecular response occurred in 35% versus 26.5%, respectively.
Importantly, in the TKI-treated group, significantly more patients in the asciminib group — 86%, remained on therapy at the data cut-off, compared with 62% of those receiving imatinib and 75% of those receiving a second generation TKI.
Adverse events of grade 3 or higher that led to discontinuation were lower with asciminib versus imatinib and second-generation TKIs (38% vs 44.4% and 54.9%, respectively), as were events leading to discontinuation (4.5% versus 11.1% and 9.8%, respectively).
The most common adverse events occurring with asciminib were low platelet count (13%) and low neutrophil count (10%). In terms of severe side effects, blood clots, a known severe side effect of TKIs, occurred in only 1% of patients.
In addition, dose adjustments and treatment interruptions were also more significantly less common in the asciminib group.
Overall, the results indicate that “asciminib has the potential to become a therapy of choice for patients with newly diagnosed chronic phase CML,” said first author Timothy P. Hughes, MD, of South Australian Health and Medical Research Institute and University of Adelaide, Australia, in presenting the findings.
Commenting on the study in an interview, Dr. Cortes underscored the importance of molecular responses as indicators of longer-term responses.
“Early responses correlate with better long-term outcomes,” he said. “Most importantly, they are associated with better probabilities of having a deep molecular response, a requirement for considerations of treatment discontinuation,” which is a highly desirable goal for many patients, he noted.
“If we can get more patients to be eligible for treatment discontinuation and to discontinue successfully, this could be a major advance,” Dr. Cortes emphasized.
“Also, for the patients who do have to stay on therapy for the rest of their lives, a treatment option that has fewer adverse events would be very desirable,” he said.
“We need to see that longer follow-up confirms the current trends, but we are very encouraged by what we see so far.”
Impressive Results; Financial Toxicity Concerns
In discussing the significance of the findings at the meeting, Pankit Vachhani, MD, assistant professor of medicine at the University of Alabama at Birmingham, said the efficacy and toxicity profiles with asciminib were impressive.
“The nearly 70% major molecular response is one of the highest rates that we have seen in clinical trials at week 48,” he said. “That’s great and maybe we will see deeper responses with time.”
He added that the toxicity profile “was better than imagined — frankly I did not expect that, so that’s a welcome surprise, but we do need longer-term data especially on arterial occlusive events not to mention some other adverse events as well.”
“The question to ask ourselves, though, is whether the use of lower dose first- or second-generation TKIs leads to comparable amounts of toxicities.”
Dr. Vachhani raised the concern of cost: “There is the issue of financial toxicity,” he noted. “At current prices, treatment using asciminib would come to approximately $260,000 per year in terms of the cost to the healthcare system,” he said.
“Meanwhile, imatinib right now, in the US, can be obtained for $500 per year, and additional TKIs are going generic [soon],” he said, noting that survival differences remain unclear.
Further commenting, Eunice Wang, MD, associate professor of medicine at the Roswell Park Cancer Institute in Buffalo, New York, agreed that the results are impressive, saying the trial supports asciminib as “the new standard of care of first line therapy of newly diagnosed CML based on both efficacy.”
Dr. Wang, who moderated the ASCO session, noted the caveat that “given the chronicity of this disease, it is important to continue to follow the patients enrolled on this study for longevity and durability of these efficacy endpoints.”
Nevertheless, “given the lower discontinuation rates versus other TKIs and the fact that, in my opinion, most patients who stop drug will do so in the first 6-12 months if not tolerated, these results are highly promising,” she said.
Dr. Wang also agreed, however, that the rising costs of the TKIs are an important concern.
“All of the BCR-ABL TKIs except imatinib already cost several thousand dollars per month, but there is a trend that newer agents are priced higher than prior,” she said. “This needs to be addressed as $10-$20K per month is not reasonable, and the pharmaceutical companies need to be aware.
“Yes, the data with asciminib is better, but if many patients who respond to imatinib just take longer and there is no difference in overall or disease-free survival long-term, the financial costs are a serious topic of discussion,” Dr. Wang noted.
The study was funded by Novartis. Dr. Cortes disclosed ties with Ascentage Pharma, Bio-Path Holdings, BMS, Novartis, Pfizer, Rigel Pharmeuticals, Sun Pharmaceutical Industries, and Takeda Oncology. Dr. Vachhani and Dr. Wang reported various disclosures.
“In the ASC4FIRST trial, asciminib is the first and only agent to demonstrate statistically significant efficacy versus standard-of-care frontline TKIs in newly diagnosed CML patients,” said senior author Jorge E. Cortes, MD, director of the Georgia Cancer Center at Augusta University in Georgia, in presenting the findings at a press briefing for the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
”Asciminib’s strong benefit-risk profile may transform the CML treatment paradigm,” Dr. Cortes said.
The study was published concurrently in The New England Journal of Medicine.
While TKIs have transformed the treatment of CML, improving the 5-year survival rates from 22% in the 1970s to 70% in recent years, nearly half of patients do not achieve a major molecular response within a year, due to either resistance or intolerance, causing the common switching of drugs.
Long-term use is further associated with common side effects, including gastrointestinal and cardiovascular events, due to off-target effects.
Asciminib is a potent and highly specific agent is an allosteric inhibitor targeting ABL myristoyl pocket, which is important in avoiding off-target effects that cause the common side effects.
The drug already has approval from the US Food and Drug Administration (FDA) for the treatment of patients with chronic phase CML who are resistant or intolerant to at least 2 prior TKIs or those with T315I mutation.
For the current pivotal phase 3 ASC4FIRST trial to evaluate the drug as a frontline therapy in recently diagnosed patients with chronic phase CML, 405 patients from cancer centers in 29 countries were enrolled.
The participants were randomized to treatment either with asciminib 80 mg once daily (n = 201) or to an investigator-selected TKI (n = 204), determined based on factors including patient age, preference, and overall health.
In the latter group, 102 patients were receiving imatinib and an equal number receive a stronger, second-generation TKI.
Overall, the patients had a median age of 52 and 65% were male. About 54% were White and 44% were Asian. Those receiving second-generation TKIs were more likely to be younger and without additional health concerns, allowing them to tolerate the more potent drugs.
The median follow-up was 16.3 months in the asciminib group and 15.7 months in the other TKIs group.
For the primary outcome, a major molecular response occurred at week 48 among 67.7% of patients in the asciminib group, compared with 49% in the combined TKI arm of imatinib and second-generation TKI groups (P < .001).
In a subanalysis of patients who were randomized to receive imatinib, a major molecular response occurred at week 48 in 69.3% in the asciminib group versus 40.2% of patients in the imatinib arm (P < .001).
The corresponding rates in the comparison of patients on second-generation TKIs were 66.0% and 57.8%, which was not a statistically significant difference.
Furthermore, a deep molecular response, which may lead to remission and discontinuation of treatment, occurred at week 48 in among 38.8% in the asciminib arm compared with the 20.6% in the combined investigator-selected TKI arm.
In the imatinib comparison analysis, the deep molecular response occurred in 42.6% of patients in the asciminib arm versus 17.8% in the imatinib arm, and in the second-generation TKI arm, the deep molecular response occurred in 35% versus 26.5%, respectively.
Importantly, in the TKI-treated group, significantly more patients in the asciminib group — 86%, remained on therapy at the data cut-off, compared with 62% of those receiving imatinib and 75% of those receiving a second generation TKI.
Adverse events of grade 3 or higher that led to discontinuation were lower with asciminib versus imatinib and second-generation TKIs (38% vs 44.4% and 54.9%, respectively), as were events leading to discontinuation (4.5% versus 11.1% and 9.8%, respectively).
The most common adverse events occurring with asciminib were low platelet count (13%) and low neutrophil count (10%). In terms of severe side effects, blood clots, a known severe side effect of TKIs, occurred in only 1% of patients.
In addition, dose adjustments and treatment interruptions were also more significantly less common in the asciminib group.
Overall, the results indicate that “asciminib has the potential to become a therapy of choice for patients with newly diagnosed chronic phase CML,” said first author Timothy P. Hughes, MD, of South Australian Health and Medical Research Institute and University of Adelaide, Australia, in presenting the findings.
Commenting on the study in an interview, Dr. Cortes underscored the importance of molecular responses as indicators of longer-term responses.
“Early responses correlate with better long-term outcomes,” he said. “Most importantly, they are associated with better probabilities of having a deep molecular response, a requirement for considerations of treatment discontinuation,” which is a highly desirable goal for many patients, he noted.
“If we can get more patients to be eligible for treatment discontinuation and to discontinue successfully, this could be a major advance,” Dr. Cortes emphasized.
“Also, for the patients who do have to stay on therapy for the rest of their lives, a treatment option that has fewer adverse events would be very desirable,” he said.
“We need to see that longer follow-up confirms the current trends, but we are very encouraged by what we see so far.”
Impressive Results; Financial Toxicity Concerns
In discussing the significance of the findings at the meeting, Pankit Vachhani, MD, assistant professor of medicine at the University of Alabama at Birmingham, said the efficacy and toxicity profiles with asciminib were impressive.
“The nearly 70% major molecular response is one of the highest rates that we have seen in clinical trials at week 48,” he said. “That’s great and maybe we will see deeper responses with time.”
He added that the toxicity profile “was better than imagined — frankly I did not expect that, so that’s a welcome surprise, but we do need longer-term data especially on arterial occlusive events not to mention some other adverse events as well.”
“The question to ask ourselves, though, is whether the use of lower dose first- or second-generation TKIs leads to comparable amounts of toxicities.”
Dr. Vachhani raised the concern of cost: “There is the issue of financial toxicity,” he noted. “At current prices, treatment using asciminib would come to approximately $260,000 per year in terms of the cost to the healthcare system,” he said.
“Meanwhile, imatinib right now, in the US, can be obtained for $500 per year, and additional TKIs are going generic [soon],” he said, noting that survival differences remain unclear.
Further commenting, Eunice Wang, MD, associate professor of medicine at the Roswell Park Cancer Institute in Buffalo, New York, agreed that the results are impressive, saying the trial supports asciminib as “the new standard of care of first line therapy of newly diagnosed CML based on both efficacy.”
Dr. Wang, who moderated the ASCO session, noted the caveat that “given the chronicity of this disease, it is important to continue to follow the patients enrolled on this study for longevity and durability of these efficacy endpoints.”
Nevertheless, “given the lower discontinuation rates versus other TKIs and the fact that, in my opinion, most patients who stop drug will do so in the first 6-12 months if not tolerated, these results are highly promising,” she said.
Dr. Wang also agreed, however, that the rising costs of the TKIs are an important concern.
“All of the BCR-ABL TKIs except imatinib already cost several thousand dollars per month, but there is a trend that newer agents are priced higher than prior,” she said. “This needs to be addressed as $10-$20K per month is not reasonable, and the pharmaceutical companies need to be aware.
“Yes, the data with asciminib is better, but if many patients who respond to imatinib just take longer and there is no difference in overall or disease-free survival long-term, the financial costs are a serious topic of discussion,” Dr. Wang noted.
The study was funded by Novartis. Dr. Cortes disclosed ties with Ascentage Pharma, Bio-Path Holdings, BMS, Novartis, Pfizer, Rigel Pharmeuticals, Sun Pharmaceutical Industries, and Takeda Oncology. Dr. Vachhani and Dr. Wang reported various disclosures.
FROM ASCO 2024
How Can Patients With Diabetes and Obesity Lose Weight?
BERLIN — What is the best way to help patients with diabetes, heart problems, and obesity lose weight and improve their outcomes? Is it exercise or medication (such as glucagon-like peptide 1 or gastric inhibitory polypeptide receptor agonists)? This was the focus of a “Battle of Experts” at the 2024 Diabetes Congress in Berlin.
Benefits of Exercise
“Exercise is ‘omnipotent,’ ” said Christine Joisten, MD, general, sports, and nutrition physician at the Sports University in Cologne, Germany. She pointed out that exercise not only helps with weight loss but also improves overall fitness, body composition, eating habits, cardiometabolic health, and quality of life, listing the benefits of exercise.
In a conversation with this news organization, Stephan Kress, MD, a diabetologist at Vinzentius Hospital in Landau, Germany, and first chair of the German Diabetes Society’s Diabetes, Sports, and Exercise Working Group, referred to a study by Pedersen et al. that examined the effect of exercise on 26 conditions. It indicated that exercise had moderate to strong positive effects on disease progression. The benefits of exercise extended beyond metabolic, cardiological, pneumological, and musculoskeletal diseases to neurological and psychiatric conditions.
The so-called myokines, which are “good” cytokines released by muscles, could play a role in this process, according to a presentation by study author Bente Klarlund Pedersen, MD, of Rigshospitalet in Copenhagen, Denmark.
For example, exercise could elevate mood in patients with depression and reduce inflammation in individuals with chronic inflammatory diseases, said Dr. Kress. Many patients, including those with diabetes, could benefit from physical activity even if their A1c levels do not decrease as desired.
Exercise As a Snack
Fat loss can be achieved with prolonged activity or with “short and intense” sessions if followed by refraining from eating immediately afterward, Dr. Joisten explained during the expert battle at the Diabetes Congress.
Different recommendations exist regarding how much exercise is necessary. According to the World Health Organization’s (WHO) recommendation, “Every step counts.” “As sports physicians, we consider physical activity to be any form of energy expenditure achieved through muscle activity,” said Dr. Joisten.
This means that even occasional standing up, walking around, climbing stairs, and everyday activities are a start. They help motivate stigmatized, discouraged patients with obesity. Dr. Joisten highlighted a clear advantage of exercise over the “weight loss injection.” “You can promise your patients that when they start or resume physical activity, they will experience the greatest increase in fitness and health right from the start.”
Just 500 more steps per day can decrease cardiovascular mortality by 7%, while a daily increase of 1000 steps reduces overall mortality by 15%, according to a recent meta-analysis. For movement in a confined space, such as a home office, one can engage in “exercise snacks.” To do this, one interrupts sedentary activities throughout the day with short bursts of movement, said Dr. Joisten.
Dr. Kress agreed with this introductory concept. “With lower intensity and longer duration, you can achieve even more than with short, intense exercise sessions,” he told this news organization. For starters, he recommended “walking without panting,” such as walking or jogging at a pace that allows for conversation.
Even the first walk improves the condition of coronary arteries, Dr. Kress explained. Fragmented exercise sessions, such as three times for 10 min/d, benefit circulation and fitness, the expert emphasized. Moderate aerobic training also ensures effective fat burning and prevents lactic acid buildup.
The Next Step
Gradual progression can lead to longer or brisker walks. The goal does not always have to be 10,000 steps per day, as shown in a meta-analysis presented by Dr. Joisten. In individuals aged < 60 years, 8000-10,000 steps significantly reduced mortality. For those aged > 60 years, 6000-8000 steps were sufficient.
More exercise is even better. The WHO recommends 150-300 min/wk of exercise for adults, including seniors, equivalent to 30-60 min/d for 5 days a week. Additionally, strength training is recommended on 2 days a week — or for seniors, 3 days of combined training sessions with strength and balance components.
In a network meta-analysis, the following exercise regimens were compared for overweight or obese individuals:
- Interval training (very high intensity, 2-3 d/wk, averaging 91 min/wk)
- Strength training (2-3 d/wk, averaging 126 min/wk)
- Continuous endurance training (moderate intensity, 3-5 d/wk, averaging 176 min/wk)
- Combined training (3-4 d/wk, averaging 187 min/wk)
- Hybrid training (high intensity, such as dancing, jumping rope, ball sports, etc., 2-3 d/wk, averaging 128 min/wk).
