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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
VIDEO: Shorter oxaliplatin-based therapy suffices for some patients with stage III CRC
CHICAGO – When it comes to oxaliplatin-based therapy for stage III colon cancer patients with low recurrence risk, 3 is preferable to 6 months and may also be preferable in those with higher recurrence risk – particularly if they are receiving oxaliplatin with capecitabine (CAPOX), according to findings from a prospective pooled analysis of data from six phase III trials.
The findings have immediate practice-changing implications, according to Axel Grothey, MD, of the Mayo Clinic Cancer Center, Rochester, Minn.
The preplanned analysis of the concurrently conducted trials (the International Duration Evaluation of Adjuvant chemotherapy [IDEA] collaboration), which included 12,834 patients receiving either oxaliplatin with fluorouracil and folinic acid (FOLFOX) or CAPOX, showed that, at a median follow-up of 39 months, the overall 3-year disease-free survival (DFS) rates differed by only 0.9% between those receiving 3 vs. 6 months of therapy (DFS, 74.6% and 75.5%, respectively). The difference between the groups was not statistically significant (estimated disease-free hazard ratio, 1.07), Dr. Grothey reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.
However, grade 2 or greater neurotoxicity was greatly reduced, occurring in 17% vs. 48% of FOLFOX patients treated for 3 vs. 6 months, respectively, and in 15% vs. 45% of CAPOX patients treated for 3 vs. 6 months, respectively.
When outcomes were analyzed based on risk of recurrence, low-risk patients (those with T1-3 N1 disease) had 3-year disease-free survival rates of 83.1% and 83.3% with 3 vs. 6 months of therapy, and high-risk patients (T4 or N2 disease) had 3-year disease-free survival of 62.7% vs. 64.4% with 3 vs. 6 months of therapy.
When outcomes were analyzed by regimen, the FOLFOX patients (about 60% of the patient population) had 3-year DFS of 73.6% and 76.0% with 3 vs. 6 months of therapy, and the CAPOX patients had 3-year DFS of 75.9% and 74.8%, respectively.
In this video interview, Dr. Grothey discusses the findings, as well as the importance of federal funding for cancer research, which is underscored by the findings.
He also discusses the IDEA Collaboration consensus based on the results, which calls for 3 months of therapy in low-risk patients and for an individualized approach based on tolerability of therapy, patient preference, assessment of recurrence risk, and treatment regimen (CAPOX vs. FOLFOX) in higher-risk patients.
“We now have very important, very solid data to engage patients in discussion [about] how to individualize the duration of therapy,” he said.
Dr. Grothey reported having no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – When it comes to oxaliplatin-based therapy for stage III colon cancer patients with low recurrence risk, 3 is preferable to 6 months and may also be preferable in those with higher recurrence risk – particularly if they are receiving oxaliplatin with capecitabine (CAPOX), according to findings from a prospective pooled analysis of data from six phase III trials.
The findings have immediate practice-changing implications, according to Axel Grothey, MD, of the Mayo Clinic Cancer Center, Rochester, Minn.
The preplanned analysis of the concurrently conducted trials (the International Duration Evaluation of Adjuvant chemotherapy [IDEA] collaboration), which included 12,834 patients receiving either oxaliplatin with fluorouracil and folinic acid (FOLFOX) or CAPOX, showed that, at a median follow-up of 39 months, the overall 3-year disease-free survival (DFS) rates differed by only 0.9% between those receiving 3 vs. 6 months of therapy (DFS, 74.6% and 75.5%, respectively). The difference between the groups was not statistically significant (estimated disease-free hazard ratio, 1.07), Dr. Grothey reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.
However, grade 2 or greater neurotoxicity was greatly reduced, occurring in 17% vs. 48% of FOLFOX patients treated for 3 vs. 6 months, respectively, and in 15% vs. 45% of CAPOX patients treated for 3 vs. 6 months, respectively.
When outcomes were analyzed based on risk of recurrence, low-risk patients (those with T1-3 N1 disease) had 3-year disease-free survival rates of 83.1% and 83.3% with 3 vs. 6 months of therapy, and high-risk patients (T4 or N2 disease) had 3-year disease-free survival of 62.7% vs. 64.4% with 3 vs. 6 months of therapy.
When outcomes were analyzed by regimen, the FOLFOX patients (about 60% of the patient population) had 3-year DFS of 73.6% and 76.0% with 3 vs. 6 months of therapy, and the CAPOX patients had 3-year DFS of 75.9% and 74.8%, respectively.
In this video interview, Dr. Grothey discusses the findings, as well as the importance of federal funding for cancer research, which is underscored by the findings.
He also discusses the IDEA Collaboration consensus based on the results, which calls for 3 months of therapy in low-risk patients and for an individualized approach based on tolerability of therapy, patient preference, assessment of recurrence risk, and treatment regimen (CAPOX vs. FOLFOX) in higher-risk patients.
“We now have very important, very solid data to engage patients in discussion [about] how to individualize the duration of therapy,” he said.
Dr. Grothey reported having no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – When it comes to oxaliplatin-based therapy for stage III colon cancer patients with low recurrence risk, 3 is preferable to 6 months and may also be preferable in those with higher recurrence risk – particularly if they are receiving oxaliplatin with capecitabine (CAPOX), according to findings from a prospective pooled analysis of data from six phase III trials.
The findings have immediate practice-changing implications, according to Axel Grothey, MD, of the Mayo Clinic Cancer Center, Rochester, Minn.
The preplanned analysis of the concurrently conducted trials (the International Duration Evaluation of Adjuvant chemotherapy [IDEA] collaboration), which included 12,834 patients receiving either oxaliplatin with fluorouracil and folinic acid (FOLFOX) or CAPOX, showed that, at a median follow-up of 39 months, the overall 3-year disease-free survival (DFS) rates differed by only 0.9% between those receiving 3 vs. 6 months of therapy (DFS, 74.6% and 75.5%, respectively). The difference between the groups was not statistically significant (estimated disease-free hazard ratio, 1.07), Dr. Grothey reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.
However, grade 2 or greater neurotoxicity was greatly reduced, occurring in 17% vs. 48% of FOLFOX patients treated for 3 vs. 6 months, respectively, and in 15% vs. 45% of CAPOX patients treated for 3 vs. 6 months, respectively.
When outcomes were analyzed based on risk of recurrence, low-risk patients (those with T1-3 N1 disease) had 3-year disease-free survival rates of 83.1% and 83.3% with 3 vs. 6 months of therapy, and high-risk patients (T4 or N2 disease) had 3-year disease-free survival of 62.7% vs. 64.4% with 3 vs. 6 months of therapy.
When outcomes were analyzed by regimen, the FOLFOX patients (about 60% of the patient population) had 3-year DFS of 73.6% and 76.0% with 3 vs. 6 months of therapy, and the CAPOX patients had 3-year DFS of 75.9% and 74.8%, respectively.
In this video interview, Dr. Grothey discusses the findings, as well as the importance of federal funding for cancer research, which is underscored by the findings.
He also discusses the IDEA Collaboration consensus based on the results, which calls for 3 months of therapy in low-risk patients and for an individualized approach based on tolerability of therapy, patient preference, assessment of recurrence risk, and treatment regimen (CAPOX vs. FOLFOX) in higher-risk patients.
“We now have very important, very solid data to engage patients in discussion [about] how to individualize the duration of therapy,” he said.
Dr. Grothey reported having no relevant disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
VIDEO: Pertuzumab prolongs disease-free survival in HER2+ early breast cancer
CHICAGO –
At a median follow-up of 45.4 months, invasive disease-free survival (IDFS) events occurred in 171 of 2,400 patients (7.1%) who received pertuzumab, compared with 210 of 2,405 patients (8.7%) who received placebo (hazard ratio, 0.81). This 19% reduction in risk of an IDFS event was statistically significant, Gunter von Minckwitz, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The estimated IDFS rate at 3 years was 94.1% in the pertuzumab arm, and 93.2% in the placebo arm, said Dr. von Minckwitz of the German Breast Group, Neu-Isenburg.
Study subjects were patients with adequately excised HER2-positive, pT1-3 early breast cancer. Patients were randomized to receive adjuvant chemotherapy plus 1 year of either trastuzumab plus pertuzumab, or trastuzumab plus placebo.
In a video interview, Dr. von Minckwitz discusses the study results, including outcomes in node-positive vs. node-negative patients, early overall survival findings, and safety.
“We are using pertuzumab right now in many countries for the neoadjuvant setting,” he said, explaining that existing approvals were granted conditionally in the absence of evidence regarding long-term benefits. “With the APHINITY study ... use of pertuzumab either in the neoadjuvant setting or in the higher-risk adjuvant setting is something that is supported now with evidence.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO –
At a median follow-up of 45.4 months, invasive disease-free survival (IDFS) events occurred in 171 of 2,400 patients (7.1%) who received pertuzumab, compared with 210 of 2,405 patients (8.7%) who received placebo (hazard ratio, 0.81). This 19% reduction in risk of an IDFS event was statistically significant, Gunter von Minckwitz, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The estimated IDFS rate at 3 years was 94.1% in the pertuzumab arm, and 93.2% in the placebo arm, said Dr. von Minckwitz of the German Breast Group, Neu-Isenburg.
Study subjects were patients with adequately excised HER2-positive, pT1-3 early breast cancer. Patients were randomized to receive adjuvant chemotherapy plus 1 year of either trastuzumab plus pertuzumab, or trastuzumab plus placebo.
In a video interview, Dr. von Minckwitz discusses the study results, including outcomes in node-positive vs. node-negative patients, early overall survival findings, and safety.
“We are using pertuzumab right now in many countries for the neoadjuvant setting,” he said, explaining that existing approvals were granted conditionally in the absence of evidence regarding long-term benefits. “With the APHINITY study ... use of pertuzumab either in the neoadjuvant setting or in the higher-risk adjuvant setting is something that is supported now with evidence.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO –
At a median follow-up of 45.4 months, invasive disease-free survival (IDFS) events occurred in 171 of 2,400 patients (7.1%) who received pertuzumab, compared with 210 of 2,405 patients (8.7%) who received placebo (hazard ratio, 0.81). This 19% reduction in risk of an IDFS event was statistically significant, Gunter von Minckwitz, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.
The estimated IDFS rate at 3 years was 94.1% in the pertuzumab arm, and 93.2% in the placebo arm, said Dr. von Minckwitz of the German Breast Group, Neu-Isenburg.
Study subjects were patients with adequately excised HER2-positive, pT1-3 early breast cancer. Patients were randomized to receive adjuvant chemotherapy plus 1 year of either trastuzumab plus pertuzumab, or trastuzumab plus placebo.
In a video interview, Dr. von Minckwitz discusses the study results, including outcomes in node-positive vs. node-negative patients, early overall survival findings, and safety.
“We are using pertuzumab right now in many countries for the neoadjuvant setting,” he said, explaining that existing approvals were granted conditionally in the absence of evidence regarding long-term benefits. “With the APHINITY study ... use of pertuzumab either in the neoadjuvant setting or in the higher-risk adjuvant setting is something that is supported now with evidence.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASCO 2017
VIDEO: Survival improves when cancer patients self-report symptoms
CHICAGO – Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial.
The median overall survival among 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the intervention arm was more than 5 months longer – a nearly 20% increase – than in 325 patients who received standard care (31.2 vs. 26 months), Ethan Basch, MD, reported at the annual meeting of the American Society of Clinical Oncology.
Additionally, 31% of patients in the intervention arm had better quality of life/physical functioning, compared with those in the control arm, and 7% fewer patients in the intervention arm visited an emergency room during the course of the study. The duration of potentially life-prolonging chemotherapy was increased by an average of 2 months in the intervention arm, he said.
The findings were simultaneously published online in a research letter in JAMA (2017 Jun 4. doi: 10.1001/jama.2017.7156).
Symptoms such as nausea, pain, and fatigue are common among patients with metastatic cancer, Dr. Basch said. “Unfortunately, they often go undetected by doctors and nurses until they become severe and physically debilitating,” he added, explaining that patients are often hesitant to call the office to report symptoms between visits.
