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PACIFIC: Patient-reported outcomes unaffected by PD-L1 expression
GENEVA – Level of programmed death-ligand 1 (PD-L1) expression does not impact patient-reported outcomes (PROs) among those receiving durvalumab for stage III non–small cell lung cancer (NSCLC), according to a retrospective analysis of the phase III PACIFIC trial.
The findings support durvalumab for all comers regardless of PD-L1 expression, reported lead author Marina Garassino, MD, of Fondazione IRCCS – Instituto Nazionale dei Tumori in Milan, who presented findings at the European Lung Cancer Congress.
The PACIFIC trial involved 713 patients with stage III NSCLC who did not progress after platinum-based concurrent chemoradiotherapy, demonstrating both improved progression-free and overall survival. Patients were randomized 2:1 to receive either durvalumab (10 mg/kg) or placebo IV every 2 weeks for up to 1 year. Out of 713 patients involved in the trial, 63% had PD-L1 tumor expression level data available for the present analysis, allowing for subgrouping into five categories: expression level of at least 25%, less than 25%, at least 1%, less than 1%, or unknown. The investigators compared PROs from these cohorts using the European Organisation for Research and Treatment of Cancer core quality of life questionnaire and lung cancer module (EORTC QLQ-C30 and -LC13). With scores ranging from 1 to 100 points, clinically meaningful differences were defined by score changes exceeding 10 points. Changes during treatment, from baseline to week 48, were analyzed by a mixed model for repeated measures, overall responses for improvement rates by logistic regression, and hazard ratios for time to deterioration (TTD) by a stratified Cox proportional-hazards model.
The investigators found that most PROs remained consistent over time, without clinically meaningful variations between PD-L1 expression levels. However, as with the entire PACIFIC treatment population, patients in the present analysis showed changes in some PROs. At the meeting presented by the European Society for Medical Oncology, Dr. Garassino noted that it would be unrealistic to describe all PRO comparisons; instead, she presented several examples. For one, in patients receiving durvalumab, dysphagia and alopecia improved in four out of five PD-L1 subgroups and all subgroups, respectively, while patients in the placebo arm reported improvements in both measures regardless of PD-L1 expression. Other improvements tended to favor the durvalumab group; for instance, compared with other subgroups, patients with PD-L1 expression of at least 25% were more likely to report improved chest pain, physical functioning, pain, emotional functioning, and hemoptysis. In contrast, patients receiving placebo with PD-L1 expression less than 25% were more likely to report improved cough. Still, the investigators concluded that the overall picture did not suggest major differences in PROs by PD-L1 expression level, noting that global quality of life did not differ, and symptom improvement rates and time-to-deterioration measures generally aligned with the intent-to-treat population, judging by overlapping 95% confidence intervals and hazard ratios.
“These data support the PACIFIC regimen for the standard of care for stage III unresectable non–small cell lung cancer patients,” Dr. Garassino concluded.
Invited discussant Fabrice Barlesi, MD, PhD, of Aix-Marseille University, said that studies such as this one are important to ensure that investigator-implemented measures of response are calibrated to patient experiences. As an example, Dr. Barlesi noted that many clinicians would say that grade 2 diarrhea is a completely manageable adverse event, but not all patients would agree.
In this light, Dr. Barlesi said that the present findings are valuable, but they are not without flaws. He noted that 11 out of 13 symptoms from the quality of life lung cancer module were not reported, and that one-third of patients in the PACIFIC trial lacked PD-L1 expression level data.
Considering these shortcomings, and more broadly, difficulties comparing patient-reported outcome studies because of various measurement techniques, Dr. Barlesi called for standardization.
“We need to standardize the analysis of quality of life data,” Dr. Barlesi said. “We should correct for the multiplicity of tests. … we should identify some specific quality of life outcomes that we want to look at in the protocol.” He continued to suggest a variety of ideal characteristics for studies evaluating patient-reported outcomes, including defined statistical measures and protocols for missing data.
Without a standardized approach, “cross trial comparison will be a nightmare for all of us,” Dr. Barlesi said.
The study was funded by AstraZeneca. The investigators reported financial relationships with Roche, BMS, Lilly, and others.
SOURCE: Garassino et al. ELCC 2019. Abstract LBA2.
GENEVA – Level of programmed death-ligand 1 (PD-L1) expression does not impact patient-reported outcomes (PROs) among those receiving durvalumab for stage III non–small cell lung cancer (NSCLC), according to a retrospective analysis of the phase III PACIFIC trial.
The findings support durvalumab for all comers regardless of PD-L1 expression, reported lead author Marina Garassino, MD, of Fondazione IRCCS – Instituto Nazionale dei Tumori in Milan, who presented findings at the European Lung Cancer Congress.
The PACIFIC trial involved 713 patients with stage III NSCLC who did not progress after platinum-based concurrent chemoradiotherapy, demonstrating both improved progression-free and overall survival. Patients were randomized 2:1 to receive either durvalumab (10 mg/kg) or placebo IV every 2 weeks for up to 1 year. Out of 713 patients involved in the trial, 63% had PD-L1 tumor expression level data available for the present analysis, allowing for subgrouping into five categories: expression level of at least 25%, less than 25%, at least 1%, less than 1%, or unknown. The investigators compared PROs from these cohorts using the European Organisation for Research and Treatment of Cancer core quality of life questionnaire and lung cancer module (EORTC QLQ-C30 and -LC13). With scores ranging from 1 to 100 points, clinically meaningful differences were defined by score changes exceeding 10 points. Changes during treatment, from baseline to week 48, were analyzed by a mixed model for repeated measures, overall responses for improvement rates by logistic regression, and hazard ratios for time to deterioration (TTD) by a stratified Cox proportional-hazards model.
The investigators found that most PROs remained consistent over time, without clinically meaningful variations between PD-L1 expression levels. However, as with the entire PACIFIC treatment population, patients in the present analysis showed changes in some PROs. At the meeting presented by the European Society for Medical Oncology, Dr. Garassino noted that it would be unrealistic to describe all PRO comparisons; instead, she presented several examples. For one, in patients receiving durvalumab, dysphagia and alopecia improved in four out of five PD-L1 subgroups and all subgroups, respectively, while patients in the placebo arm reported improvements in both measures regardless of PD-L1 expression. Other improvements tended to favor the durvalumab group; for instance, compared with other subgroups, patients with PD-L1 expression of at least 25% were more likely to report improved chest pain, physical functioning, pain, emotional functioning, and hemoptysis. In contrast, patients receiving placebo with PD-L1 expression less than 25% were more likely to report improved cough. Still, the investigators concluded that the overall picture did not suggest major differences in PROs by PD-L1 expression level, noting that global quality of life did not differ, and symptom improvement rates and time-to-deterioration measures generally aligned with the intent-to-treat population, judging by overlapping 95% confidence intervals and hazard ratios.
“These data support the PACIFIC regimen for the standard of care for stage III unresectable non–small cell lung cancer patients,” Dr. Garassino concluded.
Invited discussant Fabrice Barlesi, MD, PhD, of Aix-Marseille University, said that studies such as this one are important to ensure that investigator-implemented measures of response are calibrated to patient experiences. As an example, Dr. Barlesi noted that many clinicians would say that grade 2 diarrhea is a completely manageable adverse event, but not all patients would agree.
In this light, Dr. Barlesi said that the present findings are valuable, but they are not without flaws. He noted that 11 out of 13 symptoms from the quality of life lung cancer module were not reported, and that one-third of patients in the PACIFIC trial lacked PD-L1 expression level data.
Considering these shortcomings, and more broadly, difficulties comparing patient-reported outcome studies because of various measurement techniques, Dr. Barlesi called for standardization.
“We need to standardize the analysis of quality of life data,” Dr. Barlesi said. “We should correct for the multiplicity of tests. … we should identify some specific quality of life outcomes that we want to look at in the protocol.” He continued to suggest a variety of ideal characteristics for studies evaluating patient-reported outcomes, including defined statistical measures and protocols for missing data.
Without a standardized approach, “cross trial comparison will be a nightmare for all of us,” Dr. Barlesi said.
The study was funded by AstraZeneca. The investigators reported financial relationships with Roche, BMS, Lilly, and others.
SOURCE: Garassino et al. ELCC 2019. Abstract LBA2.
GENEVA – Level of programmed death-ligand 1 (PD-L1) expression does not impact patient-reported outcomes (PROs) among those receiving durvalumab for stage III non–small cell lung cancer (NSCLC), according to a retrospective analysis of the phase III PACIFIC trial.
The findings support durvalumab for all comers regardless of PD-L1 expression, reported lead author Marina Garassino, MD, of Fondazione IRCCS – Instituto Nazionale dei Tumori in Milan, who presented findings at the European Lung Cancer Congress.
The PACIFIC trial involved 713 patients with stage III NSCLC who did not progress after platinum-based concurrent chemoradiotherapy, demonstrating both improved progression-free and overall survival. Patients were randomized 2:1 to receive either durvalumab (10 mg/kg) or placebo IV every 2 weeks for up to 1 year. Out of 713 patients involved in the trial, 63% had PD-L1 tumor expression level data available for the present analysis, allowing for subgrouping into five categories: expression level of at least 25%, less than 25%, at least 1%, less than 1%, or unknown. The investigators compared PROs from these cohorts using the European Organisation for Research and Treatment of Cancer core quality of life questionnaire and lung cancer module (EORTC QLQ-C30 and -LC13). With scores ranging from 1 to 100 points, clinically meaningful differences were defined by score changes exceeding 10 points. Changes during treatment, from baseline to week 48, were analyzed by a mixed model for repeated measures, overall responses for improvement rates by logistic regression, and hazard ratios for time to deterioration (TTD) by a stratified Cox proportional-hazards model.
The investigators found that most PROs remained consistent over time, without clinically meaningful variations between PD-L1 expression levels. However, as with the entire PACIFIC treatment population, patients in the present analysis showed changes in some PROs. At the meeting presented by the European Society for Medical Oncology, Dr. Garassino noted that it would be unrealistic to describe all PRO comparisons; instead, she presented several examples. For one, in patients receiving durvalumab, dysphagia and alopecia improved in four out of five PD-L1 subgroups and all subgroups, respectively, while patients in the placebo arm reported improvements in both measures regardless of PD-L1 expression. Other improvements tended to favor the durvalumab group; for instance, compared with other subgroups, patients with PD-L1 expression of at least 25% were more likely to report improved chest pain, physical functioning, pain, emotional functioning, and hemoptysis. In contrast, patients receiving placebo with PD-L1 expression less than 25% were more likely to report improved cough. Still, the investigators concluded that the overall picture did not suggest major differences in PROs by PD-L1 expression level, noting that global quality of life did not differ, and symptom improvement rates and time-to-deterioration measures generally aligned with the intent-to-treat population, judging by overlapping 95% confidence intervals and hazard ratios.
“These data support the PACIFIC regimen for the standard of care for stage III unresectable non–small cell lung cancer patients,” Dr. Garassino concluded.
Invited discussant Fabrice Barlesi, MD, PhD, of Aix-Marseille University, said that studies such as this one are important to ensure that investigator-implemented measures of response are calibrated to patient experiences. As an example, Dr. Barlesi noted that many clinicians would say that grade 2 diarrhea is a completely manageable adverse event, but not all patients would agree.
In this light, Dr. Barlesi said that the present findings are valuable, but they are not without flaws. He noted that 11 out of 13 symptoms from the quality of life lung cancer module were not reported, and that one-third of patients in the PACIFIC trial lacked PD-L1 expression level data.
Considering these shortcomings, and more broadly, difficulties comparing patient-reported outcome studies because of various measurement techniques, Dr. Barlesi called for standardization.
“We need to standardize the analysis of quality of life data,” Dr. Barlesi said. “We should correct for the multiplicity of tests. … we should identify some specific quality of life outcomes that we want to look at in the protocol.” He continued to suggest a variety of ideal characteristics for studies evaluating patient-reported outcomes, including defined statistical measures and protocols for missing data.