Participants in the combined training group (which included the longest weekly training times) performed the best in all five endpoints: Body composition, blood lipid levels, blood sugar control, blood pressure, and cardiorespiratory fitness. However, hybrid training also produced good results.
First, Visit the Doctor
Patients who wish to exercise and have not done so in a while or who have cardiac-respiratory or orthopedic conditions should first undergo a medical checkup, Dr. Kress told this news organization.
In most cases, a test on a stationary bicycle at the primary care physician’s office would be sufficient. If higher athletic goals are sought, a sports physician or a cardiologist should be consulted.
However, when looking at weight loss alone, exercise may not go very far, said Dr. Joisten. Approximately 1.5-3.5 kg of body weight can be lost, as shown in a meta-analysis. Of this amount, about 1.3-2.6 kg is fat mass. Only 330-560 g of this total is visceral fat, which matters the most.
A Direct Comparison
Matthias Blüher, MD, an endocrinologist and diabetologist at the University Hospital Leipzig in Leipzig, Germany, represented the pro-injection position. He initially focused on body weight and presented a highly publicized study by Lundgren et al., which showed that treatment with 3.0 mg/d liraglutide was significantly more effective in terms of weight loss than moderate to intensive physical activity. After 12 months, patients who received the injection lost 6.8 kg, while those who exercised lost only 4.1 kg. “The injection wins in a direct comparison,” said Dr. Blüher.
The diabetologist also pointed out the risk for injury associated with exercise. Patients may become less active after a sports injury, he noted.
The LOOK-AHEAD study investigated whether a lifestyle program involving exercise and dietary changes brought cardiovascular benefits. In the long run, it did not. Patients regained weight after some time, and the combined cardiovascular endpoint did not differ between the group with an active, healthy lifestyle and the inactive control group. The study was discontinued.
The SELECT study compared the effect of treatment with once-weekly semaglutide 2.4 mg and placebo on cardiovascular events in patients with cardiovascular conditions and overweight or obesity (n = 17,604). Patients in the semaglutide arm had significantly fewer cardiovascular events over nearly 3 years than the comparison patients receiving placebo (6.5% vs 8.0%). Although the study participants did not have diabetes, they had relatively high baseline A1c levels; two thirds of the patients (n = 11,696) had prediabetes, with an A1c level ≥ 5.7%. Semaglutide significantly delayed the onset of diabetes in these patients, said Dr. Blüher.
A review in which Dr. Blüher was involved showed that treatment with 2.4 mg semaglutide or 15 mg tirzepatide over 12 months was more effective than many older medications (including orlistat) but not as effective as bariatric surgery. Participants in the Exercise and Nutrition study performed even worse than with the older medications.
Combination Therapy
Dr. Blüher and Dr. Joisten agreed that the combined prescription and use of exercise and incretin-based medications yields the best results for relevant endpoints such as weight loss and blood sugar control.
For example, data from the Lundgren study mentioned previously showed that participants in the combination group with liraglutide plus exercise lost an average of 9.5 kg of body weight. In addition, the A1c level, insulin sensitivity, and cardiorespiratory fitness of the participants in the combination group improved significantly over the course of the study.
The suggestion of an interval therapy (alternating between exercise and injections) enjoyed widespread approval during the audience discussion. Dr. Kress also supported the idea of interval therapy with incretin-based injections because it minimizes costs and could enhance insurance companies’ acceptance of this therapy.
But exercise should not be interrupted, he said, and perhaps patients would not want to take breaks either, hoping that “once someone has lost weight (for example, even under injection therapy) they gain new motivation to move and achieve more.”
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
BERLIN — What is the best way to help patients with diabetes, heart problems, and obesity lose weight and improve their outcomes? Is it exercise or medication (such as glucagon-like peptide 1 or gastric inhibitory polypeptide receptor agonists)? This was the focus of a “Battle of Experts” at the 2024 Diabetes Congress in Berlin.
Benefits of Exercise
“Exercise is ‘omnipotent,’ ” said Christine Joisten, MD, general, sports, and nutrition physician at the Sports University in Cologne, Germany. She pointed out that exercise not only helps with weight loss but also improves overall fitness, body composition, eating habits, cardiometabolic health, and quality of life, listing the benefits of exercise.
In a conversation with this news organization, Stephan Kress, MD, a diabetologist at Vinzentius Hospital in Landau, Germany, and first chair of the German Diabetes Society’s Diabetes, Sports, and Exercise Working Group, referred to a study by Pedersen et al. that examined the effect of exercise on 26 conditions. It indicated that exercise had moderate to strong positive effects on disease progression. The benefits of exercise extended beyond metabolic, cardiological, pneumological, and musculoskeletal diseases to neurological and psychiatric conditions.
The so-called myokines, which are “good” cytokines released by muscles, could play a role in this process, according to a presentation by study author Bente Klarlund Pedersen, MD, of Rigshospitalet in Copenhagen, Denmark.
For example, exercise could elevate mood in patients with depression and reduce inflammation in individuals with chronic inflammatory diseases, said Dr. Kress. Many patients, including those with diabetes, could benefit from physical activity even if their A1c levels do not decrease as desired.
Exercise As a Snack
Fat loss can be achieved with prolonged activity or with “short and intense” sessions if followed by refraining from eating immediately afterward, Dr. Joisten explained during the expert battle at the Diabetes Congress.
Different recommendations exist regarding how much exercise is necessary. According to the World Health Organization’s (WHO) recommendation, “Every step counts.” “As sports physicians, we consider physical activity to be any form of energy expenditure achieved through muscle activity,” said Dr. Joisten.
This means that even occasional standing up, walking around, climbing stairs, and everyday activities are a start. They help motivate stigmatized, discouraged patients with obesity. Dr. Joisten highlighted a clear advantage of exercise over the “weight loss injection.” “You can promise your patients that when they start or resume physical activity, they will experience the greatest increase in fitness and health right from the start.”
Just 500 more steps per day can decrease cardiovascular mortality by 7%, while a daily increase of 1000 steps reduces overall mortality by 15%, according to a recent meta-analysis. For movement in a confined space, such as a home office, one can engage in “exercise snacks.” To do this, one interrupts sedentary activities throughout the day with short bursts of movement, said Dr. Joisten.
Dr. Kress agreed with this introductory concept. “With lower intensity and longer duration, you can achieve even more than with short, intense exercise sessions,” he told this news organization. For starters, he recommended “walking without panting,” such as walking or jogging at a pace that allows for conversation.
Even the first walk improves the condition of coronary arteries, Dr. Kress explained. Fragmented exercise sessions, such as three times for 10 min/d, benefit circulation and fitness, the expert emphasized. Moderate aerobic training also ensures effective fat burning and prevents lactic acid buildup.
The Next Step
Gradual progression can lead to longer or brisker walks. The goal does not always have to be 10,000 steps per day, as shown in a meta-analysis presented by Dr. Joisten. In individuals aged < 60 years, 8000-10,000 steps significantly reduced mortality. For those aged > 60 years, 6000-8000 steps were sufficient.
More exercise is even better. The WHO recommends 150-300 min/wk of exercise for adults, including seniors, equivalent to 30-60 min/d for 5 days a week. Additionally, strength training is recommended on 2 days a week — or for seniors, 3 days of combined training sessions with strength and balance components.
In a network meta-analysis, the following exercise regimens were compared for overweight or obese individuals:
- Interval training (very high intensity, 2-3 d/wk, averaging 91 min/wk)
- Strength training (2-3 d/wk, averaging 126 min/wk)
- Continuous endurance training (moderate intensity, 3-5 d/wk, averaging 176 min/wk)
- Combined training (3-4 d/wk, averaging 187 min/wk)
- Hybrid training (high intensity, such as dancing, jumping rope, ball sports, etc., 2-3 d/wk, averaging 128 min/wk).
Participants in the combined training group (which included the longest weekly training times) performed the best in all five endpoints: Body composition, blood lipid levels, blood sugar control, blood pressure, and cardiorespiratory fitness. However, hybrid training also produced good results.
First, Visit the Doctor
Patients who wish to exercise and have not done so in a while or who have cardiac-respiratory or orthopedic conditions should first undergo a medical checkup, Dr. Kress told this news organization.
In most cases, a test on a stationary bicycle at the primary care physician’s office would be sufficient. If higher athletic goals are sought, a sports physician or a cardiologist should be consulted.
However, when looking at weight loss alone, exercise may not go very far, said Dr. Joisten. Approximately 1.5-3.5 kg of body weight can be lost, as shown in a meta-analysis. Of this amount, about 1.3-2.6 kg is fat mass. Only 330-560 g of this total is visceral fat, which matters the most.
A Direct Comparison
Matthias Blüher, MD, an endocrinologist and diabetologist at the University Hospital Leipzig in Leipzig, Germany, represented the pro-injection position. He initially focused on body weight and presented a highly publicized study by Lundgren et al., which showed that treatment with 3.0 mg/d liraglutide was significantly more effective in terms of weight loss than moderate to intensive physical activity. After 12 months, patients who received the injection lost 6.8 kg, while those who exercised lost only 4.1 kg. “The injection wins in a direct comparison,” said Dr. Blüher.
The diabetologist also pointed out the risk for injury associated with exercise. Patients may become less active after a sports injury, he noted.
The LOOK-AHEAD study investigated whether a lifestyle program involving exercise and dietary changes brought cardiovascular benefits. In the long run, it did not. Patients regained weight after some time, and the combined cardiovascular endpoint did not differ between the group with an active, healthy lifestyle and the inactive control group. The study was discontinued.
The SELECT study compared the effect of treatment with once-weekly semaglutide 2.4 mg and placebo on cardiovascular events in patients with cardiovascular conditions and overweight or obesity (n = 17,604). Patients in the semaglutide arm had significantly fewer cardiovascular events over nearly 3 years than the comparison patients receiving placebo (6.5% vs 8.0%). Although the study participants did not have diabetes, they had relatively high baseline A1c levels; two thirds of the patients (n = 11,696) had prediabetes, with an A1c level ≥ 5.7%. Semaglutide significantly delayed the onset of diabetes in these patients, said Dr. Blüher.
A review in which Dr. Blüher was involved showed that treatment with 2.4 mg semaglutide or 15 mg tirzepatide over 12 months was more effective than many older medications (including orlistat) but not as effective as bariatric surgery. Participants in the Exercise and Nutrition study performed even worse than with the older medications.
Combination Therapy
Dr. Blüher and Dr. Joisten agreed that the combined prescription and use of exercise and incretin-based medications yields the best results for relevant endpoints such as weight loss and blood sugar control.
For example, data from the Lundgren study mentioned previously showed that participants in the combination group with liraglutide plus exercise lost an average of 9.5 kg of body weight. In addition, the A1c level, insulin sensitivity, and cardiorespiratory fitness of the participants in the combination group improved significantly over the course of the study.
The suggestion of an interval therapy (alternating between exercise and injections) enjoyed widespread approval during the audience discussion. Dr. Kress also supported the idea of interval therapy with incretin-based injections because it minimizes costs and could enhance insurance companies’ acceptance of this therapy.
But exercise should not be interrupted, he said, and perhaps patients would not want to take breaks either, hoping that “once someone has lost weight (for example, even under injection therapy) they gain new motivation to move and achieve more.”
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
BERLIN — What is the best way to help patients with diabetes, heart problems, and obesity lose weight and improve their outcomes? Is it exercise or medication (such as glucagon-like peptide 1 or gastric inhibitory polypeptide receptor agonists)? This was the focus of a “Battle of Experts” at the 2024 Diabetes Congress in Berlin.
Benefits of Exercise
“Exercise is ‘omnipotent,’ ” said Christine Joisten, MD, general, sports, and nutrition physician at the Sports University in Cologne, Germany. She pointed out that exercise not only helps with weight loss but also improves overall fitness, body composition, eating habits, cardiometabolic health, and quality of life, listing the benefits of exercise.
In a conversation with this news organization, Stephan Kress, MD, a diabetologist at Vinzentius Hospital in Landau, Germany, and first chair of the German Diabetes Society’s Diabetes, Sports, and Exercise Working Group, referred to a study by Pedersen et al. that examined the effect of exercise on 26 conditions. It indicated that exercise had moderate to strong positive effects on disease progression. The benefits of exercise extended beyond metabolic, cardiological, pneumological, and musculoskeletal diseases to neurological and psychiatric conditions.
The so-called myokines, which are “good” cytokines released by muscles, could play a role in this process, according to a presentation by study author Bente Klarlund Pedersen, MD, of Rigshospitalet in Copenhagen, Denmark.
For example, exercise could elevate mood in patients with depression and reduce inflammation in individuals with chronic inflammatory diseases, said Dr. Kress. Many patients, including those with diabetes, could benefit from physical activity even if their A1c levels do not decrease as desired.
Exercise As a Snack
Fat loss can be achieved with prolonged activity or with “short and intense” sessions if followed by refraining from eating immediately afterward, Dr. Joisten explained during the expert battle at the Diabetes Congress.
Different recommendations exist regarding how much exercise is necessary. According to the World Health Organization’s (WHO) recommendation, “Every step counts.” “As sports physicians, we consider physical activity to be any form of energy expenditure achieved through muscle activity,” said Dr. Joisten.
This means that even occasional standing up, walking around, climbing stairs, and everyday activities are a start. They help motivate stigmatized, discouraged patients with obesity. Dr. Joisten highlighted a clear advantage of exercise over the “weight loss injection.” “You can promise your patients that when they start or resume physical activity, they will experience the greatest increase in fitness and health right from the start.”
Just 500 more steps per day can decrease cardiovascular mortality by 7%, while a daily increase of 1000 steps reduces overall mortality by 15%, according to a recent meta-analysis. For movement in a confined space, such as a home office, one can engage in “exercise snacks.” To do this, one interrupts sedentary activities throughout the day with short bursts of movement, said Dr. Joisten.
Dr. Kress agreed with this introductory concept. “With lower intensity and longer duration, you can achieve even more than with short, intense exercise sessions,” he told this news organization. For starters, he recommended “walking without panting,” such as walking or jogging at a pace that allows for conversation.
Even the first walk improves the condition of coronary arteries, Dr. Kress explained. Fragmented exercise sessions, such as three times for 10 min/d, benefit circulation and fitness, the expert emphasized. Moderate aerobic training also ensures effective fat burning and prevents lactic acid buildup.
The Next Step
Gradual progression can lead to longer or brisker walks. The goal does not always have to be 10,000 steps per day, as shown in a meta-analysis presented by Dr. Joisten. In individuals aged < 60 years, 8000-10,000 steps significantly reduced mortality. For those aged > 60 years, 6000-8000 steps were sufficient.
More exercise is even better. The WHO recommends 150-300 min/wk of exercise for adults, including seniors, equivalent to 30-60 min/d for 5 days a week. Additionally, strength training is recommended on 2 days a week — or for seniors, 3 days of combined training sessions with strength and balance components.
In a network meta-analysis, the following exercise regimens were compared for overweight or obese individuals:
- Interval training (very high intensity, 2-3 d/wk, averaging 91 min/wk)
- Strength training (2-3 d/wk, averaging 126 min/wk)
- Continuous endurance training (moderate intensity, 3-5 d/wk, averaging 176 min/wk)
- Combined training (3-4 d/wk, averaging 187 min/wk)
- Hybrid training (high intensity, such as dancing, jumping rope, ball sports, etc., 2-3 d/wk, averaging 128 min/wk).