Even at office visits, competing topics can interfere with communication about symptoms, he noted.
He and his colleagues hypothesized that self-reporting of patient symptoms between visits or prior to a visit while in the clinic waiting area would prompt earlier intervention and improve symptom control and outcomes.
Study subjects were patients at Memorial Sloan Kettering Cancer Center who had advanced solid genitourinary, gynecologic, breast, or lung tumors and who were receiving outpatient chemotherapy. Those assigned to the intervention group used tablet computers and an online web survey system to report on 12 symptoms commonly experienced during chemotherapy. The system triggers an alert to a nurse when a severe or worsening symptom is reported. Patients in the usual care group discussed symptoms during office visits and were encouraged to call the office between visits if they experienced concerning symptoms.
Patients remained on the study until discontinuation of all cancer treatment, hospice, or death.
One possible explanation for the findings is that this self-reporting approach prompts clinicians to manage symptoms before they cause serious downstream complications, Dr. Basch said.
The approach may also keep patients more physically functional, which is known from prior studies to have a strong association with better survival, and the approach may also improve management of chemotherapy side effects, enabling longer duration of beneficial cancer treatment, he said, explaining that, “in oncology, we often are limited in our ability to give life-prolonging treatment because people don’t tolerate it well.”
“This approach should be considered for inclusion in standard symptoms management as a component of high quality cancer care,” he concluded, noting that efforts are underway to test the next generation of systems to improve communication between patients and care teams and to figure out how best to integrate these tools into oncology practice.
The system used in the this study was designed for research, but a number of companies have tools currently available for patient-reported outcomes, and others are being developed, Dr. Basch said, noting that a National Cancer Institute questionnaire – the PRO-CTCAE – is publicly available and could be loaded into patients’ electronic health records for this purpose as well.
ASCO’s chief medical officer, Richard L. Schilsky, MD, said the findings demonstrate that “these frequent touches between the patient and their health care providers obviously can make a huge difference in their outcomes.”
Additionally, ASCO expert Harold J. Burstein, MD, of Dana-Farber Cancer Institute, Boston, said this “exciting and compelling study” validates the feeling among many clinicians that patient-focused, team-based care can improve outcomes in a meaningful way for patients. In a video interview, he further discusses the challenges with implementing a system like this and particularly with obtaining funding to support implementation.
“If this was a drug, if it was iPad-olizumab, it would be worth tens, if not hundreds of thousands, of dollars per year to have something that improved overall survival. We don’t have those same kinds of dollars to help implement these into our electronic health records or our systems. We need to find ways to support that and make it happen,” he said.
This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr. Basch and Dr. Burstein each reported having no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial.
The median overall survival among 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the intervention arm was more than 5 months longer – a nearly 20% increase – than in 325 patients who received standard care (31.2 vs. 26 months), Ethan Basch, MD, reported at the annual meeting of the American Society of Clinical Oncology.
Additionally, 31% of patients in the intervention arm had better quality of life/physical functioning, compared with those in the control arm, and 7% fewer patients in the intervention arm visited an emergency room during the course of the study. The duration of potentially life-prolonging chemotherapy was increased by an average of 2 months in the intervention arm, he said.
The findings were simultaneously published online in a research letter in JAMA (2017 Jun 4. doi: 10.1001/jama.2017.7156).
Symptoms such as nausea, pain, and fatigue are common among patients with metastatic cancer, Dr. Basch said. “Unfortunately, they often go undetected by doctors and nurses until they become severe and physically debilitating,” he added, explaining that patients are often hesitant to call the office to report symptoms between visits.
Even at office visits, competing topics can interfere with communication about symptoms, he noted.
He and his colleagues hypothesized that self-reporting of patient symptoms between visits or prior to a visit while in the clinic waiting area would prompt earlier intervention and improve symptom control and outcomes.
Study subjects were patients at Memorial Sloan Kettering Cancer Center who had advanced solid genitourinary, gynecologic, breast, or lung tumors and who were receiving outpatient chemotherapy. Those assigned to the intervention group used tablet computers and an online web survey system to report on 12 symptoms commonly experienced during chemotherapy. The system triggers an alert to a nurse when a severe or worsening symptom is reported. Patients in the usual care group discussed symptoms during office visits and were encouraged to call the office between visits if they experienced concerning symptoms.
Patients remained on the study until discontinuation of all cancer treatment, hospice, or death.
One possible explanation for the findings is that this self-reporting approach prompts clinicians to manage symptoms before they cause serious downstream complications, Dr. Basch said.
The approach may also keep patients more physically functional, which is known from prior studies to have a strong association with better survival, and the approach may also improve management of chemotherapy side effects, enabling longer duration of beneficial cancer treatment, he said, explaining that, “in oncology, we often are limited in our ability to give life-prolonging treatment because people don’t tolerate it well.”
“This approach should be considered for inclusion in standard symptoms management as a component of high quality cancer care,” he concluded, noting that efforts are underway to test the next generation of systems to improve communication between patients and care teams and to figure out how best to integrate these tools into oncology practice.
The system used in the this study was designed for research, but a number of companies have tools currently available for patient-reported outcomes, and others are being developed, Dr. Basch said, noting that a National Cancer Institute questionnaire – the PRO-CTCAE – is publicly available and could be loaded into patients’ electronic health records for this purpose as well.
ASCO’s chief medical officer, Richard L. Schilsky, MD, said the findings demonstrate that “these frequent touches between the patient and their health care providers obviously can make a huge difference in their outcomes.”
Additionally, ASCO expert Harold J. Burstein, MD, of Dana-Farber Cancer Institute, Boston, said this “exciting and compelling study” validates the feeling among many clinicians that patient-focused, team-based care can improve outcomes in a meaningful way for patients. In a video interview, he further discusses the challenges with implementing a system like this and particularly with obtaining funding to support implementation.
“If this was a drug, if it was iPad-olizumab, it would be worth tens, if not hundreds of thousands, of dollars per year to have something that improved overall survival. We don’t have those same kinds of dollars to help implement these into our electronic health records or our systems. We need to find ways to support that and make it happen,” he said.
This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr. Basch and Dr. Burstein each reported having no disclosures.
CHICAGO – Patients with metastatic cancer who self-reported symptoms during routine cancer treatment experienced a number of benefits, including a statistically significant improvement in overall survival, according to findings from a randomized, controlled clinical trial.
The median overall survival among 441 patients receiving treatment for metastatic breast, lung, genitourinary, or gynecologic cancer who were randomized to the intervention arm was more than 5 months longer – a nearly 20% increase – than in 325 patients who received standard care (31.2 vs. 26 months), Ethan Basch, MD, reported at the annual meeting of the American Society of Clinical Oncology.
Additionally, 31% of patients in the intervention arm had better quality of life/physical functioning, compared with those in the control arm, and 7% fewer patients in the intervention arm visited an emergency room during the course of the study. The duration of potentially life-prolonging chemotherapy was increased by an average of 2 months in the intervention arm, he said.
The findings were simultaneously published online in a research letter in JAMA (2017 Jun 4. doi: 10.1001/jama.2017.7156).
Symptoms such as nausea, pain, and fatigue are common among patients with metastatic cancer, Dr. Basch said. “Unfortunately, they often go undetected by doctors and nurses until they become severe and physically debilitating,” he added, explaining that patients are often hesitant to call the office to report symptoms between visits.
Even at office visits, competing topics can interfere with communication about symptoms, he noted.
He and his colleagues hypothesized that self-reporting of patient symptoms between visits or prior to a visit while in the clinic waiting area would prompt earlier intervention and improve symptom control and outcomes.
Study subjects were patients at Memorial Sloan Kettering Cancer Center who had advanced solid genitourinary, gynecologic, breast, or lung tumors and who were receiving outpatient chemotherapy. Those assigned to the intervention group used tablet computers and an online web survey system to report on 12 symptoms commonly experienced during chemotherapy. The system triggers an alert to a nurse when a severe or worsening symptom is reported. Patients in the usual care group discussed symptoms during office visits and were encouraged to call the office between visits if they experienced concerning symptoms.
Patients remained on the study until discontinuation of all cancer treatment, hospice, or death.
One possible explanation for the findings is that this self-reporting approach prompts clinicians to manage symptoms before they cause serious downstream complications, Dr. Basch said.
The approach may also keep patients more physically functional, which is known from prior studies to have a strong association with better survival, and the approach may also improve management of chemotherapy side effects, enabling longer duration of beneficial cancer treatment, he said, explaining that, “in oncology, we often are limited in our ability to give life-prolonging treatment because people don’t tolerate it well.”
“This approach should be considered for inclusion in standard symptoms management as a component of high quality cancer care,” he concluded, noting that efforts are underway to test the next generation of systems to improve communication between patients and care teams and to figure out how best to integrate these tools into oncology practice.
The system used in the this study was designed for research, but a number of companies have tools currently available for patient-reported outcomes, and others are being developed, Dr. Basch said, noting that a National Cancer Institute questionnaire – the PRO-CTCAE – is publicly available and could be loaded into patients’ electronic health records for this purpose as well.
ASCO’s chief medical officer, Richard L. Schilsky, MD, said the findings demonstrate that “these frequent touches between the patient and their health care providers obviously can make a huge difference in their outcomes.”
Additionally, ASCO expert Harold J. Burstein, MD, of Dana-Farber Cancer Institute, Boston, said this “exciting and compelling study” validates the feeling among many clinicians that patient-focused, team-based care can improve outcomes in a meaningful way for patients. In a video interview, he further discusses the challenges with implementing a system like this and particularly with obtaining funding to support implementation.
“If this was a drug, if it was iPad-olizumab, it would be worth tens, if not hundreds of thousands, of dollars per year to have something that improved overall survival. We don’t have those same kinds of dollars to help implement these into our electronic health records or our systems. We need to find ways to support that and make it happen,” he said.
This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr. Basch and Dr. Burstein each reported having no disclosures.
AT THE 2017 ASCO ANNUAL MEETING
Key clinical point:
Major finding: Median overall survival was 31.2, vs. 26 months, with self-reporting of symptoms, vs. usual care.
Data source: A randomized controlled clinical trial of 766 patients.
Disclosures: This study was supported by the National Institutes of Health and the Conquer Cancer Foundation of the American Society of Clinical Oncology. Dr. Basch and Dr. Burstein each reported having no disclosures.
NOTCH1 mutation predicts reduced ofatumumab efficacy in CLL
NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.
Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).
The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.
The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.
Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.
“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.
In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.
However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.
CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.
Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).
Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.
With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).
This effect was not explained by CD20 expression levels, Dr. Tausch said.
The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.
“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.
Dr. Tausch reported receiving research support from Novartis.
NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.
Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).
The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.
The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.
Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.
“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.
In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.
However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.
CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.
Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).
Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.
With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).
This effect was not explained by CD20 expression levels, Dr. Tausch said.
The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.
“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.
Dr. Tausch reported receiving research support from Novartis.
NEW YORK – NOTCH1 gene mutation appears to predict reduced efficacy of ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia, according to an analysis of patient DNA samples and data from the phase III COMPLEMENT 2 trial.
Recurrent mutations in NOTCH1, TP53, and SF3B1 are common in CLL and have been associated with adverse outcomes in previous studies; NOTCH1 mutation, in particular, was associated with poor outcome when rituximab was added to standard chemotherapy, indicating that the mutation is a predictive factor in the context of chemoimmunotherapy, Eugen Tausch, MD, of the University of Ulm, Germany, said at the annual International Workshop on Chronic Lymphocytic Leukemia.
The incidence and clinical impact of all three mutations were evaluated in relapsed/refractory CLL patients who were part of the COMPLEMENT 2 trial, which compared fludarabine and cyclophosphamide (FC) with FC+ofatumumab (FCO).
The mutation analysis of 325 available patient samples (out of 365) identified 221 mutations in 142 patients: 56 NOTCH1, 96 TP53, and 69 SF3B1 mutations, Dr. Tausch said.
The current study cohort was representative of the full COMPLEMENT 2 analysis set, he noted.