Without a standardized approach, “cross trial comparison will be a nightmare for all of us,” Dr. Barlesi said.
The study was funded by AstraZeneca. The investigators reported financial relationships with Roche, BMS, Lilly, and others.
SOURCE: Garassino et al. ELCC 2019. Abstract LBA2.
REPORTING FROM ELCC 2019
Survival after squamous recurrence may be unaffected by immune status
Patients who have recurrence of cutaneous squamous cell cancer of the head and neck (cSCC-HN) tend to have poor outcomes regardless of immune status, according to investigators.
Patients with surgically unsalvageable recurrent disease had the worst outcomes, reported lead author Lillian Sun, of the Cleveland Clinic, and her colleagues.
These findings support more intensive upfront therapy for patients with cSCC-HN, the investigators wrote in JAMA Dermatology. They noted that most patients with cSCC have good outcomes, with less than 5% experiencing recurrence or distant metastasis; however, “there is a subset of patients with adverse pathologic features and a more aggressive clinical course,” the investigators pointed out, “with substantially higher rates of locoregional recurrence (13%-41%) and distant metastasis (7%-16%) after surgical resection.”
According to the investigators, previous research has identified several patient factors that predict poor outcomes, such as invasiveness and differentiation, as well as chronic immunosuppression. To build on these data, and, in particular, to determine if immune suppression was linked with poor outcomes, the investigators conducted a retrospective analysis of 205 patients with cSCC-HN.
From this cohort, 72 patients had disease recurrence after surgery and radiotherapy. The average age of the patients was 71 years. About half were immunosuppressed (55.6%). On average, disease recurrence occurred slightly earlier in immunosuppressed patients (9.1 months) than in immunocompetent patients (10.1 months). Most patients had locoregional recurrence first, at rates of 65.6% and 77.5% among immunocompetent and immunosuppressed patients, respectively. Irrespective of immune status, median overall survival was 8.4 months and the 1-year overall survival rate was 43.2%. In contrast with previous findings, immune status was not statistically associated with median overall survival; immunocompetent patients did tend to live longer (12.9 months) than immunosuppressed patients (8.0 months), but this difference carried a P value of .90.
The investigators found that surgical candidacy after recurrence had the strongest impact on survival. Patients with surgically salvageable disease had a median overall survival of 26.1 months, compared with just 4.7 months for those who were not amenable to surgical salvage (P = .01). Among patients with unsalvageable disease, again, immune status did not have a significant impact on outcome.
“This study demonstrates that survival in this population is poor,” the investigators concluded. “Although we hypothesized that immunosuppressed status would be a significant contributor to outcomes in these patients, similar to findings in the upfront treatment setting, the current study suggests that this is not the case.”
The investigators reported clinical trial support from Genentech, Merck, and Bristol-Myers Squibb.
SOURCE: Sun et al. JAMA Derm. 27 Feb 2019. doi: 10.1001/jamadermatol.2018.5453.
Patients who have recurrence of cutaneous squamous cell cancer of the head and neck (cSCC-HN) tend to have poor outcomes regardless of immune status, according to investigators.
Patients with surgically unsalvageable recurrent disease had the worst outcomes, reported lead author Lillian Sun, of the Cleveland Clinic, and her colleagues.
These findings support more intensive upfront therapy for patients with cSCC-HN, the investigators wrote in JAMA Dermatology. They noted that most patients with cSCC have good outcomes, with less than 5% experiencing recurrence or distant metastasis; however, “there is a subset of patients with adverse pathologic features and a more aggressive clinical course,” the investigators pointed out, “with substantially higher rates of locoregional recurrence (13%-41%) and distant metastasis (7%-16%) after surgical resection.”
According to the investigators, previous research has identified several patient factors that predict poor outcomes, such as invasiveness and differentiation, as well as chronic immunosuppression. To build on these data, and, in particular, to determine if immune suppression was linked with poor outcomes, the investigators conducted a retrospective analysis of 205 patients with cSCC-HN.
From this cohort, 72 patients had disease recurrence after surgery and radiotherapy. The average age of the patients was 71 years. About half were immunosuppressed (55.6%). On average, disease recurrence occurred slightly earlier in immunosuppressed patients (9.1 months) than in immunocompetent patients (10.1 months). Most patients had locoregional recurrence first, at rates of 65.6% and 77.5% among immunocompetent and immunosuppressed patients, respectively. Irrespective of immune status, median overall survival was 8.4 months and the 1-year overall survival rate was 43.2%. In contrast with previous findings, immune status was not statistically associated with median overall survival; immunocompetent patients did tend to live longer (12.9 months) than immunosuppressed patients (8.0 months), but this difference carried a P value of .90.
The investigators found that surgical candidacy after recurrence had the strongest impact on survival. Patients with surgically salvageable disease had a median overall survival of 26.1 months, compared with just 4.7 months for those who were not amenable to surgical salvage (P = .01). Among patients with unsalvageable disease, again, immune status did not have a significant impact on outcome.
“This study demonstrates that survival in this population is poor,” the investigators concluded. “Although we hypothesized that immunosuppressed status would be a significant contributor to outcomes in these patients, similar to findings in the upfront treatment setting, the current study suggests that this is not the case.”
The investigators reported clinical trial support from Genentech, Merck, and Bristol-Myers Squibb.
SOURCE: Sun et al. JAMA Derm. 27 Feb 2019. doi: 10.1001/jamadermatol.2018.5453.
Patients who have recurrence of cutaneous squamous cell cancer of the head and neck (cSCC-HN) tend to have poor outcomes regardless of immune status, according to investigators.
Patients with surgically unsalvageable recurrent disease had the worst outcomes, reported lead author Lillian Sun, of the Cleveland Clinic, and her colleagues.
These findings support more intensive upfront therapy for patients with cSCC-HN, the investigators wrote in JAMA Dermatology. They noted that most patients with cSCC have good outcomes, with less than 5% experiencing recurrence or distant metastasis; however, “there is a subset of patients with adverse pathologic features and a more aggressive clinical course,” the investigators pointed out, “with substantially higher rates of locoregional recurrence (13%-41%) and distant metastasis (7%-16%) after surgical resection.”
According to the investigators, previous research has identified several patient factors that predict poor outcomes, such as invasiveness and differentiation, as well as chronic immunosuppression. To build on these data, and, in particular, to determine if immune suppression was linked with poor outcomes, the investigators conducted a retrospective analysis of 205 patients with cSCC-HN.
From this cohort, 72 patients had disease recurrence after surgery and radiotherapy. The average age of the patients was 71 years. About half were immunosuppressed (55.6%). On average, disease recurrence occurred slightly earlier in immunosuppressed patients (9.1 months) than in immunocompetent patients (10.1 months). Most patients had locoregional recurrence first, at rates of 65.6% and 77.5% among immunocompetent and immunosuppressed patients, respectively. Irrespective of immune status, median overall survival was 8.4 months and the 1-year overall survival rate was 43.2%. In contrast with previous findings, immune status was not statistically associated with median overall survival; immunocompetent patients did tend to live longer (12.9 months) than immunosuppressed patients (8.0 months), but this difference carried a P value of .90.
The investigators found that surgical candidacy after recurrence had the strongest impact on survival. Patients with surgically salvageable disease had a median overall survival of 26.1 months, compared with just 4.7 months for those who were not amenable to surgical salvage (P = .01). Among patients with unsalvageable disease, again, immune status did not have a significant impact on outcome.
“This study demonstrates that survival in this population is poor,” the investigators concluded. “Although we hypothesized that immunosuppressed status would be a significant contributor to outcomes in these patients, similar to findings in the upfront treatment setting, the current study suggests that this is not the case.”
The investigators reported clinical trial support from Genentech, Merck, and Bristol-Myers Squibb.
SOURCE: Sun et al. JAMA Derm. 27 Feb 2019. doi: 10.1001/jamadermatol.2018.5453.
FROM JAMA DERMATOLOGY
HAVEN 4: Monthly emicizumab shows value
For many patients with hemophilia A, with or without inhibitors, a monthly emicizumab injection is enough to ensure a high level of bleed control, based on results from the ongoing HAVEN 4 trial.
Most patients reported three or fewer treated bleeds, while slightly more than half had no treated bleeds at all, according to lead author Steven W. Pipe, MD, of the University of Michigan, Ann Arbor, and his colleagues. The investigators noted that results from this trial have already led to approval of a monthly dosing schedule in the United States and several other countries.
“This convenient regimen has the potential to improve the care of patients by decreasing their treatment burden, and increasing uptake and adherence to effective prophylaxis, which is known to decrease the development of debilitating secondary complications,” the investigators wrote. The report is in The Lancet Haematology.
The data were collected at 20 centers in 8 countries. Eligibility required that patients have severe congenital hemophilia A (less than 1% normal FVIII activity), or hemophilia A with FVIII inhibitors and concurrent treatment with bypassing agents or FVIII concentrates.
An initial run-in cohort that included seven patients assessed pharmacokinetics and safety. These patients received 6 mg/kg of emicizumab subcutaneously every 4 weeks for at least 24 weeks. After this group showed good responses, 41 additional patients were enrolled in an expansion cohort, which involved an initial loading phase of weekly doses at 3 mg/kg for the first month, followed by monthly dosing at 6 mg/kg for at least 6 months (24 weeks).
The efficacy endpoint of the study was bleed prevention, as measured by treated target joint bleeds, treated joint bleeds, treated spontaneous bleeds, all bleeds (untreated and treated), and annualized bleed rates for treated bleeds.
In the expansion cohort, the median number of bleeds in the 24-week period preceding enrollment was five. In the same group, five patients (12%) had FVIII inhibitors and 61% of patients exhibited at least one target joint.
After a median treatment of 25.6 weeks, the model-based annualized bleed rate for treated bleeds was 2.4, while the median annualized bleed rate was zero.
Slightly more than half of the patients (56.1%) reported no treated bleeds, 90% of patients reported 0-3 treated bleeds, and 85% of patients did not require treatment for targeted joint bleeds.
When untreated bleeds were included, the model-based annualized bleed rate was 4.5, while the median annualized bleed rate was 2.1. Almost one-third of patients (29%) had no bleeding events of any kind and most (80%) had 0-3 treated or untreated bleeds.
Overall, treatment was well tolerated, with no patients withdrawing from the study, discontinuing treatment, or requiring dose modifications. Laboratory parameters remained stable throughout. The most common treatment-related adverse event was injection-site reaction (22%), followed distantly by pre-syncope, chills, rash, and erythema, each of which occurred in 2% of patients.
“Overall, the results of HAVEN 4 are consistent with the findings of other HAVEN studies,” the investigators wrote. “The option of treatment with emicizumab every 4 weeks broadens the range of administration frequencies and allows clinicians to tailor treatment to each patient’s needs and preferences.”
F. Hoffman-La Roche and Chugai funded the study. The investigators reported financial relationships with the study sponsors and other companies.
SOURCE: Pipe SW et al. Lancet Haem. 2019 Apr 16. doi: 10.1016/S2352-3026(19)30054-7.
For many patients with hemophilia A, with or without inhibitors, a monthly emicizumab injection is enough to ensure a high level of bleed control, based on results from the ongoing HAVEN 4 trial.
Most patients reported three or fewer treated bleeds, while slightly more than half had no treated bleeds at all, according to lead author Steven W. Pipe, MD, of the University of Michigan, Ann Arbor, and his colleagues. The investigators noted that results from this trial have already led to approval of a monthly dosing schedule in the United States and several other countries.
“This convenient regimen has the potential to improve the care of patients by decreasing their treatment burden, and increasing uptake and adherence to effective prophylaxis, which is known to decrease the development of debilitating secondary complications,” the investigators wrote. The report is in The Lancet Haematology.