Participants in the combined training group (which included the longest weekly training times) performed the best in all five endpoints: Body composition, blood lipid levels, blood sugar control, blood pressure, and cardiorespiratory fitness. However, hybrid training also produced good results.
First, Visit the Doctor
Patients who wish to exercise and have not done so in a while or who have cardiac-respiratory or orthopedic conditions should first undergo a medical checkup, Dr. Kress told this news organization.
In most cases, a test on a stationary bicycle at the primary care physician’s office would be sufficient. If higher athletic goals are sought, a sports physician or a cardiologist should be consulted.
However, when looking at weight loss alone, exercise may not go very far, said Dr. Joisten. Approximately 1.5-3.5 kg of body weight can be lost, as shown in a meta-analysis. Of this amount, about 1.3-2.6 kg is fat mass. Only 330-560 g of this total is visceral fat, which matters the most.
A Direct Comparison
Matthias Blüher, MD, an endocrinologist and diabetologist at the University Hospital Leipzig in Leipzig, Germany, represented the pro-injection position. He initially focused on body weight and presented a highly publicized study by Lundgren et al., which showed that treatment with 3.0 mg/d liraglutide was significantly more effective in terms of weight loss than moderate to intensive physical activity. After 12 months, patients who received the injection lost 6.8 kg, while those who exercised lost only 4.1 kg. “The injection wins in a direct comparison,” said Dr. Blüher.
The diabetologist also pointed out the risk for injury associated with exercise. Patients may become less active after a sports injury, he noted.
The LOOK-AHEAD study investigated whether a lifestyle program involving exercise and dietary changes brought cardiovascular benefits. In the long run, it did not. Patients regained weight after some time, and the combined cardiovascular endpoint did not differ between the group with an active, healthy lifestyle and the inactive control group. The study was discontinued.
The SELECT study compared the effect of treatment with once-weekly semaglutide 2.4 mg and placebo on cardiovascular events in patients with cardiovascular conditions and overweight or obesity (n = 17,604). Patients in the semaglutide arm had significantly fewer cardiovascular events over nearly 3 years than the comparison patients receiving placebo (6.5% vs 8.0%). Although the study participants did not have diabetes, they had relatively high baseline A1c levels; two thirds of the patients (n = 11,696) had prediabetes, with an A1c level ≥ 5.7%. Semaglutide significantly delayed the onset of diabetes in these patients, said Dr. Blüher.
A review in which Dr. Blüher was involved showed that treatment with 2.4 mg semaglutide or 15 mg tirzepatide over 12 months was more effective than many older medications (including orlistat) but not as effective as bariatric surgery. Participants in the Exercise and Nutrition study performed even worse than with the older medications.
Combination Therapy
Dr. Blüher and Dr. Joisten agreed that the combined prescription and use of exercise and incretin-based medications yields the best results for relevant endpoints such as weight loss and blood sugar control.
For example, data from the Lundgren study mentioned previously showed that participants in the combination group with liraglutide plus exercise lost an average of 9.5 kg of body weight. In addition, the A1c level, insulin sensitivity, and cardiorespiratory fitness of the participants in the combination group improved significantly over the course of the study.
The suggestion of an interval therapy (alternating between exercise and injections) enjoyed widespread approval during the audience discussion. Dr. Kress also supported the idea of interval therapy with incretin-based injections because it minimizes costs and could enhance insurance companies’ acceptance of this therapy.
But exercise should not be interrupted, he said, and perhaps patients would not want to take breaks either, hoping that “once someone has lost weight (for example, even under injection therapy) they gain new motivation to move and achieve more.”
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
Colorectal Cancer Is Spiking Among Some Young Americans
WASHINGTON — Despite encouraging drops in overall colorectal cancer rates in the past two decades, one group stands out as an exception: Americans younger than 45.
, according to new research presented at the annual Digestive Disease Week®.
As high as those percentages appear, the number of people affected at these ages remains small compared with rates in Americans 45 and older, said Loren Laine, MD, AGAF, professor of medicine (digestive diseases) at Yale School of Medicine, who co-moderated a news briefing discussing the research.
“The trends are alarming [but] the actual numbers of colorectal cancer cases among children and teens are not high enough to suggest widespread screening,” agreed lead investigator Islam Mohamed, MD, an internal medicine resident at the University of Missouri-Kansas City.
For example, 1 out of every 333,000 15- to-19-year-olds developed colorectal cancer in 1999. Colorectal cancer became more common by 2020, when 1 out of every 77,000 teens developed it.
At the same time, the number of cases in young adults 20 to 24 increased from less than 1 to 2 per 100,000 in 2020.
Even if the risk is relatively low in terms of absolute numbers, experts are keeping an eye on why the rates are increasing. It’s also about raising awareness. If someone younger than 45 experiences colorectal cancer symptoms like blood in their stool, stomach pain, changes in bowel habits, or others, they should seek medical attention, Dr. Laine said.
“If you have symptoms like rectal bleeding, you shouldn’t take it lightly. It’s still pretty unlikely that they’re going to have colon cancer ... but obviously you should still not totally dismiss it,” Dr. Laine said.
“Colorectal cancer is no longer considered just a disease of the elderly population,” Dr. Mohamed said during the briefing. “It’s important that the public is aware of signs and symptoms of colorectal cancer.”
Dr. Mohamed and colleagues studied colorectal cancer cases using numbers from the CDC Wonder Database, a central database of public health information. They calculated increases by comparing rates in 1999 to 2020.
Colorectal cancer is a major cause of cancer-related death in the United States. It currently ranks third in terms of new cases and cancer-related deaths once some skin cancers are excluded, American Cancer Society data indicates.
Some Risk Factors Can Be Changed
The colorectal cancer rates in younger people “have been consistently rising. It might be related to the environmental factors, lifestyle factors, and genetic factors as well,” Dr. Mohamed said. “It also might mean that we are doing better. Maybe we’re screening patients more, and maybe we’re doing a greater job of picking patients who are at high risk of colorectal cancer in the younger population.”
“Adopting a healthy lifestyle would be a great approach to curb the rising incidence of colorectal cancer as we saw metabolic syndrome is a big [factor],” Dr. Mohamed added. Patients should be encouraged to maintain a balanced diet, engage in regular physical activity, and maybe limit alcohol consumption, he said.
On the other hand, up to one third of early-onset colorectal cancer cases are linked to factors that cannot be changed. A family history of colorectal cancer, presence of inflammatory bowel disease, and certain types of cancers linked to genetic mutations are examples. “When you think about it, most of those young people [with colorectal cancer] probably have genetic syndromes,” Dr. Laine said. “The big issue is, frankly, finding better ways to identify families that have genetic syndromes. That’s probably the biggest message.”
Risk Varied by Age
In addition to the increases in the 15- to 19-year-old and 20- to 24-year-old groups, the rates in 2020 compared with 1999 showed a
- 68% increase for ages 25 to 29.
- 71% increase for ages 30 to 34.
- 58% increase for ages 35 to 39.
- 45% increase for ages 40 to 44.
“These findings all emphasize the urgent needs for public awareness and personalized screening approaches,” Dr. Mohamed said, “particularly among younger populations who had the most substantial increase in colorectal cancer incidence we observed.”
The US Preventive Services Task Force lowered the recommended age for colorectal cancer screening from 50 to 45 in 2021. Dr. Mohamed suggested more targeted screening for people under 45 at higher risk.
“I think also staying informed about the rising incidence and the latest research and recommendations in terms of colorectal cancer prevention and screening will be really, really helpful.”
A version of this article appeared on WebMD Health News.
WASHINGTON — Despite encouraging drops in overall colorectal cancer rates in the past two decades, one group stands out as an exception: Americans younger than 45.
, according to new research presented at the annual Digestive Disease Week®.
As high as those percentages appear, the number of people affected at these ages remains small compared with rates in Americans 45 and older, said Loren Laine, MD, AGAF, professor of medicine (digestive diseases) at Yale School of Medicine, who co-moderated a news briefing discussing the research.
“The trends are alarming [but] the actual numbers of colorectal cancer cases among children and teens are not high enough to suggest widespread screening,” agreed lead investigator Islam Mohamed, MD, an internal medicine resident at the University of Missouri-Kansas City.
For example, 1 out of every 333,000 15- to-19-year-olds developed colorectal cancer in 1999. Colorectal cancer became more common by 2020, when 1 out of every 77,000 teens developed it.
At the same time, the number of cases in young adults 20 to 24 increased from less than 1 to 2 per 100,000 in 2020.
Even if the risk is relatively low in terms of absolute numbers, experts are keeping an eye on why the rates are increasing. It’s also about raising awareness. If someone younger than 45 experiences colorectal cancer symptoms like blood in their stool, stomach pain, changes in bowel habits, or others, they should seek medical attention, Dr. Laine said.
“If you have symptoms like rectal bleeding, you shouldn’t take it lightly. It’s still pretty unlikely that they’re going to have colon cancer ... but obviously you should still not totally dismiss it,” Dr. Laine said.
“Colorectal cancer is no longer considered just a disease of the elderly population,” Dr. Mohamed said during the briefing. “It’s important that the public is aware of signs and symptoms of colorectal cancer.”
Dr. Mohamed and colleagues studied colorectal cancer cases using numbers from the CDC Wonder Database, a central database of public health information. They calculated increases by comparing rates in 1999 to 2020.
Colorectal cancer is a major cause of cancer-related death in the United States. It currently ranks third in terms of new cases and cancer-related deaths once some skin cancers are excluded, American Cancer Society data indicates.
Some Risk Factors Can Be Changed
The colorectal cancer rates in younger people “have been consistently rising. It might be related to the environmental factors, lifestyle factors, and genetic factors as well,” Dr. Mohamed said. “It also might mean that we are doing better. Maybe we’re screening patients more, and maybe we’re doing a greater job of picking patients who are at high risk of colorectal cancer in the younger population.”
“Adopting a healthy lifestyle would be a great approach to curb the rising incidence of colorectal cancer as we saw metabolic syndrome is a big [factor],” Dr. Mohamed added. Patients should be encouraged to maintain a balanced diet, engage in regular physical activity, and maybe limit alcohol consumption, he said.
On the other hand, up to one third of early-onset colorectal cancer cases are linked to factors that cannot be changed. A family history of colorectal cancer, presence of inflammatory bowel disease, and certain types of cancers linked to genetic mutations are examples. “When you think about it, most of those young people [with colorectal cancer] probably have genetic syndromes,” Dr. Laine said. “The big issue is, frankly, finding better ways to identify families that have genetic syndromes. That’s probably the biggest message.”
Risk Varied by Age
In addition to the increases in the 15- to 19-year-old and 20- to 24-year-old groups, the rates in 2020 compared with 1999 showed a
- 68% increase for ages 25 to 29.
- 71% increase for ages 30 to 34.
- 58% increase for ages 35 to 39.
- 45% increase for ages 40 to 44.
“These findings all emphasize the urgent needs for public awareness and personalized screening approaches,” Dr. Mohamed said, “particularly among younger populations who had the most substantial increase in colorectal cancer incidence we observed.”
The US Preventive Services Task Force lowered the recommended age for colorectal cancer screening from 50 to 45 in 2021. Dr. Mohamed suggested more targeted screening for people under 45 at higher risk.
“I think also staying informed about the rising incidence and the latest research and recommendations in terms of colorectal cancer prevention and screening will be really, really helpful.”
A version of this article appeared on WebMD Health News.
WASHINGTON — Despite encouraging drops in overall colorectal cancer rates in the past two decades, one group stands out as an exception: Americans younger than 45.
, according to new research presented at the annual Digestive Disease Week®.
As high as those percentages appear, the number of people affected at these ages remains small compared with rates in Americans 45 and older, said Loren Laine, MD, AGAF, professor of medicine (digestive diseases) at Yale School of Medicine, who co-moderated a news briefing discussing the research.
“The trends are alarming [but] the actual numbers of colorectal cancer cases among children and teens are not high enough to suggest widespread screening,” agreed lead investigator Islam Mohamed, MD, an internal medicine resident at the University of Missouri-Kansas City.
For example, 1 out of every 333,000 15- to-19-year-olds developed colorectal cancer in 1999. Colorectal cancer became more common by 2020, when 1 out of every 77,000 teens developed it.
At the same time, the number of cases in young adults 20 to 24 increased from less than 1 to 2 per 100,000 in 2020.
Even if the risk is relatively low in terms of absolute numbers, experts are keeping an eye on why the rates are increasing. It’s also about raising awareness. If someone younger than 45 experiences colorectal cancer symptoms like blood in their stool, stomach pain, changes in bowel habits, or others, they should seek medical attention, Dr. Laine said.
“If you have symptoms like rectal bleeding, you shouldn’t take it lightly. It’s still pretty unlikely that they’re going to have colon cancer ... but obviously you should still not totally dismiss it,” Dr. Laine said.
“Colorectal cancer is no longer considered just a disease of the elderly population,” Dr. Mohamed said during the briefing. “It’s important that the public is aware of signs and symptoms of colorectal cancer.”
Dr. Mohamed and colleagues studied colorectal cancer cases using numbers from the CDC Wonder Database, a central database of public health information. They calculated increases by comparing rates in 1999 to 2020.
Colorectal cancer is a major cause of cancer-related death in the United States. It currently ranks third in terms of new cases and cancer-related deaths once some skin cancers are excluded, American Cancer Society data indicates.
Some Risk Factors Can Be Changed
The colorectal cancer rates in younger people “have been consistently rising. It might be related to the environmental factors, lifestyle factors, and genetic factors as well,” Dr. Mohamed said. “It also might mean that we are doing better. Maybe we’re screening patients more, and maybe we’re doing a greater job of picking patients who are at high risk of colorectal cancer in the younger population.”
“Adopting a healthy lifestyle would be a great approach to curb the rising incidence of colorectal cancer as we saw metabolic syndrome is a big [factor],” Dr. Mohamed added. Patients should be encouraged to maintain a balanced diet, engage in regular physical activity, and maybe limit alcohol consumption, he said.
On the other hand, up to one third of early-onset colorectal cancer cases are linked to factors that cannot be changed. A family history of colorectal cancer, presence of inflammatory bowel disease, and certain types of cancers linked to genetic mutations are examples. “When you think about it, most of those young people [with colorectal cancer] probably have genetic syndromes,” Dr. Laine said. “The big issue is, frankly, finding better ways to identify families that have genetic syndromes. That’s probably the biggest message.”
Risk Varied by Age
In addition to the increases in the 15- to 19-year-old and 20- to 24-year-old groups, the rates in 2020 compared with 1999 showed a
- 68% increase for ages 25 to 29.
- 71% increase for ages 30 to 34.
- 58% increase for ages 35 to 39.
- 45% increase for ages 40 to 44.
“These findings all emphasize the urgent needs for public awareness and personalized screening approaches,” Dr. Mohamed said, “particularly among younger populations who had the most substantial increase in colorectal cancer incidence we observed.”
The US Preventive Services Task Force lowered the recommended age for colorectal cancer screening from 50 to 45 in 2021. Dr. Mohamed suggested more targeted screening for people under 45 at higher risk.
“I think also staying informed about the rising incidence and the latest research and recommendations in terms of colorectal cancer prevention and screening will be really, really helpful.”
A version of this article appeared on WebMD Health News.