Additional TP53 mutations were found in 20 of 61 TP53 mutation patients, whereas only 4 of 64 SF3B1 mutation patients and 3 of 53 NOTCH1 mutation patients had additional mutations in SF3B1 and NOTCH1, respectively. TP53 mutation was associated with del(17p), and NOTCH1 mutation with +12q and elevated b2MG.
“We did not find associations with IGHV, gender, age, Binet stage, ECOG performance state, B symptoms, or WBC,” Dr. Tausch said.
In terms of outcomes as associated with the mutations, patients with TP53 mutation or SF3B1 mutation had a significantly worse overall response to treatment (overall response rate 67.8% vs. 84.4% for TP53 mutated vs. wild type, and 71.9% vs. 83.75% SF3B1 mutated vs. wild type, respectively). The findings were similar when looking at the treatment arms separately, he noted.
However, as in the full analysis set, progression-free survival among the subset of patients included in the current analysis was better in those who received FCO than in those who received FC (28.1 months vs. 18.1 months; hazard ratio, 0.67). TP53 mutation was an adverse prognostic factor overall in the current analysis (HR, 1.93), as well as in each treatment arm (HR for the FC arm, 2.14, and for the FCO arm, 1.81). TP53 mutation also was associated with decreased overall survival (HR, 2.11). Neither SF3B1 mutation nor NOTCH1 mutation were associated with differences in progression-free or overall survival, Dr. Tausch said.
CD20 expression on cell surface as measured using flow cytometry did not differ in wild-type vs. mutated patients, he said.
Multivariate analysis showed that independent prognostic factors for progression-free survival included FCO therapy (HR, 0.66), del(17p) (HR, 4.47), unmutated IGHV (HR, 2.17), and TP53 mutation (HR, 1.80), and independent prognostic factors for overall survival included del(17p) (HR, 5.02), unmutated IGHV (HR, 1.85), and TP53 mutation (HR, 1.68).
Adding ofatumumab to chemotherapy was beneficial, irrespective of TP53 mutation (HR, 0.52 for TP53 mutation, and HR, 0.68 for TP53 wild type), which confirms the prognostic value of TP53 mutation, he said.
With respect to NOTCH1, ofatumumab was beneficial in patients with NOTCH1 wild type but not in patients with NOTCH1 mutation (HR, 0.64 and 0.86, respectively).
This effect was not explained by CD20 expression levels, Dr. Tausch said.
The findings of this analysis suggest that NOTCH1 mutation is an independent predictive factor for reduced efficacy of ofatumumab, he said.
“Therefore, patients with a NOTCH1 mutation may be considered for chemotherapy without type1 CD20 antibodies or a treatment with novel compounds,” he concluded.
Dr. Tausch reported receiving research support from Novartis.
AT iwCLL MEETING
Key clinical point:
Major finding: Ofatumumab was beneficial in patients with NOTCH1 wild-type, but not in patients with NOTCH1 mutation (hazard ratios, 0.64 and 0.86, respectively).
Data source: A mutation analysis of 325 DNA samples from patients in the phase III COMPLEMENT 2 trial.
Disclosures: Dr. Tausch reported receiving research support from Novartis.
VIDEO: Abiraterone improves survival in high-risk prostate cancer
CHICAGO – Adding abiraterone acetate plus prednisone to androgen deprivation therapy in hormone-naive high-risk prostate cancer patients significantly improves overall survival, according to “practice-changing” results from the phase III LATITUDE trial and the multiarm, multistage STAMPEDE trial.
In the double-blind, randomized, placebo-controlled LATITUDE trial, 597 patients with newly diagnosed high-risk metastatic prostate cancer who received 1,000 mg of abiraterone acetate daily plus 5 mg of prednisone daily in addition to androgen deprivation therapy experienced a 38% reduction in the risk of death and a 53% reduction in the risk of radiographic progression or death at a median follow-up of 30.4 months, compared with 602 such patients who received placebo and androgen deprivation, Karim Fizazi, MD, PhD, of the Institut Gustave Roussy, Villejuif, France, reported at the annual meeting of the American Society of Clinical Oncology.
Significant improvements also were seen in the treatment vs. placebo group for all secondary endpoints, including time to prostate-specific-antigen progression (hazard ratio, 0.30), time to pain progression (HR, 0.70), time to next symptomatic skeletal event (HR, 0.70), time to chemotherapy (HR, 0.44), and time to subsequent prostate cancer therapy (HR, 0.42), Dr. Fizazi said.
He discussed the findings, including side effects, and ongoing and future studies, in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Based on these findings, I believe that using abiraterone up front, together with androgen deprivation therapy, will become the next standard of care for these men,” he said.
Similarly, in the STAMPEDE trial, abiraterone acetate plus prednisone was associated with significantly improved overall survival in 960 high-risk prostate cancer patients starting hormone therapy, compared with 957 such patients receiving placebo and standard-of-care hormone therapy, according to Nicholas D. James, BSc MBBS, PhD, of the Institute of Cancer and Genomic Sciences, University of Birmingham, England.
“Overall, we’ve got about a 30% improvement in survival times for the upfront use of abiraterone. For our metastatic patients, we haven’t reached the median survival yet for the abiraterone patients, but it’s around 3.5 years median survival in the control arm, and we’re projecting that’s going to go up to 6.5 or 7 years in the abiraterone patients,” he said in a video interview, adding that he and his colleagues think this will be one of the biggest survival gains ever reported in adults in such a setting.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. James also discussed findings with respect to secondary endpoints, including a 70% improvement in failure-free survival in the treatment vs. placebo group – an improvement that he called an “absolutely spectacularly big gain” – and skeletal-related events, which decreased by 55% in the treatment group.
Both investigators discussed ongoing and recently completed studies that could shed additional light on the use of abiraterone in prostate cancer patients, including plans to look at the effects of giving both abiraterone and docetaxel together.
“My prediction will be that we will be giving both treatments in due course,” Dr. James said, adding, “I think these findings will certainly be practice changing.”
CHICAGO – Adding abiraterone acetate plus prednisone to androgen deprivation therapy in hormone-naive high-risk prostate cancer patients significantly improves overall survival, according to “practice-changing” results from the phase III LATITUDE trial and the multiarm, multistage STAMPEDE trial.
In the double-blind, randomized, placebo-controlled LATITUDE trial, 597 patients with newly diagnosed high-risk metastatic prostate cancer who received 1,000 mg of abiraterone acetate daily plus 5 mg of prednisone daily in addition to androgen deprivation therapy experienced a 38% reduction in the risk of death and a 53% reduction in the risk of radiographic progression or death at a median follow-up of 30.4 months, compared with 602 such patients who received placebo and androgen deprivation, Karim Fizazi, MD, PhD, of the Institut Gustave Roussy, Villejuif, France, reported at the annual meeting of the American Society of Clinical Oncology.
Significant improvements also were seen in the treatment vs. placebo group for all secondary endpoints, including time to prostate-specific-antigen progression (hazard ratio, 0.30), time to pain progression (HR, 0.70), time to next symptomatic skeletal event (HR, 0.70), time to chemotherapy (HR, 0.44), and time to subsequent prostate cancer therapy (HR, 0.42), Dr. Fizazi said.
He discussed the findings, including side effects, and ongoing and future studies, in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Based on these findings, I believe that using abiraterone up front, together with androgen deprivation therapy, will become the next standard of care for these men,” he said.
Similarly, in the STAMPEDE trial, abiraterone acetate plus prednisone was associated with significantly improved overall survival in 960 high-risk prostate cancer patients starting hormone therapy, compared with 957 such patients receiving placebo and standard-of-care hormone therapy, according to Nicholas D. James, BSc MBBS, PhD, of the Institute of Cancer and Genomic Sciences, University of Birmingham, England.
“Overall, we’ve got about a 30% improvement in survival times for the upfront use of abiraterone. For our metastatic patients, we haven’t reached the median survival yet for the abiraterone patients, but it’s around 3.5 years median survival in the control arm, and we’re projecting that’s going to go up to 6.5 or 7 years in the abiraterone patients,” he said in a video interview, adding that he and his colleagues think this will be one of the biggest survival gains ever reported in adults in such a setting.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. James also discussed findings with respect to secondary endpoints, including a 70% improvement in failure-free survival in the treatment vs. placebo group – an improvement that he called an “absolutely spectacularly big gain” – and skeletal-related events, which decreased by 55% in the treatment group.
Both investigators discussed ongoing and recently completed studies that could shed additional light on the use of abiraterone in prostate cancer patients, including plans to look at the effects of giving both abiraterone and docetaxel together.
“My prediction will be that we will be giving both treatments in due course,” Dr. James said, adding, “I think these findings will certainly be practice changing.”
CHICAGO – Adding abiraterone acetate plus prednisone to androgen deprivation therapy in hormone-naive high-risk prostate cancer patients significantly improves overall survival, according to “practice-changing” results from the phase III LATITUDE trial and the multiarm, multistage STAMPEDE trial.
In the double-blind, randomized, placebo-controlled LATITUDE trial, 597 patients with newly diagnosed high-risk metastatic prostate cancer who received 1,000 mg of abiraterone acetate daily plus 5 mg of prednisone daily in addition to androgen deprivation therapy experienced a 38% reduction in the risk of death and a 53% reduction in the risk of radiographic progression or death at a median follow-up of 30.4 months, compared with 602 such patients who received placebo and androgen deprivation, Karim Fizazi, MD, PhD, of the Institut Gustave Roussy, Villejuif, France, reported at the annual meeting of the American Society of Clinical Oncology.
Significant improvements also were seen in the treatment vs. placebo group for all secondary endpoints, including time to prostate-specific-antigen progression (hazard ratio, 0.30), time to pain progression (HR, 0.70), time to next symptomatic skeletal event (HR, 0.70), time to chemotherapy (HR, 0.44), and time to subsequent prostate cancer therapy (HR, 0.42), Dr. Fizazi said.
He discussed the findings, including side effects, and ongoing and future studies, in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
“Based on these findings, I believe that using abiraterone up front, together with androgen deprivation therapy, will become the next standard of care for these men,” he said.
Similarly, in the STAMPEDE trial, abiraterone acetate plus prednisone was associated with significantly improved overall survival in 960 high-risk prostate cancer patients starting hormone therapy, compared with 957 such patients receiving placebo and standard-of-care hormone therapy, according to Nicholas D. James, BSc MBBS, PhD, of the Institute of Cancer and Genomic Sciences, University of Birmingham, England.
“Overall, we’ve got about a 30% improvement in survival times for the upfront use of abiraterone. For our metastatic patients, we haven’t reached the median survival yet for the abiraterone patients, but it’s around 3.5 years median survival in the control arm, and we’re projecting that’s going to go up to 6.5 or 7 years in the abiraterone patients,” he said in a video interview, adding that he and his colleagues think this will be one of the biggest survival gains ever reported in adults in such a setting.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Dr. James also discussed findings with respect to secondary endpoints, including a 70% improvement in failure-free survival in the treatment vs. placebo group – an improvement that he called an “absolutely spectacularly big gain” – and skeletal-related events, which decreased by 55% in the treatment group.
Both investigators discussed ongoing and recently completed studies that could shed additional light on the use of abiraterone in prostate cancer patients, including plans to look at the effects of giving both abiraterone and docetaxel together.
“My prediction will be that we will be giving both treatments in due course,” Dr. James said, adding, “I think these findings will certainly be practice changing.”
AT ASCO 2017
FDA advisory committee supports neratinib approval
of adults with early-stage HER2-positive breast cancer who received prior adjuvant trastuzumab-based therapy.
Members voting during the May 24 meeting expressed concern about the broadness of the indication proposed by the drug’s maker, Puma Biotechnology, but the majority said the risk-benefit profile of the drug is sufficient to support approval, particularly given the unmet need for such an agent. Those voting against approval argued that more data are needed to identify subpopulations of patients who would be most likely to benefit from treatment in order to narrow the indication.