The data were collected at 20 centers in 8 countries. Eligibility required that patients have severe congenital hemophilia A (less than 1% normal FVIII activity), or hemophilia A with FVIII inhibitors and concurrent treatment with bypassing agents or FVIII concentrates.
An initial run-in cohort that included seven patients assessed pharmacokinetics and safety. These patients received 6 mg/kg of emicizumab subcutaneously every 4 weeks for at least 24 weeks. After this group showed good responses, 41 additional patients were enrolled in an expansion cohort, which involved an initial loading phase of weekly doses at 3 mg/kg for the first month, followed by monthly dosing at 6 mg/kg for at least 6 months (24 weeks).
The efficacy endpoint of the study was bleed prevention, as measured by treated target joint bleeds, treated joint bleeds, treated spontaneous bleeds, all bleeds (untreated and treated), and annualized bleed rates for treated bleeds.
In the expansion cohort, the median number of bleeds in the 24-week period preceding enrollment was five. In the same group, five patients (12%) had FVIII inhibitors and 61% of patients exhibited at least one target joint.
After a median treatment of 25.6 weeks, the model-based annualized bleed rate for treated bleeds was 2.4, while the median annualized bleed rate was zero.
Slightly more than half of the patients (56.1%) reported no treated bleeds, 90% of patients reported 0-3 treated bleeds, and 85% of patients did not require treatment for targeted joint bleeds.
When untreated bleeds were included, the model-based annualized bleed rate was 4.5, while the median annualized bleed rate was 2.1. Almost one-third of patients (29%) had no bleeding events of any kind and most (80%) had 0-3 treated or untreated bleeds.
Overall, treatment was well tolerated, with no patients withdrawing from the study, discontinuing treatment, or requiring dose modifications. Laboratory parameters remained stable throughout. The most common treatment-related adverse event was injection-site reaction (22%), followed distantly by pre-syncope, chills, rash, and erythema, each of which occurred in 2% of patients.
“Overall, the results of HAVEN 4 are consistent with the findings of other HAVEN studies,” the investigators wrote. “The option of treatment with emicizumab every 4 weeks broadens the range of administration frequencies and allows clinicians to tailor treatment to each patient’s needs and preferences.”
F. Hoffman-La Roche and Chugai funded the study. The investigators reported financial relationships with the study sponsors and other companies.
SOURCE: Pipe SW et al. Lancet Haem. 2019 Apr 16. doi: 10.1016/S2352-3026(19)30054-7.
For many patients with hemophilia A, with or without inhibitors, a monthly emicizumab injection is enough to ensure a high level of bleed control, based on results from the ongoing HAVEN 4 trial.
Most patients reported three or fewer treated bleeds, while slightly more than half had no treated bleeds at all, according to lead author Steven W. Pipe, MD, of the University of Michigan, Ann Arbor, and his colleagues. The investigators noted that results from this trial have already led to approval of a monthly dosing schedule in the United States and several other countries.
“This convenient regimen has the potential to improve the care of patients by decreasing their treatment burden, and increasing uptake and adherence to effective prophylaxis, which is known to decrease the development of debilitating secondary complications,” the investigators wrote. The report is in The Lancet Haematology.
The data were collected at 20 centers in 8 countries. Eligibility required that patients have severe congenital hemophilia A (less than 1% normal FVIII activity), or hemophilia A with FVIII inhibitors and concurrent treatment with bypassing agents or FVIII concentrates.
An initial run-in cohort that included seven patients assessed pharmacokinetics and safety. These patients received 6 mg/kg of emicizumab subcutaneously every 4 weeks for at least 24 weeks. After this group showed good responses, 41 additional patients were enrolled in an expansion cohort, which involved an initial loading phase of weekly doses at 3 mg/kg for the first month, followed by monthly dosing at 6 mg/kg for at least 6 months (24 weeks).
The efficacy endpoint of the study was bleed prevention, as measured by treated target joint bleeds, treated joint bleeds, treated spontaneous bleeds, all bleeds (untreated and treated), and annualized bleed rates for treated bleeds.
In the expansion cohort, the median number of bleeds in the 24-week period preceding enrollment was five. In the same group, five patients (12%) had FVIII inhibitors and 61% of patients exhibited at least one target joint.
After a median treatment of 25.6 weeks, the model-based annualized bleed rate for treated bleeds was 2.4, while the median annualized bleed rate was zero.
Slightly more than half of the patients (56.1%) reported no treated bleeds, 90% of patients reported 0-3 treated bleeds, and 85% of patients did not require treatment for targeted joint bleeds.
When untreated bleeds were included, the model-based annualized bleed rate was 4.5, while the median annualized bleed rate was 2.1. Almost one-third of patients (29%) had no bleeding events of any kind and most (80%) had 0-3 treated or untreated bleeds.
Overall, treatment was well tolerated, with no patients withdrawing from the study, discontinuing treatment, or requiring dose modifications. Laboratory parameters remained stable throughout. The most common treatment-related adverse event was injection-site reaction (22%), followed distantly by pre-syncope, chills, rash, and erythema, each of which occurred in 2% of patients.
“Overall, the results of HAVEN 4 are consistent with the findings of other HAVEN studies,” the investigators wrote. “The option of treatment with emicizumab every 4 weeks broadens the range of administration frequencies and allows clinicians to tailor treatment to each patient’s needs and preferences.”
F. Hoffman-La Roche and Chugai funded the study. The investigators reported financial relationships with the study sponsors and other companies.
SOURCE: Pipe SW et al. Lancet Haem. 2019 Apr 16. doi: 10.1016/S2352-3026(19)30054-7.
FROM THE LANCET HAEMATOLOGY
Osimertinib again shows strength in NSCLC with leptomeningeal metastases
GENEVA – Treatment with osimertinib leads to clinically meaningful responses in about half of patients with epidermal growth factor receptor (EGFR) T790M–positive non–small cell lung cancer (NSCLC) who have asymptomatic leptomeningeal metastases, according to a post hoc analysis of patients from multiple AURA studies.
This conclusion aligns with previous encouraging findings delivered by the BLOOM trial, with the notable caveat that AURA patients received the Food and Drug Administration–approved dose of 80 mg osimertinib daily, instead of 160 mg, as given to BLOOM patients, reported lead author Myung Ju Ahn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and her colleagues.
At the European Lung Cancer Congress, invited discussant Pasi A. Jänne, MD, PhD of the Dana-Farber Cancer Institute in Boston, provided additional background for the study. “Leptomeningeal disease is really a devastating complication for our patients with lung cancer,” Dr. Jänne said, noting that effective treatments have been historically lacking; apart from osimertinib, other treatment strategies have included whole brain radiation therapy, high-dose pemetrexed, and pulsatile erlotinib, which were largely based on anecdotal evidence. Like other next-generation tyrosine kinase inhibitors, osimertinib stands apart from older agents because of its greater ability to penetrate the blood-brain barrier.
The present, retrospective analysis involved 22 patients with advanced, EGFR T790M–positive NSCLC with asymptomatic leptomeningeal metastases (LM) that was radiographically detected by blinded independent review. Patients received 80 mg osimertinib daily after progressing on another EGFR tyrosine kinase inhibitor. Follow-up brain scans were evaluated using Response Assessment in Neuro-Oncology LM criteria. Median overall survival was determined, as were progression-free survival, duration of response, and objective response rate, with these latter parameters analyzed specifically for LM disease.
Demographically, the patient population was consistent with previous AURA trials, with a predominance of Asian (82%) and female (59%) patients. Patients received treatment for a median of 7.3 months. Analysis showed that slightly more than half of patients (55%) responded to therapy, with an even split between partial (27%) and complete responders (27%). Median progression-free survival reached almost 1 year (11.1 months), while overall survival exceeded a year and a half (18.8 months), with a 1-year overall survival rate of 65%. Duration of response data are still immature. Graphical longitudinal analysis showed comparable responses between the AURA and BLOOM trials, suggesting that an 80-mg dose is likely to provide a similar efficacy to a 160-mg dose, Dr. Ahn said, although she also urged a cautionary interpretation because of study design.
Dr. Ahn described the survival statistics as “encouraging” at the meeting presented by the European Society for Medical Oncology, as the outcomes were better than those typically seen in historical controls.
Discussing these findings, Dr. Jänne suggested that the patient assessment criteria were “pretty subjective in nature.”
“You could get a score of plus one or minus one if the scans are kind of better or kind of worse,” Dr. Jänne said. “There’s really no objective criteria there.” He noted that imaging results may not reflect clinical impact of LM disease, and suggested that additional assessment criteria would have been welcome, such as assessments involving neurologic status or cerebrospinal fluid characteristics, both of which were included in the BLOOM trial.
“The real question comes, when we’re facing someone with leptomeningeal disease, is 80 milligrams as effective as 160 milligrams?” Dr. Jänne asked. “I don’t think we have the answer to that because the [AURA and BLOOM] studies are different, including different endpoints, and they’re not comparative.” He also noted that, in the United States, when met with LM disease progression, clinicians commonly increase the osimertinib dose from 80 mg to 160 mg; however, “it is without any data,” and warrants an actual clinical study.
The study was funded by AstraZeneca. The investigators reported financial relationships with Novartis, Pfizer, Roche, and others.
SOURCE: Ahn MJ et al. ELCC 2019, Abstract 105O.
GENEVA – Treatment with osimertinib leads to clinically meaningful responses in about half of patients with epidermal growth factor receptor (EGFR) T790M–positive non–small cell lung cancer (NSCLC) who have asymptomatic leptomeningeal metastases, according to a post hoc analysis of patients from multiple AURA studies.
This conclusion aligns with previous encouraging findings delivered by the BLOOM trial, with the notable caveat that AURA patients received the Food and Drug Administration–approved dose of 80 mg osimertinib daily, instead of 160 mg, as given to BLOOM patients, reported lead author Myung Ju Ahn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and her colleagues.
At the European Lung Cancer Congress, invited discussant Pasi A. Jänne, MD, PhD of the Dana-Farber Cancer Institute in Boston, provided additional background for the study. “Leptomeningeal disease is really a devastating complication for our patients with lung cancer,” Dr. Jänne said, noting that effective treatments have been historically lacking; apart from osimertinib, other treatment strategies have included whole brain radiation therapy, high-dose pemetrexed, and pulsatile erlotinib, which were largely based on anecdotal evidence. Like other next-generation tyrosine kinase inhibitors, osimertinib stands apart from older agents because of its greater ability to penetrate the blood-brain barrier.
The present, retrospective analysis involved 22 patients with advanced, EGFR T790M–positive NSCLC with asymptomatic leptomeningeal metastases (LM) that was radiographically detected by blinded independent review. Patients received 80 mg osimertinib daily after progressing on another EGFR tyrosine kinase inhibitor. Follow-up brain scans were evaluated using Response Assessment in Neuro-Oncology LM criteria. Median overall survival was determined, as were progression-free survival, duration of response, and objective response rate, with these latter parameters analyzed specifically for LM disease.
Demographically, the patient population was consistent with previous AURA trials, with a predominance of Asian (82%) and female (59%) patients. Patients received treatment for a median of 7.3 months. Analysis showed that slightly more than half of patients (55%) responded to therapy, with an even split between partial (27%) and complete responders (27%). Median progression-free survival reached almost 1 year (11.1 months), while overall survival exceeded a year and a half (18.8 months), with a 1-year overall survival rate of 65%. Duration of response data are still immature. Graphical longitudinal analysis showed comparable responses between the AURA and BLOOM trials, suggesting that an 80-mg dose is likely to provide a similar efficacy to a 160-mg dose, Dr. Ahn said, although she also urged a cautionary interpretation because of study design.
Dr. Ahn described the survival statistics as “encouraging” at the meeting presented by the European Society for Medical Oncology, as the outcomes were better than those typically seen in historical controls.
Discussing these findings, Dr. Jänne suggested that the patient assessment criteria were “pretty subjective in nature.”