FROM DDW 2024
Semaglutide Kidney Benefits Extend to Those Without Diabetes
STOCKHOLM — Improvements in kidney function outcomes observed with glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes extend to patients who are overweight or obese but don›t yet have type 2 diabetes, new research shows.
“These data are important because they are the first data to suggest a kidney benefit of semaglutide in this patient population in the absence of diabetes,” lead author Helen M. Colhoun, MD, of the Institute of Genetics and Cancer, University of Edinburgh, Scotland, United Kingdom, told this news organization.
“This is a population at high risk of chronic kidney disease with an increased need for kidney protection,” she said.
The late-breaking study was presented this week at the 61st European Renal Association (ERA) Congress 2024 and simultaneously published in Nature Medicine.
SELECT Trial Patients Without Diabetes
The findings are from a secondary analysis of the randomized SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity) trial, which evaluated cardiovascular outcomes of semaglutide treatment among 17,604 adults with preexisting cardiovascular disease who were overweight or obese — but did not have diabetes.
For its primary endpoint, the trial showed semaglutide was associated with a 20% reduction in major adverse cardiovascular events compared with placebo.
With obesity also associated with a significantly increased risk of chronic kidney disease — and the headline-making FLOW trial, also presented at the congress, showing key benefits of semaglutide in improving kidney function in people with CKD and type 2 diabetes the secondary analysis of SELECT was conducted to investigate whether those kidney benefits extended to people without type 2 diabetes.
Patients were randomized 1:1 to once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. Baseline patient characteristics were well-balanced, including kidney function and albuminuria status.
The primary endpoint for the analysis was a nephropathy composite of time from randomization to the first occurrence of death from kidney causes; initiation of chronic kidney replacement therapy; onset of persistent estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2; persistent ≥ 50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria.
With a median follow-up of 182 weeks, the results showed that the semaglutide group was significantly less likely to develop the primary composite endpoint compared with the placebo group (1.8% vs 2.2%; hazard ratio [HR], 0.78; P = .02).
A significantly reduced decline in eGFR in the semaglutide group was observed at a prespecified 104-week time point, with a treatment effect of 0.75 mL/min/1.73 m2 (P < .001), and the effect was more pronounced among participants with baseline eGFR < 60 mL/min/1.73 m2 (P < .001).
Furthermore, those in the semaglutide group had a significantly lower proportionate increase in urinary albumin-to-creatinine ratio (UACR) compared with placebo (–10.7%; P < .001) at the prespecified 104 weeks, with a net treatment benefit of –27.2% and –31.4% among those with randomization to UACR 30 to < 300 mg/g and 2300 mg/g, respectively.
Improvements varied according to baseline UACR status and were more pronounced among those with macroalbuminuria, at –8.1% for those with normoalbuminuria (n = 14,848), –27% for microalbuminuria (n = 1968), and –31% for macroalbuminuria (n = 325).
There were no reports of acute kidney injury associated with semaglutide, regardless of baseline eGFR.
“We were hopeful that there would be similar benefits as those observed in the diabetes studies, but there are differences in kidney disease among those with and without type 2 diabetes, so we weren’t sure,” Dr. Colhoun told this news organization.
Benefits the Result of Weight Loss or Something Else?
Considering the beneficial effects of semaglutide on weight loss, underscored in an analysis also published this month that showed a mean 10.2% reduction in weight sustained for up to 4 years, a key question is whether the kidney benefits are a direct result of weight loss — or the drug mechanism or something else.
But Dr. Colhoun said the role of weight loss in terms of the kidney benefits is still uncertain, particularly considering the various other factors, including cardiometabolic improvements, which could also have an effect.
“It’s a very difficult question to answer,” she said. “We did do a mediation exploratory analysis suggesting a substantial part of the effect might be due to the weight change, but it’s difficult to demonstrate that because you have weight change going on in the placebo arm as well, but for different reasons,” she said.
“So, I would say the data suggest there is some component of this that is attributable to weight, but we certainly can’t attribute all of the [effects] to weight change.”
Small studies involving animals have shown a direct effect of semaglutide on kidney hemodynamics “but they’re small and not definitive,” Dr. Colhoun added.
And although weight loss achieved through other measures such as lifestyle changes show a small benefit on eGFR, “interestingly, those studies showed no effect at all on albuminuria, whereas we see a really substantial effect on albuminuria with semaglutide,” Dr. Colhoun said.
Studies of weight loss through bariatric surgery have shown kidney benefits; however, those were in the context of type 2 diabetes, unlike the current analysis.
In terms of whether the benefits may extend to tirzepatide, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, increasingly used in weight loss, results from another secondary analysis also show encouraging kidney benefits in people with type 2 diabetes, and there is ongoing research in patients with type 2 diabetes and those with obesity without diabetes, Dr. Colhoun noted.
Primary Prevention of CKD?
Limitations of the current analysis include that only about a fifth of participants in SELECT had an eGFR < 60 mL/min/1.73 m2 or UACR ≥ 30 mg/g at baseline, suggesting a relatively low proportion of participants with kidney disease.
Importantly, however, the kidney benefits observed in patients who are at such high risk of kidney disease but do not yet have diabetes or CKD, is encouraging, said Alberto Ortiz, MD, PhD, commenting on the study. Dr. Ortiz is chief of nephrology and the Hypertension Renal Unit, Health Research Institute of the Jiménez Díaz Foundation, Madrid, Spain.
“It is especially significant that protection was observed in participants with an eGFR > 60 mL/min/1.73 m2 and across UACR categories, ie, including people without CKD at baseline, in whom it appeared to decrease the incidence of de novo CKD,” Dr. Ortiz told this news organization.
“This suggests a potential role in primary prevention of CKD in this population,” he said.
To further investigate this, he said, “It would have been extremely interesting to assess whether there is a potential role for primary prevention of CKD in people without baseline CKD by assessing subgroup results for the no-CKD, low-risk KDIGO [Kidney Disease: Improving Global Outcomes] category [of patients].”
SELECT was funded by Novo Nordisk. Dr. Colhoun has reported consulting, research, and/or other relationships with Novo Nordisk, Bayer, Sanofi, Roche, and IQVIA. Dr. Ortiz has reported being a member of the European Renal Association council and Madrid Society of Nephrology (SOMANE), which developed a document in 2022 on the treatment of diabetic kidney disease sponsored by Novo Nordisk. He also reported collaborating with companies developing drugs for kidney disease.
A version of this article first appeared on Medscape.com.
STOCKHOLM — Improvements in kidney function outcomes observed with glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes extend to patients who are overweight or obese but don›t yet have type 2 diabetes, new research shows.
“These data are important because they are the first data to suggest a kidney benefit of semaglutide in this patient population in the absence of diabetes,” lead author Helen M. Colhoun, MD, of the Institute of Genetics and Cancer, University of Edinburgh, Scotland, United Kingdom, told this news organization.
“This is a population at high risk of chronic kidney disease with an increased need for kidney protection,” she said.
The late-breaking study was presented this week at the 61st European Renal Association (ERA) Congress 2024 and simultaneously published in Nature Medicine.
SELECT Trial Patients Without Diabetes
The findings are from a secondary analysis of the randomized SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity) trial, which evaluated cardiovascular outcomes of semaglutide treatment among 17,604 adults with preexisting cardiovascular disease who were overweight or obese — but did not have diabetes.
For its primary endpoint, the trial showed semaglutide was associated with a 20% reduction in major adverse cardiovascular events compared with placebo.
With obesity also associated with a significantly increased risk of chronic kidney disease — and the headline-making FLOW trial, also presented at the congress, showing key benefits of semaglutide in improving kidney function in people with CKD and type 2 diabetes the secondary analysis of SELECT was conducted to investigate whether those kidney benefits extended to people without type 2 diabetes.
Patients were randomized 1:1 to once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. Baseline patient characteristics were well-balanced, including kidney function and albuminuria status.
The primary endpoint for the analysis was a nephropathy composite of time from randomization to the first occurrence of death from kidney causes; initiation of chronic kidney replacement therapy; onset of persistent estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2; persistent ≥ 50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria.
With a median follow-up of 182 weeks, the results showed that the semaglutide group was significantly less likely to develop the primary composite endpoint compared with the placebo group (1.8% vs 2.2%; hazard ratio [HR], 0.78; P = .02).
A significantly reduced decline in eGFR in the semaglutide group was observed at a prespecified 104-week time point, with a treatment effect of 0.75 mL/min/1.73 m2 (P < .001), and the effect was more pronounced among participants with baseline eGFR < 60 mL/min/1.73 m2 (P < .001).
Furthermore, those in the semaglutide group had a significantly lower proportionate increase in urinary albumin-to-creatinine ratio (UACR) compared with placebo (–10.7%; P < .001) at the prespecified 104 weeks, with a net treatment benefit of –27.2% and –31.4% among those with randomization to UACR 30 to < 300 mg/g and 2300 mg/g, respectively.
Improvements varied according to baseline UACR status and were more pronounced among those with macroalbuminuria, at –8.1% for those with normoalbuminuria (n = 14,848), –27% for microalbuminuria (n = 1968), and –31% for macroalbuminuria (n = 325).
There were no reports of acute kidney injury associated with semaglutide, regardless of baseline eGFR.
“We were hopeful that there would be similar benefits as those observed in the diabetes studies, but there are differences in kidney disease among those with and without type 2 diabetes, so we weren’t sure,” Dr. Colhoun told this news organization.
Benefits the Result of Weight Loss or Something Else?
Considering the beneficial effects of semaglutide on weight loss, underscored in an analysis also published this month that showed a mean 10.2% reduction in weight sustained for up to 4 years, a key question is whether the kidney benefits are a direct result of weight loss — or the drug mechanism or something else.
But Dr. Colhoun said the role of weight loss in terms of the kidney benefits is still uncertain, particularly considering the various other factors, including cardiometabolic improvements, which could also have an effect.
“It’s a very difficult question to answer,” she said. “We did do a mediation exploratory analysis suggesting a substantial part of the effect might be due to the weight change, but it’s difficult to demonstrate that because you have weight change going on in the placebo arm as well, but for different reasons,” she said.
“So, I would say the data suggest there is some component of this that is attributable to weight, but we certainly can’t attribute all of the [effects] to weight change.”
Small studies involving animals have shown a direct effect of semaglutide on kidney hemodynamics “but they’re small and not definitive,” Dr. Colhoun added.
And although weight loss achieved through other measures such as lifestyle changes show a small benefit on eGFR, “interestingly, those studies showed no effect at all on albuminuria, whereas we see a really substantial effect on albuminuria with semaglutide,” Dr. Colhoun said.
Studies of weight loss through bariatric surgery have shown kidney benefits; however, those were in the context of type 2 diabetes, unlike the current analysis.
In terms of whether the benefits may extend to tirzepatide, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, increasingly used in weight loss, results from another secondary analysis also show encouraging kidney benefits in people with type 2 diabetes, and there is ongoing research in patients with type 2 diabetes and those with obesity without diabetes, Dr. Colhoun noted.
Primary Prevention of CKD?
Limitations of the current analysis include that only about a fifth of participants in SELECT had an eGFR < 60 mL/min/1.73 m2 or UACR ≥ 30 mg/g at baseline, suggesting a relatively low proportion of participants with kidney disease.
Importantly, however, the kidney benefits observed in patients who are at such high risk of kidney disease but do not yet have diabetes or CKD, is encouraging, said Alberto Ortiz, MD, PhD, commenting on the study. Dr. Ortiz is chief of nephrology and the Hypertension Renal Unit, Health Research Institute of the Jiménez Díaz Foundation, Madrid, Spain.
“It is especially significant that protection was observed in participants with an eGFR > 60 mL/min/1.73 m2 and across UACR categories, ie, including people without CKD at baseline, in whom it appeared to decrease the incidence of de novo CKD,” Dr. Ortiz told this news organization.
“This suggests a potential role in primary prevention of CKD in this population,” he said.
To further investigate this, he said, “It would have been extremely interesting to assess whether there is a potential role for primary prevention of CKD in people without baseline CKD by assessing subgroup results for the no-CKD, low-risk KDIGO [Kidney Disease: Improving Global Outcomes] category [of patients].”
SELECT was funded by Novo Nordisk. Dr. Colhoun has reported consulting, research, and/or other relationships with Novo Nordisk, Bayer, Sanofi, Roche, and IQVIA. Dr. Ortiz has reported being a member of the European Renal Association council and Madrid Society of Nephrology (SOMANE), which developed a document in 2022 on the treatment of diabetic kidney disease sponsored by Novo Nordisk. He also reported collaborating with companies developing drugs for kidney disease.
A version of this article first appeared on Medscape.com.
STOCKHOLM — Improvements in kidney function outcomes observed with glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes extend to patients who are overweight or obese but don›t yet have type 2 diabetes, new research shows.
“These data are important because they are the first data to suggest a kidney benefit of semaglutide in this patient population in the absence of diabetes,” lead author Helen M. Colhoun, MD, of the Institute of Genetics and Cancer, University of Edinburgh, Scotland, United Kingdom, told this news organization.
“This is a population at high risk of chronic kidney disease with an increased need for kidney protection,” she said.
The late-breaking study was presented this week at the 61st European Renal Association (ERA) Congress 2024 and simultaneously published in Nature Medicine.
SELECT Trial Patients Without Diabetes
The findings are from a secondary analysis of the randomized SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity) trial, which evaluated cardiovascular outcomes of semaglutide treatment among 17,604 adults with preexisting cardiovascular disease who were overweight or obese — but did not have diabetes.
For its primary endpoint, the trial showed semaglutide was associated with a 20% reduction in major adverse cardiovascular events compared with placebo.
With obesity also associated with a significantly increased risk of chronic kidney disease — and the headline-making FLOW trial, also presented at the congress, showing key benefits of semaglutide in improving kidney function in people with CKD and type 2 diabetes the secondary analysis of SELECT was conducted to investigate whether those kidney benefits extended to people without type 2 diabetes.
Patients were randomized 1:1 to once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. Baseline patient characteristics were well-balanced, including kidney function and albuminuria status.
The primary endpoint for the analysis was a nephropathy composite of time from randomization to the first occurrence of death from kidney causes; initiation of chronic kidney replacement therapy; onset of persistent estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2; persistent ≥ 50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria.
With a median follow-up of 182 weeks, the results showed that the semaglutide group was significantly less likely to develop the primary composite endpoint compared with the placebo group (1.8% vs 2.2%; hazard ratio [HR], 0.78; P = .02).
A significantly reduced decline in eGFR in the semaglutide group was observed at a prespecified 104-week time point, with a treatment effect of 0.75 mL/min/1.73 m2 (P < .001), and the effect was more pronounced among participants with baseline eGFR < 60 mL/min/1.73 m2 (P < .001).
Furthermore, those in the semaglutide group had a significantly lower proportionate increase in urinary albumin-to-creatinine ratio (UACR) compared with placebo (–10.7%; P < .001) at the prespecified 104 weeks, with a net treatment benefit of –27.2% and –31.4% among those with randomization to UACR 30 to < 300 mg/g and 2300 mg/g, respectively.
Improvements varied according to baseline UACR status and were more pronounced among those with macroalbuminuria, at –8.1% for those with normoalbuminuria (n = 14,848), –27% for microalbuminuria (n = 1968), and –31% for macroalbuminuria (n = 325).
There were no reports of acute kidney injury associated with semaglutide, regardless of baseline eGFR.
“We were hopeful that there would be similar benefits as those observed in the diabetes studies, but there are differences in kidney disease among those with and without type 2 diabetes, so we weren’t sure,” Dr. Colhoun told this news organization.