“There are some unknowns that concern me. ... I don’t think I would treat as broadly as the indication describes,” he said, adding that it would be very difficult to decide which patients to treat, and it would be nice to have more data that provide predictive biomarkers to help determine who should be treated. “But at the end of the day I think it’s useful to have this as an option for treating patients.”
Lori M. Minasian, MD, also a temporary voting member from the National Institutes of Health, agreed.
“I think the option should be available,” she said, adding that the analysis was thorough. However, she, too, questioned the proposed indication.
“I remain concerned that the indication is far too broad, and ... I think we need greater understanding of which subsets of patients would be most responsive to this therapy,” she said.
Heidi D. Klepin, MD, of Wake Forest University in Winston-Salem, N.C. said she voted “yes” for similar reasons, despite concerns about the lack of data to help narrow the indication.
“I particularly felt it was important to support this indication because I think this is an unmet need, and I think the primary outcome is an important and relevant outcome for our patients, even though what we’re seeing effect-wise may be modest,” she said.
Patricia A. Spears, a breast cancer survivor and patient representative from Raleigh, N.C., however, voted against approval.
“I think it is important to get drugs out to patients, and I think this will benefit a certain subset of patients. I’m just not sure we know which ones yet. What we do is tend to put a lot of patients at risk to benefit just a few. We do that a lot,” she said.
She expressed concern that the treatment would be “tacked on to the end of trastuzumab” in too many cases without concern for whether the patient is likely to benefit.
Another member who voted no, Courtney J. Preusse, who was a consumer representative on the committee, said she struggled with the decision but ultimately decided that the benefit this drug adds beyond what already exists is “just not compelling.”
Neratinib is a kinase inhibitor that irreversibly binds to epidermal growth factor receptors, HER2, and HER4, and results of the phase III ExteNET trial presented to the committee by representatives of the applicant showed a statistically significant invasive disease-free survival benefit with treatment.
The invasive disease-free survival at 2 years in 1,420 patients with early stage HER2-positive breast cancer after adjuvant treatment with trastuzumab who were randomized to receive neratinib was 94.2%, compared with 91.9% in 1,420 who received placebo (stratified hazard ratio 0.66). Follow-up data from patients who reconsented to participate showed similar outcomes from 2 to 5 years post-randomization.
An exploratory subgroup analysis suggested a possible difference in the magnitude of benefit based on hormone receptor status, with a 51% reduction in recurrence risk among HR-positive patients, compared with a 7% reduction in HR-negative patients (hazard ratios, 0.49 and 0.93, respectively).
Some concern was raised regarding multiple amendments to the protocol during the study, but committee members who spoke about this expressed satisfaction with the way these issues were handled in terms of sensitivity analysis.
As for safety, diarrhea was the most frequently reported adverse reaction, occurring in 95% of treated patients. Grade 3 diarrhea occurred in 40% of treated patients. Additional data were presented showing that antidiarrheal prophylaxis was effective. Several patients who spoke during the public hearing portion of the meeting–some of whom had travel expenses paid by the applicant, said they either had no problem with diarrhea or that it was manageable. Nearly all of those who spoke during the open public hearing, including patients and family members, shared emotional stories about their personal battles with breast cancer and urged the committee to support approval of neratinib to expand the options available to patients.
The FDA will now consider the new drug application for neratinib, and although it is not bound by the advisory committee’s recommendation, it usually follows such recommendations.
The advisory committee members reported having no relevant conflicts of interest.
of adults with early-stage HER2-positive breast cancer who received prior adjuvant trastuzumab-based therapy.
Members voting during the May 24 meeting expressed concern about the broadness of the indication proposed by the drug’s maker, Puma Biotechnology, but the majority said the risk-benefit profile of the drug is sufficient to support approval, particularly given the unmet need for such an agent. Those voting against approval argued that more data are needed to identify subpopulations of patients who would be most likely to benefit from treatment in order to narrow the indication.
“There are some unknowns that concern me. ... I don’t think I would treat as broadly as the indication describes,” he said, adding that it would be very difficult to decide which patients to treat, and it would be nice to have more data that provide predictive biomarkers to help determine who should be treated. “But at the end of the day I think it’s useful to have this as an option for treating patients.”
Lori M. Minasian, MD, also a temporary voting member from the National Institutes of Health, agreed.
“I think the option should be available,” she said, adding that the analysis was thorough. However, she, too, questioned the proposed indication.
“I remain concerned that the indication is far too broad, and ... I think we need greater understanding of which subsets of patients would be most responsive to this therapy,” she said.
Heidi D. Klepin, MD, of Wake Forest University in Winston-Salem, N.C. said she voted “yes” for similar reasons, despite concerns about the lack of data to help narrow the indication.
“I particularly felt it was important to support this indication because I think this is an unmet need, and I think the primary outcome is an important and relevant outcome for our patients, even though what we’re seeing effect-wise may be modest,” she said.
Patricia A. Spears, a breast cancer survivor and patient representative from Raleigh, N.C., however, voted against approval.
“I think it is important to get drugs out to patients, and I think this will benefit a certain subset of patients. I’m just not sure we know which ones yet. What we do is tend to put a lot of patients at risk to benefit just a few. We do that a lot,” she said.
She expressed concern that the treatment would be “tacked on to the end of trastuzumab” in too many cases without concern for whether the patient is likely to benefit.
Another member who voted no, Courtney J. Preusse, who was a consumer representative on the committee, said she struggled with the decision but ultimately decided that the benefit this drug adds beyond what already exists is “just not compelling.”
Neratinib is a kinase inhibitor that irreversibly binds to epidermal growth factor receptors, HER2, and HER4, and results of the phase III ExteNET trial presented to the committee by representatives of the applicant showed a statistically significant invasive disease-free survival benefit with treatment.
The invasive disease-free survival at 2 years in 1,420 patients with early stage HER2-positive breast cancer after adjuvant treatment with trastuzumab who were randomized to receive neratinib was 94.2%, compared with 91.9% in 1,420 who received placebo (stratified hazard ratio 0.66). Follow-up data from patients who reconsented to participate showed similar outcomes from 2 to 5 years post-randomization.
An exploratory subgroup analysis suggested a possible difference in the magnitude of benefit based on hormone receptor status, with a 51% reduction in recurrence risk among HR-positive patients, compared with a 7% reduction in HR-negative patients (hazard ratios, 0.49 and 0.93, respectively).
Some concern was raised regarding multiple amendments to the protocol during the study, but committee members who spoke about this expressed satisfaction with the way these issues were handled in terms of sensitivity analysis.
As for safety, diarrhea was the most frequently reported adverse reaction, occurring in 95% of treated patients. Grade 3 diarrhea occurred in 40% of treated patients. Additional data were presented showing that antidiarrheal prophylaxis was effective. Several patients who spoke during the public hearing portion of the meeting–some of whom had travel expenses paid by the applicant, said they either had no problem with diarrhea or that it was manageable. Nearly all of those who spoke during the open public hearing, including patients and family members, shared emotional stories about their personal battles with breast cancer and urged the committee to support approval of neratinib to expand the options available to patients.
The FDA will now consider the new drug application for neratinib, and although it is not bound by the advisory committee’s recommendation, it usually follows such recommendations.
The advisory committee members reported having no relevant conflicts of interest.
of adults with early-stage HER2-positive breast cancer who received prior adjuvant trastuzumab-based therapy.
Members voting during the May 24 meeting expressed concern about the broadness of the indication proposed by the drug’s maker, Puma Biotechnology, but the majority said the risk-benefit profile of the drug is sufficient to support approval, particularly given the unmet need for such an agent. Those voting against approval argued that more data are needed to identify subpopulations of patients who would be most likely to benefit from treatment in order to narrow the indication.
“There are some unknowns that concern me. ... I don’t think I would treat as broadly as the indication describes,” he said, adding that it would be very difficult to decide which patients to treat, and it would be nice to have more data that provide predictive biomarkers to help determine who should be treated. “But at the end of the day I think it’s useful to have this as an option for treating patients.”
Lori M. Minasian, MD, also a temporary voting member from the National Institutes of Health, agreed.
“I think the option should be available,” she said, adding that the analysis was thorough. However, she, too, questioned the proposed indication.
“I remain concerned that the indication is far too broad, and ... I think we need greater understanding of which subsets of patients would be most responsive to this therapy,” she said.
Heidi D. Klepin, MD, of Wake Forest University in Winston-Salem, N.C. said she voted “yes” for similar reasons, despite concerns about the lack of data to help narrow the indication.
“I particularly felt it was important to support this indication because I think this is an unmet need, and I think the primary outcome is an important and relevant outcome for our patients, even though what we’re seeing effect-wise may be modest,” she said.
Patricia A. Spears, a breast cancer survivor and patient representative from Raleigh, N.C., however, voted against approval.
“I think it is important to get drugs out to patients, and I think this will benefit a certain subset of patients. I’m just not sure we know which ones yet. What we do is tend to put a lot of patients at risk to benefit just a few. We do that a lot,” she said.
She expressed concern that the treatment would be “tacked on to the end of trastuzumab” in too many cases without concern for whether the patient is likely to benefit.
Another member who voted no, Courtney J. Preusse, who was a consumer representative on the committee, said she struggled with the decision but ultimately decided that the benefit this drug adds beyond what already exists is “just not compelling.”
Neratinib is a kinase inhibitor that irreversibly binds to epidermal growth factor receptors, HER2, and HER4, and results of the phase III ExteNET trial presented to the committee by representatives of the applicant showed a statistically significant invasive disease-free survival benefit with treatment.
The invasive disease-free survival at 2 years in 1,420 patients with early stage HER2-positive breast cancer after adjuvant treatment with trastuzumab who were randomized to receive neratinib was 94.2%, compared with 91.9% in 1,420 who received placebo (stratified hazard ratio 0.66). Follow-up data from patients who reconsented to participate showed similar outcomes from 2 to 5 years post-randomization.
An exploratory subgroup analysis suggested a possible difference in the magnitude of benefit based on hormone receptor status, with a 51% reduction in recurrence risk among HR-positive patients, compared with a 7% reduction in HR-negative patients (hazard ratios, 0.49 and 0.93, respectively).
Some concern was raised regarding multiple amendments to the protocol during the study, but committee members who spoke about this expressed satisfaction with the way these issues were handled in terms of sensitivity analysis.
As for safety, diarrhea was the most frequently reported adverse reaction, occurring in 95% of treated patients. Grade 3 diarrhea occurred in 40% of treated patients. Additional data were presented showing that antidiarrheal prophylaxis was effective. Several patients who spoke during the public hearing portion of the meeting–some of whom had travel expenses paid by the applicant, said they either had no problem with diarrhea or that it was manageable. Nearly all of those who spoke during the open public hearing, including patients and family members, shared emotional stories about their personal battles with breast cancer and urged the committee to support approval of neratinib to expand the options available to patients.
The FDA will now consider the new drug application for neratinib, and although it is not bound by the advisory committee’s recommendation, it usually follows such recommendations.
The advisory committee members reported having no relevant conflicts of interest.
iFCG achieves high MRD-negative remission in untreated CLL
NEW YORK – Three courses of treatment with the novel combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) was well tolerated and associated with a high rate of minimal residual disease (MRD)–negative remission in the bone marrow of favorable-risk, treatment-naive patients with chronic lymphocytic leukemia, based on early results from an ongoing investigator-initiated phase II trial.
Of 29 patients, 24 had completed treatment and been followed for a median of 8.3 months. All 24 had an overall response rate (42% complete response/complete remission with incomplete blood count recovery and 58% partial response), and 83% of patients achieved MRD negativity (100% with complete response and 71% with partial response), Nitin Jain, MD, reported at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
All nine patients who reached the 12-month time point are off therapy and are being monitored, he said.
Patients with IGHV mutations generally have favorable long-term outcomes with 10-year progression-free survival rates greater than 60% after receiving standard first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, ibrutinib is approved for patients with CLL, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was superior to rituximab in the CLL11 trial, Dr. Jain said.
Further, data from the HELIOS trial indicated that combining targeted therapies with chemoimmunotherapy is safe and effective.
iFCG was developed with the intent to limit fludarabine and cyclophosphamide to three courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab, he explained.