“You could get a score of plus one or minus one if the scans are kind of better or kind of worse,” Dr. Jänne said. “There’s really no objective criteria there.” He noted that imaging results may not reflect clinical impact of LM disease, and suggested that additional assessment criteria would have been welcome, such as assessments involving neurologic status or cerebrospinal fluid characteristics, both of which were included in the BLOOM trial.
“The real question comes, when we’re facing someone with leptomeningeal disease, is 80 milligrams as effective as 160 milligrams?” Dr. Jänne asked. “I don’t think we have the answer to that because the [AURA and BLOOM] studies are different, including different endpoints, and they’re not comparative.” He also noted that, in the United States, when met with LM disease progression, clinicians commonly increase the osimertinib dose from 80 mg to 160 mg; however, “it is without any data,” and warrants an actual clinical study.
The study was funded by AstraZeneca. The investigators reported financial relationships with Novartis, Pfizer, Roche, and others.
SOURCE: Ahn MJ et al. ELCC 2019, Abstract 105O.
GENEVA – Treatment with osimertinib leads to clinically meaningful responses in about half of patients with epidermal growth factor receptor (EGFR) T790M–positive non–small cell lung cancer (NSCLC) who have asymptomatic leptomeningeal metastases, according to a post hoc analysis of patients from multiple AURA studies.
This conclusion aligns with previous encouraging findings delivered by the BLOOM trial, with the notable caveat that AURA patients received the Food and Drug Administration–approved dose of 80 mg osimertinib daily, instead of 160 mg, as given to BLOOM patients, reported lead author Myung Ju Ahn, MD, PhD, of Samsung Medical Center in Seoul, South Korea, and her colleagues.
At the European Lung Cancer Congress, invited discussant Pasi A. Jänne, MD, PhD of the Dana-Farber Cancer Institute in Boston, provided additional background for the study. “Leptomeningeal disease is really a devastating complication for our patients with lung cancer,” Dr. Jänne said, noting that effective treatments have been historically lacking; apart from osimertinib, other treatment strategies have included whole brain radiation therapy, high-dose pemetrexed, and pulsatile erlotinib, which were largely based on anecdotal evidence. Like other next-generation tyrosine kinase inhibitors, osimertinib stands apart from older agents because of its greater ability to penetrate the blood-brain barrier.
The present, retrospective analysis involved 22 patients with advanced, EGFR T790M–positive NSCLC with asymptomatic leptomeningeal metastases (LM) that was radiographically detected by blinded independent review. Patients received 80 mg osimertinib daily after progressing on another EGFR tyrosine kinase inhibitor. Follow-up brain scans were evaluated using Response Assessment in Neuro-Oncology LM criteria. Median overall survival was determined, as were progression-free survival, duration of response, and objective response rate, with these latter parameters analyzed specifically for LM disease.
Demographically, the patient population was consistent with previous AURA trials, with a predominance of Asian (82%) and female (59%) patients. Patients received treatment for a median of 7.3 months. Analysis showed that slightly more than half of patients (55%) responded to therapy, with an even split between partial (27%) and complete responders (27%). Median progression-free survival reached almost 1 year (11.1 months), while overall survival exceeded a year and a half (18.8 months), with a 1-year overall survival rate of 65%. Duration of response data are still immature. Graphical longitudinal analysis showed comparable responses between the AURA and BLOOM trials, suggesting that an 80-mg dose is likely to provide a similar efficacy to a 160-mg dose, Dr. Ahn said, although she also urged a cautionary interpretation because of study design.
Dr. Ahn described the survival statistics as “encouraging” at the meeting presented by the European Society for Medical Oncology, as the outcomes were better than those typically seen in historical controls.
Discussing these findings, Dr. Jänne suggested that the patient assessment criteria were “pretty subjective in nature.”
“You could get a score of plus one or minus one if the scans are kind of better or kind of worse,” Dr. Jänne said. “There’s really no objective criteria there.” He noted that imaging results may not reflect clinical impact of LM disease, and suggested that additional assessment criteria would have been welcome, such as assessments involving neurologic status or cerebrospinal fluid characteristics, both of which were included in the BLOOM trial.
“The real question comes, when we’re facing someone with leptomeningeal disease, is 80 milligrams as effective as 160 milligrams?” Dr. Jänne asked. “I don’t think we have the answer to that because the [AURA and BLOOM] studies are different, including different endpoints, and they’re not comparative.” He also noted that, in the United States, when met with LM disease progression, clinicians commonly increase the osimertinib dose from 80 mg to 160 mg; however, “it is without any data,” and warrants an actual clinical study.
The study was funded by AstraZeneca. The investigators reported financial relationships with Novartis, Pfizer, Roche, and others.
SOURCE: Ahn MJ et al. ELCC 2019, Abstract 105O.
REPORTING FROM ELCC 2019
Mouthwash shows some efficacy for oral mucositis pain
Doxepin mouthwash and diphenhydramine/lidocaine/antacid (DLA) mouthwash can offer 4 hours of pain relief for cancer patients with oral mucositis, according to investigators.
Although these agents led to statistical improvements in pain, neither met predetermined clinical efficacy thresholds, reported lead author Terence T. Sio, MD, of the Mayo Clinic Hospital in Phoenix and his colleagues, who suggested that more safety and efficacy research is needed.
“Few pharmacological agents or interventions have been shown to effectively reduce the severity of radiotherapy-related oral mucositis and its associated pain,” the investigators wrote in JAMA.
They noted that this knowledge gap affects everyday practice since “more than 80% of patients develop oral mucositis during radiotherapy, and mouthwashes and systemic analgesic agents are frequently used to treat the condition.”
Small studies have shown that doxepin, a tricyclic antidepressant, could be an effective agent for oral mucositis, while a variety of DLA mouthwashes are commonly prescribed, despite a dearth of relevant Cochrane reviews or randomized placebo-controlled trials.
This background led to the present study, which included 275 patients who had developed oral mucositis while undergoing head and neck radiotherapy for cancer. The patients were randomized evenly into three mouthwash groups: placebo (2.5 mL Ora-Sweet SF oral solution and 2.5 mL of water), doxepin (25 mg in 5 mL solution), or diphenhydramine (12.5 mg in 5 mL alcohol-free solution), lidocaine (2% viscous solution), and antacid (20 mg of simethicone, 200 mg of magnesium hydroxide, and 200 mg of aluminum hydroxide in 355 mL solution). The study was divided into two cycles; in the first, patients used their assigned mouthwash once, whereas in the second cycle, which was optional, patients used their assigned treatment every 4 hours for up to 7 days.
The primary endpoint was oral mucositis pain. Multiple secondary endpoints were assessed, including patient preference for continued therapy and various adverse effects, such as drowsiness and taste. Responses were assessed using a combination of the Oral Mucositis Daily Questionnaire and the Oral Mucositis Weekly Questionnaire–Head and Neck Cancer. This modified questionnaire was conducted prior to treatment, then after treatment at 5, 15, 30, 60, 120, and 240 minutes. Pain improvements were compared by area under the curve after adjustment for baseline score. Clinical improvement was defined as a 3.5 point difference in pain score, compared with placebo.
Data analysis showed that pain in the first 4 hours decreased the most in the DLA group (11.7 points), slightly less in the doxepin group (11.6 points), and least in the placebo group (8.7 points). Compared with placebo, both treatments offered statistical improvements. DLA patients responded the most (3.0 points; P = .004), while, again, the average doxepin response was similar, albeit with a slightly higher P value. (2.9 points; P = .02). The investigators discouraged direct comparisons between the two agents because the study was not designed for this purpose.
Neither intervention met the predetermined 3.5-point threshold for clinical improvement, although the investigators suggested that some patients may have had meaningful responses.
“There is some suggestion in post hoc analyses that the findings may have been clinically relevant for some patients,” the investigators wrote, noting that responder analysis favored treatment with DLA versus placebo, but not doxepin versus placebo. “However,” they noted, “the overall clinical importance of the statistically significant primary findings remains uncertain.”
Compared with placebo, doxepin mouthwash was associated with stinging or burning, unpleasant taste, drowsiness, and fatigue. Of note, fatigue only occurred in the doxepin group, at a rate of 6%. Both treatment groups had a maximum grade 3 adverse event rate of 4%, while the placebo arm had an adverse event rate of 2%.
“Further research is needed to assess longer-term efficacy and safety for both mouthwashes,” the investigators concluded.
The study was funded by the National Cancer Institute and the Mayo Clinic Symptom Intervention Program. One investigator reported a nonfinancial support from CutisPharma. The other investigators declared no conflicts of interest.
SOURCE: Sio TT et al. JAMA. 2019 Apr 16. doi: 10.1001/jama.2019.3504.
Oral mucositis is a common and serious complication of cancer, but quality research and reliable treatments for the condition are lacking, according to Sharon Elad, DMD, of the University of Rochester (N.Y.) Medical Center and Noam Yarom, DMD, of Tel Aviv University.
“Despite the strengths of the randomized clinical trial (RCT) design in general, some studies evaluating therapies for oral mucositis have been underpowered, are of low quality, or have yielded conflicting results about the benefits of the interventions,” Dr. Elad and Dr. Yarom wrote in a JAMA editorial.
“These issues highlight the need for well-designed RCTs that test interventions for oral mucositis appropriately.”
In this context, the doctors reviewed the simultaneously published study by Sio et al., in which patients were given either of two topical therapies for oral mucositis: diphenhydramine/lidocaine/antacid mouthwash or doxepin mouthwash. Both interventions led to statistically significant improvements in pain, compared with placebo; however, these improvements were not clinically significant, according to the investigators’ predetermined threshold.
“The distinction between statistical significance and clinical importance is relevant in this study,” Dr. Elad and Dr. Yarom wrote, “and the findings suggest that pain relief was short-term and limited among many of the patients. Nevertheless, this limited effect may be beneficial if doxepin is used as a supplemental analgesic (eg, to reduce the dose of systemic opioids).”
“The severity of oral pain in oral mucositis may exceed the beneficial effect of local anesthesia,” they added. “In severe oral mucositis–associated pain, clinicians may elect to use a stronger pain medication as a first-line treatment. Optional pain management approaches include patient-controlled analgesics, topical morphine, and fentanyl transdermal patch or nasal spray.”
Dr. Elad and Dr. Yarom said that future oral mucositis studies should evaluate treatments head-to-head and against placebo, with a watchful eye for severe, adverse events, which can occur even with local treatments, because of damaged mucosal barriers that allow for systemic absorption. They also pointed out that emerging technologies such as proton-beam radiotherapy should minimize rates of mucositis. However, “until these advances are routinely used,” they wrote, “the search for an effective, safe therapy for oral mucositis and its associated pain needs to continue.”
Dr. Elad reported relationships with Falk Pharma and the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology. Dr. Yarom reported no conflicts.
Dr. Elad is a professor of dentistry and a professor of oncology at the University of Rochester (N.Y.) Medical Center. Dr. Yarom is a senior lecturer of oral medicine and the program director of the postgraduate oral medicine in the department of oral pathology and oral medicine at Tel Aviv University, as well as the director of the oral medicine clinic at Sheba Medical Center in Tel HaShomer, Israel.
Oral mucositis is a common and serious complication of cancer, but quality research and reliable treatments for the condition are lacking, according to Sharon Elad, DMD, of the University of Rochester (N.Y.) Medical Center and Noam Yarom, DMD, of Tel Aviv University.
“Despite the strengths of the randomized clinical trial (RCT) design in general, some studies evaluating therapies for oral mucositis have been underpowered, are of low quality, or have yielded conflicting results about the benefits of the interventions,” Dr. Elad and Dr. Yarom wrote in a JAMA editorial.
“These issues highlight the need for well-designed RCTs that test interventions for oral mucositis appropriately.”
In this context, the doctors reviewed the simultaneously published study by Sio et al., in which patients were given either of two topical therapies for oral mucositis: diphenhydramine/lidocaine/antacid mouthwash or doxepin mouthwash. Both interventions led to statistically significant improvements in pain, compared with placebo; however, these improvements were not clinically significant, according to the investigators’ predetermined threshold.