Benefits the Result of Weight Loss or Something Else?
Considering the beneficial effects of semaglutide on weight loss, underscored in an analysis also published this month that showed a mean 10.2% reduction in weight sustained for up to 4 years, a key question is whether the kidney benefits are a direct result of weight loss — or the drug mechanism or something else.
But Dr. Colhoun said the role of weight loss in terms of the kidney benefits is still uncertain, particularly considering the various other factors, including cardiometabolic improvements, which could also have an effect.
“It’s a very difficult question to answer,” she said. “We did do a mediation exploratory analysis suggesting a substantial part of the effect might be due to the weight change, but it’s difficult to demonstrate that because you have weight change going on in the placebo arm as well, but for different reasons,” she said.
“So, I would say the data suggest there is some component of this that is attributable to weight, but we certainly can’t attribute all of the [effects] to weight change.”
Small studies involving animals have shown a direct effect of semaglutide on kidney hemodynamics “but they’re small and not definitive,” Dr. Colhoun added.
And although weight loss achieved through other measures such as lifestyle changes show a small benefit on eGFR, “interestingly, those studies showed no effect at all on albuminuria, whereas we see a really substantial effect on albuminuria with semaglutide,” Dr. Colhoun said.
Studies of weight loss through bariatric surgery have shown kidney benefits; however, those were in the context of type 2 diabetes, unlike the current analysis.
In terms of whether the benefits may extend to tirzepatide, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, increasingly used in weight loss, results from another secondary analysis also show encouraging kidney benefits in people with type 2 diabetes, and there is ongoing research in patients with type 2 diabetes and those with obesity without diabetes, Dr. Colhoun noted.
Primary Prevention of CKD?
Limitations of the current analysis include that only about a fifth of participants in SELECT had an eGFR < 60 mL/min/1.73 m2 or UACR ≥ 30 mg/g at baseline, suggesting a relatively low proportion of participants with kidney disease.
Importantly, however, the kidney benefits observed in patients who are at such high risk of kidney disease but do not yet have diabetes or CKD, is encouraging, said Alberto Ortiz, MD, PhD, commenting on the study. Dr. Ortiz is chief of nephrology and the Hypertension Renal Unit, Health Research Institute of the Jiménez Díaz Foundation, Madrid, Spain.
“It is especially significant that protection was observed in participants with an eGFR > 60 mL/min/1.73 m2 and across UACR categories, ie, including people without CKD at baseline, in whom it appeared to decrease the incidence of de novo CKD,” Dr. Ortiz told this news organization.
“This suggests a potential role in primary prevention of CKD in this population,” he said.
To further investigate this, he said, “It would have been extremely interesting to assess whether there is a potential role for primary prevention of CKD in people without baseline CKD by assessing subgroup results for the no-CKD, low-risk KDIGO [Kidney Disease: Improving Global Outcomes] category [of patients].”
SELECT was funded by Novo Nordisk. Dr. Colhoun has reported consulting, research, and/or other relationships with Novo Nordisk, Bayer, Sanofi, Roche, and IQVIA. Dr. Ortiz has reported being a member of the European Renal Association council and Madrid Society of Nephrology (SOMANE), which developed a document in 2022 on the treatment of diabetic kidney disease sponsored by Novo Nordisk. He also reported collaborating with companies developing drugs for kidney disease.
A version of this article first appeared on Medscape.com.
FROM ERA 2024
Mailed Outreach for CRC Screening Appeals Across Races and Ethnicities
WASHINGTON — , according to a study presented at the annual Digestive Disease Week® (DDW).
In a comparison of four outreach approaches, sending a FIT kit to people between the ages of 45 and 49 via mail garnered better response rates than opt-in strategies to participate in FIT, inviting them to undergo colonoscopy, or asking them to choose between FIT or colonoscopy. At the same time, when given a choice between colonoscopy and FIT, colonoscopy was preferred across all racial and ethnic groups.
“It is well known that colorectal cancer is the second-leading cause of cancer-related deaths in the United States. The good news is that for the past several decades, we’ve seen a decline in colorectal cancer incidence and mortality in ages 50 and above. However, there has been a recent rise in incidence and mortality in people younger than 50,” said lead author Rebecca Ekeanyanwu, a third-year medical student at Meharry Medical College School of Medicine in Nashville, Tennessee. She was awarded the 2024 AGA Institute Council Healthcare Disparities Research Award for the top oral presentation for research in racial and ethnic health care disparities.
CRC incidence, screening rates, and mortality also vary by race and ethnicity, with higher incidence and mortality rates seen among non-Hispanic Black patients, more late-stage diagnoses among Hispanic patients, and lower screening rates among Asian patients.
“There’s no formal guidance on how to screen the population under age 50,” she said. “With the disparities in race and ethnicity, it remains unclear what would be the best population health strategy to optimize colorectal screening participation in young minorities.”
Ms. Ekeanyanwu and colleagues conducted a subanalysis of a 2022 randomized controlled trial at the University of California, Los Angeles, that looked at screening strategies for average-risk patients between ages 45 and 49. The study population included patients who were assigned to a primary care provider in the UCLA Health system and had active electronic portal use and excluded those with a personal or family history of adenoma or CRC, history of IBD or gastrointestinal cancer, and a prior FIT or colonoscopy.
In this study, the research team focused on the completion of any CRC screening at 26 weeks, stratified by race and ethnicity. They included four outreach scenarios: FIT invitation, colonoscopy invitation, a choice between FIT or colonoscopy invitation, or a default mailed FIT kit, which served as the control and typically is sent to UCLA patients overdue for screening among ages 50 and older. The researchers sent letters via US Postal Service and the online patient portal, as well as two texts about CRC screening.
Among 20,509 patients, 8918 were White (43.5%), 2757 were Hispanic (13.4%), 2613 were Asian (12.7%), and 797 were Black (3.9%).
The overall screening participation rate was 18.6%, with the lowest percentage among Black participants at 16.7% and the highest among Asian participants at 23.8%. These numbers varied significantly from the 20% seen among both White and Hispanic participants.
The default mailed outreach approach had the highest uptake with higher screening rates, at 26.2% overall, and had the highest participation in each racial and ethnic group. The rates were 28.7% among White patients, 20.1% among Black patients, 27.5% among Hispanic patients, and 31% among Asian patients.
Participation was lowest among the colonoscopy invitation group — as well as for White (14.8%), Hispanic (16%), and Asian (19.3%) patients. Among Black patients, participation was lowest in the FIT invitation group (12.8%).
Notably, in the choice group, more participants chose colonoscopy above FIT — across all racial and ethnic groups — at 12.1% versus 5.6% overall. In addition, among both FIT groups, there was significant crossover to colonoscopy, with about 7%-14% among the racial and ethnic groups preferring colonoscopy.
Ms. Ekeanyanwu noted the study may be limited by variations in sample size by race and ethnicity, as well as the socioeconomic status of typical patients at UCLA, who tend to fall in middle class and affluent groups. Demographic and socioeconomic factors may play a part in patients’ decision to get screened, she noted.
Patient participation in the digital portal may affect response rates as well, said Benjamin Lebwohl, MD, AGAF, an associate professor of medicine and epidemiology at Columbia University Medical Center, New York, who moderated the DDW session titled Reducing the Burden of GI Cancers Through Early Interventions.
“At least at my institution, we have a large number of such patients [not on the digital portal] who tend to be of lower socioeconomic status and tend to be at higher risk of not getting screened,” Dr. Lebwohl said. It would be important to consider “those who might need this intervention the most.”
Ms. Ekeanyanwu declared no relevant disclosures.
WASHINGTON — , according to a study presented at the annual Digestive Disease Week® (DDW).
In a comparison of four outreach approaches, sending a FIT kit to people between the ages of 45 and 49 via mail garnered better response rates than opt-in strategies to participate in FIT, inviting them to undergo colonoscopy, or asking them to choose between FIT or colonoscopy. At the same time, when given a choice between colonoscopy and FIT, colonoscopy was preferred across all racial and ethnic groups.
“It is well known that colorectal cancer is the second-leading cause of cancer-related deaths in the United States. The good news is that for the past several decades, we’ve seen a decline in colorectal cancer incidence and mortality in ages 50 and above. However, there has been a recent rise in incidence and mortality in people younger than 50,” said lead author Rebecca Ekeanyanwu, a third-year medical student at Meharry Medical College School of Medicine in Nashville, Tennessee. She was awarded the 2024 AGA Institute Council Healthcare Disparities Research Award for the top oral presentation for research in racial and ethnic health care disparities.
CRC incidence, screening rates, and mortality also vary by race and ethnicity, with higher incidence and mortality rates seen among non-Hispanic Black patients, more late-stage diagnoses among Hispanic patients, and lower screening rates among Asian patients.
“There’s no formal guidance on how to screen the population under age 50,” she said. “With the disparities in race and ethnicity, it remains unclear what would be the best population health strategy to optimize colorectal screening participation in young minorities.”
Ms. Ekeanyanwu and colleagues conducted a subanalysis of a 2022 randomized controlled trial at the University of California, Los Angeles, that looked at screening strategies for average-risk patients between ages 45 and 49. The study population included patients who were assigned to a primary care provider in the UCLA Health system and had active electronic portal use and excluded those with a personal or family history of adenoma or CRC, history of IBD or gastrointestinal cancer, and a prior FIT or colonoscopy.
In this study, the research team focused on the completion of any CRC screening at 26 weeks, stratified by race and ethnicity. They included four outreach scenarios: FIT invitation, colonoscopy invitation, a choice between FIT or colonoscopy invitation, or a default mailed FIT kit, which served as the control and typically is sent to UCLA patients overdue for screening among ages 50 and older. The researchers sent letters via US Postal Service and the online patient portal, as well as two texts about CRC screening.
Among 20,509 patients, 8918 were White (43.5%), 2757 were Hispanic (13.4%), 2613 were Asian (12.7%), and 797 were Black (3.9%).
The overall screening participation rate was 18.6%, with the lowest percentage among Black participants at 16.7% and the highest among Asian participants at 23.8%. These numbers varied significantly from the 20% seen among both White and Hispanic participants.
The default mailed outreach approach had the highest uptake with higher screening rates, at 26.2% overall, and had the highest participation in each racial and ethnic group. The rates were 28.7% among White patients, 20.1% among Black patients, 27.5% among Hispanic patients, and 31% among Asian patients.
Participation was lowest among the colonoscopy invitation group — as well as for White (14.8%), Hispanic (16%), and Asian (19.3%) patients. Among Black patients, participation was lowest in the FIT invitation group (12.8%).
Notably, in the choice group, more participants chose colonoscopy above FIT — across all racial and ethnic groups — at 12.1% versus 5.6% overall. In addition, among both FIT groups, there was significant crossover to colonoscopy, with about 7%-14% among the racial and ethnic groups preferring colonoscopy.
Ms. Ekeanyanwu noted the study may be limited by variations in sample size by race and ethnicity, as well as the socioeconomic status of typical patients at UCLA, who tend to fall in middle class and affluent groups. Demographic and socioeconomic factors may play a part in patients’ decision to get screened, she noted.
Patient participation in the digital portal may affect response rates as well, said Benjamin Lebwohl, MD, AGAF, an associate professor of medicine and epidemiology at Columbia University Medical Center, New York, who moderated the DDW session titled Reducing the Burden of GI Cancers Through Early Interventions.
“At least at my institution, we have a large number of such patients [not on the digital portal] who tend to be of lower socioeconomic status and tend to be at higher risk of not getting screened,” Dr. Lebwohl said. It would be important to consider “those who might need this intervention the most.”
Ms. Ekeanyanwu declared no relevant disclosures.
WASHINGTON — , according to a study presented at the annual Digestive Disease Week® (DDW).
In a comparison of four outreach approaches, sending a FIT kit to people between the ages of 45 and 49 via mail garnered better response rates than opt-in strategies to participate in FIT, inviting them to undergo colonoscopy, or asking them to choose between FIT or colonoscopy. At the same time, when given a choice between colonoscopy and FIT, colonoscopy was preferred across all racial and ethnic groups.
“It is well known that colorectal cancer is the second-leading cause of cancer-related deaths in the United States. The good news is that for the past several decades, we’ve seen a decline in colorectal cancer incidence and mortality in ages 50 and above. However, there has been a recent rise in incidence and mortality in people younger than 50,” said lead author Rebecca Ekeanyanwu, a third-year medical student at Meharry Medical College School of Medicine in Nashville, Tennessee. She was awarded the 2024 AGA Institute Council Healthcare Disparities Research Award for the top oral presentation for research in racial and ethnic health care disparities.
CRC incidence, screening rates, and mortality also vary by race and ethnicity, with higher incidence and mortality rates seen among non-Hispanic Black patients, more late-stage diagnoses among Hispanic patients, and lower screening rates among Asian patients.
“There’s no formal guidance on how to screen the population under age 50,” she said. “With the disparities in race and ethnicity, it remains unclear what would be the best population health strategy to optimize colorectal screening participation in young minorities.”
Ms. Ekeanyanwu and colleagues conducted a subanalysis of a 2022 randomized controlled trial at the University of California, Los Angeles, that looked at screening strategies for average-risk patients between ages 45 and 49. The study population included patients who were assigned to a primary care provider in the UCLA Health system and had active electronic portal use and excluded those with a personal or family history of adenoma or CRC, history of IBD or gastrointestinal cancer, and a prior FIT or colonoscopy.
In this study, the research team focused on the completion of any CRC screening at 26 weeks, stratified by race and ethnicity. They included four outreach scenarios: FIT invitation, colonoscopy invitation, a choice between FIT or colonoscopy invitation, or a default mailed FIT kit, which served as the control and typically is sent to UCLA patients overdue for screening among ages 50 and older. The researchers sent letters via US Postal Service and the online patient portal, as well as two texts about CRC screening.
Among 20,509 patients, 8918 were White (43.5%), 2757 were Hispanic (13.4%), 2613 were Asian (12.7%), and 797 were Black (3.9%).
The overall screening participation rate was 18.6%, with the lowest percentage among Black participants at 16.7% and the highest among Asian participants at 23.8%. These numbers varied significantly from the 20% seen among both White and Hispanic participants.
The default mailed outreach approach had the highest uptake with higher screening rates, at 26.2% overall, and had the highest participation in each racial and ethnic group. The rates were 28.7% among White patients, 20.1% among Black patients, 27.5% among Hispanic patients, and 31% among Asian patients.
Participation was lowest among the colonoscopy invitation group — as well as for White (14.8%), Hispanic (16%), and Asian (19.3%) patients. Among Black patients, participation was lowest in the FIT invitation group (12.8%).
Notably, in the choice group, more participants chose colonoscopy above FIT — across all racial and ethnic groups — at 12.1% versus 5.6% overall. In addition, among both FIT groups, there was significant crossover to colonoscopy, with about 7%-14% among the racial and ethnic groups preferring colonoscopy.
Ms. Ekeanyanwu noted the study may be limited by variations in sample size by race and ethnicity, as well as the socioeconomic status of typical patients at UCLA, who tend to fall in middle class and affluent groups. Demographic and socioeconomic factors may play a part in patients’ decision to get screened, she noted.
Patient participation in the digital portal may affect response rates as well, said Benjamin Lebwohl, MD, AGAF, an associate professor of medicine and epidemiology at Columbia University Medical Center, New York, who moderated the DDW session titled Reducing the Burden of GI Cancers Through Early Interventions.