Of note, higher pretreatment levels of beta-2 microglobulin were associated with a lower MRD-negativity rate after 3 cycles of iFCG, he said.
In six patients with beta-2 microglobulin of 4 mg/dL or greater, the rate was 50%, compared with 94% in 18 patients with beta-2 microglobulin less than 4 mg/dL.
The patients in the current analysis had a median age of 60 years and adequate organ function. All had IGHV mutation and did not have del(17p) or TP53 mutation. They received three courses of iFCG, including ibrutinib at 420 mg once daily continuously starting at day 1 of course 1 (C1D1); obinutuzumab at 100 mg C1D1, 900 mg C1D2, 1000 mg C1D8, 1000 mg C1D15, 1000 mg C2D1, and 1000 mg C3D1; fludarabine at 25 mg/m2 daily for 3 days each course; and cyclophosphamide at 250mg/m2 daily for 3 days each course.
Per study protocol, all patients receive ibrutinib with obinutuzumab for courses 4-6. Patients meeting the primary endpoint of complete response/complete remission with incomplete blood count recovery and bone marrow MRD negativity received ibrutinib monotherapy for courses 7-12. Those who did not achieve the primary endpoint received six more courses of ibrutinib and obinutuzumab. All patients who are MRD negative at 1 year stop all therapy, including ibrutinib, while those who are MRD positive at 1 year may continue ibrutinib monotherapy until disease progression.
The target bone marrow MRD-negative rate after 3 cycles of iFCG is 45%. The historic C3 bone marrow MRD-negative rate with standard FCR therapy in patients with IGHV mutation is 26%, Dr. Jain said, noting that the rate in the current analysis compared favorably with both.
The treatment thus far has been generally well tolerated. Toxicities included neutropenia (grade 3 and 4 occurring in 9 and 12 patients, respectively), thrombocytopenia (grade 3 and 4 occurring in 12 and 1 patients, respectively), ALT/AST (grade 3 and 4 occurring in 3 and 1 patients respectively), atrial fibrillation (grade 3 occurring in 1 patient), arthralgia (grade 3 occurring in 1 patient), and infusion-related reaction (grade 2 and 3 occurring in 9 patients and 1 patient, respectively).
Infections included herpes zoster, acute cholecystitis, pulmonary mycobacterium avium complex infection, and pneumocystis pneumonia, which occurred in 1 patient each, and neutropenic fever, which occurred in 4 patients.
“Notably, no patient has progressed or died in the study so far,” Dr. Jain said.
The trial continues to enroll patients, with plans for enrolling a total of 45.
Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis Novimmune, and Adaptive Biotechnologies.
NEW YORK – Three courses of treatment with the novel combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) was well tolerated and associated with a high rate of minimal residual disease (MRD)–negative remission in the bone marrow of favorable-risk, treatment-naive patients with chronic lymphocytic leukemia, based on early results from an ongoing investigator-initiated phase II trial.
Of 29 patients, 24 had completed treatment and been followed for a median of 8.3 months. All 24 had an overall response rate (42% complete response/complete remission with incomplete blood count recovery and 58% partial response), and 83% of patients achieved MRD negativity (100% with complete response and 71% with partial response), Nitin Jain, MD, reported at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
All nine patients who reached the 12-month time point are off therapy and are being monitored, he said.
Patients with IGHV mutations generally have favorable long-term outcomes with 10-year progression-free survival rates greater than 60% after receiving standard first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, ibrutinib is approved for patients with CLL, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was superior to rituximab in the CLL11 trial, Dr. Jain said.
Further, data from the HELIOS trial indicated that combining targeted therapies with chemoimmunotherapy is safe and effective.
iFCG was developed with the intent to limit fludarabine and cyclophosphamide to three courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab, he explained.
Of note, higher pretreatment levels of beta-2 microglobulin were associated with a lower MRD-negativity rate after 3 cycles of iFCG, he said.
In six patients with beta-2 microglobulin of 4 mg/dL or greater, the rate was 50%, compared with 94% in 18 patients with beta-2 microglobulin less than 4 mg/dL.
The patients in the current analysis had a median age of 60 years and adequate organ function. All had IGHV mutation and did not have del(17p) or TP53 mutation. They received three courses of iFCG, including ibrutinib at 420 mg once daily continuously starting at day 1 of course 1 (C1D1); obinutuzumab at 100 mg C1D1, 900 mg C1D2, 1000 mg C1D8, 1000 mg C1D15, 1000 mg C2D1, and 1000 mg C3D1; fludarabine at 25 mg/m2 daily for 3 days each course; and cyclophosphamide at 250mg/m2 daily for 3 days each course.
Per study protocol, all patients receive ibrutinib with obinutuzumab for courses 4-6. Patients meeting the primary endpoint of complete response/complete remission with incomplete blood count recovery and bone marrow MRD negativity received ibrutinib monotherapy for courses 7-12. Those who did not achieve the primary endpoint received six more courses of ibrutinib and obinutuzumab. All patients who are MRD negative at 1 year stop all therapy, including ibrutinib, while those who are MRD positive at 1 year may continue ibrutinib monotherapy until disease progression.
The target bone marrow MRD-negative rate after 3 cycles of iFCG is 45%. The historic C3 bone marrow MRD-negative rate with standard FCR therapy in patients with IGHV mutation is 26%, Dr. Jain said, noting that the rate in the current analysis compared favorably with both.
The treatment thus far has been generally well tolerated. Toxicities included neutropenia (grade 3 and 4 occurring in 9 and 12 patients, respectively), thrombocytopenia (grade 3 and 4 occurring in 12 and 1 patients, respectively), ALT/AST (grade 3 and 4 occurring in 3 and 1 patients respectively), atrial fibrillation (grade 3 occurring in 1 patient), arthralgia (grade 3 occurring in 1 patient), and infusion-related reaction (grade 2 and 3 occurring in 9 patients and 1 patient, respectively).
Infections included herpes zoster, acute cholecystitis, pulmonary mycobacterium avium complex infection, and pneumocystis pneumonia, which occurred in 1 patient each, and neutropenic fever, which occurred in 4 patients.
“Notably, no patient has progressed or died in the study so far,” Dr. Jain said.
The trial continues to enroll patients, with plans for enrolling a total of 45.
Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis Novimmune, and Adaptive Biotechnologies.
NEW YORK – Three courses of treatment with the novel combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) was well tolerated and associated with a high rate of minimal residual disease (MRD)–negative remission in the bone marrow of favorable-risk, treatment-naive patients with chronic lymphocytic leukemia, based on early results from an ongoing investigator-initiated phase II trial.
Of 29 patients, 24 had completed treatment and been followed for a median of 8.3 months. All 24 had an overall response rate (42% complete response/complete remission with incomplete blood count recovery and 58% partial response), and 83% of patients achieved MRD negativity (100% with complete response and 71% with partial response), Nitin Jain, MD, reported at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
All nine patients who reached the 12-month time point are off therapy and are being monitored, he said.
Patients with IGHV mutations generally have favorable long-term outcomes with 10-year progression-free survival rates greater than 60% after receiving standard first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, ibrutinib is approved for patients with CLL, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was superior to rituximab in the CLL11 trial, Dr. Jain said.
Further, data from the HELIOS trial indicated that combining targeted therapies with chemoimmunotherapy is safe and effective.
iFCG was developed with the intent to limit fludarabine and cyclophosphamide to three courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab, he explained.
Of note, higher pretreatment levels of beta-2 microglobulin were associated with a lower MRD-negativity rate after 3 cycles of iFCG, he said.
In six patients with beta-2 microglobulin of 4 mg/dL or greater, the rate was 50%, compared with 94% in 18 patients with beta-2 microglobulin less than 4 mg/dL.
The patients in the current analysis had a median age of 60 years and adequate organ function. All had IGHV mutation and did not have del(17p) or TP53 mutation. They received three courses of iFCG, including ibrutinib at 420 mg once daily continuously starting at day 1 of course 1 (C1D1); obinutuzumab at 100 mg C1D1, 900 mg C1D2, 1000 mg C1D8, 1000 mg C1D15, 1000 mg C2D1, and 1000 mg C3D1; fludarabine at 25 mg/m2 daily for 3 days each course; and cyclophosphamide at 250mg/m2 daily for 3 days each course.
Per study protocol, all patients receive ibrutinib with obinutuzumab for courses 4-6. Patients meeting the primary endpoint of complete response/complete remission with incomplete blood count recovery and bone marrow MRD negativity received ibrutinib monotherapy for courses 7-12. Those who did not achieve the primary endpoint received six more courses of ibrutinib and obinutuzumab. All patients who are MRD negative at 1 year stop all therapy, including ibrutinib, while those who are MRD positive at 1 year may continue ibrutinib monotherapy until disease progression.
The target bone marrow MRD-negative rate after 3 cycles of iFCG is 45%. The historic C3 bone marrow MRD-negative rate with standard FCR therapy in patients with IGHV mutation is 26%, Dr. Jain said, noting that the rate in the current analysis compared favorably with both.
The treatment thus far has been generally well tolerated. Toxicities included neutropenia (grade 3 and 4 occurring in 9 and 12 patients, respectively), thrombocytopenia (grade 3 and 4 occurring in 12 and 1 patients, respectively), ALT/AST (grade 3 and 4 occurring in 3 and 1 patients respectively), atrial fibrillation (grade 3 occurring in 1 patient), arthralgia (grade 3 occurring in 1 patient), and infusion-related reaction (grade 2 and 3 occurring in 9 patients and 1 patient, respectively).
Infections included herpes zoster, acute cholecystitis, pulmonary mycobacterium avium complex infection, and pneumocystis pneumonia, which occurred in 1 patient each, and neutropenic fever, which occurred in 4 patients.
“Notably, no patient has progressed or died in the study so far,” Dr. Jain said.
The trial continues to enroll patients, with plans for enrolling a total of 45.
Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis Novimmune, and Adaptive Biotechnologies.
AT THE IWCLL MEETING
Key clinical point:
Major finding: The overall response rate was 100%, and 83% of patients achieved MRD-negativity after three courses.
Data source: 29 patients from an investigator-initiated phase II trial.
Disclosures: Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis, Novimmune, and Adaptive Biotechnologies.
FDA panel backs licensure for epoetin alfa biosimilar
A Food and Drug Administration advisory committee voted overwhelmingly in support of licensure for Epoetin Hospira as a biosimilar product to epoetin alfa (Epogen/Procrit) for all approved Epogen/Procrit indications.
Most committee members who voted “yes” said they were hesitant to do so, however, because of safety concerns, particularly in HIV and oncology patients.
“I voted yes. I came in with concerns about the HIV and oncology patients. However, I do believe ... after hearing the justification, that it meets the [FDA regulatory guideline],” said temporary voting member and patient representative Karen E. Arscott, DO, of the Commonwealth Medical College, Scranton, Penn. “I would like to see extensive follow-up in these two population groups,” she said.
The concerns about HIV and oncology patients are related to the potential for immunogenicity-related events. Some members noted that the study populations were likely too small to detect these rare events.
Scott A. Waldman, MD, of Thomas Jefferson University, Philadelphia, also a temporary member, said he voted “yes” because there was “no substantial difference analytically, biologically, or clinically in what was tested.”
“I think the residual uncertainty of immunogenicity and hypersensitivity and the extrapolation across different patient populations will emerge in postmarketing surveillance. I think that’s when we’ll get the clearest picture of whether there really is any uncertainty in how these drugs perform,” he said.
For one member, however, the concerns were enough for a “no” vote.
“The analytical, clinical, and preclinical data support biosimilarity, and I strongly support approval for indications 1 and 4 based on the clinical data ... but I have residual concerns about lack of data, immunogenicity, basic safety data in patients with HIV and cancer and, for that reason, voted no for the broader indication,” said Thomas S. Uldrick, MD, of the HIV & AIDS Malignancy Branch at the Center for Cancer Research, National Cancer Institute, Bethesda, Md.
Gregory J. Riely, MD, of Memorial Sloan-Kettering Cancer Center in New York expressed similar concerns but said he found the data compelling.