“The distinction between statistical significance and clinical importance is relevant in this study,” Dr. Elad and Dr. Yarom wrote, “and the findings suggest that pain relief was short-term and limited among many of the patients. Nevertheless, this limited effect may be beneficial if doxepin is used as a supplemental analgesic (eg, to reduce the dose of systemic opioids).”
“The severity of oral pain in oral mucositis may exceed the beneficial effect of local anesthesia,” they added. “In severe oral mucositis–associated pain, clinicians may elect to use a stronger pain medication as a first-line treatment. Optional pain management approaches include patient-controlled analgesics, topical morphine, and fentanyl transdermal patch or nasal spray.”
Dr. Elad and Dr. Yarom said that future oral mucositis studies should evaluate treatments head-to-head and against placebo, with a watchful eye for severe, adverse events, which can occur even with local treatments, because of damaged mucosal barriers that allow for systemic absorption. They also pointed out that emerging technologies such as proton-beam radiotherapy should minimize rates of mucositis. However, “until these advances are routinely used,” they wrote, “the search for an effective, safe therapy for oral mucositis and its associated pain needs to continue.”
Dr. Elad reported relationships with Falk Pharma and the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology. Dr. Yarom reported no conflicts.
Dr. Elad is a professor of dentistry and a professor of oncology at the University of Rochester (N.Y.) Medical Center. Dr. Yarom is a senior lecturer of oral medicine and the program director of the postgraduate oral medicine in the department of oral pathology and oral medicine at Tel Aviv University, as well as the director of the oral medicine clinic at Sheba Medical Center in Tel HaShomer, Israel.
Oral mucositis is a common and serious complication of cancer, but quality research and reliable treatments for the condition are lacking, according to Sharon Elad, DMD, of the University of Rochester (N.Y.) Medical Center and Noam Yarom, DMD, of Tel Aviv University.
“Despite the strengths of the randomized clinical trial (RCT) design in general, some studies evaluating therapies for oral mucositis have been underpowered, are of low quality, or have yielded conflicting results about the benefits of the interventions,” Dr. Elad and Dr. Yarom wrote in a JAMA editorial.
“These issues highlight the need for well-designed RCTs that test interventions for oral mucositis appropriately.”
In this context, the doctors reviewed the simultaneously published study by Sio et al., in which patients were given either of two topical therapies for oral mucositis: diphenhydramine/lidocaine/antacid mouthwash or doxepin mouthwash. Both interventions led to statistically significant improvements in pain, compared with placebo; however, these improvements were not clinically significant, according to the investigators’ predetermined threshold.
“The distinction between statistical significance and clinical importance is relevant in this study,” Dr. Elad and Dr. Yarom wrote, “and the findings suggest that pain relief was short-term and limited among many of the patients. Nevertheless, this limited effect may be beneficial if doxepin is used as a supplemental analgesic (eg, to reduce the dose of systemic opioids).”
“The severity of oral pain in oral mucositis may exceed the beneficial effect of local anesthesia,” they added. “In severe oral mucositis–associated pain, clinicians may elect to use a stronger pain medication as a first-line treatment. Optional pain management approaches include patient-controlled analgesics, topical morphine, and fentanyl transdermal patch or nasal spray.”
Dr. Elad and Dr. Yarom said that future oral mucositis studies should evaluate treatments head-to-head and against placebo, with a watchful eye for severe, adverse events, which can occur even with local treatments, because of damaged mucosal barriers that allow for systemic absorption. They also pointed out that emerging technologies such as proton-beam radiotherapy should minimize rates of mucositis. However, “until these advances are routinely used,” they wrote, “the search for an effective, safe therapy for oral mucositis and its associated pain needs to continue.”
Dr. Elad reported relationships with Falk Pharma and the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology. Dr. Yarom reported no conflicts.
Dr. Elad is a professor of dentistry and a professor of oncology at the University of Rochester (N.Y.) Medical Center. Dr. Yarom is a senior lecturer of oral medicine and the program director of the postgraduate oral medicine in the department of oral pathology and oral medicine at Tel Aviv University, as well as the director of the oral medicine clinic at Sheba Medical Center in Tel HaShomer, Israel.
Doxepin mouthwash and diphenhydramine/lidocaine/antacid (DLA) mouthwash can offer 4 hours of pain relief for cancer patients with oral mucositis, according to investigators.
Although these agents led to statistical improvements in pain, neither met predetermined clinical efficacy thresholds, reported lead author Terence T. Sio, MD, of the Mayo Clinic Hospital in Phoenix and his colleagues, who suggested that more safety and efficacy research is needed.
“Few pharmacological agents or interventions have been shown to effectively reduce the severity of radiotherapy-related oral mucositis and its associated pain,” the investigators wrote in JAMA.
They noted that this knowledge gap affects everyday practice since “more than 80% of patients develop oral mucositis during radiotherapy, and mouthwashes and systemic analgesic agents are frequently used to treat the condition.”
Small studies have shown that doxepin, a tricyclic antidepressant, could be an effective agent for oral mucositis, while a variety of DLA mouthwashes are commonly prescribed, despite a dearth of relevant Cochrane reviews or randomized placebo-controlled trials.
This background led to the present study, which included 275 patients who had developed oral mucositis while undergoing head and neck radiotherapy for cancer. The patients were randomized evenly into three mouthwash groups: placebo (2.5 mL Ora-Sweet SF oral solution and 2.5 mL of water), doxepin (25 mg in 5 mL solution), or diphenhydramine (12.5 mg in 5 mL alcohol-free solution), lidocaine (2% viscous solution), and antacid (20 mg of simethicone, 200 mg of magnesium hydroxide, and 200 mg of aluminum hydroxide in 355 mL solution). The study was divided into two cycles; in the first, patients used their assigned mouthwash once, whereas in the second cycle, which was optional, patients used their assigned treatment every 4 hours for up to 7 days.
The primary endpoint was oral mucositis pain. Multiple secondary endpoints were assessed, including patient preference for continued therapy and various adverse effects, such as drowsiness and taste. Responses were assessed using a combination of the Oral Mucositis Daily Questionnaire and the Oral Mucositis Weekly Questionnaire–Head and Neck Cancer. This modified questionnaire was conducted prior to treatment, then after treatment at 5, 15, 30, 60, 120, and 240 minutes. Pain improvements were compared by area under the curve after adjustment for baseline score. Clinical improvement was defined as a 3.5 point difference in pain score, compared with placebo.
Data analysis showed that pain in the first 4 hours decreased the most in the DLA group (11.7 points), slightly less in the doxepin group (11.6 points), and least in the placebo group (8.7 points). Compared with placebo, both treatments offered statistical improvements. DLA patients responded the most (3.0 points; P = .004), while, again, the average doxepin response was similar, albeit with a slightly higher P value. (2.9 points; P = .02). The investigators discouraged direct comparisons between the two agents because the study was not designed for this purpose.
Neither intervention met the predetermined 3.5-point threshold for clinical improvement, although the investigators suggested that some patients may have had meaningful responses.
“There is some suggestion in post hoc analyses that the findings may have been clinically relevant for some patients,” the investigators wrote, noting that responder analysis favored treatment with DLA versus placebo, but not doxepin versus placebo. “However,” they noted, “the overall clinical importance of the statistically significant primary findings remains uncertain.”
Compared with placebo, doxepin mouthwash was associated with stinging or burning, unpleasant taste, drowsiness, and fatigue. Of note, fatigue only occurred in the doxepin group, at a rate of 6%. Both treatment groups had a maximum grade 3 adverse event rate of 4%, while the placebo arm had an adverse event rate of 2%.
“Further research is needed to assess longer-term efficacy and safety for both mouthwashes,” the investigators concluded.
The study was funded by the National Cancer Institute and the Mayo Clinic Symptom Intervention Program. One investigator reported a nonfinancial support from CutisPharma. The other investigators declared no conflicts of interest.
SOURCE: Sio TT et al. JAMA. 2019 Apr 16. doi: 10.1001/jama.2019.3504.
Doxepin mouthwash and diphenhydramine/lidocaine/antacid (DLA) mouthwash can offer 4 hours of pain relief for cancer patients with oral mucositis, according to investigators.
Although these agents led to statistical improvements in pain, neither met predetermined clinical efficacy thresholds, reported lead author Terence T. Sio, MD, of the Mayo Clinic Hospital in Phoenix and his colleagues, who suggested that more safety and efficacy research is needed.
“Few pharmacological agents or interventions have been shown to effectively reduce the severity of radiotherapy-related oral mucositis and its associated pain,” the investigators wrote in JAMA.
They noted that this knowledge gap affects everyday practice since “more than 80% of patients develop oral mucositis during radiotherapy, and mouthwashes and systemic analgesic agents are frequently used to treat the condition.”
Small studies have shown that doxepin, a tricyclic antidepressant, could be an effective agent for oral mucositis, while a variety of DLA mouthwashes are commonly prescribed, despite a dearth of relevant Cochrane reviews or randomized placebo-controlled trials.
This background led to the present study, which included 275 patients who had developed oral mucositis while undergoing head and neck radiotherapy for cancer. The patients were randomized evenly into three mouthwash groups: placebo (2.5 mL Ora-Sweet SF oral solution and 2.5 mL of water), doxepin (25 mg in 5 mL solution), or diphenhydramine (12.5 mg in 5 mL alcohol-free solution), lidocaine (2% viscous solution), and antacid (20 mg of simethicone, 200 mg of magnesium hydroxide, and 200 mg of aluminum hydroxide in 355 mL solution). The study was divided into two cycles; in the first, patients used their assigned mouthwash once, whereas in the second cycle, which was optional, patients used their assigned treatment every 4 hours for up to 7 days.
The primary endpoint was oral mucositis pain. Multiple secondary endpoints were assessed, including patient preference for continued therapy and various adverse effects, such as drowsiness and taste. Responses were assessed using a combination of the Oral Mucositis Daily Questionnaire and the Oral Mucositis Weekly Questionnaire–Head and Neck Cancer. This modified questionnaire was conducted prior to treatment, then after treatment at 5, 15, 30, 60, 120, and 240 minutes. Pain improvements were compared by area under the curve after adjustment for baseline score. Clinical improvement was defined as a 3.5 point difference in pain score, compared with placebo.
Data analysis showed that pain in the first 4 hours decreased the most in the DLA group (11.7 points), slightly less in the doxepin group (11.6 points), and least in the placebo group (8.7 points). Compared with placebo, both treatments offered statistical improvements. DLA patients responded the most (3.0 points; P = .004), while, again, the average doxepin response was similar, albeit with a slightly higher P value. (2.9 points; P = .02). The investigators discouraged direct comparisons between the two agents because the study was not designed for this purpose.
Neither intervention met the predetermined 3.5-point threshold for clinical improvement, although the investigators suggested that some patients may have had meaningful responses.
“There is some suggestion in post hoc analyses that the findings may have been clinically relevant for some patients,” the investigators wrote, noting that responder analysis favored treatment with DLA versus placebo, but not doxepin versus placebo. “However,” they noted, “the overall clinical importance of the statistically significant primary findings remains uncertain.”
Compared with placebo, doxepin mouthwash was associated with stinging or burning, unpleasant taste, drowsiness, and fatigue. Of note, fatigue only occurred in the doxepin group, at a rate of 6%. Both treatment groups had a maximum grade 3 adverse event rate of 4%, while the placebo arm had an adverse event rate of 2%.
“Further research is needed to assess longer-term efficacy and safety for both mouthwashes,” the investigators concluded.
The study was funded by the National Cancer Institute and the Mayo Clinic Symptom Intervention Program. One investigator reported a nonfinancial support from CutisPharma. The other investigators declared no conflicts of interest.
SOURCE: Sio TT et al. JAMA. 2019 Apr 16. doi: 10.1001/jama.2019.3504.