“At least at my institution, we have a large number of such patients [not on the digital portal] who tend to be of lower socioeconomic status and tend to be at higher risk of not getting screened,” Dr. Lebwohl said. It would be important to consider “those who might need this intervention the most.”
Ms. Ekeanyanwu declared no relevant disclosures.
FROM DDW 2024
A Simple Stress Intervention for MS
NASHVILLE, TENNESSEE — Stress in patients with multiple sclerosis (MS) can have serious effects on quality of life, but there is some evidence that it could worsen inflammation through activation of pro-inflammatory cytokines, leading to more relapses.
Observational studies have suggested that stress may lead to relapses, according to Amy Sullivan, PsyD, who spoke during a session at the annual meeting of the Consortium of Multiple Sclerosis Centers.
She cited a study conducted during the 34-day war between Israel and Lebanon in 2006, which found more exacerbations among 156 Israeli patients with relapsing-remitting MS patients during the period of hostilities. There were 18 relapses that occurred during the war, and 44% of those who experienced a relapse reported experience intense subjective stress, versus 20% of those who did not experience a relapse, and 67% of relapsers reported high levels of distress linked to rocket attack exposure, versus 42% of those who did not have a relapse (P = .05).
Another study of 216 Lebanese MS patients found 23 relapses during the 2-month war period, compared with a mean of 8.4 during other 2-month periods.
“So we have two observational studies that are showing us that there’s a pretty strong link or correlation between war, a very stressful life event, and MS relapses,” said Dr. Sullivan.
That relationship has prompted development of interventions to reduce stress in MS patients in hopes of improving clinical outcomes. One that “shaped our practice,” according to Dr. Sullivan, was published in 2012. It was the first high-quality randomized controlled trial of such an intervention, she said.
The program was based on cognitive behavioral therapy (CBT) and lasted 24 weeks and 16 psychotherapy sessions. Compared with controls, participants had fewer MRI brain lesions, but there were no differences after week 24. “[That] tells us that when people stopped the stress management techniques, the intervention did not give them protection,” said Dr. Sullivan.
Her group aimed to build on that work by developing a program that would be easier for busy patients to learn and incorporate into their lives. “Being in a psychotherapist office for 24 weeks to me was not feasible. I didn’t think that this was something that individuals would have interest in,” said Dr. Sullivan.
They focused on skills to manage stress, delivered over four sessions and designed to be employed in their private life. “We want them to go into the world for 4 to 6 weeks to do the skills that we taught them in that particular session, and then they come back and they tell us how that worked. We also recognize that each skill is not going to work. It’s not a one-size-fits-all for each person,” said Dr. Sullivan.
In addition to patient self-reports, the team measured physiological indicators of stress like pulse (beats per minute), breath rate (breaths per minute), and saturated oxygen (%SpO2). The measures were taken before and after stress management exercises.
The first session included psychoeducation and diaphragmatic breathing for relaxation. The second reviewed the nervous system and the stress response. The third introduced visualization and guided imagery that was individualized for each patient. The fourth focused on mindfulness and distress tolerance.
The study included 195 individuals (mean age, 44.4 years; 72.0% female, 71.5% White).
In all four sessions, patients achieved significant in-session improvements in breath rate, pulse, and saturated oxygen, as well as improvements from the first to the final session: Among 124 patients who completed at least 2 sessions, Patient Health Questionnaire-9 (PHQ-9) scores improved by 1.61 (P < .001), Generalized Anxiety Disorder (GAD) scores by 1.08 (P = .004), breaths per minute by 3.38 (P = .001), and SpO2 by 1.67 (P = .016). There was no significant change in pulse.
The high dropout rate could be seen as a weakness, but it was actually designed into the program. “We encouraged people to drop out when they were done. Our program is built on feasibility, and it’s built based on wanting our patients to get what they need out of our treatment, and then go live their lives. We don’t want them to feel tied to our offices, so they voluntarily discontinued after they felt they had sufficiently mastered stress management skills,” said Dr. Sullivan.
The results “suggest that short-term treatment with stress management skills can impact physiological and emotional stress in MS. [The] stress management protocol is likely a great adjunctive treatment to bolster skills traditionally taught during psychotherapy sessions,” said Dr. Sullivan.
During the Q&A period, an audience member asked why the group deviated from traditional cognitive behavioral therapy and moved into more right-brain activities. “In our practice, we’re very eclectic. We don’t believe that just CBT helps, or just behavioral therapy helps, or just [dialectical behavior therapy] helps. We want to teach the skills which we believe are the most important skills to train people on,” said Dr. Sullivan.
Dr. Sullivan did not report any relevant disclosures.
NASHVILLE, TENNESSEE — Stress in patients with multiple sclerosis (MS) can have serious effects on quality of life, but there is some evidence that it could worsen inflammation through activation of pro-inflammatory cytokines, leading to more relapses.
Observational studies have suggested that stress may lead to relapses, according to Amy Sullivan, PsyD, who spoke during a session at the annual meeting of the Consortium of Multiple Sclerosis Centers.
She cited a study conducted during the 34-day war between Israel and Lebanon in 2006, which found more exacerbations among 156 Israeli patients with relapsing-remitting MS patients during the period of hostilities. There were 18 relapses that occurred during the war, and 44% of those who experienced a relapse reported experience intense subjective stress, versus 20% of those who did not experience a relapse, and 67% of relapsers reported high levels of distress linked to rocket attack exposure, versus 42% of those who did not have a relapse (P = .05).
Another study of 216 Lebanese MS patients found 23 relapses during the 2-month war period, compared with a mean of 8.4 during other 2-month periods.
“So we have two observational studies that are showing us that there’s a pretty strong link or correlation between war, a very stressful life event, and MS relapses,” said Dr. Sullivan.
That relationship has prompted development of interventions to reduce stress in MS patients in hopes of improving clinical outcomes. One that “shaped our practice,” according to Dr. Sullivan, was published in 2012. It was the first high-quality randomized controlled trial of such an intervention, she said.
The program was based on cognitive behavioral therapy (CBT) and lasted 24 weeks and 16 psychotherapy sessions. Compared with controls, participants had fewer MRI brain lesions, but there were no differences after week 24. “[That] tells us that when people stopped the stress management techniques, the intervention did not give them protection,” said Dr. Sullivan.
Her group aimed to build on that work by developing a program that would be easier for busy patients to learn and incorporate into their lives. “Being in a psychotherapist office for 24 weeks to me was not feasible. I didn’t think that this was something that individuals would have interest in,” said Dr. Sullivan.
They focused on skills to manage stress, delivered over four sessions and designed to be employed in their private life. “We want them to go into the world for 4 to 6 weeks to do the skills that we taught them in that particular session, and then they come back and they tell us how that worked. We also recognize that each skill is not going to work. It’s not a one-size-fits-all for each person,” said Dr. Sullivan.
In addition to patient self-reports, the team measured physiological indicators of stress like pulse (beats per minute), breath rate (breaths per minute), and saturated oxygen (%SpO2). The measures were taken before and after stress management exercises.
The first session included psychoeducation and diaphragmatic breathing for relaxation. The second reviewed the nervous system and the stress response. The third introduced visualization and guided imagery that was individualized for each patient. The fourth focused on mindfulness and distress tolerance.
The study included 195 individuals (mean age, 44.4 years; 72.0% female, 71.5% White).
In all four sessions, patients achieved significant in-session improvements in breath rate, pulse, and saturated oxygen, as well as improvements from the first to the final session: Among 124 patients who completed at least 2 sessions, Patient Health Questionnaire-9 (PHQ-9) scores improved by 1.61 (P < .001), Generalized Anxiety Disorder (GAD) scores by 1.08 (P = .004), breaths per minute by 3.38 (P = .001), and SpO2 by 1.67 (P = .016). There was no significant change in pulse.
The high dropout rate could be seen as a weakness, but it was actually designed into the program. “We encouraged people to drop out when they were done. Our program is built on feasibility, and it’s built based on wanting our patients to get what they need out of our treatment, and then go live their lives. We don’t want them to feel tied to our offices, so they voluntarily discontinued after they felt they had sufficiently mastered stress management skills,” said Dr. Sullivan.
The results “suggest that short-term treatment with stress management skills can impact physiological and emotional stress in MS. [The] stress management protocol is likely a great adjunctive treatment to bolster skills traditionally taught during psychotherapy sessions,” said Dr. Sullivan.
During the Q&A period, an audience member asked why the group deviated from traditional cognitive behavioral therapy and moved into more right-brain activities. “In our practice, we’re very eclectic. We don’t believe that just CBT helps, or just behavioral therapy helps, or just [dialectical behavior therapy] helps. We want to teach the skills which we believe are the most important skills to train people on,” said Dr. Sullivan.
Dr. Sullivan did not report any relevant disclosures.
NASHVILLE, TENNESSEE — Stress in patients with multiple sclerosis (MS) can have serious effects on quality of life, but there is some evidence that it could worsen inflammation through activation of pro-inflammatory cytokines, leading to more relapses.
Observational studies have suggested that stress may lead to relapses, according to Amy Sullivan, PsyD, who spoke during a session at the annual meeting of the Consortium of Multiple Sclerosis Centers.
She cited a study conducted during the 34-day war between Israel and Lebanon in 2006, which found more exacerbations among 156 Israeli patients with relapsing-remitting MS patients during the period of hostilities. There were 18 relapses that occurred during the war, and 44% of those who experienced a relapse reported experience intense subjective stress, versus 20% of those who did not experience a relapse, and 67% of relapsers reported high levels of distress linked to rocket attack exposure, versus 42% of those who did not have a relapse (P = .05).
Another study of 216 Lebanese MS patients found 23 relapses during the 2-month war period, compared with a mean of 8.4 during other 2-month periods.
“So we have two observational studies that are showing us that there’s a pretty strong link or correlation between war, a very stressful life event, and MS relapses,” said Dr. Sullivan.
That relationship has prompted development of interventions to reduce stress in MS patients in hopes of improving clinical outcomes. One that “shaped our practice,” according to Dr. Sullivan, was published in 2012. It was the first high-quality randomized controlled trial of such an intervention, she said.
The program was based on cognitive behavioral therapy (CBT) and lasted 24 weeks and 16 psychotherapy sessions. Compared with controls, participants had fewer MRI brain lesions, but there were no differences after week 24. “[That] tells us that when people stopped the stress management techniques, the intervention did not give them protection,” said Dr. Sullivan.
Her group aimed to build on that work by developing a program that would be easier for busy patients to learn and incorporate into their lives. “Being in a psychotherapist office for 24 weeks to me was not feasible. I didn’t think that this was something that individuals would have interest in,” said Dr. Sullivan.
They focused on skills to manage stress, delivered over four sessions and designed to be employed in their private life. “We want them to go into the world for 4 to 6 weeks to do the skills that we taught them in that particular session, and then they come back and they tell us how that worked. We also recognize that each skill is not going to work. It’s not a one-size-fits-all for each person,” said Dr. Sullivan.
In addition to patient self-reports, the team measured physiological indicators of stress like pulse (beats per minute), breath rate (breaths per minute), and saturated oxygen (%SpO2). The measures were taken before and after stress management exercises.
The first session included psychoeducation and diaphragmatic breathing for relaxation. The second reviewed the nervous system and the stress response. The third introduced visualization and guided imagery that was individualized for each patient. The fourth focused on mindfulness and distress tolerance.
The study included 195 individuals (mean age, 44.4 years; 72.0% female, 71.5% White).
In all four sessions, patients achieved significant in-session improvements in breath rate, pulse, and saturated oxygen, as well as improvements from the first to the final session: Among 124 patients who completed at least 2 sessions, Patient Health Questionnaire-9 (PHQ-9) scores improved by 1.61 (P < .001), Generalized Anxiety Disorder (GAD) scores by 1.08 (P = .004), breaths per minute by 3.38 (P = .001), and SpO2 by 1.67 (P = .016). There was no significant change in pulse.
The high dropout rate could be seen as a weakness, but it was actually designed into the program. “We encouraged people to drop out when they were done. Our program is built on feasibility, and it’s built based on wanting our patients to get what they need out of our treatment, and then go live their lives. We don’t want them to feel tied to our offices, so they voluntarily discontinued after they felt they had sufficiently mastered stress management skills,” said Dr. Sullivan.
The results “suggest that short-term treatment with stress management skills can impact physiological and emotional stress in MS. [The] stress management protocol is likely a great adjunctive treatment to bolster skills traditionally taught during psychotherapy sessions,” said Dr. Sullivan.
During the Q&A period, an audience member asked why the group deviated from traditional cognitive behavioral therapy and moved into more right-brain activities. “In our practice, we’re very eclectic. We don’t believe that just CBT helps, or just behavioral therapy helps, or just [dialectical behavior therapy] helps. We want to teach the skills which we believe are the most important skills to train people on,” said Dr. Sullivan.
Dr. Sullivan did not report any relevant disclosures.
FROM CMSC 2024
Carefully Designing De-escalation Trials in Breast Cancer
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
FROM ESMO BREAST CANCER 2024
ADCs for Breast Cancer: Clear Benefits, Manageable Risks
These medications, which are designed to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens such as human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (TROP2), can be highly effective but can also come with significant toxicities.
The latest data on several ADCs — their clinical benefit and safety — were the focus of three presentations here at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
TROPION-Breast01
In her presentation, Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported additional safety analyses from the phase 3 TROPION-Breast01 trial looking at datopotamab deruxtecan (Dato-DXd) in patients with metastatic hormone receptor–positive (HR+)/HER2− breast cancer resistant to endocrine therapy.
Dato-DXd is an investigational ADC composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.
As previously reported by this news organization, median progression-free survival was 6.9 months with Dato-DXd compared with 4.9 months for investigator’s choice of chemotherapy (eribulin mesylate, vinorelbine, gemcitabine, or capecitabine), which translated into a 37% (hazard ratio [HR], 0.63; P < .0001) reduction in risk for disease progression.
In addition, the rate of grade 3 or higher treatment-related adverse events with Dato-DXd was less than half that with standard chemotherapy and led to fewer dose interruptions or reductions, indicating that Dato-DXd is better tolerated.
Dr. Jhaveri focused on three treatment-related adverse events of special interest: Stomatitis/oral mucositis, ocular surface events, and adjudicated drug-related interstitial lung disease.
The rate of any grade oral mucositis with Dato-DXd was 56%, she reported. Most were grade 1 (25%) or grade 2 (23%), with only 7% grade 3. About 13% of patients had a dose reduction for oral mucositis, and only one (0.3%) patient discontinued treatment.
The median time to onset was 22 days, and median time to resolution (for events recovered/resolved at data cutoff) was 36 days.
“The study did provide toxicity management guidelines for patients who experienced stomatitis,” Dr. Jhaveri told attendees. The guidelines highly recommended daily use of a steroid-containing mouthwash as prophylaxis or, if that wasn’t available, an inert, bland mouth rinse.
“Prophylactic cryotherapy — ice chips or ice water held in the mouth throughout the infusion — was also suggested,” she said.
The overall rate of ocular surface events with Dato-DXd was 40%, with most grade 1 (32%) or grade 2 (7%), with only 0.8% grade 3. Rates of dose reduction/interruption (3.3%) and discontinuation (0.3%) were low. Most ocular events were either dry eye (22%) or keratitis (14%).
The incidence of ocular events in the chemotherapy group was 12%, higher than typically seen. The study mandated regular ocular assessments, and Jhaveri noted that it was possible that this contributed to the high rate of low-grade ocular events found in both arms.