“I understand the concerns around immunogenicity for HIV and cancer patients. I was somewhat reassured by the nonclinical data showing an absence of increased immunogenicity for this biosimilar,” he said.
To support its BLA for Epoetin Hospira, Hospira submitted data from four studies comparing it with the U.S.-licensed Epogen/Procrit and presented an analytical biosimilarity assessment and a nonclinical, clinical pharmacology and clinical biosimilarity assessment. The FDA analysis of the data considered chemistry, manufacturing, and controls, as well as pharmacology/toxicology, immunogenicity, clinical pharmacology, and clinical efficacy and safety.
Sumant Ramachandra, MD, of Pfizer Essential Health noted that the company is not currently seeking an interchangeability designation and that, while this is the first application for a biosimilar product to Amgen’s Epogen/Procrit product, which was approved in 1989, a “highly related epoetin product” from Pfizer (Retacrit) has been available in Europe for 9 years, with more than 363,000 patient years of treatment administered.
The demonstration of biosimilarity in the Epoetin Hospira data presented to the FDA, coupled with well-characterized nature of the reference product, “together support extrapolation across all conditions of use for the reference product,” he said, noting that the data demonstrate that the mechanism of action for both the biosimilar and reference product is the same, and that the immunogenicity profiles are consistent.
The FDA assessment of the data led to a similar conclusion that no clinically significant differences were found between the biosimilar and reference product.
Among other concerns expressed by advisory committee members and/or the public were in regard to the extrapolation of data from patients with chronic kidney disease on hemodialysis to other indications (although this is considered acceptable, according to FDA regulations) and to populations that weren’t studied and about the possibility that Epoetin Hospira would be forced on patients inappropriately, despite the fact that Hospira is not seeking an interchangeability designation. Patients and others speaking on behalf of various patient groups and advocacy organizations called for safeguards against such inappropriate substitution.
Acting committee chair, Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Clinic, Ohio, said he voted “yes” because the product met all regulatory requirements but agreed that the “need for vigilance is exceedingly important not only for this drug but for all drugs in this circumstance.”
The FDA, which usually follows the recommendations of its advisory committees, will now consider the BLA for Epoetin Hospira.
In a statement released after the vote, Diem Nguyen, Pfizer Essential Health global president, Americas, said the committee’s recommendation for approval “reinforces the potential value of biosimilars in expanding access to additional high-quality treatment options for the patients in the U.S. who need them.”
The advisory committee members were screened and found to have no relevant conflicts of interest.
A Food and Drug Administration advisory committee voted overwhelmingly in support of licensure for Epoetin Hospira as a biosimilar product to epoetin alfa (Epogen/Procrit) for all approved Epogen/Procrit indications.
Most committee members who voted “yes” said they were hesitant to do so, however, because of safety concerns, particularly in HIV and oncology patients.
“I voted yes. I came in with concerns about the HIV and oncology patients. However, I do believe ... after hearing the justification, that it meets the [FDA regulatory guideline],” said temporary voting member and patient representative Karen E. Arscott, DO, of the Commonwealth Medical College, Scranton, Penn. “I would like to see extensive follow-up in these two population groups,” she said.
The concerns about HIV and oncology patients are related to the potential for immunogenicity-related events. Some members noted that the study populations were likely too small to detect these rare events.
Scott A. Waldman, MD, of Thomas Jefferson University, Philadelphia, also a temporary member, said he voted “yes” because there was “no substantial difference analytically, biologically, or clinically in what was tested.”
“I think the residual uncertainty of immunogenicity and hypersensitivity and the extrapolation across different patient populations will emerge in postmarketing surveillance. I think that’s when we’ll get the clearest picture of whether there really is any uncertainty in how these drugs perform,” he said.
For one member, however, the concerns were enough for a “no” vote.
“The analytical, clinical, and preclinical data support biosimilarity, and I strongly support approval for indications 1 and 4 based on the clinical data ... but I have residual concerns about lack of data, immunogenicity, basic safety data in patients with HIV and cancer and, for that reason, voted no for the broader indication,” said Thomas S. Uldrick, MD, of the HIV & AIDS Malignancy Branch at the Center for Cancer Research, National Cancer Institute, Bethesda, Md.
Gregory J. Riely, MD, of Memorial Sloan-Kettering Cancer Center in New York expressed similar concerns but said he found the data compelling.
“I understand the concerns around immunogenicity for HIV and cancer patients. I was somewhat reassured by the nonclinical data showing an absence of increased immunogenicity for this biosimilar,” he said.
To support its BLA for Epoetin Hospira, Hospira submitted data from four studies comparing it with the U.S.-licensed Epogen/Procrit and presented an analytical biosimilarity assessment and a nonclinical, clinical pharmacology and clinical biosimilarity assessment. The FDA analysis of the data considered chemistry, manufacturing, and controls, as well as pharmacology/toxicology, immunogenicity, clinical pharmacology, and clinical efficacy and safety.
Sumant Ramachandra, MD, of Pfizer Essential Health noted that the company is not currently seeking an interchangeability designation and that, while this is the first application for a biosimilar product to Amgen’s Epogen/Procrit product, which was approved in 1989, a “highly related epoetin product” from Pfizer (Retacrit) has been available in Europe for 9 years, with more than 363,000 patient years of treatment administered.
The demonstration of biosimilarity in the Epoetin Hospira data presented to the FDA, coupled with well-characterized nature of the reference product, “together support extrapolation across all conditions of use for the reference product,” he said, noting that the data demonstrate that the mechanism of action for both the biosimilar and reference product is the same, and that the immunogenicity profiles are consistent.
The FDA assessment of the data led to a similar conclusion that no clinically significant differences were found between the biosimilar and reference product.
Among other concerns expressed by advisory committee members and/or the public were in regard to the extrapolation of data from patients with chronic kidney disease on hemodialysis to other indications (although this is considered acceptable, according to FDA regulations) and to populations that weren’t studied and about the possibility that Epoetin Hospira would be forced on patients inappropriately, despite the fact that Hospira is not seeking an interchangeability designation. Patients and others speaking on behalf of various patient groups and advocacy organizations called for safeguards against such inappropriate substitution.
Acting committee chair, Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Clinic, Ohio, said he voted “yes” because the product met all regulatory requirements but agreed that the “need for vigilance is exceedingly important not only for this drug but for all drugs in this circumstance.”
The FDA, which usually follows the recommendations of its advisory committees, will now consider the BLA for Epoetin Hospira.
In a statement released after the vote, Diem Nguyen, Pfizer Essential Health global president, Americas, said the committee’s recommendation for approval “reinforces the potential value of biosimilars in expanding access to additional high-quality treatment options for the patients in the U.S. who need them.”
The advisory committee members were screened and found to have no relevant conflicts of interest.
A Food and Drug Administration advisory committee voted overwhelmingly in support of licensure for Epoetin Hospira as a biosimilar product to epoetin alfa (Epogen/Procrit) for all approved Epogen/Procrit indications.
Most committee members who voted “yes” said they were hesitant to do so, however, because of safety concerns, particularly in HIV and oncology patients.
“I voted yes. I came in with concerns about the HIV and oncology patients. However, I do believe ... after hearing the justification, that it meets the [FDA regulatory guideline],” said temporary voting member and patient representative Karen E. Arscott, DO, of the Commonwealth Medical College, Scranton, Penn. “I would like to see extensive follow-up in these two population groups,” she said.
The concerns about HIV and oncology patients are related to the potential for immunogenicity-related events. Some members noted that the study populations were likely too small to detect these rare events.
Scott A. Waldman, MD, of Thomas Jefferson University, Philadelphia, also a temporary member, said he voted “yes” because there was “no substantial difference analytically, biologically, or clinically in what was tested.”
“I think the residual uncertainty of immunogenicity and hypersensitivity and the extrapolation across different patient populations will emerge in postmarketing surveillance. I think that’s when we’ll get the clearest picture of whether there really is any uncertainty in how these drugs perform,” he said.
For one member, however, the concerns were enough for a “no” vote.
“The analytical, clinical, and preclinical data support biosimilarity, and I strongly support approval for indications 1 and 4 based on the clinical data ... but I have residual concerns about lack of data, immunogenicity, basic safety data in patients with HIV and cancer and, for that reason, voted no for the broader indication,” said Thomas S. Uldrick, MD, of the HIV & AIDS Malignancy Branch at the Center for Cancer Research, National Cancer Institute, Bethesda, Md.
Gregory J. Riely, MD, of Memorial Sloan-Kettering Cancer Center in New York expressed similar concerns but said he found the data compelling.
“I understand the concerns around immunogenicity for HIV and cancer patients. I was somewhat reassured by the nonclinical data showing an absence of increased immunogenicity for this biosimilar,” he said.
To support its BLA for Epoetin Hospira, Hospira submitted data from four studies comparing it with the U.S.-licensed Epogen/Procrit and presented an analytical biosimilarity assessment and a nonclinical, clinical pharmacology and clinical biosimilarity assessment. The FDA analysis of the data considered chemistry, manufacturing, and controls, as well as pharmacology/toxicology, immunogenicity, clinical pharmacology, and clinical efficacy and safety.
Sumant Ramachandra, MD, of Pfizer Essential Health noted that the company is not currently seeking an interchangeability designation and that, while this is the first application for a biosimilar product to Amgen’s Epogen/Procrit product, which was approved in 1989, a “highly related epoetin product” from Pfizer (Retacrit) has been available in Europe for 9 years, with more than 363,000 patient years of treatment administered.
The demonstration of biosimilarity in the Epoetin Hospira data presented to the FDA, coupled with well-characterized nature of the reference product, “together support extrapolation across all conditions of use for the reference product,” he said, noting that the data demonstrate that the mechanism of action for both the biosimilar and reference product is the same, and that the immunogenicity profiles are consistent.
The FDA assessment of the data led to a similar conclusion that no clinically significant differences were found between the biosimilar and reference product.
Among other concerns expressed by advisory committee members and/or the public were in regard to the extrapolation of data from patients with chronic kidney disease on hemodialysis to other indications (although this is considered acceptable, according to FDA regulations) and to populations that weren’t studied and about the possibility that Epoetin Hospira would be forced on patients inappropriately, despite the fact that Hospira is not seeking an interchangeability designation. Patients and others speaking on behalf of various patient groups and advocacy organizations called for safeguards against such inappropriate substitution.
Acting committee chair, Brian I. Rini, MD, of the Cleveland Clinic Taussig Cancer Clinic, Ohio, said he voted “yes” because the product met all regulatory requirements but agreed that the “need for vigilance is exceedingly important not only for this drug but for all drugs in this circumstance.”
The FDA, which usually follows the recommendations of its advisory committees, will now consider the BLA for Epoetin Hospira.
In a statement released after the vote, Diem Nguyen, Pfizer Essential Health global president, Americas, said the committee’s recommendation for approval “reinforces the potential value of biosimilars in expanding access to additional high-quality treatment options for the patients in the U.S. who need them.”
The advisory committee members were screened and found to have no relevant conflicts of interest.
Key clinical point:
Major finding: The data demonstrate that the mechanism of action for both the biosimilar and reference product is the same, and that the immunogenicity profiles are consistent.
Data source: An FDA advisory committee review of epoetin alfa biosimilar Epoetin Hospira.
Disclosures: The advisory committee members were screened and found to have no relevant conflicts of interest.
FDA advisory committee supports L-glutamine for SCD
The available data on the use of L-glutamine powder for treating sickle cell disease is favorable in terms of the agent’s overall benefit-risk profile, a majority of the Food and Drug Administration’s Oncologic Drugs Advisory Committee agreed during a meeting May 24.
L-glutamine powder, which is used as an oral solution for treating sickle cell disease, showed moderate benefit in a phase III study and a smaller phase II study, and if approved by the FDA – which usually follows the recommendations of its advisory committees – would be only the second treatment approved for the debilitating and sometimes deadly disease. The first, hydroxyurea, was approved for use in adults in 1998.
The committee voted 10-3 in favor of L-glutamate, after hearing from representatives of the new drug marketing applicant, Emmaus Medical, about the efficacy and safety data, as well as from FDA representatives who analyzed the data, physicians who treat sickle cell patients, patient advocates, and patients and their family members who gave emotional testimony in favor of approving this treatment.
“This is clearly a bad disease. It’s worse than cancer in many ways. I think probably mostly from a stigma standpoint it has a desperate need [for treatments],” said acting committee chair Brian I. Rini, MD, who voted in favor of the agent.
While there were some concerns about the data, including questions about methodologies, differential dropout rates between study arms, baseline characteristics that may have affected outcomes, and discrepancies between the Emmaus Medical data and the FDA’s analyses of the data, “all seemed to come down in favor of the agent,” Dr. Rini said, citing its “modest but consistent benefit” and low risk.
“I think one thing that’s strikingly clear is that even any sort of modest benefit in this community, given the sequelae of crises, is significant; it doesn’t take much to produce a clinical impact, and that should be motivation to study more drugs in this disease,” he said.
Another focus among those who voted “yes” was on the overwhelming need for treatment for sickle cell patients, who spend “a hugely disproportionate part of their life in the health care system, and who have had a tremendous burden imposed on them by their disease,” according to Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston, who said he was swayed by the low risk of toxicity and the corroborating evidence in the phase II and III trials.
“What I took away was that one fewer hospital visit per year was a clinically compelling benefit for any individual or family or hospital that might be caring for patients with sickle cell disease,” he said, referencing a finding that treated patients had three visits, compared with four visits among patients in the placebo group, in the phase III study.
The data presented to the committee during the meeting by Yutaka Niihara, MD, of Emmaus Medical, included findings from a phase III randomized, placebo-controlled multicenter study (GLUSCC09-01) involving patients aged 5 years and older with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises within the 12 months prior to screening. A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
The Emmaus Medical analysis demonstrated a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients, and the time to second crisis was delayed by 79 days in the treatment group (hazard ratio 0.68). The analysis, however, was complicated by the differential dropout rates (36% vs. 24% in the treatment and placebo arms, respectively), necessitating the use of imputation methods. Various methods were used to handle the missing data, and the findings with each of them favored L-glutamine, but each had important limitations, and while the FDA’s analysis of the various approaches showed that each favored L-glutamine over placebo with a range of reduction in the rates of crises from 0.4 to 0.9, this contributed to the decision by some panel member to vote against the agent.
The phase II study (Study 10478), which had a similar design, failed to meet its specified significance level for primary efficacy analysis, but showed a trend in favor of L-glutamine vs. placebo, Dr. Niihara said.
As for safety, Dr. Niihara reported that a safety population of 187 patients treated with L-glutamine and 111 treated with placebo in the phase II and III studies showed that most patients experienced a treatment-emergent adverse event – most often sickle cell anemia with crisis (66% and 72% in the groups, respectively) and acute chest syndrome (7% and 19%, respectively). Treatment-emergent adverse events led to withdrawal in 2.7% and 0.9% of patients, respectively. The most common adverse reactions were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
Bernard F. Cole, PhD, who was among the “no” votes, said he had concerns about “the limitations resulting from differential dropout” rates, which may have artificially shifted the risk profile.
“As a result of those limitations, it’s not clear whether patients at higher risk of a [sickle cell crisis] event might have disproportionately dropped out of the L-glutamine arm,” he explained. “My hope is that the sponsors can more thoroughly address the limitations of this pivotal trial with the FDA,” said Dr. Cole, a professor in the department of mathematics and statistics at the University of Vermont, Burlington.
Dr. Rini, despite his “yes” vote, agreed with the need for more data, noting that additional data analysis could help when it comes to clinical application of L-glutamine.
Specifically, more data regarding duration of therapy and quality data collection that “borrows from the cancer world ... in terms of rigor or data collection,” is needed, he said.
The committee members had no relevant conflicts of interests to disclose.
The available data on the use of L-glutamine powder for treating sickle cell disease is favorable in terms of the agent’s overall benefit-risk profile, a majority of the Food and Drug Administration’s Oncologic Drugs Advisory Committee agreed during a meeting May 24.
L-glutamine powder, which is used as an oral solution for treating sickle cell disease, showed moderate benefit in a phase III study and a smaller phase II study, and if approved by the FDA – which usually follows the recommendations of its advisory committees – would be only the second treatment approved for the debilitating and sometimes deadly disease. The first, hydroxyurea, was approved for use in adults in 1998.
The committee voted 10-3 in favor of L-glutamate, after hearing from representatives of the new drug marketing applicant, Emmaus Medical, about the efficacy and safety data, as well as from FDA representatives who analyzed the data, physicians who treat sickle cell patients, patient advocates, and patients and their family members who gave emotional testimony in favor of approving this treatment.
“This is clearly a bad disease. It’s worse than cancer in many ways. I think probably mostly from a stigma standpoint it has a desperate need [for treatments],” said acting committee chair Brian I. Rini, MD, who voted in favor of the agent.
While there were some concerns about the data, including questions about methodologies, differential dropout rates between study arms, baseline characteristics that may have affected outcomes, and discrepancies between the Emmaus Medical data and the FDA’s analyses of the data, “all seemed to come down in favor of the agent,” Dr. Rini said, citing its “modest but consistent benefit” and low risk.
“I think one thing that’s strikingly clear is that even any sort of modest benefit in this community, given the sequelae of crises, is significant; it doesn’t take much to produce a clinical impact, and that should be motivation to study more drugs in this disease,” he said.
Another focus among those who voted “yes” was on the overwhelming need for treatment for sickle cell patients, who spend “a hugely disproportionate part of their life in the health care system, and who have had a tremendous burden imposed on them by their disease,” according to Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston, who said he was swayed by the low risk of toxicity and the corroborating evidence in the phase II and III trials.
“What I took away was that one fewer hospital visit per year was a clinically compelling benefit for any individual or family or hospital that might be caring for patients with sickle cell disease,” he said, referencing a finding that treated patients had three visits, compared with four visits among patients in the placebo group, in the phase III study.
The data presented to the committee during the meeting by Yutaka Niihara, MD, of Emmaus Medical, included findings from a phase III randomized, placebo-controlled multicenter study (GLUSCC09-01) involving patients aged 5 years and older with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises within the 12 months prior to screening. A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
The Emmaus Medical analysis demonstrated a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients, and the time to second crisis was delayed by 79 days in the treatment group (hazard ratio 0.68). The analysis, however, was complicated by the differential dropout rates (36% vs. 24% in the treatment and placebo arms, respectively), necessitating the use of imputation methods. Various methods were used to handle the missing data, and the findings with each of them favored L-glutamine, but each had important limitations, and while the FDA’s analysis of the various approaches showed that each favored L-glutamine over placebo with a range of reduction in the rates of crises from 0.4 to 0.9, this contributed to the decision by some panel member to vote against the agent.
The phase II study (Study 10478), which had a similar design, failed to meet its specified significance level for primary efficacy analysis, but showed a trend in favor of L-glutamine vs. placebo, Dr. Niihara said.
As for safety, Dr. Niihara reported that a safety population of 187 patients treated with L-glutamine and 111 treated with placebo in the phase II and III studies showed that most patients experienced a treatment-emergent adverse event – most often sickle cell anemia with crisis (66% and 72% in the groups, respectively) and acute chest syndrome (7% and 19%, respectively). Treatment-emergent adverse events led to withdrawal in 2.7% and 0.9% of patients, respectively. The most common adverse reactions were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
Bernard F. Cole, PhD, who was among the “no” votes, said he had concerns about “the limitations resulting from differential dropout” rates, which may have artificially shifted the risk profile.
“As a result of those limitations, it’s not clear whether patients at higher risk of a [sickle cell crisis] event might have disproportionately dropped out of the L-glutamine arm,” he explained. “My hope is that the sponsors can more thoroughly address the limitations of this pivotal trial with the FDA,” said Dr. Cole, a professor in the department of mathematics and statistics at the University of Vermont, Burlington.
Dr. Rini, despite his “yes” vote, agreed with the need for more data, noting that additional data analysis could help when it comes to clinical application of L-glutamine.
Specifically, more data regarding duration of therapy and quality data collection that “borrows from the cancer world ... in terms of rigor or data collection,” is needed, he said.
The committee members had no relevant conflicts of interests to disclose.
The available data on the use of L-glutamine powder for treating sickle cell disease is favorable in terms of the agent’s overall benefit-risk profile, a majority of the Food and Drug Administration’s Oncologic Drugs Advisory Committee agreed during a meeting May 24.
L-glutamine powder, which is used as an oral solution for treating sickle cell disease, showed moderate benefit in a phase III study and a smaller phase II study, and if approved by the FDA – which usually follows the recommendations of its advisory committees – would be only the second treatment approved for the debilitating and sometimes deadly disease. The first, hydroxyurea, was approved for use in adults in 1998.
The committee voted 10-3 in favor of L-glutamate, after hearing from representatives of the new drug marketing applicant, Emmaus Medical, about the efficacy and safety data, as well as from FDA representatives who analyzed the data, physicians who treat sickle cell patients, patient advocates, and patients and their family members who gave emotional testimony in favor of approving this treatment.
“This is clearly a bad disease. It’s worse than cancer in many ways. I think probably mostly from a stigma standpoint it has a desperate need [for treatments],” said acting committee chair Brian I. Rini, MD, who voted in favor of the agent.
While there were some concerns about the data, including questions about methodologies, differential dropout rates between study arms, baseline characteristics that may have affected outcomes, and discrepancies between the Emmaus Medical data and the FDA’s analyses of the data, “all seemed to come down in favor of the agent,” Dr. Rini said, citing its “modest but consistent benefit” and low risk.
“I think one thing that’s strikingly clear is that even any sort of modest benefit in this community, given the sequelae of crises, is significant; it doesn’t take much to produce a clinical impact, and that should be motivation to study more drugs in this disease,” he said.
Another focus among those who voted “yes” was on the overwhelming need for treatment for sickle cell patients, who spend “a hugely disproportionate part of their life in the health care system, and who have had a tremendous burden imposed on them by their disease,” according to Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston, who said he was swayed by the low risk of toxicity and the corroborating evidence in the phase II and III trials.
“What I took away was that one fewer hospital visit per year was a clinically compelling benefit for any individual or family or hospital that might be caring for patients with sickle cell disease,” he said, referencing a finding that treated patients had three visits, compared with four visits among patients in the placebo group, in the phase III study.
The data presented to the committee during the meeting by Yutaka Niihara, MD, of Emmaus Medical, included findings from a phase III randomized, placebo-controlled multicenter study (GLUSCC09-01) involving patients aged 5 years and older with sickle cell disease or beta-0 thalassemia who had at least two episodes of painful crises within the 12 months prior to screening. A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
The Emmaus Medical analysis demonstrated a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients, and the time to second crisis was delayed by 79 days in the treatment group (hazard ratio 0.68). The analysis, however, was complicated by the differential dropout rates (36% vs. 24% in the treatment and placebo arms, respectively), necessitating the use of imputation methods. Various methods were used to handle the missing data, and the findings with each of them favored L-glutamine, but each had important limitations, and while the FDA’s analysis of the various approaches showed that each favored L-glutamine over placebo with a range of reduction in the rates of crises from 0.4 to 0.9, this contributed to the decision by some panel member to vote against the agent.
The phase II study (Study 10478), which had a similar design, failed to meet its specified significance level for primary efficacy analysis, but showed a trend in favor of L-glutamine vs. placebo, Dr. Niihara said.
As for safety, Dr. Niihara reported that a safety population of 187 patients treated with L-glutamine and 111 treated with placebo in the phase II and III studies showed that most patients experienced a treatment-emergent adverse event – most often sickle cell anemia with crisis (66% and 72% in the groups, respectively) and acute chest syndrome (7% and 19%, respectively). Treatment-emergent adverse events led to withdrawal in 2.7% and 0.9% of patients, respectively. The most common adverse reactions were constipation, nausea, headache, cough, pain in the extremities, back pain, chest pain, and abdominal pain.