FROM JAMA
C3 inhibitor shows potential in PNH and AIHA
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
GLASGOW – APL-2, a complement factor 3 (C3) inhibitor, may be a future treatment option for paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA), according to investigators from two separate studies.
Early results from the phase 1b PADDOCK trial for PNH and the phase 2 PLAUDIT trial for AIHA showed that APL-2 significantly increased hemoglobin levels, with additional improvements reported in lactate dehydrogenase (LDH), absolute reticulocyte count, and bilirubin. The findings were presented at the annual meeting of the British Society for Haematology.
By blocking C3, APL-2 acts further upstream than approved C5 inhibitors eculizumab and ravulizumab, thereby controlling extravascular hemolysis in addition to intravascular hemolysis. This broader level of control is needed for some patients, the investigators said, such as those with PNH who have inadequate responses to C5 inhibition.
PNH
“Even in PNH patients treated with eculizumab, up to 70% may have suboptimal hemoglobin responses and about 30% may still require blood transfusions,” said lead author of the PADDOCK trial, Raymond Wong, MD, of the Prince of Wales Hospital in Hong Kong.
PNH patients included in the open-label, dose-escalation PADDOCK study had greater than 10% white blood cell clones, LDH that was at least twice the upper limit of normal, at least one transfusion within the past year, a platelet count below 30,000/mm3, and an absolute neutrophil count greater than 500 x 109/L.
Dr. Wong described experiences with a cohort of 20 patients who received 270 mg APL-2 subcutaneously daily for at least 28 days, with the option to continue treatment for up to 2 years thereafter, if desired.
From these 20 patients, 2 patients completed the initial 28-day period but did not elect to continue and 2 patients withdrew because of adverse events (ovarian cancer and severe aplastic anemia), leaving 16 patients in the present analysis. Before treatment, these individuals were transfusion dependent, with an average transfusion rate of 8.7 transfusions per year.
Results showed that mean hemoglobin increased from 8.0 g/dL at baseline to 10.8 g/dL at day 29 and 12.2 g/dL at day 85. LDH dropped 900%, from 2,416 U/L (9 times the upper limit of normal) to 271 U/L (0.9 times the upper limit of normal). Absolute reticulocyte count and bilirubin also normalized.
Overall, these improvements led to a meaningful clinical impact, Dr. Wong said, with fatigue scores improving and most patients becoming transfusion independent on maintenance therapy, with the exception of one patient who developed severe aplastic anemia after 1 year. No significant infections or thromboses occurred.
When asked where APL-2 might fit in with current treatment paradigm, Dr. Wong said that multiple applications for PNH are being investigated, including first-line therapy and after failure of eculizumab.
AIHA
Results from the phase 2 PLAUDIT trial, presented by Bruno Fattizzo, MD, of the University of Milan, offered a glimpse at APL-2 in a different setting: AIHA.
Eligibility required hemoglobin levels of less than 11 g/dL, signs of hemolysis, and positive direct antiglobulin test for IgG and/or complement C3.
Dr. Fattizzo discussed results from five patients with cold agglutinin disease and five patients with C3-positive warm AIHA who had received 56 days of therapy.
Among the five patients with cold agglutinin disease, mean hemoglobin increased from 8.7 g/dL to 12.1 g/dL, while patients with warm C3-positive AIHA had a mean increase from 9.3 g/dL to 11.3 g/dL. As with the PNH study, absolute reticulocyte count, LDH, and indirect bilirubin normalized across all 10 patients.
“Some of the patients included in the trial have already reached more than 48 weeks, something like 64 weeks in the study, and they are still doing well,” Dr. Fattizzo said. “So it really seems that those who are do respond really keep the response with ongoing treatment.”
Nine out of 12 patients with cold agglutinin disease (75%) and 8 out of 9 patients (89%) with warm AIHA experienced adverse events, although these were mostly grade 1 or 2 and deemed unrelated to APL-2 by the investigators.
Five grade 3 adverse events in six patients included oral squamous carcinoma, hemolytic flare, pneumonia, purpura, and acute kidney injury. Five grade 4 adverse events in two patients included high calcium, high creatinine, hypoxia, and hemolytic flare, causing these two patients to withdraw from the study. No grade 3 or 4 adverse events were considered related to APL-2.
“APL-2 appears to be well tolerated and safe,” Dr. Fattizzo said, adding that a phase 3 trial for cold agglutinin disease and C3-positive warm AIHA C3+ is planned.
Both studies are sponsored by Apellis Pharmaceuticals. Dr. Wong and his colleagues reported financial relationships with Alexion Pharmaceuticals, Apellis, Celgene, Janssen, and other companies. Dr. Fattizzo reported having no conflicts of interest.
REPORTING FROM BSH 2019
First-line afatinib responses encouraging across diverse population of EGFR TKI-naive patients
GENEVA – For EGFR TKI-naive patients with EGFR-positive non–small cell lung cancer (NSCLC), afatinib appears safe and effective in a “real-world” setting, based on results of a phase 3b study.
Across a diverse population of patients, including those with brain metastases, uncommon mutations, multiple lines of prior therapy, and/or an Eastern Cooperative Oncology Group (ECOG) performance status of 2, afatinib delivered “encouraging” responses, reported lead author Antonio Passaro, MD, PhD, of the European Institute of Oncology in Milan. During his presentation at the European Lung Cancer Conference, Dr. Passaro described the safety profile as “predictable and manageable.”
The findings follow on the heels of the LUX-Lung trials, which showed that afatinib could match the progression-free survival (PFS) achieved with gefitinib, at about 11 months, while beating chemotherapy, which was associated with a PFS of approximately 5-7 months.
“However,” the investigators noted in their abstract, “in real-world practice chemotherapy remains a first-line choice.”
The present study aimed to demonstrate the real-world potential of afatinib across treatment lines, Dr. Passaro said at the meeting, presented by the European Society for Medical Oncology.
The patient population was diverse, with multiple treatment lines represented. The majority of patients (78%) received afatinib as first-line treatment, while smaller groups received the treatment as second-line (17%), or third-line or greater (5%). About one-third of the patients (36%) had an ECOG score of 0, about half (57%) had a score of 1, and a small group (8%) had a score of 2. A minority of patients had brain metastases (17%) and/or uncommon mutations (13%). Patients received 40 mg of afatinib daily; dose reduction to 20 mg was allowed if necessary.
Analysis showed that patients received afatinib for a median of almost 1 year (359 days). Slightly more than half of the patients (54%) got reduced doses because of adverse events, most commonly, diarrhea (25%) and rash (11%). About one out of five patients (22%) discontinued treatment entirely.
Secondarily, the investigators analyzed efficacy, reporting that the objective response rate was 46% and the disease control rate was 86%. During his presentation, Dr. Passaro focused on median time to symptomatic progression (TTSP) and median progression-free survival (PFS), describing these outcomes in relation to patient subgroups. Across all patients, TTSP was 14.9 months and PFS was 13.4 months. Among subgroups, patients receiving afatinib as first-line therapy had the best median PFS, at 13.8 months, which was comparable with those who received the treatment second-line (13.2 months). In contrast, patients receiving afatinib as a third-line treatment or later had noticeably shorter PFS, at 6.6 months. Baseline ECOG performance status showed a similar trend; patients with scores of 0 had a median PFS of 15.4 months, compared with 12.9 months for those with a score of 1, and 6.2 months with a score of 2. Patients with brain metastases fared worse than did those without (PFS 10.1 months vs. 13.9 months), and patients with uncommon mutations had shorter PFS than that of those with common mutations (6.0 months vs. 14.1 months). TTSP durations paralleled the above PFS trends.Boehringer Ingelheim funded the study. The investigators reported financial relationships with Roche, MSD, Bristol-Myers Squibb, AstraZeneca, and others.
SOURCE: Passaro et al. ELCC 2019. Abstract 115O.
GENEVA – For EGFR TKI-naive patients with EGFR-positive non–small cell lung cancer (NSCLC), afatinib appears safe and effective in a “real-world” setting, based on results of a phase 3b study.
Across a diverse population of patients, including those with brain metastases, uncommon mutations, multiple lines of prior therapy, and/or an Eastern Cooperative Oncology Group (ECOG) performance status of 2, afatinib delivered “encouraging” responses, reported lead author Antonio Passaro, MD, PhD, of the European Institute of Oncology in Milan. During his presentation at the European Lung Cancer Conference, Dr. Passaro described the safety profile as “predictable and manageable.”
The findings follow on the heels of the LUX-Lung trials, which showed that afatinib could match the progression-free survival (PFS) achieved with gefitinib, at about 11 months, while beating chemotherapy, which was associated with a PFS of approximately 5-7 months.
“However,” the investigators noted in their abstract, “in real-world practice chemotherapy remains a first-line choice.”
The present study aimed to demonstrate the real-world potential of afatinib across treatment lines, Dr. Passaro said at the meeting, presented by the European Society for Medical Oncology.
The patient population was diverse, with multiple treatment lines represented. The majority of patients (78%) received afatinib as first-line treatment, while smaller groups received the treatment as second-line (17%), or third-line or greater (5%). About one-third of the patients (36%) had an ECOG score of 0, about half (57%) had a score of 1, and a small group (8%) had a score of 2. A minority of patients had brain metastases (17%) and/or uncommon mutations (13%). Patients received 40 mg of afatinib daily; dose reduction to 20 mg was allowed if necessary.
Analysis showed that patients received afatinib for a median of almost 1 year (359 days). Slightly more than half of the patients (54%) got reduced doses because of adverse events, most commonly, diarrhea (25%) and rash (11%). About one out of five patients (22%) discontinued treatment entirely.
Secondarily, the investigators analyzed efficacy, reporting that the objective response rate was 46% and the disease control rate was 86%. During his presentation, Dr. Passaro focused on median time to symptomatic progression (TTSP) and median progression-free survival (PFS), describing these outcomes in relation to patient subgroups. Across all patients, TTSP was 14.9 months and PFS was 13.4 months. Among subgroups, patients receiving afatinib as first-line therapy had the best median PFS, at 13.8 months, which was comparable with those who received the treatment second-line (13.2 months). In contrast, patients receiving afatinib as a third-line treatment or later had noticeably shorter PFS, at 6.6 months. Baseline ECOG performance status showed a similar trend; patients with scores of 0 had a median PFS of 15.4 months, compared with 12.9 months for those with a score of 1, and 6.2 months with a score of 2. Patients with brain metastases fared worse than did those without (PFS 10.1 months vs. 13.9 months), and patients with uncommon mutations had shorter PFS than that of those with common mutations (6.0 months vs. 14.1 months). TTSP durations paralleled the above PFS trends.Boehringer Ingelheim funded the study. The investigators reported financial relationships with Roche, MSD, Bristol-Myers Squibb, AstraZeneca, and others.
SOURCE: Passaro et al. ELCC 2019. Abstract 115O.
GENEVA – For EGFR TKI-naive patients with EGFR-positive non–small cell lung cancer (NSCLC), afatinib appears safe and effective in a “real-world” setting, based on results of a phase 3b study.
Across a diverse population of patients, including those with brain metastases, uncommon mutations, multiple lines of prior therapy, and/or an Eastern Cooperative Oncology Group (ECOG) performance status of 2, afatinib delivered “encouraging” responses, reported lead author Antonio Passaro, MD, PhD, of the European Institute of Oncology in Milan. During his presentation at the European Lung Cancer Conference, Dr. Passaro described the safety profile as “predictable and manageable.”
The findings follow on the heels of the LUX-Lung trials, which showed that afatinib could match the progression-free survival (PFS) achieved with gefitinib, at about 11 months, while beating chemotherapy, which was associated with a PFS of approximately 5-7 months.
“However,” the investigators noted in their abstract, “in real-world practice chemotherapy remains a first-line choice.”
The present study aimed to demonstrate the real-world potential of afatinib across treatment lines, Dr. Passaro said at the meeting, presented by the European Society for Medical Oncology.