Median time to onset of ocular events was 65 days, and median time to resolution was 67 days.
Toxicity management guidelines were also incorporated for ocular events, suggesting daily use of artificial tears and avoidance of contact lenses, Dr. Jhaveri said.
In the Dato-DXd group, there were 12 adjudicated cases (3.3%) of drug-related interstitial lung disease; most were grade 1 (1.4%) and grade 2 (1.1%).
“There was one patient who had a grade 5 event, which was characterized by the investigator as grade 3 pneumonitis, with death attributed to disease progression,” Dr. Jhaveri said. This was subsequently adjudicated to be a grade 5 drug-related death.
The median time to onset of interstitial lung disease was 84.5 days, and median time to resolution was 28 days.
Among other treatment-related adverse events of clinical interest, any grade nausea was the most common event with Dato-DXd, reported by 51% of patients, with only 1.4% grade 3 or higher.
“Prophylactic antiemetic agents are highly recommended prior to infusion of Dato-DXd and on subsequent days as needed,” Dr. Jhaveri said.
Any grade diarrhea was reported in 7.5%, with no grade 3+ diarrhea. Alopecia was reported in 36.4%, of which grade 1 was 21% and grade 2 was 15%.
Summing up, the researcher said the new safety data suggest that Dato-DXd offers “better tolerability” than standard chemotherapy. Coupled with the efficacy data, this further supports “Dato-DXd as a potential new therapeutic option for patients with previously treated, inoperable, or metastatic HR+/HER2− breast cancer.”
DESTINY-Breast02
New data from the phase 3 DESTINY-Breast02 study confirm a long-term survival benefit, as well as a favorable benefit/risk profile of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), reported Sung-Bae Kim, MD, PhD, with University of Ulsan College of Medicine, Seoul, Republic of Korea.
In the phase 3 randomized, multicenter, open-label clinical trial, study participants received either trastuzumab deruxtecan or physician’s choice of trastuzumab plus capecitabine or lapatinib or capecitabine. The primary results of the trial were published last year in The Lancet.
As previously reported by this news organization, after median follow-up of 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of choice group, median progression-free survival was 17.8 months for trastuzumab deruxtecan vs 6.9 months for the physician’s choice group (HR, 0.36; P < .000001).
The latest data show that after a median follow-up of 30.2 months in the trastuzumab deruxtecan group and 20.5 months in the treatment of choice group, median progression-free survival was 16.7 months with trastuzumab deruxtecan vs 5.5 months with the treatment of choice — a 70% reduction in risk for progression (HR, 0.30), Dr. Kim said.
From time of randomization to progression to next line of therapy or death, median progression-free survival was 33.0 months with trastuzumab deruxtecan vs 15.0 with treatment of choice (HR, 0.42).
Median overall survival was 35.7 months with trastuzumab deruxtecan vs 25.0 months with the treatment of choice, with the risk for death reduced by 31% with trastuzumab deruxtecan (HR, 0.69).
The safety profile of trastuzumab deruxtecan continues to be “manageable, with no long-term toxicity observed with longer follow-up,” Dr. Kim told attendees. The most common treatment-emergent adverse events were nausea (73%), fatigue (62%), and vomiting (38%).
There were a total of 46 (11.4%) adjudicated drug-related interstitial lung disease/pneumonitis cases with trastuzumab deruxtecan. Most were grade 1 or 2. This risk did not increase with longer treatment duration; most events occurred within 12 months of starting treatment, Dr. Kim noted.
With longer follow-up, results of DESTINY-Breast02 “reinforce the substantial benefit” of trastuzumab deruxtecan over the treatment of physician’s choice in patients with HER2+ metastatic breast cancer previously treated with T-DM1, he concluded.
Pooled Data from TROPiCS-02 and EVER-132-002
Hope S. Rugo, MD, of the University of California San Francisco, and colleagues reported a meta-analysis of data from the phase 3 TROPiCS-02 and EVER-132-002 trials of the TROP2-directed ADC sacituzumab govitecan vs the treatment of physician’s choice in HR+/HER2− metastatic breast cancer.
In the pooled analysis, median overall survival was significantly longer with sacituzumab govitecan than with the treatment of physician’s choice in the overall population (16.2 vs 12.7 months) and in patients who received prior CDK4/6 inhibitor treatment (15.4 vs 11.5 months). Progression-free survival also favored sacituzumab govitecan.
These results are consistent with trial-level results from TROPICS-02 and EVER-132-002, reinforcing the efficacy benefits of sacituzumab govitecan over the treatment of physician’s choice, the study team said.
Evolving Landscape of ADCs in Breast Cancer
Giuseppe Curigliano, MD, PhD, with the University of Milan, Italy, who served as discussant for the TROPION-Breast01 safety analysis, noted that the clinical landscape of ADCs has “evolved over time.”
He added that despite having a similar target and similar payload, the anti-TROP2 ADCs in development for HR+/HER2− metastatic breast cancer — Dato-DXd, sacituzumab govitecan, and sacituzumab tirumotecan — appear to have different spectrums of toxicity.
Looking ahead, he said it will be important to determine whether toxicity of these agents can be predicted with a pharmacogenomic analysis and whether toxicity is related to the payload or to the linker antibody complex.
“The science and chemistry of ADCs has shown significant promise in terms of clinical activity, but we also need to better understand safety,” Dr. Curigliano told attendees.
“We need to pay attention to signals in the early phase trials of ADCs and be willing to adjust accordingly to maximize therapeutic benefit and minimize toxicity. Team science will be important in the future developmental ADCs,” he added.
TROPION-Breast01 was sponsored by AstraZeneca. DESTINY-Breast-02 was sponsored by Daiichi Sankyo. TROPiCS-02 and EVER-132-002 were supported by Gilead Sciences. Several trial investigators have disclosed various relationships with these and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
These medications, which are designed to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens such as human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (TROP2), can be highly effective but can also come with significant toxicities.
The latest data on several ADCs — their clinical benefit and safety — were the focus of three presentations here at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
TROPION-Breast01
In her presentation, Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported additional safety analyses from the phase 3 TROPION-Breast01 trial looking at datopotamab deruxtecan (Dato-DXd) in patients with metastatic hormone receptor–positive (HR+)/HER2− breast cancer resistant to endocrine therapy.
Dato-DXd is an investigational ADC composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.
As previously reported by this news organization, median progression-free survival was 6.9 months with Dato-DXd compared with 4.9 months for investigator’s choice of chemotherapy (eribulin mesylate, vinorelbine, gemcitabine, or capecitabine), which translated into a 37% (hazard ratio [HR], 0.63; P < .0001) reduction in risk for disease progression.
In addition, the rate of grade 3 or higher treatment-related adverse events with Dato-DXd was less than half that with standard chemotherapy and led to fewer dose interruptions or reductions, indicating that Dato-DXd is better tolerated.
Dr. Jhaveri focused on three treatment-related adverse events of special interest: Stomatitis/oral mucositis, ocular surface events, and adjudicated drug-related interstitial lung disease.
The rate of any grade oral mucositis with Dato-DXd was 56%, she reported. Most were grade 1 (25%) or grade 2 (23%), with only 7% grade 3. About 13% of patients had a dose reduction for oral mucositis, and only one (0.3%) patient discontinued treatment.
The median time to onset was 22 days, and median time to resolution (for events recovered/resolved at data cutoff) was 36 days.
“The study did provide toxicity management guidelines for patients who experienced stomatitis,” Dr. Jhaveri told attendees. The guidelines highly recommended daily use of a steroid-containing mouthwash as prophylaxis or, if that wasn’t available, an inert, bland mouth rinse.
“Prophylactic cryotherapy — ice chips or ice water held in the mouth throughout the infusion — was also suggested,” she said.
The overall rate of ocular surface events with Dato-DXd was 40%, with most grade 1 (32%) or grade 2 (7%), with only 0.8% grade 3. Rates of dose reduction/interruption (3.3%) and discontinuation (0.3%) were low. Most ocular events were either dry eye (22%) or keratitis (14%).
The incidence of ocular events in the chemotherapy group was 12%, higher than typically seen. The study mandated regular ocular assessments, and Jhaveri noted that it was possible that this contributed to the high rate of low-grade ocular events found in both arms.
Median time to onset of ocular events was 65 days, and median time to resolution was 67 days.
Toxicity management guidelines were also incorporated for ocular events, suggesting daily use of artificial tears and avoidance of contact lenses, Dr. Jhaveri said.
In the Dato-DXd group, there were 12 adjudicated cases (3.3%) of drug-related interstitial lung disease; most were grade 1 (1.4%) and grade 2 (1.1%).
“There was one patient who had a grade 5 event, which was characterized by the investigator as grade 3 pneumonitis, with death attributed to disease progression,” Dr. Jhaveri said. This was subsequently adjudicated to be a grade 5 drug-related death.
The median time to onset of interstitial lung disease was 84.5 days, and median time to resolution was 28 days.
Among other treatment-related adverse events of clinical interest, any grade nausea was the most common event with Dato-DXd, reported by 51% of patients, with only 1.4% grade 3 or higher.
“Prophylactic antiemetic agents are highly recommended prior to infusion of Dato-DXd and on subsequent days as needed,” Dr. Jhaveri said.
Any grade diarrhea was reported in 7.5%, with no grade 3+ diarrhea. Alopecia was reported in 36.4%, of which grade 1 was 21% and grade 2 was 15%.
Summing up, the researcher said the new safety data suggest that Dato-DXd offers “better tolerability” than standard chemotherapy. Coupled with the efficacy data, this further supports “Dato-DXd as a potential new therapeutic option for patients with previously treated, inoperable, or metastatic HR+/HER2− breast cancer.”
DESTINY-Breast02
New data from the phase 3 DESTINY-Breast02 study confirm a long-term survival benefit, as well as a favorable benefit/risk profile of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), reported Sung-Bae Kim, MD, PhD, with University of Ulsan College of Medicine, Seoul, Republic of Korea.
In the phase 3 randomized, multicenter, open-label clinical trial, study participants received either trastuzumab deruxtecan or physician’s choice of trastuzumab plus capecitabine or lapatinib or capecitabine. The primary results of the trial were published last year in The Lancet.
As previously reported by this news organization, after median follow-up of 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of choice group, median progression-free survival was 17.8 months for trastuzumab deruxtecan vs 6.9 months for the physician’s choice group (HR, 0.36; P < .000001).
The latest data show that after a median follow-up of 30.2 months in the trastuzumab deruxtecan group and 20.5 months in the treatment of choice group, median progression-free survival was 16.7 months with trastuzumab deruxtecan vs 5.5 months with the treatment of choice — a 70% reduction in risk for progression (HR, 0.30), Dr. Kim said.
From time of randomization to progression to next line of therapy or death, median progression-free survival was 33.0 months with trastuzumab deruxtecan vs 15.0 with treatment of choice (HR, 0.42).
Median overall survival was 35.7 months with trastuzumab deruxtecan vs 25.0 months with the treatment of choice, with the risk for death reduced by 31% with trastuzumab deruxtecan (HR, 0.69).
The safety profile of trastuzumab deruxtecan continues to be “manageable, with no long-term toxicity observed with longer follow-up,” Dr. Kim told attendees. The most common treatment-emergent adverse events were nausea (73%), fatigue (62%), and vomiting (38%).
There were a total of 46 (11.4%) adjudicated drug-related interstitial lung disease/pneumonitis cases with trastuzumab deruxtecan. Most were grade 1 or 2. This risk did not increase with longer treatment duration; most events occurred within 12 months of starting treatment, Dr. Kim noted.
With longer follow-up, results of DESTINY-Breast02 “reinforce the substantial benefit” of trastuzumab deruxtecan over the treatment of physician’s choice in patients with HER2+ metastatic breast cancer previously treated with T-DM1, he concluded.
Pooled Data from TROPiCS-02 and EVER-132-002
Hope S. Rugo, MD, of the University of California San Francisco, and colleagues reported a meta-analysis of data from the phase 3 TROPiCS-02 and EVER-132-002 trials of the TROP2-directed ADC sacituzumab govitecan vs the treatment of physician’s choice in HR+/HER2− metastatic breast cancer.
In the pooled analysis, median overall survival was significantly longer with sacituzumab govitecan than with the treatment of physician’s choice in the overall population (16.2 vs 12.7 months) and in patients who received prior CDK4/6 inhibitor treatment (15.4 vs 11.5 months). Progression-free survival also favored sacituzumab govitecan.
These results are consistent with trial-level results from TROPICS-02 and EVER-132-002, reinforcing the efficacy benefits of sacituzumab govitecan over the treatment of physician’s choice, the study team said.
Evolving Landscape of ADCs in Breast Cancer
Giuseppe Curigliano, MD, PhD, with the University of Milan, Italy, who served as discussant for the TROPION-Breast01 safety analysis, noted that the clinical landscape of ADCs has “evolved over time.”
He added that despite having a similar target and similar payload, the anti-TROP2 ADCs in development for HR+/HER2− metastatic breast cancer — Dato-DXd, sacituzumab govitecan, and sacituzumab tirumotecan — appear to have different spectrums of toxicity.
Looking ahead, he said it will be important to determine whether toxicity of these agents can be predicted with a pharmacogenomic analysis and whether toxicity is related to the payload or to the linker antibody complex.
“The science and chemistry of ADCs has shown significant promise in terms of clinical activity, but we also need to better understand safety,” Dr. Curigliano told attendees.
“We need to pay attention to signals in the early phase trials of ADCs and be willing to adjust accordingly to maximize therapeutic benefit and minimize toxicity. Team science will be important in the future developmental ADCs,” he added.
TROPION-Breast01 was sponsored by AstraZeneca. DESTINY-Breast-02 was sponsored by Daiichi Sankyo. TROPiCS-02 and EVER-132-002 were supported by Gilead Sciences. Several trial investigators have disclosed various relationships with these and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
These medications, which are designed to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens such as human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (TROP2), can be highly effective but can also come with significant toxicities.
The latest data on several ADCs — their clinical benefit and safety — were the focus of three presentations here at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
TROPION-Breast01
In her presentation, Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported additional safety analyses from the phase 3 TROPION-Breast01 trial looking at datopotamab deruxtecan (Dato-DXd) in patients with metastatic hormone receptor–positive (HR+)/HER2− breast cancer resistant to endocrine therapy.
Dato-DXd is an investigational ADC composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.
As previously reported by this news organization, median progression-free survival was 6.9 months with Dato-DXd compared with 4.9 months for investigator’s choice of chemotherapy (eribulin mesylate, vinorelbine, gemcitabine, or capecitabine), which translated into a 37% (hazard ratio [HR], 0.63; P < .0001) reduction in risk for disease progression.
In addition, the rate of grade 3 or higher treatment-related adverse events with Dato-DXd was less than half that with standard chemotherapy and led to fewer dose interruptions or reductions, indicating that Dato-DXd is better tolerated.
Dr. Jhaveri focused on three treatment-related adverse events of special interest: Stomatitis/oral mucositis, ocular surface events, and adjudicated drug-related interstitial lung disease.
The rate of any grade oral mucositis with Dato-DXd was 56%, she reported. Most were grade 1 (25%) or grade 2 (23%), with only 7% grade 3. About 13% of patients had a dose reduction for oral mucositis, and only one (0.3%) patient discontinued treatment.
The median time to onset was 22 days, and median time to resolution (for events recovered/resolved at data cutoff) was 36 days.
“The study did provide toxicity management guidelines for patients who experienced stomatitis,” Dr. Jhaveri told attendees. The guidelines highly recommended daily use of a steroid-containing mouthwash as prophylaxis or, if that wasn’t available, an inert, bland mouth rinse.
“Prophylactic cryotherapy — ice chips or ice water held in the mouth throughout the infusion — was also suggested,” she said.
The overall rate of ocular surface events with Dato-DXd was 40%, with most grade 1 (32%) or grade 2 (7%), with only 0.8% grade 3. Rates of dose reduction/interruption (3.3%) and discontinuation (0.3%) were low. Most ocular events were either dry eye (22%) or keratitis (14%).
The incidence of ocular events in the chemotherapy group was 12%, higher than typically seen. The study mandated regular ocular assessments, and Jhaveri noted that it was possible that this contributed to the high rate of low-grade ocular events found in both arms.
Median time to onset of ocular events was 65 days, and median time to resolution was 67 days.
Toxicity management guidelines were also incorporated for ocular events, suggesting daily use of artificial tears and avoidance of contact lenses, Dr. Jhaveri said.
In the Dato-DXd group, there were 12 adjudicated cases (3.3%) of drug-related interstitial lung disease; most were grade 1 (1.4%) and grade 2 (1.1%).
“There was one patient who had a grade 5 event, which was characterized by the investigator as grade 3 pneumonitis, with death attributed to disease progression,” Dr. Jhaveri said. This was subsequently adjudicated to be a grade 5 drug-related death.
The median time to onset of interstitial lung disease was 84.5 days, and median time to resolution was 28 days.
Among other treatment-related adverse events of clinical interest, any grade nausea was the most common event with Dato-DXd, reported by 51% of patients, with only 1.4% grade 3 or higher.
“Prophylactic antiemetic agents are highly recommended prior to infusion of Dato-DXd and on subsequent days as needed,” Dr. Jhaveri said.
Any grade diarrhea was reported in 7.5%, with no grade 3+ diarrhea. Alopecia was reported in 36.4%, of which grade 1 was 21% and grade 2 was 15%.
Summing up, the researcher said the new safety data suggest that Dato-DXd offers “better tolerability” than standard chemotherapy. Coupled with the efficacy data, this further supports “Dato-DXd as a potential new therapeutic option for patients with previously treated, inoperable, or metastatic HR+/HER2− breast cancer.”
DESTINY-Breast02
New data from the phase 3 DESTINY-Breast02 study confirm a long-term survival benefit, as well as a favorable benefit/risk profile of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), reported Sung-Bae Kim, MD, PhD, with University of Ulsan College of Medicine, Seoul, Republic of Korea.
In the phase 3 randomized, multicenter, open-label clinical trial, study participants received either trastuzumab deruxtecan or physician’s choice of trastuzumab plus capecitabine or lapatinib or capecitabine. The primary results of the trial were published last year in The Lancet.
As previously reported by this news organization, after median follow-up of 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of choice group, median progression-free survival was 17.8 months for trastuzumab deruxtecan vs 6.9 months for the physician’s choice group (HR, 0.36; P < .000001).
The latest data show that after a median follow-up of 30.2 months in the trastuzumab deruxtecan group and 20.5 months in the treatment of choice group, median progression-free survival was 16.7 months with trastuzumab deruxtecan vs 5.5 months with the treatment of choice — a 70% reduction in risk for progression (HR, 0.30), Dr. Kim said.
From time of randomization to progression to next line of therapy or death, median progression-free survival was 33.0 months with trastuzumab deruxtecan vs 15.0 with treatment of choice (HR, 0.42).
Median overall survival was 35.7 months with trastuzumab deruxtecan vs 25.0 months with the treatment of choice, with the risk for death reduced by 31% with trastuzumab deruxtecan (HR, 0.69).
The safety profile of trastuzumab deruxtecan continues to be “manageable, with no long-term toxicity observed with longer follow-up,” Dr. Kim told attendees. The most common treatment-emergent adverse events were nausea (73%), fatigue (62%), and vomiting (38%).
There were a total of 46 (11.4%) adjudicated drug-related interstitial lung disease/pneumonitis cases with trastuzumab deruxtecan. Most were grade 1 or 2. This risk did not increase with longer treatment duration; most events occurred within 12 months of starting treatment, Dr. Kim noted.
With longer follow-up, results of DESTINY-Breast02 “reinforce the substantial benefit” of trastuzumab deruxtecan over the treatment of physician’s choice in patients with HER2+ metastatic breast cancer previously treated with T-DM1, he concluded.
Pooled Data from TROPiCS-02 and EVER-132-002
Hope S. Rugo, MD, of the University of California San Francisco, and colleagues reported a meta-analysis of data from the phase 3 TROPiCS-02 and EVER-132-002 trials of the TROP2-directed ADC sacituzumab govitecan vs the treatment of physician’s choice in HR+/HER2− metastatic breast cancer.
In the pooled analysis, median overall survival was significantly longer with sacituzumab govitecan than with the treatment of physician’s choice in the overall population (16.2 vs 12.7 months) and in patients who received prior CDK4/6 inhibitor treatment (15.4 vs 11.5 months). Progression-free survival also favored sacituzumab govitecan.
These results are consistent with trial-level results from TROPICS-02 and EVER-132-002, reinforcing the efficacy benefits of sacituzumab govitecan over the treatment of physician’s choice, the study team said.
Evolving Landscape of ADCs in Breast Cancer
Giuseppe Curigliano, MD, PhD, with the University of Milan, Italy, who served as discussant for the TROPION-Breast01 safety analysis, noted that the clinical landscape of ADCs has “evolved over time.”
He added that despite having a similar target and similar payload, the anti-TROP2 ADCs in development for HR+/HER2− metastatic breast cancer — Dato-DXd, sacituzumab govitecan, and sacituzumab tirumotecan — appear to have different spectrums of toxicity.
Looking ahead, he said it will be important to determine whether toxicity of these agents can be predicted with a pharmacogenomic analysis and whether toxicity is related to the payload or to the linker antibody complex.
“The science and chemistry of ADCs has shown significant promise in terms of clinical activity, but we also need to better understand safety,” Dr. Curigliano told attendees.
“We need to pay attention to signals in the early phase trials of ADCs and be willing to adjust accordingly to maximize therapeutic benefit and minimize toxicity. Team science will be important in the future developmental ADCs,” he added.
TROPION-Breast01 was sponsored by AstraZeneca. DESTINY-Breast-02 was sponsored by Daiichi Sankyo. TROPiCS-02 and EVER-132-002 were supported by Gilead Sciences. Several trial investigators have disclosed various relationships with these and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
FROM ESMO BREAST CANCER 2024
Semaglutide Aids Weight Loss With or Without Bariatric Surgery
, a first-of-its-kind study reveals.
In addition, insurance coverage/expense was the most common issue for people wishing to start the popular medications, known as GLP-1 receptor agonists. Side effects and drug shortages were among the reasons people stopped taking the medication.
Overall, people lost an average of 6% of their total body weight in almost 1 year of taking semaglutide, the class of drugs that includes Wegovy and Ozempic. When researchers compared people who had weight loss surgery with those who had not, total weight loss was almost identical: 5.8% in those who had surgery, vs 6.0% in those who had not.
People in this study lost a lower percentage of their total body weight, compared with people in clinical trials for the drugs, who tended to lose up to 15%, said lead investigator Pourya Medhati, MD, a postdoctoral research fellow at Brigham and Women’s Hospital in Boston.
These results suggest real-world weight loss results may be different than those in carefully controlled research studies. Dr. Medhati presented the findings at Digestive Disease Week® (DDW) 2024 in Washington.
Total weight loss was not significantly different between men and women in the surgery group. But in the nonsurgery group, women lost 6.4%, compared with 4.8% among men, a significant difference.
Dr. Medhati and Ali Tavakkoli, MD, chief of the Division of General and GI Surgery at Brigham and Women’s Hospital, used electronic health records to study 2491 adults prescribed semaglutide between 2018 and 2023 at Brigham and Women’s Hospital. Average age was 51, 74% were White, and 78% were women. A total of 13% had a history of weight loss surgery.
Costs, Side Effects, and Other Concerns
The investigators looked at issues around starting and staying on semaglutide in a subgroup of 500 patients. A total of 75 people never started the drug, for example. The majority, 72%, of this group said it was because of insurance coverage or the cost of the medication. Another 19% did not give a reason, and 9% said it was because of side effects.
People with higher body mass indexes and diabetes were less likely to start taking semaglutide, Dr. Medhati said.
Another 100 of the 500 patients started and then stopped semaglutide. Again, insurance coverage and cost were reasons, this time cited by 13%. About 36% stopped because of side effects; 21% pointed to a shortage of semaglutide; and 30% stopped for an unspecified reason.
“Our study highlights the importance of addressing insurance to ensure broader access,” Dr. Medhati said.
The 325 people who stayed on semaglutide lost an average of 8.5% of their total body weight at 50 weeks.
Access Remains Unequal
“These medications are incredibly powerful to treat obesity and weight-related disease both for people with a history of bariatric surgery and those without,” said session co-moderator Matthew Kroh, MD, vice chair of innovation and technology in the Department of General Surgery at Cleveland Clinic.
More equitable access to semaglutide and other GLP-1s is needed, he said. “Because the cost is so high and they’re not covered by most insurance plans at this point, people with better financial means have access to these medications,” while others may not.
Dr. Kroh said the findings may only apply to the patients, most of whom were female, White, and middle-aged. But he applauded the researchers for doing the study outside of a clinical trial. “Real-world data will help guide these decisions in the future,” he said.
A version of this article appeared on WebMD.com.
, a first-of-its-kind study reveals.
In addition, insurance coverage/expense was the most common issue for people wishing to start the popular medications, known as GLP-1 receptor agonists. Side effects and drug shortages were among the reasons people stopped taking the medication.
Overall, people lost an average of 6% of their total body weight in almost 1 year of taking semaglutide, the class of drugs that includes Wegovy and Ozempic. When researchers compared people who had weight loss surgery with those who had not, total weight loss was almost identical: 5.8% in those who had surgery, vs 6.0% in those who had not.
People in this study lost a lower percentage of their total body weight, compared with people in clinical trials for the drugs, who tended to lose up to 15%, said lead investigator Pourya Medhati, MD, a postdoctoral research fellow at Brigham and Women’s Hospital in Boston.
These results suggest real-world weight loss results may be different than those in carefully controlled research studies. Dr. Medhati presented the findings at Digestive Disease Week® (DDW) 2024 in Washington.
Total weight loss was not significantly different between men and women in the surgery group. But in the nonsurgery group, women lost 6.4%, compared with 4.8% among men, a significant difference.
Dr. Medhati and Ali Tavakkoli, MD, chief of the Division of General and GI Surgery at Brigham and Women’s Hospital, used electronic health records to study 2491 adults prescribed semaglutide between 2018 and 2023 at Brigham and Women’s Hospital. Average age was 51, 74% were White, and 78% were women. A total of 13% had a history of weight loss surgery.
Costs, Side Effects, and Other Concerns
The investigators looked at issues around starting and staying on semaglutide in a subgroup of 500 patients. A total of 75 people never started the drug, for example. The majority, 72%, of this group said it was because of insurance coverage or the cost of the medication. Another 19% did not give a reason, and 9% said it was because of side effects.
People with higher body mass indexes and diabetes were less likely to start taking semaglutide, Dr. Medhati said.
Another 100 of the 500 patients started and then stopped semaglutide. Again, insurance coverage and cost were reasons, this time cited by 13%. About 36% stopped because of side effects; 21% pointed to a shortage of semaglutide; and 30% stopped for an unspecified reason.
“Our study highlights the importance of addressing insurance to ensure broader access,” Dr. Medhati said.
The 325 people who stayed on semaglutide lost an average of 8.5% of their total body weight at 50 weeks.
Access Remains Unequal
“These medications are incredibly powerful to treat obesity and weight-related disease both for people with a history of bariatric surgery and those without,” said session co-moderator Matthew Kroh, MD, vice chair of innovation and technology in the Department of General Surgery at Cleveland Clinic.
More equitable access to semaglutide and other GLP-1s is needed, he said. “Because the cost is so high and they’re not covered by most insurance plans at this point, people with better financial means have access to these medications,” while others may not.
Dr. Kroh said the findings may only apply to the patients, most of whom were female, White, and middle-aged. But he applauded the researchers for doing the study outside of a clinical trial. “Real-world data will help guide these decisions in the future,” he said.
A version of this article appeared on WebMD.com.
, a first-of-its-kind study reveals.
In addition, insurance coverage/expense was the most common issue for people wishing to start the popular medications, known as GLP-1 receptor agonists. Side effects and drug shortages were among the reasons people stopped taking the medication.
Overall, people lost an average of 6% of their total body weight in almost 1 year of taking semaglutide, the class of drugs that includes Wegovy and Ozempic. When researchers compared people who had weight loss surgery with those who had not, total weight loss was almost identical: 5.8% in those who had surgery, vs 6.0% in those who had not.
People in this study lost a lower percentage of their total body weight, compared with people in clinical trials for the drugs, who tended to lose up to 15%, said lead investigator Pourya Medhati, MD, a postdoctoral research fellow at Brigham and Women’s Hospital in Boston.
These results suggest real-world weight loss results may be different than those in carefully controlled research studies. Dr. Medhati presented the findings at Digestive Disease Week® (DDW) 2024 in Washington.
Total weight loss was not significantly different between men and women in the surgery group. But in the nonsurgery group, women lost 6.4%, compared with 4.8% among men, a significant difference.
Dr. Medhati and Ali Tavakkoli, MD, chief of the Division of General and GI Surgery at Brigham and Women’s Hospital, used electronic health records to study 2491 adults prescribed semaglutide between 2018 and 2023 at Brigham and Women’s Hospital. Average age was 51, 74% were White, and 78% were women. A total of 13% had a history of weight loss surgery.
Costs, Side Effects, and Other Concerns
The investigators looked at issues around starting and staying on semaglutide in a subgroup of 500 patients. A total of 75 people never started the drug, for example. The majority, 72%, of this group said it was because of insurance coverage or the cost of the medication. Another 19% did not give a reason, and 9% said it was because of side effects.
People with higher body mass indexes and diabetes were less likely to start taking semaglutide, Dr. Medhati said.
Another 100 of the 500 patients started and then stopped semaglutide. Again, insurance coverage and cost were reasons, this time cited by 13%. About 36% stopped because of side effects; 21% pointed to a shortage of semaglutide; and 30% stopped for an unspecified reason.
“Our study highlights the importance of addressing insurance to ensure broader access,” Dr. Medhati said.
The 325 people who stayed on semaglutide lost an average of 8.5% of their total body weight at 50 weeks.
Access Remains Unequal
“These medications are incredibly powerful to treat obesity and weight-related disease both for people with a history of bariatric surgery and those without,” said session co-moderator Matthew Kroh, MD, vice chair of innovation and technology in the Department of General Surgery at Cleveland Clinic.
More equitable access to semaglutide and other GLP-1s is needed, he said. “Because the cost is so high and they’re not covered by most insurance plans at this point, people with better financial means have access to these medications,” while others may not.
Dr. Kroh said the findings may only apply to the patients, most of whom were female, White, and middle-aged. But he applauded the researchers for doing the study outside of a clinical trial. “Real-world data will help guide these decisions in the future,” he said.
A version of this article appeared on WebMD.com.