Bernard F. Cole, PhD, who was among the “no” votes, said he had concerns about “the limitations resulting from differential dropout” rates, which may have artificially shifted the risk profile.
“As a result of those limitations, it’s not clear whether patients at higher risk of a [sickle cell crisis] event might have disproportionately dropped out of the L-glutamine arm,” he explained. “My hope is that the sponsors can more thoroughly address the limitations of this pivotal trial with the FDA,” said Dr. Cole, a professor in the department of mathematics and statistics at the University of Vermont, Burlington.
Dr. Rini, despite his “yes” vote, agreed with the need for more data, noting that additional data analysis could help when it comes to clinical application of L-glutamine.
Specifically, more data regarding duration of therapy and quality data collection that “borrows from the cancer world ... in terms of rigor or data collection,” is needed, he said.
The committee members had no relevant conflicts of interests to disclose.
Key clinical point:
Major finding: In a phase III study, there was a significant decrease in crisis events (median of 3 vs. 4) among treatment vs. placebo group patients.
Data source: A total of 152 patients were randomized to receive oral L-glutamine at a dose of 0.3 mg/kg per day for 48 weeks followed by a 3-week tapering period, and 78 received placebo.
Disclosures: The committee members had no relevant conflicts of interests to disclose.
ACT2: Noninvasive vagus nerve stimulation benefits episodic cluster headache
BOSTON – Noninvasive vagus nerve stimulation (nVNS) proved safe and effective for the treatment of episodic cluster headaches in the pivotal, multicenter ACT2 study.
The findings confirmed those of the ACT1 study – and together, the results led to the April 18 approval by the Food and Drug Administration of the gammaCore stimulation device for the treatment of episodic cluster headaches (eCH).
In ACT2, nVNS was used to treat 495 cluster headache attacks in 50 patients randomized to the treatment group, and a sham treatment was used for 400 attacks in 52 patients. The proportion of patients who achieved pain freedom within 15 minutes (responders) was 13.5% with stimulation, compared with 11.5% with the sham treatment (odds ratio, 1.22).
Stimulation led to pain freedom within 15 minutes in 47.5% of 101 attacks in 14 patients with eCH, compared with 6.2% of 81 attacks in eCH patients in the sham treatment group (OR, 9.19), said Dr. Goadsby of King’s College, London. Conversely, the proportion of responders was only 4.8% with stimulation for 394 attacks in 34 patients with cCH, compared with 12.9% in 319 attacks in 31 patients in the sham treatment group (OR, 0.41).
Further, the proportion of patients with any type of cluster headache who achieved responder status for at least 50% of attacks was 39.5% with stimulation vs. 13.6% with sham. Among those with eCH, the proportions were 64.3% and 15.4%, respectively, and with cCH they were 29.4% and 12.9%, respectively.
Study patients were adults with eCH or cCH who were enrolled from nine tertiary care centers in four European countries. Patients agreed to not start any new treatment and to not change the dose of any existing treatment during a 1-week run-in period and during a 2-week double-blind period.
Vagus nerve stimulation was self administered using the gammaCore study device at the onset of a cluster headache attack. Three consecutive 120-second stimulations were administered, and if pain freedom was not achieved by 9 minutes, three additional stimulations could be administered.
Patients were asked to refrain from use of rescue treatments for 15 minutes after beginning stimulation (use of rescue treatments constituted a treatment failure), and an initial assessment of pain intensity was conducted at 15 minutes. All patients were eligible for nVNS during a 2-week open-label period after the double-blind period. Patients recorded cluster headache attack data in diaries.
Treatment was safe and well tolerated. A total of 20 and 14 patients in the treatment and sham groups experienced adverse events in the double-blind period (total number of events, 65 and 39, respectively); and 9 and 10 in the groups, respectively, experienced adverse drug events. The adverse events occurring more often in the treatment group included application-site irritation in two patients, application-site paresthesia in two patients, and skin irritation in two patients.
Vagus nerve stimulation is a well-established neuromodulation therapy for epilepsy and medication-resistant depression. The gammaCore device used in the ACT1 and ACT2 studies delivers treatment to the cervical branch of the vagus nerve transcutaneously, whereas prior methods involved surgically implanted devices, which are more prone to cause infection and other complications and costs.
The current study’s findings demonstrate the superiority of nVNS over sham therapy for the acute treatment of attacks in patients with eCH, Dr. Goadsby noted. The lack of benefit in those with cCH likely affected the results for the total population, he added.
The findings indicate the nVNS can be safely and easily incorporated into existing therapeutic regimens, Dr. Goadsby concluded.
The ACT1 and ACT2 studies were sponsored by electroCore, the maker of gammaCore. Dr. Goadsby reported receiving funding from electroCore and numerous other companies. He also reported having a pending patent for magnetic stimulation for headache.
BOSTON – Noninvasive vagus nerve stimulation (nVNS) proved safe and effective for the treatment of episodic cluster headaches in the pivotal, multicenter ACT2 study.
The findings confirmed those of the ACT1 study – and together, the results led to the April 18 approval by the Food and Drug Administration of the gammaCore stimulation device for the treatment of episodic cluster headaches (eCH).
In ACT2, nVNS was used to treat 495 cluster headache attacks in 50 patients randomized to the treatment group, and a sham treatment was used for 400 attacks in 52 patients. The proportion of patients who achieved pain freedom within 15 minutes (responders) was 13.5% with stimulation, compared with 11.5% with the sham treatment (odds ratio, 1.22).
Stimulation led to pain freedom within 15 minutes in 47.5% of 101 attacks in 14 patients with eCH, compared with 6.2% of 81 attacks in eCH patients in the sham treatment group (OR, 9.19), said Dr. Goadsby of King’s College, London. Conversely, the proportion of responders was only 4.8% with stimulation for 394 attacks in 34 patients with cCH, compared with 12.9% in 319 attacks in 31 patients in the sham treatment group (OR, 0.41).
Further, the proportion of patients with any type of cluster headache who achieved responder status for at least 50% of attacks was 39.5% with stimulation vs. 13.6% with sham. Among those with eCH, the proportions were 64.3% and 15.4%, respectively, and with cCH they were 29.4% and 12.9%, respectively.
Study patients were adults with eCH or cCH who were enrolled from nine tertiary care centers in four European countries. Patients agreed to not start any new treatment and to not change the dose of any existing treatment during a 1-week run-in period and during a 2-week double-blind period.
Vagus nerve stimulation was self administered using the gammaCore study device at the onset of a cluster headache attack. Three consecutive 120-second stimulations were administered, and if pain freedom was not achieved by 9 minutes, three additional stimulations could be administered.
Patients were asked to refrain from use of rescue treatments for 15 minutes after beginning stimulation (use of rescue treatments constituted a treatment failure), and an initial assessment of pain intensity was conducted at 15 minutes. All patients were eligible for nVNS during a 2-week open-label period after the double-blind period. Patients recorded cluster headache attack data in diaries.
Treatment was safe and well tolerated. A total of 20 and 14 patients in the treatment and sham groups experienced adverse events in the double-blind period (total number of events, 65 and 39, respectively); and 9 and 10 in the groups, respectively, experienced adverse drug events. The adverse events occurring more often in the treatment group included application-site irritation in two patients, application-site paresthesia in two patients, and skin irritation in two patients.
Vagus nerve stimulation is a well-established neuromodulation therapy for epilepsy and medication-resistant depression. The gammaCore device used in the ACT1 and ACT2 studies delivers treatment to the cervical branch of the vagus nerve transcutaneously, whereas prior methods involved surgically implanted devices, which are more prone to cause infection and other complications and costs.
The current study’s findings demonstrate the superiority of nVNS over sham therapy for the acute treatment of attacks in patients with eCH, Dr. Goadsby noted. The lack of benefit in those with cCH likely affected the results for the total population, he added.
The findings indicate the nVNS can be safely and easily incorporated into existing therapeutic regimens, Dr. Goadsby concluded.
The ACT1 and ACT2 studies were sponsored by electroCore, the maker of gammaCore. Dr. Goadsby reported receiving funding from electroCore and numerous other companies. He also reported having a pending patent for magnetic stimulation for headache.
BOSTON – Noninvasive vagus nerve stimulation (nVNS) proved safe and effective for the treatment of episodic cluster headaches in the pivotal, multicenter ACT2 study.
The findings confirmed those of the ACT1 study – and together, the results led to the April 18 approval by the Food and Drug Administration of the gammaCore stimulation device for the treatment of episodic cluster headaches (eCH).
In ACT2, nVNS was used to treat 495 cluster headache attacks in 50 patients randomized to the treatment group, and a sham treatment was used for 400 attacks in 52 patients. The proportion of patients who achieved pain freedom within 15 minutes (responders) was 13.5% with stimulation, compared with 11.5% with the sham treatment (odds ratio, 1.22).
Stimulation led to pain freedom within 15 minutes in 47.5% of 101 attacks in 14 patients with eCH, compared with 6.2% of 81 attacks in eCH patients in the sham treatment group (OR, 9.19), said Dr. Goadsby of King’s College, London. Conversely, the proportion of responders was only 4.8% with stimulation for 394 attacks in 34 patients with cCH, compared with 12.9% in 319 attacks in 31 patients in the sham treatment group (OR, 0.41).
Further, the proportion of patients with any type of cluster headache who achieved responder status for at least 50% of attacks was 39.5% with stimulation vs. 13.6% with sham. Among those with eCH, the proportions were 64.3% and 15.4%, respectively, and with cCH they were 29.4% and 12.9%, respectively.
Study patients were adults with eCH or cCH who were enrolled from nine tertiary care centers in four European countries. Patients agreed to not start any new treatment and to not change the dose of any existing treatment during a 1-week run-in period and during a 2-week double-blind period.
Vagus nerve stimulation was self administered using the gammaCore study device at the onset of a cluster headache attack. Three consecutive 120-second stimulations were administered, and if pain freedom was not achieved by 9 minutes, three additional stimulations could be administered.
Patients were asked to refrain from use of rescue treatments for 15 minutes after beginning stimulation (use of rescue treatments constituted a treatment failure), and an initial assessment of pain intensity was conducted at 15 minutes. All patients were eligible for nVNS during a 2-week open-label period after the double-blind period. Patients recorded cluster headache attack data in diaries.
Treatment was safe and well tolerated. A total of 20 and 14 patients in the treatment and sham groups experienced adverse events in the double-blind period (total number of events, 65 and 39, respectively); and 9 and 10 in the groups, respectively, experienced adverse drug events. The adverse events occurring more often in the treatment group included application-site irritation in two patients, application-site paresthesia in two patients, and skin irritation in two patients.
Vagus nerve stimulation is a well-established neuromodulation therapy for epilepsy and medication-resistant depression. The gammaCore device used in the ACT1 and ACT2 studies delivers treatment to the cervical branch of the vagus nerve transcutaneously, whereas prior methods involved surgically implanted devices, which are more prone to cause infection and other complications and costs.
The current study’s findings demonstrate the superiority of nVNS over sham therapy for the acute treatment of attacks in patients with eCH, Dr. Goadsby noted. The lack of benefit in those with cCH likely affected the results for the total population, he added.
The findings indicate the nVNS can be safely and easily incorporated into existing therapeutic regimens, Dr. Goadsby concluded.
The ACT1 and ACT2 studies were sponsored by electroCore, the maker of gammaCore. Dr. Goadsby reported receiving funding from electroCore and numerous other companies. He also reported having a pending patent for magnetic stimulation for headache.
AT AAN 2017
Key clinical point:
Major finding: The proportion of patients who achieved pain freedom within 15 minutes was 13.5% with noninvasive vagus nerve stimulation, compared with 11.5% with the sham treatment (odds ratio, 1.22).
Data source: The randomized, sham-controlled, multicenter ACT2 study of 102 patients.
Disclosures: The ACT1 and ACT2 studies were sponsored by electroCore, the maker of the gammaCore device. Dr. Goadsby reported receiving funding from electroCore and numerous other companies. He also reported having a pending patent for magnetic stimulation for headache.