The patient population was diverse, with multiple treatment lines represented. The majority of patients (78%) received afatinib as first-line treatment, while smaller groups received the treatment as second-line (17%), or third-line or greater (5%). About one-third of the patients (36%) had an ECOG score of 0, about half (57%) had a score of 1, and a small group (8%) had a score of 2. A minority of patients had brain metastases (17%) and/or uncommon mutations (13%). Patients received 40 mg of afatinib daily; dose reduction to 20 mg was allowed if necessary.
Analysis showed that patients received afatinib for a median of almost 1 year (359 days). Slightly more than half of the patients (54%) got reduced doses because of adverse events, most commonly, diarrhea (25%) and rash (11%). About one out of five patients (22%) discontinued treatment entirely.
Secondarily, the investigators analyzed efficacy, reporting that the objective response rate was 46% and the disease control rate was 86%. During his presentation, Dr. Passaro focused on median time to symptomatic progression (TTSP) and median progression-free survival (PFS), describing these outcomes in relation to patient subgroups. Across all patients, TTSP was 14.9 months and PFS was 13.4 months. Among subgroups, patients receiving afatinib as first-line therapy had the best median PFS, at 13.8 months, which was comparable with those who received the treatment second-line (13.2 months). In contrast, patients receiving afatinib as a third-line treatment or later had noticeably shorter PFS, at 6.6 months. Baseline ECOG performance status showed a similar trend; patients with scores of 0 had a median PFS of 15.4 months, compared with 12.9 months for those with a score of 1, and 6.2 months with a score of 2. Patients with brain metastases fared worse than did those without (PFS 10.1 months vs. 13.9 months), and patients with uncommon mutations had shorter PFS than that of those with common mutations (6.0 months vs. 14.1 months). TTSP durations paralleled the above PFS trends.Boehringer Ingelheim funded the study. The investigators reported financial relationships with Roche, MSD, Bristol-Myers Squibb, AstraZeneca, and others.
SOURCE: Passaro et al. ELCC 2019. Abstract 115O.
REPORTING FROM ELCC 2019
Liquid biopsy falls short for isolated brain lesions in lung cancer
GENEVA – Liquid biopsy appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression, according to investigators.
Plasma circulating tumor DNA (ctDNA) analysis detected molecular abnormalities in almost all patients with systemic disease progression, compared with just two out of five patients with isolated brain lesions, reported lead author Mihaela Aldea, MD, who presented findings at the European Lung Cancer Conference.
Dr. Aldea, of Gustave Roussy Institute in Villejuif, France, said that “central nervous system progression is an example of hard-to-biopsy disease and is common in oncogene addicted non–small cell lung cancer, making it a potential setting to employ ctDNA analysis.” However, Dr. Aldea noted that the blood-brain barrier limits passage of molecules such as ctDNA into systemic circulation, leading to hypothetical skepticism within the medical community, despite “very limited” data.
“Currently, the actual performance of ctDNA in patients with lung cancer and isolated CNS progression remains largely unknown,” Dr. Aldea said, “so this is the question that we put in our study.”
Dr. Aldea and her colleagues screened 959 patients with NSCLC who were involved in prospective trials at Gustave Roussy between 2016 and 2018. Study inclusion required that patients have a molecular alteration detected via tissue sample and at least 1 ctDNA sample available from the time of CNS progression. Molecular alterations included ALK, EGFR, KRAS, ROS1, HER2, BRAF, TP53, and MET. Through these criteria, the study population was narrowed to 58 patients and 66 ctDNA samples, of which 21 were from patients with isolated CNS (I-CNS) progression and 45 were from patients with systemic disease progression (S-CNS). CtDNA was conducted with next generation sequencing and compared with imaging, molecular, and clinical patient data.
Most patients in the I-CNS group were female (94%), compared with about half of the S-CNS group (59%). Rates of adenocarcinoma and smoking history were relatively similar between I-CNS and S-CNS patients; in contrast, S-CNS patients had a median of two metastatic sites, compared with one in the I-CNS group. Rates of ALK, KRAS, and EGFR aberrations were slightly higher in the I-CNS group, whereas HER2, TP53, MET, and BRAF abnormalities were found only in the S-CNS group. Relating to the central hypothesis, 98% of S-CNS patients tested positive for at least one actionable driver via ctDNA analysis, compared with just 38% of I-CNS patients (P less than .0001). Resistance mutations were detected more commonly in the S-CNS group, although not significantly, which Dr. Aldea attributed to small population size.
“Plasma liquid biopsy is not a reliable marker for analyzing the molecular landscape of CNS progression,” Dr. Aldea concluded, adding that patients with isolated brain lesions may need to be treated with “more potent drugs” even when resistance mutations are not detected.
The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.
SOURCE: Aldea et al. ELCC 2019. Abstract 110O.
GENEVA – Liquid biopsy appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression, according to investigators.
Plasma circulating tumor DNA (ctDNA) analysis detected molecular abnormalities in almost all patients with systemic disease progression, compared with just two out of five patients with isolated brain lesions, reported lead author Mihaela Aldea, MD, who presented findings at the European Lung Cancer Conference.
Dr. Aldea, of Gustave Roussy Institute in Villejuif, France, said that “central nervous system progression is an example of hard-to-biopsy disease and is common in oncogene addicted non–small cell lung cancer, making it a potential setting to employ ctDNA analysis.” However, Dr. Aldea noted that the blood-brain barrier limits passage of molecules such as ctDNA into systemic circulation, leading to hypothetical skepticism within the medical community, despite “very limited” data.
“Currently, the actual performance of ctDNA in patients with lung cancer and isolated CNS progression remains largely unknown,” Dr. Aldea said, “so this is the question that we put in our study.”
Dr. Aldea and her colleagues screened 959 patients with NSCLC who were involved in prospective trials at Gustave Roussy between 2016 and 2018. Study inclusion required that patients have a molecular alteration detected via tissue sample and at least 1 ctDNA sample available from the time of CNS progression. Molecular alterations included ALK, EGFR, KRAS, ROS1, HER2, BRAF, TP53, and MET. Through these criteria, the study population was narrowed to 58 patients and 66 ctDNA samples, of which 21 were from patients with isolated CNS (I-CNS) progression and 45 were from patients with systemic disease progression (S-CNS). CtDNA was conducted with next generation sequencing and compared with imaging, molecular, and clinical patient data.
Most patients in the I-CNS group were female (94%), compared with about half of the S-CNS group (59%). Rates of adenocarcinoma and smoking history were relatively similar between I-CNS and S-CNS patients; in contrast, S-CNS patients had a median of two metastatic sites, compared with one in the I-CNS group. Rates of ALK, KRAS, and EGFR aberrations were slightly higher in the I-CNS group, whereas HER2, TP53, MET, and BRAF abnormalities were found only in the S-CNS group. Relating to the central hypothesis, 98% of S-CNS patients tested positive for at least one actionable driver via ctDNA analysis, compared with just 38% of I-CNS patients (P less than .0001). Resistance mutations were detected more commonly in the S-CNS group, although not significantly, which Dr. Aldea attributed to small population size.
“Plasma liquid biopsy is not a reliable marker for analyzing the molecular landscape of CNS progression,” Dr. Aldea concluded, adding that patients with isolated brain lesions may need to be treated with “more potent drugs” even when resistance mutations are not detected.
The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.
SOURCE: Aldea et al. ELCC 2019. Abstract 110O.
GENEVA – Liquid biopsy appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression, according to investigators.
Plasma circulating tumor DNA (ctDNA) analysis detected molecular abnormalities in almost all patients with systemic disease progression, compared with just two out of five patients with isolated brain lesions, reported lead author Mihaela Aldea, MD, who presented findings at the European Lung Cancer Conference.
Dr. Aldea, of Gustave Roussy Institute in Villejuif, France, said that “central nervous system progression is an example of hard-to-biopsy disease and is common in oncogene addicted non–small cell lung cancer, making it a potential setting to employ ctDNA analysis.” However, Dr. Aldea noted that the blood-brain barrier limits passage of molecules such as ctDNA into systemic circulation, leading to hypothetical skepticism within the medical community, despite “very limited” data.
“Currently, the actual performance of ctDNA in patients with lung cancer and isolated CNS progression remains largely unknown,” Dr. Aldea said, “so this is the question that we put in our study.”
Dr. Aldea and her colleagues screened 959 patients with NSCLC who were involved in prospective trials at Gustave Roussy between 2016 and 2018. Study inclusion required that patients have a molecular alteration detected via tissue sample and at least 1 ctDNA sample available from the time of CNS progression. Molecular alterations included ALK, EGFR, KRAS, ROS1, HER2, BRAF, TP53, and MET. Through these criteria, the study population was narrowed to 58 patients and 66 ctDNA samples, of which 21 were from patients with isolated CNS (I-CNS) progression and 45 were from patients with systemic disease progression (S-CNS). CtDNA was conducted with next generation sequencing and compared with imaging, molecular, and clinical patient data.
Most patients in the I-CNS group were female (94%), compared with about half of the S-CNS group (59%). Rates of adenocarcinoma and smoking history were relatively similar between I-CNS and S-CNS patients; in contrast, S-CNS patients had a median of two metastatic sites, compared with one in the I-CNS group. Rates of ALK, KRAS, and EGFR aberrations were slightly higher in the I-CNS group, whereas HER2, TP53, MET, and BRAF abnormalities were found only in the S-CNS group. Relating to the central hypothesis, 98% of S-CNS patients tested positive for at least one actionable driver via ctDNA analysis, compared with just 38% of I-CNS patients (P less than .0001). Resistance mutations were detected more commonly in the S-CNS group, although not significantly, which Dr. Aldea attributed to small population size.
“Plasma liquid biopsy is not a reliable marker for analyzing the molecular landscape of CNS progression,” Dr. Aldea concluded, adding that patients with isolated brain lesions may need to be treated with “more potent drugs” even when resistance mutations are not detected.
The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.
SOURCE: Aldea et al. ELCC 2019. Abstract 110O.
REPORTING FROM ELCC 2019
Key clinical point: Plasma circulating tumor DNA (ctDNA) analysis appears inadequate to detect molecular aberrations in patients with non–small cell lung cancer (NSCLC) who have isolated central nervous system (CNS) progression.
Major finding: In patients with at least 1 known NSCLC molecular alteration, ctDNA analysis was positive in 38% of those with isolated CNS disease, compared with 98% of those with systemic disease progression (P less than .0001).
Study details: A retrospective analysis of 66 patients with NSCLC, drawn from a screened population of 959 patients.
Disclosures: The investigators disclosed financial relationships with Celgene, Daiichi Sankyo, Eli Lilly, and others.
Source: Aldea et al. ELCC 2019. Abstract 110O.
Afatinib shows safety and efficacy among elderly
GENEVA – Afatinib appears safe and effective for elderly patients with EGFR-positive non–small cell lung cancer (NSCLC), according to investigators.
A retrospective analysis of the phase 3 GIDEON trial showed similar objective responses, disease control rates, and progression-free survival rates among elderly patients, compared with younger patients, reported lead author Wolfgang M. Brückl, MD, of Universitätsklinik der Paracelsus Medizinischen Privatuniversität in Nürnberg, Germany, and his colleagues. These findings were presented in a poster at the European Lung Cancer Congress.
“Elderly patients are often underrepresented in clinical trials,” the investigators wrote, “which can lead to uncertainties regarding optimal treatment of such patients in routine clinical practice. The GIDEON noninterventional study enrolled a high proportion of patients aged 70 years or older, providing an opportunity to study the real-world use of afatinib in older individuals.”
The GIDEON study involved 160 patients with EGFR-positive NSCLC who were treated at 49 centers in Germany between 2014 and 2016. From this total, 151 patients were available for interim analysis, and 67 patients (44%) were at least 70-years old. Among this elderly group, about one out of five patients (22%) had brain metastases and Eastern Cooperative Oncology Group (ECOG) performance status scores were typically 1 (45%) or 0 (42%).
Compared with younger patients, elderly patients were more likely to receive a lower starting dose of afatinib (62% vs. 83%), which usually entailed a decrease from 40 mg to 30 mg. Thereafter, dose reduction rates were similar between age groups, with 58% of younger patients requiring lower doses and 55% of elderly patients requiring reduced doses. Adverse events were comparable across age groups, although a fraction more of the patients 70 years or older discontinued treatment because of serious adverse drug reactions (12% vs. 7%).
Efficacy results were also comparable between age groups. Overall response rates were slightly higher among elderly patients than younger patients, with a 70-year age threshold (78% vs. 70%); disease control rate was marginally higher among the elderly (93% vs. 89%); and elderly patients had a slightly better 12-month PFS rate (62.2% vs. 49.1%).
“Data from the GIDEON noninterventional study provide important information on the routine clinical use of afatinib in elderly patients,” the investigators concluded.
The study was funded by Boehringer Ingelheim. The investigators did not report conflicts of interest.
SOURCE: Brückl WM et al. ELCC 2019. Abstract 125P.
GENEVA – Afatinib appears safe and effective for elderly patients with EGFR-positive non–small cell lung cancer (NSCLC), according to investigators.
A retrospective analysis of the phase 3 GIDEON trial showed similar objective responses, disease control rates, and progression-free survival rates among elderly patients, compared with younger patients, reported lead author Wolfgang M. Brückl, MD, of Universitätsklinik der Paracelsus Medizinischen Privatuniversität in Nürnberg, Germany, and his colleagues. These findings were presented in a poster at the European Lung Cancer Congress.
“Elderly patients are often underrepresented in clinical trials,” the investigators wrote, “which can lead to uncertainties regarding optimal treatment of such patients in routine clinical practice. The GIDEON noninterventional study enrolled a high proportion of patients aged 70 years or older, providing an opportunity to study the real-world use of afatinib in older individuals.”
The GIDEON study involved 160 patients with EGFR-positive NSCLC who were treated at 49 centers in Germany between 2014 and 2016. From this total, 151 patients were available for interim analysis, and 67 patients (44%) were at least 70-years old. Among this elderly group, about one out of five patients (22%) had brain metastases and Eastern Cooperative Oncology Group (ECOG) performance status scores were typically 1 (45%) or 0 (42%).
Compared with younger patients, elderly patients were more likely to receive a lower starting dose of afatinib (62% vs. 83%), which usually entailed a decrease from 40 mg to 30 mg. Thereafter, dose reduction rates were similar between age groups, with 58% of younger patients requiring lower doses and 55% of elderly patients requiring reduced doses. Adverse events were comparable across age groups, although a fraction more of the patients 70 years or older discontinued treatment because of serious adverse drug reactions (12% vs. 7%).
Efficacy results were also comparable between age groups. Overall response rates were slightly higher among elderly patients than younger patients, with a 70-year age threshold (78% vs. 70%); disease control rate was marginally higher among the elderly (93% vs. 89%); and elderly patients had a slightly better 12-month PFS rate (62.2% vs. 49.1%).
“Data from the GIDEON noninterventional study provide important information on the routine clinical use of afatinib in elderly patients,” the investigators concluded.
The study was funded by Boehringer Ingelheim. The investigators did not report conflicts of interest.
SOURCE: Brückl WM et al. ELCC 2019. Abstract 125P.
GENEVA – Afatinib appears safe and effective for elderly patients with EGFR-positive non–small cell lung cancer (NSCLC), according to investigators.
A retrospective analysis of the phase 3 GIDEON trial showed similar objective responses, disease control rates, and progression-free survival rates among elderly patients, compared with younger patients, reported lead author Wolfgang M. Brückl, MD, of Universitätsklinik der Paracelsus Medizinischen Privatuniversität in Nürnberg, Germany, and his colleagues. These findings were presented in a poster at the European Lung Cancer Congress.
“Elderly patients are often underrepresented in clinical trials,” the investigators wrote, “which can lead to uncertainties regarding optimal treatment of such patients in routine clinical practice. The GIDEON noninterventional study enrolled a high proportion of patients aged 70 years or older, providing an opportunity to study the real-world use of afatinib in older individuals.”
The GIDEON study involved 160 patients with EGFR-positive NSCLC who were treated at 49 centers in Germany between 2014 and 2016. From this total, 151 patients were available for interim analysis, and 67 patients (44%) were at least 70-years old. Among this elderly group, about one out of five patients (22%) had brain metastases and Eastern Cooperative Oncology Group (ECOG) performance status scores were typically 1 (45%) or 0 (42%).
Compared with younger patients, elderly patients were more likely to receive a lower starting dose of afatinib (62% vs. 83%), which usually entailed a decrease from 40 mg to 30 mg. Thereafter, dose reduction rates were similar between age groups, with 58% of younger patients requiring lower doses and 55% of elderly patients requiring reduced doses. Adverse events were comparable across age groups, although a fraction more of the patients 70 years or older discontinued treatment because of serious adverse drug reactions (12% vs. 7%).
Efficacy results were also comparable between age groups. Overall response rates were slightly higher among elderly patients than younger patients, with a 70-year age threshold (78% vs. 70%); disease control rate was marginally higher among the elderly (93% vs. 89%); and elderly patients had a slightly better 12-month PFS rate (62.2% vs. 49.1%).
“Data from the GIDEON noninterventional study provide important information on the routine clinical use of afatinib in elderly patients,” the investigators concluded.
The study was funded by Boehringer Ingelheim. The investigators did not report conflicts of interest.
SOURCE: Brückl WM et al. ELCC 2019. Abstract 125P.
REPORTING FROM ELCC 2019
MicroRNA-375 may be key to fibrolamellar carcinoma
Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.
Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.
“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.
FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.
“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.
Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.
First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.
The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.
Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).
“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.
Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.
Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.
“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.
“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.
SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
For several decades, fibrolamellar carcinoma was the enigmatic liver cancer. Neither etiology nor molecular causes were known. The breakthrough came when tumor sequencing identified a hitherto undescribed fusion gene in 15 out of 15 patients analyzed: A small portion of the heat shock protein DNAJB1 was fused to the catalytic subunit of protein kinase A (PKA, or PRKACA), which retained full kinase activity.
Underscoring the significance of this finding, the DNAJB1-PRKACA fusion gene was shown to be sufficient to elicit tumors similar to human fibrolamellar carcinoma when engineered in mice. The absence of conspicuous codriver genes makes DNAJB1-PRKACA a primary candidate for therapeutic target. However, PKA inhibitors would be problematic in the clinic because of the vital physiological functions of PKA. Consequently, the hunt is on to decipher the oncogenic signaling pathways emanating from DNAJB1-PRKACA with the hope to identify alternative targets among its downstream mediators.
In this work, the Sethupathy lab performed a thorough study on abnormally regulated microRNAs in fibrolamellar carcinoma tumors. Intriguingly, they identified several microRNAs controlled by DNAJB1-PRKACA that have oncogenic or tumor suppressor function in other cancers. In particular, the tumor suppressor microRNA-375 was massively down-regulated by DNAJB1-PRKACA. Furthermore, introducing a microRNA-375 mimic in fibrolamellar cancer cells suppressed proliferation and motility. Important studies like this open up new avenues aiming to manipulate cancer microRNAs as alternative or complementary approaches for targeting DNAJB1-PRKACA signaling in the highly fatal fibrolamellar carcinoma.
Morten Frödin, MSc, PhD, is an associate professor and group leader of the Biotech Research and Innovation Centre, University of Copenhagen.
Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.
Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.
“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.
FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.
“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.
Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.
First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.
The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.
Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).
“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.
Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.
Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.
“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.
“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.
SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.
Up-regulation of microRNA-375 may be a future therapeutic strategy for patients with fibrolamellar carcinoma (FLC), according to investigators.
Analysis of primary FLC tumors showed that microRNA-375 was the most abnormal microRNA, down-regulated 27-fold, reported lead author Timothy A. Dinh, MD, of the University of North Carolina at Chapel Hill and his colleagues. Overexpression of microRNA-375 in an FLC cell line suppressed cell migration and proliferation, hinting at therapeutic potential.
“Overall, our results show that miR-375 [microRNA-375] functions as a tumor suppressor in FLC and points toward future therapies based on miR-375 mimics that may provide a viable option for patients,” the investigators wrote in a Cellular and Molecular Gastroenterology and Hepatology.
FLC is an uncommon liver cancer in adolescents and young adults. Currently, surgery is the only effective treatment; unfortunately, many patients have metastatic disease at the time of diagnosis, disallowing surgical cure.
“The lack of knowledge of underlying disease mechanisms has hindered our understanding of this cancer and the development of novel therapeutics for FLC patients,” the investigators wrote.
Previous research has shown that almost all patients with FLC (80%-100%) have a heterozygous deletion mutation on chromosome 19. However, it is not a loss of genetic information that incites neoplasia; instead, the deletion causes a fusion of genes DNAJB1 and PRKACA. This fusion is capable of triggering liver tumors, a phenomenon confirmed through mouse models. The present study built on these findings, along with recent awareness that several microRNAs are dysregulated in FLC, compared with normal liver tissue.
First, the investigators performed small RNA-sequencing in six primary FLC tumors from The Cancer Genome Atlas (TCGA). They found that 30 microRNAs were up-regulated and 46 microRNAs were down-regulated. Among these, microRNA-375 was the most significantly down-regulated, at 27-fold (P = .009). To confirm these findings, the same process was repeated in 18 independent samples, with the same result.
The investigators explained that, in addition to magnitude of down-regulation, microRNA-375 deserved attention for at least three other reasons: It is down-regulated in numerous cancer types, it directly targets known oncogenes, and it is suppressed by the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling axis, which is overactive in FLC.
Further testing confirmed that microRNA-375 was consistently more down-regulated in samples of FLC, by up to 20-fold, than it was in nonmalignant liver tissue. To confirm that loss of microRNA-375 expression occurred in FLC tumor cells instead of other cell types, such as stromal cells, a patient-derived xenograft of FLC was compared with liver lineage cells, including adult hepatocytes, hepatoblasts, hepatic stem cells, and biliary tree stem cells. Again, microRNA-375 was down-regulated most in the FLC cells. Additional comparisons within the TCGA showed that microRNA-375 was more down-regulated in FLC than 21 out of 22 other tumor types (second only to melanoma).
“Taken together with our findings from primary tumor tissue, our results strongly suggest that miR-375 may function as a tumor suppressor in FLC,” the investigators wrote.
Having confirmed the ubiquity of microRNA-375 down-regulation in FLC, the investigators turned to the relationship between the DNAJB1-PRKACA fusion and microRNA-375. Using two methods – gene deletion with CRISPR/Cas9 and transposon injection – the investigators found that creating the DNAJB1-PRKACA fusion in cells of mice was sufficient to suppress microRNA-375 expression, which supports a downstream relationship.
Finally, the investigators showed that treating an FLC cell line with an microRNA-375 mimic suppressed the Hippo signaling pathway, including connective tissue growth factor (CTGF) and yes-associated protein 1 (YAP1). These events translated to reduced cellular activity, which suggests that up-regulating microRNA-375 could, indeed, control FLC.
“Importantly, introduction of a miR-375 mimic significantly reduced colony formation, EdU incorporation, and migration, indicative of reduced survival, proliferation, and metastatic potential, respectively,” the investigators wrote.
“With RNA-based therapies showing increasing promise, miR-375–based therapies merit future consideration for FLC therapeutics,” they concluded.
The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Alcohol Abuse and Alcoholism, and the Fibrolamellar Cancer Foundation. The investigators declared no conflicts of interest.
SOURCE: Dinh TA et al. Cell Mol Gastroenterol Hepatol. 2019 Feb 11. doi: 10.1016/j.jcmgh.2019.01.008.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY