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American Society of Clinical Oncology (ASCO): Annual Meeting
ASCO: New hope for immunotherapy in advanced ovarian cancer
CHICAGO – Two monoclonal antibodies were clinically active in heavily pretreated advanced ovarian cancer in a pair of phase Ib studies presented at the annual meeting of the American Society of Clinical Oncology.
In the JAVELIN trial, the objective response rate with avelumab was 10.7% after a median follow-up of 5 months in patients who were not preselected for PD-L1 (programmed death ligand 1) positivity at enrollment.
The objective response rate in the KEYNOTE-028 trial was 11.5% with the PD-1 inhibitor pembrolizumab (Keytruda) after a median follow-up of 11 months in PD-L1–positive patients.
The investigational agent avelumab inhibits PD-1 and PD-L1 interactions, but preclinical models have also suggested that antibody-dependent cellular cytotoxicity, which can directly result in lysing of tumor cells, is an additional mechanism of action, lead investigator Dr. Mary “Nora” L. Disis of the Fred Hutchinson Cancer Research Center, Seattle, and the Seattle Cancer Care Alliance said.
The expansion phase of the phase Ib JAVELIN trial has enrolled more than 840 patients with solid tumors in 11 indications and evaluated avelumab 10 mg/kg IV every 2 weeks until progression in 75 unselected patients with refractory or recurrent ovarian cancer. Most had received at least three previous lines of therapy (68%), and 70.7% had serous histology.
The objective response rate of 10.7% was based on eight partial responses by RECIST (Response Evaluation Criteria in Solid Tumors). In addition, 44% of patients have stable disease, resulting in a disease control rate of 54.7%. The median time to response was 9 weeks, and the median duration of response was 21 weeks.
“The majority of responses are durable and ongoing at the time of this report,” Dr. Disis said.
Tumor shrinkage by at least 30% was observed in 11 patients (14.7%), including both patients enrolled with clear cell histology. Two additional patients have a partial response by immune-related response criteria, boosting the objective response rate to about 15%, she said.
A subgroup analysis showed intriguing trends for higher response rates in patients with lower vs. higher tumor burden (15% vs. 5.7%), with at least one prior line of treatment vs. two lines or at least three lines (21.4% vs. 10% vs. 7.8%, respectively), and with platinum-sensitive vs. platinum-resistant disease (20% vs. 9.1%), Dr. Disis said.
“These data, of course, because of the short follow-up rate are fairly immature, but we’ll continue to explore these trends as the data do mature,” she said.
Treatment-related adverse events of any grade were reported in 69.3% of patients, most commonly fatigue, chills, nausea, and diarrhea. Six patients (8%) had a grade 3 treatment-related adverse event, with no grade 4 or 5 adverse events or deaths related to avelumab reported, Dr. Disis said. Nine patients (12%) discontinued treatment because of an adverse event.
She noted that this is the largest reported dataset of patients with refractory or recurrent ovarian cancer treated with anti–PD-L1 therapy and that phase III clinical development is planned.
Pembrolizumab
The KEYSTONE-028 trial was conducted in 26 women with PD-L1–positive ovarian cancer, of whom 81% had received at least four previous lines of therapy, Dr. Andrea Varga of Institut Gustave Roussy, Villejuif, France, said. The histology was adenocarcinoma in 46.2%, high-grade serous carcinoma in 34.6%, and other in 19.3%.
Of the 96 patients screened for the trial, 51% had PD-L1–positive tumors.
The 11.5% response rate for pembrolizumab 10 mg/kg every 2 weeks was based on one complete response and two partial responses. Stable disease was reported in six patients, for a disease control rate of 34.6%, Dr. Varga said. “Keep in mind, we are talking about a very heavily pretreated cohort of patients,” she added.
Overall, 23% of patients had at least a 30% decrease in tumor size. At the time of the analysis, the complete response and two partial responses were ongoing.
The median time to response was relatively early at 8 weeks, and the median duration of response has not been reached, indicating the durable nature of the responses, she said.
Adverse events of any grade were reported in 69.2% of patients, typically arthralgia, diarrhea, and nausea that was tolerable and easily managed. One patient had a grade 3-4 treatment-related increase in transaminase levels, and one patient had grade 3 pancreatitis. There were no treatment-related deaths or discontinuations because of an adverse event.
An analysis of the relationship between response and PD-L1 expression as well as other potential predictive biomarkers is ongoing, Dr. Varga said.
Pembrolizumab is approved as second-line therapy in advanced melanoma.
The JAVELIN trial was sponsored by Merck KGaA. Dr. Disis reported owning stock in Epiphany Biosciences and VentiRx; receiving honoraria from Celgene and Emergent BioSolutions; consulting or advising for Celgene, EMD Serono, Emergent BioSolutions, and VentiRx; receiving research funding from Seattle Genetics and VentiRx; and holding patents with the University of Washington. KEYNOTE-028 was supported by Merck Sharp & Dohme, with editorial assistance provided by Merck and the APO Group. Dr. Varga reported no relevant financial conflicts.
pwendling@frontlinemedcom.com
On Twitter @pwendl
CHICAGO – Two monoclonal antibodies were clinically active in heavily pretreated advanced ovarian cancer in a pair of phase Ib studies presented at the annual meeting of the American Society of Clinical Oncology.
In the JAVELIN trial, the objective response rate with avelumab was 10.7% after a median follow-up of 5 months in patients who were not preselected for PD-L1 (programmed death ligand 1) positivity at enrollment.
The objective response rate in the KEYNOTE-028 trial was 11.5% with the PD-1 inhibitor pembrolizumab (Keytruda) after a median follow-up of 11 months in PD-L1–positive patients.
The investigational agent avelumab inhibits PD-1 and PD-L1 interactions, but preclinical models have also suggested that antibody-dependent cellular cytotoxicity, which can directly result in lysing of tumor cells, is an additional mechanism of action, lead investigator Dr. Mary “Nora” L. Disis of the Fred Hutchinson Cancer Research Center, Seattle, and the Seattle Cancer Care Alliance said.
The expansion phase of the phase Ib JAVELIN trial has enrolled more than 840 patients with solid tumors in 11 indications and evaluated avelumab 10 mg/kg IV every 2 weeks until progression in 75 unselected patients with refractory or recurrent ovarian cancer. Most had received at least three previous lines of therapy (68%), and 70.7% had serous histology.
The objective response rate of 10.7% was based on eight partial responses by RECIST (Response Evaluation Criteria in Solid Tumors). In addition, 44% of patients have stable disease, resulting in a disease control rate of 54.7%. The median time to response was 9 weeks, and the median duration of response was 21 weeks.
“The majority of responses are durable and ongoing at the time of this report,” Dr. Disis said.
Tumor shrinkage by at least 30% was observed in 11 patients (14.7%), including both patients enrolled with clear cell histology. Two additional patients have a partial response by immune-related response criteria, boosting the objective response rate to about 15%, she said.
A subgroup analysis showed intriguing trends for higher response rates in patients with lower vs. higher tumor burden (15% vs. 5.7%), with at least one prior line of treatment vs. two lines or at least three lines (21.4% vs. 10% vs. 7.8%, respectively), and with platinum-sensitive vs. platinum-resistant disease (20% vs. 9.1%), Dr. Disis said.
“These data, of course, because of the short follow-up rate are fairly immature, but we’ll continue to explore these trends as the data do mature,” she said.
Treatment-related adverse events of any grade were reported in 69.3% of patients, most commonly fatigue, chills, nausea, and diarrhea. Six patients (8%) had a grade 3 treatment-related adverse event, with no grade 4 or 5 adverse events or deaths related to avelumab reported, Dr. Disis said. Nine patients (12%) discontinued treatment because of an adverse event.
She noted that this is the largest reported dataset of patients with refractory or recurrent ovarian cancer treated with anti–PD-L1 therapy and that phase III clinical development is planned.
Pembrolizumab
The KEYSTONE-028 trial was conducted in 26 women with PD-L1–positive ovarian cancer, of whom 81% had received at least four previous lines of therapy, Dr. Andrea Varga of Institut Gustave Roussy, Villejuif, France, said. The histology was adenocarcinoma in 46.2%, high-grade serous carcinoma in 34.6%, and other in 19.3%.
Of the 96 patients screened for the trial, 51% had PD-L1–positive tumors.
The 11.5% response rate for pembrolizumab 10 mg/kg every 2 weeks was based on one complete response and two partial responses. Stable disease was reported in six patients, for a disease control rate of 34.6%, Dr. Varga said. “Keep in mind, we are talking about a very heavily pretreated cohort of patients,” she added.
Overall, 23% of patients had at least a 30% decrease in tumor size. At the time of the analysis, the complete response and two partial responses were ongoing.
The median time to response was relatively early at 8 weeks, and the median duration of response has not been reached, indicating the durable nature of the responses, she said.
Adverse events of any grade were reported in 69.2% of patients, typically arthralgia, diarrhea, and nausea that was tolerable and easily managed. One patient had a grade 3-4 treatment-related increase in transaminase levels, and one patient had grade 3 pancreatitis. There were no treatment-related deaths or discontinuations because of an adverse event.
An analysis of the relationship between response and PD-L1 expression as well as other potential predictive biomarkers is ongoing, Dr. Varga said.
Pembrolizumab is approved as second-line therapy in advanced melanoma.
The JAVELIN trial was sponsored by Merck KGaA. Dr. Disis reported owning stock in Epiphany Biosciences and VentiRx; receiving honoraria from Celgene and Emergent BioSolutions; consulting or advising for Celgene, EMD Serono, Emergent BioSolutions, and VentiRx; receiving research funding from Seattle Genetics and VentiRx; and holding patents with the University of Washington. KEYNOTE-028 was supported by Merck Sharp & Dohme, with editorial assistance provided by Merck and the APO Group. Dr. Varga reported no relevant financial conflicts.
pwendling@frontlinemedcom.com
On Twitter @pwendl
CHICAGO – Two monoclonal antibodies were clinically active in heavily pretreated advanced ovarian cancer in a pair of phase Ib studies presented at the annual meeting of the American Society of Clinical Oncology.
In the JAVELIN trial, the objective response rate with avelumab was 10.7% after a median follow-up of 5 months in patients who were not preselected for PD-L1 (programmed death ligand 1) positivity at enrollment.
The objective response rate in the KEYNOTE-028 trial was 11.5% with the PD-1 inhibitor pembrolizumab (Keytruda) after a median follow-up of 11 months in PD-L1–positive patients.
The investigational agent avelumab inhibits PD-1 and PD-L1 interactions, but preclinical models have also suggested that antibody-dependent cellular cytotoxicity, which can directly result in lysing of tumor cells, is an additional mechanism of action, lead investigator Dr. Mary “Nora” L. Disis of the Fred Hutchinson Cancer Research Center, Seattle, and the Seattle Cancer Care Alliance said.
The expansion phase of the phase Ib JAVELIN trial has enrolled more than 840 patients with solid tumors in 11 indications and evaluated avelumab 10 mg/kg IV every 2 weeks until progression in 75 unselected patients with refractory or recurrent ovarian cancer. Most had received at least three previous lines of therapy (68%), and 70.7% had serous histology.
The objective response rate of 10.7% was based on eight partial responses by RECIST (Response Evaluation Criteria in Solid Tumors). In addition, 44% of patients have stable disease, resulting in a disease control rate of 54.7%. The median time to response was 9 weeks, and the median duration of response was 21 weeks.
“The majority of responses are durable and ongoing at the time of this report,” Dr. Disis said.
Tumor shrinkage by at least 30% was observed in 11 patients (14.7%), including both patients enrolled with clear cell histology. Two additional patients have a partial response by immune-related response criteria, boosting the objective response rate to about 15%, she said.
A subgroup analysis showed intriguing trends for higher response rates in patients with lower vs. higher tumor burden (15% vs. 5.7%), with at least one prior line of treatment vs. two lines or at least three lines (21.4% vs. 10% vs. 7.8%, respectively), and with platinum-sensitive vs. platinum-resistant disease (20% vs. 9.1%), Dr. Disis said.
“These data, of course, because of the short follow-up rate are fairly immature, but we’ll continue to explore these trends as the data do mature,” she said.
Treatment-related adverse events of any grade were reported in 69.3% of patients, most commonly fatigue, chills, nausea, and diarrhea. Six patients (8%) had a grade 3 treatment-related adverse event, with no grade 4 or 5 adverse events or deaths related to avelumab reported, Dr. Disis said. Nine patients (12%) discontinued treatment because of an adverse event.
She noted that this is the largest reported dataset of patients with refractory or recurrent ovarian cancer treated with anti–PD-L1 therapy and that phase III clinical development is planned.
Pembrolizumab
The KEYSTONE-028 trial was conducted in 26 women with PD-L1–positive ovarian cancer, of whom 81% had received at least four previous lines of therapy, Dr. Andrea Varga of Institut Gustave Roussy, Villejuif, France, said. The histology was adenocarcinoma in 46.2%, high-grade serous carcinoma in 34.6%, and other in 19.3%.
Of the 96 patients screened for the trial, 51% had PD-L1–positive tumors.
The 11.5% response rate for pembrolizumab 10 mg/kg every 2 weeks was based on one complete response and two partial responses. Stable disease was reported in six patients, for a disease control rate of 34.6%, Dr. Varga said. “Keep in mind, we are talking about a very heavily pretreated cohort of patients,” she added.
Overall, 23% of patients had at least a 30% decrease in tumor size. At the time of the analysis, the complete response and two partial responses were ongoing.
The median time to response was relatively early at 8 weeks, and the median duration of response has not been reached, indicating the durable nature of the responses, she said.
Adverse events of any grade were reported in 69.2% of patients, typically arthralgia, diarrhea, and nausea that was tolerable and easily managed. One patient had a grade 3-4 treatment-related increase in transaminase levels, and one patient had grade 3 pancreatitis. There were no treatment-related deaths or discontinuations because of an adverse event.
An analysis of the relationship between response and PD-L1 expression as well as other potential predictive biomarkers is ongoing, Dr. Varga said.
Pembrolizumab is approved as second-line therapy in advanced melanoma.
The JAVELIN trial was sponsored by Merck KGaA. Dr. Disis reported owning stock in Epiphany Biosciences and VentiRx; receiving honoraria from Celgene and Emergent BioSolutions; consulting or advising for Celgene, EMD Serono, Emergent BioSolutions, and VentiRx; receiving research funding from Seattle Genetics and VentiRx; and holding patents with the University of Washington. KEYNOTE-028 was supported by Merck Sharp & Dohme, with editorial assistance provided by Merck and the APO Group. Dr. Varga reported no relevant financial conflicts.
pwendling@frontlinemedcom.com
On Twitter @pwendl
AT 2015 ASCO ANNUAL MEETING
Key clinical point: The monoclonal antibodies avelumab and pembrolizumab produced good antitumor activity in patients with advanced ovarian cancer.
Major finding: The objective response rate was 10.7% with avelumab in unselected patients and 11.5% with pembrolizumab in PD-L1–positive patients.
Data source: Two phase Ib studies in patients with pretreated recurrent or refractory ovarian cancer.
Disclosures: The JAVELIN trial was sponsored by Merck KGaA. Dr. Disis reported owning stock in Epiphany Biosciences and VentiRx; receiving honoraria from Celgene and Emergent BioSolutions; consulting or advising for Celgene, EMD Serono, Emergent BioSolutions, and VentiRx; receiving research funding from Seattle Genetics and VentiRx; and holding patents with the University of Washington. KEYNOTE-028 was supported by Merck Sharp & Dohme, with editorial assistance provided by Merck and the APO Group. Dr. Varga reported no relevant financial conflicts.
ASCO: Etirinotecan pegol prolongs life for women with brain, liver mets of breast cancer
CHICAGO – Etirinotecan pegol is an efficacious treatment option for selected women with heavily pretreated advanced breast cancer, suggests the international phase III BEACON study (Breast Cancer Outcomes With NKTR-102).
Compared with a treatment of the physician’s choice, the novel drug – an encapsulated form of irinotecan that inhibits topoisomerase 1—did not significantly improve overall survival in the trial population as a whole, first author Dr. Edith A. Perez reported at the annual meeting of the American Society of Clinical Oncology. But it reduced the risk of death by nearly half for the subset of women with a history of brain metastases and by more than a quarter for the subset of women with a history of liver metastases, with less toxicity and better quality of life.
“Etirinotecan pegol … [has] clinical activity and good tolerability in patients with heavily pretreated advanced breast cancer,” summarized Dr. Perez, who is deputy director at large for the Mayo Clinic Cancer Center in Jacksonville, Florida, as well as director of the Mayo Clinic Breast Cancer Translational Genomics Program and chair of the Breast Cancer Specialty Council.
“The 2.1-month improvement in median survival favoring etirinotecan pegol did not reach statistical significance. However, provocative and potentially very important survival results in predefined subgroups of patients deserve further study, specifically, patients with brain metastases or liver metastases,” she said. “Exploration of potential predictive biomarkers is ongoing.”
The findings regarding brain metastases are “an intriguing nugget,” according to invited discussant Dr. Harold J. Burstein, a senior physician at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston. “I think these data and the growing literature on the effectiveness of systemic therapy for brain metastases … suggest that it’s time for us to be doing trials where we are comparing standards of care of radiotherapy against chemotherapy, trying to optimize our chemotherapy regimens for the palliation of metastatic disease of the brain.”
He pointed to a set of trials in patients with advanced lung cancer testing the benefits of early palliative care on outcomes and finding improvements in overall survival or in quality of life with no detriment to overall survival.
“I used to look at these and think this didn’t really speak to the breast cancer population. But when you start to see data in the heavily refractory patients as we have observed today, it turns out that their survival is unfortunately essentially the same as for all the patients who participated in these trials,” he said. “So when we think about what direction we should go for advanced breast cancer that’s heavily refractory to chemotherapy, in addition to exploring a variety of exciting new immunologic therapies, and targeted therapies … I think we need to begin to lean more on our palliation care specialists and colleagues to help us truly take optimal care of these patients.”
The 852 women studied in the BEACON trial had experienced progression after anthracycline, taxane, and capecitabine therapy and had received two to five prior therapies for their advanced disease. The trial, sponsored by Nektar Therapeutics, was unusual in that it allowed patients with stable brain metastases to enroll and set a high bar of overall survival as its primary endpoint, Dr. Perez noted.
The patients were randomized evenly to receive single-agent etirinotecan pegol or a single agent of the physician’s choice, which was most commonly eribulin.
Main results showed no significant improvement in overall survival among the entire trial population comparing etirinotecan pegol with physician’s choice (12.4 vs. 10.3 months; hazard ratio, 0.87; P = .08).
However, preplanned subgroup analyses showed that in the 8% of women who had a history of brain metastases, median overall survival was 10.0 months with the drug and 4.8 months with physician’s choice (HR, 0.51; P = .0099). The curves began to separate within 3 months of randomization, and the difference in the proportion of women alive at 12 months was “pretty amazing,” Dr. Perez noted, at 44% versus 19%.
There was a similar although smaller survival advantage of etirinotecan pegol among the 53% of patients with a history of liver metastases (10.9 vs. 8.3 months; HR, 0.73; P = .002).
A variety of biomarkers for etirinotecan benefit are still being analyzed, according to Dr. Perez. The most promising signal thus far has been a reduction in the number of topoisomerase 1–positive circulating tumor cells, with patients going from high (above the baseline median) to low (below the baseline median) numbers surviving significantly longer than peers having persistently high numbers (14.9 vs. 10.7 months; HR, 0.54; P = .007).
The rate of grade 3 or worse toxicity was lower with etirinotecan pegol than with physician’s choice (48% vs. 63%). The former was associated with a higher rate of diarrhea, whereas the latter was associated with higher rates of neutropenia and peripheral neuropathy.
Patients in the etirinotecan pegol group had a more favorable change from baseline in global health status and in physical functioning, reported Dr. Perez.
CHICAGO – Etirinotecan pegol is an efficacious treatment option for selected women with heavily pretreated advanced breast cancer, suggests the international phase III BEACON study (Breast Cancer Outcomes With NKTR-102).
Compared with a treatment of the physician’s choice, the novel drug – an encapsulated form of irinotecan that inhibits topoisomerase 1—did not significantly improve overall survival in the trial population as a whole, first author Dr. Edith A. Perez reported at the annual meeting of the American Society of Clinical Oncology. But it reduced the risk of death by nearly half for the subset of women with a history of brain metastases and by more than a quarter for the subset of women with a history of liver metastases, with less toxicity and better quality of life.
“Etirinotecan pegol … [has] clinical activity and good tolerability in patients with heavily pretreated advanced breast cancer,” summarized Dr. Perez, who is deputy director at large for the Mayo Clinic Cancer Center in Jacksonville, Florida, as well as director of the Mayo Clinic Breast Cancer Translational Genomics Program and chair of the Breast Cancer Specialty Council.
“The 2.1-month improvement in median survival favoring etirinotecan pegol did not reach statistical significance. However, provocative and potentially very important survival results in predefined subgroups of patients deserve further study, specifically, patients with brain metastases or liver metastases,” she said. “Exploration of potential predictive biomarkers is ongoing.”
The findings regarding brain metastases are “an intriguing nugget,” according to invited discussant Dr. Harold J. Burstein, a senior physician at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston. “I think these data and the growing literature on the effectiveness of systemic therapy for brain metastases … suggest that it’s time for us to be doing trials where we are comparing standards of care of radiotherapy against chemotherapy, trying to optimize our chemotherapy regimens for the palliation of metastatic disease of the brain.”
He pointed to a set of trials in patients with advanced lung cancer testing the benefits of early palliative care on outcomes and finding improvements in overall survival or in quality of life with no detriment to overall survival.
“I used to look at these and think this didn’t really speak to the breast cancer population. But when you start to see data in the heavily refractory patients as we have observed today, it turns out that their survival is unfortunately essentially the same as for all the patients who participated in these trials,” he said. “So when we think about what direction we should go for advanced breast cancer that’s heavily refractory to chemotherapy, in addition to exploring a variety of exciting new immunologic therapies, and targeted therapies … I think we need to begin to lean more on our palliation care specialists and colleagues to help us truly take optimal care of these patients.”
The 852 women studied in the BEACON trial had experienced progression after anthracycline, taxane, and capecitabine therapy and had received two to five prior therapies for their advanced disease. The trial, sponsored by Nektar Therapeutics, was unusual in that it allowed patients with stable brain metastases to enroll and set a high bar of overall survival as its primary endpoint, Dr. Perez noted.
The patients were randomized evenly to receive single-agent etirinotecan pegol or a single agent of the physician’s choice, which was most commonly eribulin.
Main results showed no significant improvement in overall survival among the entire trial population comparing etirinotecan pegol with physician’s choice (12.4 vs. 10.3 months; hazard ratio, 0.87; P = .08).
However, preplanned subgroup analyses showed that in the 8% of women who had a history of brain metastases, median overall survival was 10.0 months with the drug and 4.8 months with physician’s choice (HR, 0.51; P = .0099). The curves began to separate within 3 months of randomization, and the difference in the proportion of women alive at 12 months was “pretty amazing,” Dr. Perez noted, at 44% versus 19%.
There was a similar although smaller survival advantage of etirinotecan pegol among the 53% of patients with a history of liver metastases (10.9 vs. 8.3 months; HR, 0.73; P = .002).
A variety of biomarkers for etirinotecan benefit are still being analyzed, according to Dr. Perez. The most promising signal thus far has been a reduction in the number of topoisomerase 1–positive circulating tumor cells, with patients going from high (above the baseline median) to low (below the baseline median) numbers surviving significantly longer than peers having persistently high numbers (14.9 vs. 10.7 months; HR, 0.54; P = .007).
The rate of grade 3 or worse toxicity was lower with etirinotecan pegol than with physician’s choice (48% vs. 63%). The former was associated with a higher rate of diarrhea, whereas the latter was associated with higher rates of neutropenia and peripheral neuropathy.
Patients in the etirinotecan pegol group had a more favorable change from baseline in global health status and in physical functioning, reported Dr. Perez.
CHICAGO – Etirinotecan pegol is an efficacious treatment option for selected women with heavily pretreated advanced breast cancer, suggests the international phase III BEACON study (Breast Cancer Outcomes With NKTR-102).
Compared with a treatment of the physician’s choice, the novel drug – an encapsulated form of irinotecan that inhibits topoisomerase 1—did not significantly improve overall survival in the trial population as a whole, first author Dr. Edith A. Perez reported at the annual meeting of the American Society of Clinical Oncology. But it reduced the risk of death by nearly half for the subset of women with a history of brain metastases and by more than a quarter for the subset of women with a history of liver metastases, with less toxicity and better quality of life.
“Etirinotecan pegol … [has] clinical activity and good tolerability in patients with heavily pretreated advanced breast cancer,” summarized Dr. Perez, who is deputy director at large for the Mayo Clinic Cancer Center in Jacksonville, Florida, as well as director of the Mayo Clinic Breast Cancer Translational Genomics Program and chair of the Breast Cancer Specialty Council.
“The 2.1-month improvement in median survival favoring etirinotecan pegol did not reach statistical significance. However, provocative and potentially very important survival results in predefined subgroups of patients deserve further study, specifically, patients with brain metastases or liver metastases,” she said. “Exploration of potential predictive biomarkers is ongoing.”
The findings regarding brain metastases are “an intriguing nugget,” according to invited discussant Dr. Harold J. Burstein, a senior physician at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston. “I think these data and the growing literature on the effectiveness of systemic therapy for brain metastases … suggest that it’s time for us to be doing trials where we are comparing standards of care of radiotherapy against chemotherapy, trying to optimize our chemotherapy regimens for the palliation of metastatic disease of the brain.”
He pointed to a set of trials in patients with advanced lung cancer testing the benefits of early palliative care on outcomes and finding improvements in overall survival or in quality of life with no detriment to overall survival.
“I used to look at these and think this didn’t really speak to the breast cancer population. But when you start to see data in the heavily refractory patients as we have observed today, it turns out that their survival is unfortunately essentially the same as for all the patients who participated in these trials,” he said. “So when we think about what direction we should go for advanced breast cancer that’s heavily refractory to chemotherapy, in addition to exploring a variety of exciting new immunologic therapies, and targeted therapies … I think we need to begin to lean more on our palliation care specialists and colleagues to help us truly take optimal care of these patients.”
The 852 women studied in the BEACON trial had experienced progression after anthracycline, taxane, and capecitabine therapy and had received two to five prior therapies for their advanced disease. The trial, sponsored by Nektar Therapeutics, was unusual in that it allowed patients with stable brain metastases to enroll and set a high bar of overall survival as its primary endpoint, Dr. Perez noted.
The patients were randomized evenly to receive single-agent etirinotecan pegol or a single agent of the physician’s choice, which was most commonly eribulin.
Main results showed no significant improvement in overall survival among the entire trial population comparing etirinotecan pegol with physician’s choice (12.4 vs. 10.3 months; hazard ratio, 0.87; P = .08).
However, preplanned subgroup analyses showed that in the 8% of women who had a history of brain metastases, median overall survival was 10.0 months with the drug and 4.8 months with physician’s choice (HR, 0.51; P = .0099). The curves began to separate within 3 months of randomization, and the difference in the proportion of women alive at 12 months was “pretty amazing,” Dr. Perez noted, at 44% versus 19%.
There was a similar although smaller survival advantage of etirinotecan pegol among the 53% of patients with a history of liver metastases (10.9 vs. 8.3 months; HR, 0.73; P = .002).
A variety of biomarkers for etirinotecan benefit are still being analyzed, according to Dr. Perez. The most promising signal thus far has been a reduction in the number of topoisomerase 1–positive circulating tumor cells, with patients going from high (above the baseline median) to low (below the baseline median) numbers surviving significantly longer than peers having persistently high numbers (14.9 vs. 10.7 months; HR, 0.54; P = .007).
The rate of grade 3 or worse toxicity was lower with etirinotecan pegol than with physician’s choice (48% vs. 63%). The former was associated with a higher rate of diarrhea, whereas the latter was associated with higher rates of neutropenia and peripheral neuropathy.
Patients in the etirinotecan pegol group had a more favorable change from baseline in global health status and in physical functioning, reported Dr. Perez.
AT THE 2015 ASCO ANNUAL MEETING
Key clinical point: Etirinotecan pegol is efficacious in patients with brain or liver metastases of breast cancer.
Major finding: Etirinotecan pegol was associated with 49% and 27% reductions in the risk of death for patients with brain and liver metastases, respectively.
Data source: A randomized phase III trial of etirinotecan pegol versus treatment of physician’s choice among 852 women with advanced breast cancer.
Disclosures: Dr. Perez disclosed that she had no relevant conflicts of interest. The trial was sponsored by Nektar Therapeutics.
ASCO: Omitting adjuvant radiation after pCR ups locoregional recurrence risk
CHICAGO – Women with breast cancer treated with neoadjuvant chemotherapy and surgery are more likely to have a recurrence in the breast, chest wall, or axilla or to die if they don’t receive adjuvant radiation therapy, even if they had a pathologic complete response to the chemotherapy, new data show.
In a meta-analysis of three Gepar trials conducted by the German Breast Group, radiation therapy was associated with a 38% lower multivariate risk of locoregional recurrence or death, investigators reported at the annual meeting of the American Society of Clinical Oncology. Significant benefit was seen regardless of pathologic complete response, although findings across other subgroups were not consistent, possibly due to selection bias or underlying confounders.
“Radiotherapy is an independent prognostic factor for locoregional recurrence–free survival after neoadjuvant chemotherapy in breast cancer. However, the optimal selection criteria remain unclear,” commented first author Dr. David Krug of University Hospital Heidelberg (Germany).
“We are eagerly awaiting the results of prospective studies that are currently recruiting patients,” he added, referring to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-51 trial and the Radiotherapy After Primary Chemotherapy for Breast Cancer (RAPCHEM) trial.
Findings of this meta-analysis are not practice changing, according to invited discussant Dr. Monica Morrow, chief of the breast service, department of surgery, and the Anne Burnett Windfohr Chair of Clinical Oncology at the Memorial Sloan Kettering Cancer Center in New York. “The Gepar data is not consistent enough across subsets to draw any different conclusions other than we need more data,” she said.
Focusing on the women who underwent mastectomy, she noted that only a small number who had a pathologic complete response did not receive radiation therapy, “so this study unfortunately lacks the power to tell us anything about the ability to eliminate radiation in this group.”
“What we’d really like to know about local control after neoadjuvant therapy is what’s the relative contribution of pretreatment stage and posttreatment stage to the risk of locoregional recurrence, especially in patients who achieve pathologic complete response? And if we try to address that question with this study, the results were a little murky,” Dr. Morrow further noted. For example, patients with higher–T stage primary tumors benefited from postmastectomy radiation, but patients who were clinically node positive did not.
“I think right now, what we have to say is we need to continue to do what we have been doing up until the present time, namely, patients whose presenting stage clearly indicates the need for radiotherapy should receive it, and patients who have lower-stage disease perhaps not,” she concluded, agreeing that the NSABP B-51 trial should help put this issue to rest.
Dr. Krug and his colleagues performed a pooled meta-analysis of data from the GeparTrio, GeparQuattro, and GeparQuinto trials of neoadjuvant chemotherapy, in which guidelines specified when adjuvant radiation therapy should be used. Those guidelines called for whole-breast radiation therapy with a boost after breast-conserving surgery (with omission of the boost in low-risk patients); radiation therapy after mastectomy for patients having more extensive disease before neoadjuvant chemotherapy; and radiation therapy for those with greater involvement of the regional lymphatics.
The meta-analysis was based on a total of 3,370 women. Overall, 94% received radiation therapy (99% of those who had undergone breast-conserving surgery and 85% of those who had undergone mastectomy).
With a median follow-up of 4.2 years, the 5-year rate of locoregional recurrence–free survival was 89.2% in the entire study population, according to Dr. Krug.
Women who did not receive radiation therapy had a significantly elevated risk of such recurrence or death compared with peers who received it. In subgroups analyses, benefit was significant whether women had had a pathologic complete response to neoadjuvant chemotherapy or not. Greatest absolute benefit was seen in those with a pathologic complete response, clinically positive nodes, or pathologically negative nodes.
The 5-year rate of disease-free survival was 74.0% in the entire study population. Here, there was only a trend toward a higher risk of events for women who did not receive radiation therapy.
In multivariate analyses, radiation therapy independently predicted better locoregional recurrence–free survival (hazard ratio, 0.62; P = .038) but not disease-free survival.
When analyses were restricted to women who had undergone mastectomy, radiation therapy was associated with significantly better locoregional recurrence–free survival among those with clinical stage T3/4 disease, pathologically negative nodes, a conversion from clinically positive to pathologically negative nodes, or hormone receptor–negative, HER2-positive disease.
It was associated with poorer disease-free survival for patients who did not achieve a pathologic complete response, had clinical stage T1/2 disease, or were clinically node negative.
Multivariate analysis here again showed that radiation therapy independently predicted better locoregional recurrence–free survival (HR, 0.56; P = .029) but not disease-free survival.
CHICAGO – Women with breast cancer treated with neoadjuvant chemotherapy and surgery are more likely to have a recurrence in the breast, chest wall, or axilla or to die if they don’t receive adjuvant radiation therapy, even if they had a pathologic complete response to the chemotherapy, new data show.
In a meta-analysis of three Gepar trials conducted by the German Breast Group, radiation therapy was associated with a 38% lower multivariate risk of locoregional recurrence or death, investigators reported at the annual meeting of the American Society of Clinical Oncology. Significant benefit was seen regardless of pathologic complete response, although findings across other subgroups were not consistent, possibly due to selection bias or underlying confounders.
“Radiotherapy is an independent prognostic factor for locoregional recurrence–free survival after neoadjuvant chemotherapy in breast cancer. However, the optimal selection criteria remain unclear,” commented first author Dr. David Krug of University Hospital Heidelberg (Germany).
“We are eagerly awaiting the results of prospective studies that are currently recruiting patients,” he added, referring to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-51 trial and the Radiotherapy After Primary Chemotherapy for Breast Cancer (RAPCHEM) trial.
Findings of this meta-analysis are not practice changing, according to invited discussant Dr. Monica Morrow, chief of the breast service, department of surgery, and the Anne Burnett Windfohr Chair of Clinical Oncology at the Memorial Sloan Kettering Cancer Center in New York. “The Gepar data is not consistent enough across subsets to draw any different conclusions other than we need more data,” she said.
Focusing on the women who underwent mastectomy, she noted that only a small number who had a pathologic complete response did not receive radiation therapy, “so this study unfortunately lacks the power to tell us anything about the ability to eliminate radiation in this group.”
“What we’d really like to know about local control after neoadjuvant therapy is what’s the relative contribution of pretreatment stage and posttreatment stage to the risk of locoregional recurrence, especially in patients who achieve pathologic complete response? And if we try to address that question with this study, the results were a little murky,” Dr. Morrow further noted. For example, patients with higher–T stage primary tumors benefited from postmastectomy radiation, but patients who were clinically node positive did not.
“I think right now, what we have to say is we need to continue to do what we have been doing up until the present time, namely, patients whose presenting stage clearly indicates the need for radiotherapy should receive it, and patients who have lower-stage disease perhaps not,” she concluded, agreeing that the NSABP B-51 trial should help put this issue to rest.
Dr. Krug and his colleagues performed a pooled meta-analysis of data from the GeparTrio, GeparQuattro, and GeparQuinto trials of neoadjuvant chemotherapy, in which guidelines specified when adjuvant radiation therapy should be used. Those guidelines called for whole-breast radiation therapy with a boost after breast-conserving surgery (with omission of the boost in low-risk patients); radiation therapy after mastectomy for patients having more extensive disease before neoadjuvant chemotherapy; and radiation therapy for those with greater involvement of the regional lymphatics.
The meta-analysis was based on a total of 3,370 women. Overall, 94% received radiation therapy (99% of those who had undergone breast-conserving surgery and 85% of those who had undergone mastectomy).
With a median follow-up of 4.2 years, the 5-year rate of locoregional recurrence–free survival was 89.2% in the entire study population, according to Dr. Krug.
Women who did not receive radiation therapy had a significantly elevated risk of such recurrence or death compared with peers who received it. In subgroups analyses, benefit was significant whether women had had a pathologic complete response to neoadjuvant chemotherapy or not. Greatest absolute benefit was seen in those with a pathologic complete response, clinically positive nodes, or pathologically negative nodes.
The 5-year rate of disease-free survival was 74.0% in the entire study population. Here, there was only a trend toward a higher risk of events for women who did not receive radiation therapy.
In multivariate analyses, radiation therapy independently predicted better locoregional recurrence–free survival (hazard ratio, 0.62; P = .038) but not disease-free survival.
When analyses were restricted to women who had undergone mastectomy, radiation therapy was associated with significantly better locoregional recurrence–free survival among those with clinical stage T3/4 disease, pathologically negative nodes, a conversion from clinically positive to pathologically negative nodes, or hormone receptor–negative, HER2-positive disease.
It was associated with poorer disease-free survival for patients who did not achieve a pathologic complete response, had clinical stage T1/2 disease, or were clinically node negative.
Multivariate analysis here again showed that radiation therapy independently predicted better locoregional recurrence–free survival (HR, 0.56; P = .029) but not disease-free survival.
CHICAGO – Women with breast cancer treated with neoadjuvant chemotherapy and surgery are more likely to have a recurrence in the breast, chest wall, or axilla or to die if they don’t receive adjuvant radiation therapy, even if they had a pathologic complete response to the chemotherapy, new data show.
In a meta-analysis of three Gepar trials conducted by the German Breast Group, radiation therapy was associated with a 38% lower multivariate risk of locoregional recurrence or death, investigators reported at the annual meeting of the American Society of Clinical Oncology. Significant benefit was seen regardless of pathologic complete response, although findings across other subgroups were not consistent, possibly due to selection bias or underlying confounders.
“Radiotherapy is an independent prognostic factor for locoregional recurrence–free survival after neoadjuvant chemotherapy in breast cancer. However, the optimal selection criteria remain unclear,” commented first author Dr. David Krug of University Hospital Heidelberg (Germany).
“We are eagerly awaiting the results of prospective studies that are currently recruiting patients,” he added, referring to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-51 trial and the Radiotherapy After Primary Chemotherapy for Breast Cancer (RAPCHEM) trial.
Findings of this meta-analysis are not practice changing, according to invited discussant Dr. Monica Morrow, chief of the breast service, department of surgery, and the Anne Burnett Windfohr Chair of Clinical Oncology at the Memorial Sloan Kettering Cancer Center in New York. “The Gepar data is not consistent enough across subsets to draw any different conclusions other than we need more data,” she said.
Focusing on the women who underwent mastectomy, she noted that only a small number who had a pathologic complete response did not receive radiation therapy, “so this study unfortunately lacks the power to tell us anything about the ability to eliminate radiation in this group.”
“What we’d really like to know about local control after neoadjuvant therapy is what’s the relative contribution of pretreatment stage and posttreatment stage to the risk of locoregional recurrence, especially in patients who achieve pathologic complete response? And if we try to address that question with this study, the results were a little murky,” Dr. Morrow further noted. For example, patients with higher–T stage primary tumors benefited from postmastectomy radiation, but patients who were clinically node positive did not.
“I think right now, what we have to say is we need to continue to do what we have been doing up until the present time, namely, patients whose presenting stage clearly indicates the need for radiotherapy should receive it, and patients who have lower-stage disease perhaps not,” she concluded, agreeing that the NSABP B-51 trial should help put this issue to rest.
Dr. Krug and his colleagues performed a pooled meta-analysis of data from the GeparTrio, GeparQuattro, and GeparQuinto trials of neoadjuvant chemotherapy, in which guidelines specified when adjuvant radiation therapy should be used. Those guidelines called for whole-breast radiation therapy with a boost after breast-conserving surgery (with omission of the boost in low-risk patients); radiation therapy after mastectomy for patients having more extensive disease before neoadjuvant chemotherapy; and radiation therapy for those with greater involvement of the regional lymphatics.
The meta-analysis was based on a total of 3,370 women. Overall, 94% received radiation therapy (99% of those who had undergone breast-conserving surgery and 85% of those who had undergone mastectomy).
With a median follow-up of 4.2 years, the 5-year rate of locoregional recurrence–free survival was 89.2% in the entire study population, according to Dr. Krug.
Women who did not receive radiation therapy had a significantly elevated risk of such recurrence or death compared with peers who received it. In subgroups analyses, benefit was significant whether women had had a pathologic complete response to neoadjuvant chemotherapy or not. Greatest absolute benefit was seen in those with a pathologic complete response, clinically positive nodes, or pathologically negative nodes.
The 5-year rate of disease-free survival was 74.0% in the entire study population. Here, there was only a trend toward a higher risk of events for women who did not receive radiation therapy.
In multivariate analyses, radiation therapy independently predicted better locoregional recurrence–free survival (hazard ratio, 0.62; P = .038) but not disease-free survival.
When analyses were restricted to women who had undergone mastectomy, radiation therapy was associated with significantly better locoregional recurrence–free survival among those with clinical stage T3/4 disease, pathologically negative nodes, a conversion from clinically positive to pathologically negative nodes, or hormone receptor–negative, HER2-positive disease.
It was associated with poorer disease-free survival for patients who did not achieve a pathologic complete response, had clinical stage T1/2 disease, or were clinically node negative.
Multivariate analysis here again showed that radiation therapy independently predicted better locoregional recurrence–free survival (HR, 0.56; P = .029) but not disease-free survival.
AT THE 2015 ASCO ANNUAL MEETING
Key clinical point: Adjuvant radiation therapy improves locoregional recurrence–free survival after neoadjuvant chemo and surgery for breast cancer.
Major finding: Women who received adjuvant radiation therapy had a 38% lower risk of locoregional recurrence or death.
Data source: A meta-analysis of three randomized trials among 3,370 women who underwent neoadjuvant chemotherapy and surgery for breast cancer.
Disclosures: Dr. Krug disclosed that he receives travel expenses from Accuray.
BCL-2 inhibitor shows potential for treating MM
to an attendee at ASCO 2015
© ASCO/Zach Boyden-Holmes
CHICAGO—A BCL-2 inhibitor that has shown activity in patients with chronic and acute leukemias could be a feasible treatment option for multiple myeloma (MM) too, according to research presented at the 2015 ASCO Annual Meeting.
In a pair of phase 1 studies, the drug, venetoclax, prompted responses in certain patients with relapsed or refractory MM, both when given alone and in combination with bortezomib and dexamethasone.
As monotherapy, venetoclax induced complete responses (CRs) in 2 patients with t(11;14), but the overall response rate (ORR) was low, and most patients discontinued treatment, largely due to progression.
Venetoclax in combination with bortezomib and dexamethasone prompted a response in nearly half of the patients studied, but more than half discontinued treatment. The combination produced a high ORR in patients who were bortezomib-naïve and bortezomib-sensitive, but there was no response among bortezomib-refractory patients.
“Multiple myeloma remains a high area of unmet medical need, and additional research to identify new therapies is important,” said investigator Cyrille Touzeau, MD, of the University of Nantes in France.
“The response rates shown in these studies suggest potential of venetoclax in this patient population and warrant further evaluation.”
Dr Touzeau and his colleagues presented these studies at ASCO as abstracts 8580 and 8576. Both studies were funded by AbbVie, the company developing venetoclax.
Venetoclax in combination
In a phase 1b study (abstract 8580*), the researchers evaluated venetoclax in combination with bortezomib and dexamethasone in 38 patients with relapsed or refractory MM.
The patients’ median age was 65 (range, 38-79). Five patients were t(11;14)-positive, 3 were t(4;14)-positive, 9 had del17p, and 19 had del13q. They had received a median of 5 prior lines of therapy (range, 1-15). Ten patients were bortezomib-refractory, 21 were lenalidomide-refractory, and 8 patients were refractory to both drugs.
The patients received venetoclax at doses ranging from 50 mg to 600 mg daily (with a 1-week lead-in period for the 50 mg cohort). On cycles 1-8, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m2) with venetoclax on days 1, 4, 8, and 11. They received dexamethasone (20 mg) with venetoclax on days 2, 5, 9, and 12.
On cycles 9-11, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m2) with venetoclax on days 1, 8, 15, and 22. Patients received venetoclax monotherapy for cycles 12 and beyond. They also received prophylaxis for tumor lysis syndrome.
Twenty-five patients (66%) discontinued treatment, 19 due to disease progression (including 4 deaths), 2 due to adverse events (AEs), 3 due to patient decision, and 1 due to withdrawn consent.
The ORR was 47% among the 36 evaluable patients, 83% for bortezomib-naïve patients (5/6), 60% for bortezomib-sensitive patients (12/20), and 0% for bortezomib-refractory patients (0/10).
Two patients had a stringent CR, 1 had a CR, 4 had a very good partial response, 10 had a partial response, and 2 had a minimal response. Six patients had stable disease, and 9 progressed.
The most common AEs—occurring in at least 20% of patients—were constipation (37%), diarrhea (32%), insomnia (32%), thrombocytopenia (29%), peripheral neuropathy (26%), asthenia (26%), dyspnea (26%), peripheral edema (24%), and anemia (21%).
Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (21%), anemia (13%), and dyspnea (11%). Serious AEs—each occurring in 5% of patients—were cardiac failure, pyrexia, sepsis, respiratory failure, pneumonia, and embolism.
Venetoclax as monotherapy
In a phase 1 study (abstract 8576*), researchers evaluated venetoclax as monotherapy in 29 patients with relapsed or refractory MM. Eleven patients were t(11;14)-positive, 2 were t(4;14)-positive, 4 had del17p, and 14 had del13q.
The patients’ median age was 66 (range, 42-79), and they had received a median of 6 prior therapies (range, 1-13). Fifteen patients were bortezomib-refractory, 12 were refractory to lenalidomide, and 10 patients were refractory to both drugs.
After a 2-week lead-in period, patients received venetoclax daily on a 21-day cycle, ranging from 300 mg to 1200 mg on a 3+3 design. They also received prophylaxis for tumor lysis syndrome. Patients who progressed during treatment were allowed to receive dexamethasone as well and continue the study.
Twenty-three patients (79%) discontinued treatment, 18 due to disease progression, 4 due to AEs, and 1 due to patient decision.
The ORR was 7% (n=2). Both patients achieved a CR, and both were t(11;14)-positive. One of the patients is in the 600 mg cohort and is still responding to treatment. The duration of response, thus far, is 2.1 months.
The other patient with a CR is in the 900 mg dose cohort. This patient is still responding as well, and the response duration, thus far, is 2.8 months.
Common AEs—occurring in at least 20% of patients—were diarrhea (41%), nausea (41%), fatigue (24%), vomiting (21%), asthenia (21%), and neutropenia (21%).
Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (24%), neutropenia (14%), and anemia (10%). Serious AEs—each occurring in 7% of patients—were pyrexia, malignant neoplasm progression, and cough.
Two patients had dose-limiting toxicities at the 600 mg dose of venetoclax. However, the researchers said the maximum tolerated dose was not reached, and the recommended phase 2 dose is 1200 mg. 
*Information in the abstract differs from that presented at the meeting.
to an attendee at ASCO 2015
© ASCO/Zach Boyden-Holmes
CHICAGO—A BCL-2 inhibitor that has shown activity in patients with chronic and acute leukemias could be a feasible treatment option for multiple myeloma (MM) too, according to research presented at the 2015 ASCO Annual Meeting.
In a pair of phase 1 studies, the drug, venetoclax, prompted responses in certain patients with relapsed or refractory MM, both when given alone and in combination with bortezomib and dexamethasone.
As monotherapy, venetoclax induced complete responses (CRs) in 2 patients with t(11;14), but the overall response rate (ORR) was low, and most patients discontinued treatment, largely due to progression.
Venetoclax in combination with bortezomib and dexamethasone prompted a response in nearly half of the patients studied, but more than half discontinued treatment. The combination produced a high ORR in patients who were bortezomib-naïve and bortezomib-sensitive, but there was no response among bortezomib-refractory patients.
“Multiple myeloma remains a high area of unmet medical need, and additional research to identify new therapies is important,” said investigator Cyrille Touzeau, MD, of the University of Nantes in France.
“The response rates shown in these studies suggest potential of venetoclax in this patient population and warrant further evaluation.”
Dr Touzeau and his colleagues presented these studies at ASCO as abstracts 8580 and 8576. Both studies were funded by AbbVie, the company developing venetoclax.
Venetoclax in combination
In a phase 1b study (abstract 8580*), the researchers evaluated venetoclax in combination with bortezomib and dexamethasone in 38 patients with relapsed or refractory MM.
The patients’ median age was 65 (range, 38-79). Five patients were t(11;14)-positive, 3 were t(4;14)-positive, 9 had del17p, and 19 had del13q. They had received a median of 5 prior lines of therapy (range, 1-15). Ten patients were bortezomib-refractory, 21 were lenalidomide-refractory, and 8 patients were refractory to both drugs.
The patients received venetoclax at doses ranging from 50 mg to 600 mg daily (with a 1-week lead-in period for the 50 mg cohort). On cycles 1-8, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m2) with venetoclax on days 1, 4, 8, and 11. They received dexamethasone (20 mg) with venetoclax on days 2, 5, 9, and 12.
On cycles 9-11, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m2) with venetoclax on days 1, 8, 15, and 22. Patients received venetoclax monotherapy for cycles 12 and beyond. They also received prophylaxis for tumor lysis syndrome.
Twenty-five patients (66%) discontinued treatment, 19 due to disease progression (including 4 deaths), 2 due to adverse events (AEs), 3 due to patient decision, and 1 due to withdrawn consent.
The ORR was 47% among the 36 evaluable patients, 83% for bortezomib-naïve patients (5/6), 60% for bortezomib-sensitive patients (12/20), and 0% for bortezomib-refractory patients (0/10).
Two patients had a stringent CR, 1 had a CR, 4 had a very good partial response, 10 had a partial response, and 2 had a minimal response. Six patients had stable disease, and 9 progressed.
The most common AEs—occurring in at least 20% of patients—were constipation (37%), diarrhea (32%), insomnia (32%), thrombocytopenia (29%), peripheral neuropathy (26%), asthenia (26%), dyspnea (26%), peripheral edema (24%), and anemia (21%).
Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (21%), anemia (13%), and dyspnea (11%). Serious AEs—each occurring in 5% of patients—were cardiac failure, pyrexia, sepsis, respiratory failure, pneumonia, and embolism.
Venetoclax as monotherapy
In a phase 1 study (abstract 8576*), researchers evaluated venetoclax as monotherapy in 29 patients with relapsed or refractory MM. Eleven patients were t(11;14)-positive, 2 were t(4;14)-positive, 4 had del17p, and 14 had del13q.
The patients’ median age was 66 (range, 42-79), and they had received a median of 6 prior therapies (range, 1-13). Fifteen patients were bortezomib-refractory, 12 were refractory to lenalidomide, and 10 patients were refractory to both drugs.
After a 2-week lead-in period, patients received venetoclax daily on a 21-day cycle, ranging from 300 mg to 1200 mg on a 3+3 design. They also received prophylaxis for tumor lysis syndrome. Patients who progressed during treatment were allowed to receive dexamethasone as well and continue the study.
Twenty-three patients (79%) discontinued treatment, 18 due to disease progression, 4 due to AEs, and 1 due to patient decision.
The ORR was 7% (n=2). Both patients achieved a CR, and both were t(11;14)-positive. One of the patients is in the 600 mg cohort and is still responding to treatment. The duration of response, thus far, is 2.1 months.
The other patient with a CR is in the 900 mg dose cohort. This patient is still responding as well, and the response duration, thus far, is 2.8 months.
Common AEs—occurring in at least 20% of patients—were diarrhea (41%), nausea (41%), fatigue (24%), vomiting (21%), asthenia (21%), and neutropenia (21%).
Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (24%), neutropenia (14%), and anemia (10%). Serious AEs—each occurring in 7% of patients—were pyrexia, malignant neoplasm progression, and cough.
Two patients had dose-limiting toxicities at the 600 mg dose of venetoclax. However, the researchers said the maximum tolerated dose was not reached, and the recommended phase 2 dose is 1200 mg.
*Information in the abstract differs from that presented at the meeting.
to an attendee at ASCO 2015
© ASCO/Zach Boyden-Holmes
CHICAGO—A BCL-2 inhibitor that has shown activity in patients with chronic and acute leukemias could be a feasible treatment option for multiple myeloma (MM) too, according to research presented at the 2015 ASCO Annual Meeting.
In a pair of phase 1 studies, the drug, venetoclax, prompted responses in certain patients with relapsed or refractory MM, both when given alone and in combination with bortezomib and dexamethasone.
As monotherapy, venetoclax induced complete responses (CRs) in 2 patients with t(11;14), but the overall response rate (ORR) was low, and most patients discontinued treatment, largely due to progression.
Venetoclax in combination with bortezomib and dexamethasone prompted a response in nearly half of the patients studied, but more than half discontinued treatment. The combination produced a high ORR in patients who were bortezomib-naïve and bortezomib-sensitive, but there was no response among bortezomib-refractory patients.
“Multiple myeloma remains a high area of unmet medical need, and additional research to identify new therapies is important,” said investigator Cyrille Touzeau, MD, of the University of Nantes in France.
“The response rates shown in these studies suggest potential of venetoclax in this patient population and warrant further evaluation.”
Dr Touzeau and his colleagues presented these studies at ASCO as abstracts 8580 and 8576. Both studies were funded by AbbVie, the company developing venetoclax.
Venetoclax in combination
In a phase 1b study (abstract 8580*), the researchers evaluated venetoclax in combination with bortezomib and dexamethasone in 38 patients with relapsed or refractory MM.
The patients’ median age was 65 (range, 38-79). Five patients were t(11;14)-positive, 3 were t(4;14)-positive, 9 had del17p, and 19 had del13q. They had received a median of 5 prior lines of therapy (range, 1-15). Ten patients were bortezomib-refractory, 21 were lenalidomide-refractory, and 8 patients were refractory to both drugs.
The patients received venetoclax at doses ranging from 50 mg to 600 mg daily (with a 1-week lead-in period for the 50 mg cohort). On cycles 1-8, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m2) with venetoclax on days 1, 4, 8, and 11. They received dexamethasone (20 mg) with venetoclax on days 2, 5, 9, and 12.
On cycles 9-11, patients received dexamethasone (20 mg) and bortezomib (1.3 mg/m2) with venetoclax on days 1, 8, 15, and 22. Patients received venetoclax monotherapy for cycles 12 and beyond. They also received prophylaxis for tumor lysis syndrome.
Twenty-five patients (66%) discontinued treatment, 19 due to disease progression (including 4 deaths), 2 due to adverse events (AEs), 3 due to patient decision, and 1 due to withdrawn consent.
The ORR was 47% among the 36 evaluable patients, 83% for bortezomib-naïve patients (5/6), 60% for bortezomib-sensitive patients (12/20), and 0% for bortezomib-refractory patients (0/10).
Two patients had a stringent CR, 1 had a CR, 4 had a very good partial response, 10 had a partial response, and 2 had a minimal response. Six patients had stable disease, and 9 progressed.
The most common AEs—occurring in at least 20% of patients—were constipation (37%), diarrhea (32%), insomnia (32%), thrombocytopenia (29%), peripheral neuropathy (26%), asthenia (26%), dyspnea (26%), peripheral edema (24%), and anemia (21%).
Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (21%), anemia (13%), and dyspnea (11%). Serious AEs—each occurring in 5% of patients—were cardiac failure, pyrexia, sepsis, respiratory failure, pneumonia, and embolism.
Venetoclax as monotherapy
In a phase 1 study (abstract 8576*), researchers evaluated venetoclax as monotherapy in 29 patients with relapsed or refractory MM. Eleven patients were t(11;14)-positive, 2 were t(4;14)-positive, 4 had del17p, and 14 had del13q.
The patients’ median age was 66 (range, 42-79), and they had received a median of 6 prior therapies (range, 1-13). Fifteen patients were bortezomib-refractory, 12 were refractory to lenalidomide, and 10 patients were refractory to both drugs.
After a 2-week lead-in period, patients received venetoclax daily on a 21-day cycle, ranging from 300 mg to 1200 mg on a 3+3 design. They also received prophylaxis for tumor lysis syndrome. Patients who progressed during treatment were allowed to receive dexamethasone as well and continue the study.
Twenty-three patients (79%) discontinued treatment, 18 due to disease progression, 4 due to AEs, and 1 due to patient decision.
The ORR was 7% (n=2). Both patients achieved a CR, and both were t(11;14)-positive. One of the patients is in the 600 mg cohort and is still responding to treatment. The duration of response, thus far, is 2.1 months.
The other patient with a CR is in the 900 mg dose cohort. This patient is still responding as well, and the response duration, thus far, is 2.8 months.
Common AEs—occurring in at least 20% of patients—were diarrhea (41%), nausea (41%), fatigue (24%), vomiting (21%), asthenia (21%), and neutropenia (21%).
Grade 3/4 AEs—occurring in at least 10% of patients—were thrombocytopenia (24%), neutropenia (14%), and anemia (10%). Serious AEs—each occurring in 7% of patients—were pyrexia, malignant neoplasm progression, and cough.
Two patients had dose-limiting toxicities at the 600 mg dose of venetoclax. However, the researchers said the maximum tolerated dose was not reached, and the recommended phase 2 dose is 1200 mg.
*Information in the abstract differs from that presented at the meeting.
ASCO: Two hits and a miss against advanced urothelial cancer
CHICAGO – Immunotherapies showed their mettle against advanced urothelial cancers in two clinical trials presented at the annual meeting of the American Society of Clinical Oncology, but the targeted agent lapatinib was a total bust as maintenance therapy following chemotherapy in patients with HER1/HER2-positive metastatic bladder cancers.
In a phase Ia trial of an investigational monoclonal antibody (atezolizumab; MPDL3280A)) targeted against the programmed death ligand 1 (PD-L1, also targeted by pembrolizumab [Keytruda]), the overall response rate (ORR) among patients with heavily pretreated urothelial bladder cancer whose tumors had high levels of PD-L1 expression was 50%, and the 1-year overall survival (OS) rate was 57%, reported Dr. Daniel P. Petrylak from the Yale Cancer Center in New Haven, Conn.
In a separate trial, also in a heavily pretreated population, pembrolizumab, which blocks both PD-L1 and PD-L2, was associated with a 28% ORR, a 10% complete response rate (CR), and 1-year overall survival of 50%, said Dr. Elizabeth Plimack from the Fox Chase Cancer Center, Philadelphia.
“I would say we are so far past the end of the old era of cytotoxic, nonselected trials, that we can’t even see it in the rearview mirror anymore,” said Dr. Noah M. Hahn from the Johns Hopkins Medical Institutions, Baltimore, commenting on the immunotherapy abstracts. Dr. Hahn was the invited discussant.
But at the same oral abstract session, results of a phase II/III double-blind, randomized trial comparing maintenance lapatinib (Tykerb) with placebo following chemotherapy for metastatic HER1/HER2-positive bladder cancer showed absolutely no benefit from the drug, no matter how the data were sliced, dissected, or rearranged, reported Dr. Thomas Powles from the Barts Cancer Institute at Queen Mary University of London.
“We desperately need new drugs here,” Dr. Powles said.
Atezolizumab trial
“Metastatic urothelial bladder cancer [UBC] is associated with poor outcomes. There are no FDA-approved therapies for patients who relapse after platinum-based therapy, and the overall survival is approximately 5-7 months. Urothelial bladder cancer has a high mutational load, due to tobacco and environmental carcinogen exposures. In other cancers, high somatic nonsynonomous mutational burden has been associated with durable clinical benefit of PD-L1/PD-1-directed therapy, thus the justification for examining this in urothelial bladder cancer,” Dr. Petrylak said.
He presented data on a cohort of 92 patients with metastatic UBC who were enrolled in a larger trial of atezolizumab against UBC and other cancers. The cohort originally included patients with high levels of PD-L1 expression on immunochemical staining (IC 2/3), but was later expanded to include all comers, the majority of whom had low or no detectable levels of PD-L1 expression (IC 0/1).
The patients received atezolizumab via intravenous administration every 3 weeks at either 15 mg/kg of body weight, or in a 1200-mg flat dose.
Responses to atezolizumab among 87 patients evaluable for efficacy correlated with PD-L1 expression, with the 12 patients in the highest quartile (IC 3) having an ORR of 67%, and 34 patients with IC2 having an ORR of 44%, for a combined ORR of 50%. This included 9 patients with a complete response, and 14 with a partial response.
In contrast, the combined ORR for patients with IC 1 or IC 0 was 17%, with no complete responses, and 7 partial responses.
Among 80 patients with postbaseline tumor assessments, 44 had a reduction in tumor burden. There was also a decrease in circulation C-reactive protein, an inflammatory marker, as well as in the tumor markers carcinoembryonic antigen and cancer antigen 19-9 among patients who had responses to atezolizumab.
Patients generally tolerated the treatment well at a median safety follow-up of 16 weeks, with no treatment-related deaths, and only one discontinuation due to a treatment-related adverse event. Grade 3 or 4 immune-mediated events occurred in 5% of patients, and included an increase in aspartate aminotransferase, increased blood bilirubin, and hypophysitis.
Pembrolizumab trial
Dr. Plimack presented updated results and a biomarker analysis from the KEYNOTE 012 study, a phase I study of pembrolizumab in patients with urothelial tract cancers as well as triple-negative breast cancer, head and neck cancer, and gastric cancer.
In the urothelial cohort, 33 patients with recurrent or metastatic cancer of the renal pelvis, ureter, bladder, or urethra received pembrolizumab 10 mg/kg IV every other week until either complete response, after which therapy could be discontinued if desired; partial response or stable disease, which could be followed by 24 months of additional therapy or until disease progression or intolerable toxicity; or confirmed disease progression, whereupon treatment would stop.
Among 29 patients evaluable for response, 8 (27.6%) had a response, including 3 complete responses, and 5 partial responses. There were 3 cases with stable disease, and 14 with disease progression. Four patients did not have a response assessment due to early discontinuation.
Of the eight responders, all had a more than 30% decrease in the size of target lesions.
The patients tolerated the therapy well, with 85% having either grade 1 or 2 adverse events, or none, and no new safety signals were seen. Grade 3 or 4 adverse events occurred in five patients, with no event occurring more than once, but some occurring concurrently in more than one patient. These events included AST elevation, dehydration, hypercalcemia, myalgia, myositis, neuromyopathy, maculopapular and pruritic rashes, rhabdomyolysis, thrombocytopenia, and toxic encephalopathy.
The atezolizumab study was sponsored by Genentech. The pembrolizumab study was supported by Merck. Dr. Petrylak disclosed research funding and travel honoraria from Genentech. Dr. Plimack is an advisory board member for Merck and receives institutional research funding from the company. Dr. Hahn is a consultant/advisor to Genentech and Merck, and receives institutional research funds from the companies.
CHICAGO – Immunotherapies showed their mettle against advanced urothelial cancers in two clinical trials presented at the annual meeting of the American Society of Clinical Oncology, but the targeted agent lapatinib was a total bust as maintenance therapy following chemotherapy in patients with HER1/HER2-positive metastatic bladder cancers.
In a phase Ia trial of an investigational monoclonal antibody (atezolizumab; MPDL3280A)) targeted against the programmed death ligand 1 (PD-L1, also targeted by pembrolizumab [Keytruda]), the overall response rate (ORR) among patients with heavily pretreated urothelial bladder cancer whose tumors had high levels of PD-L1 expression was 50%, and the 1-year overall survival (OS) rate was 57%, reported Dr. Daniel P. Petrylak from the Yale Cancer Center in New Haven, Conn.
In a separate trial, also in a heavily pretreated population, pembrolizumab, which blocks both PD-L1 and PD-L2, was associated with a 28% ORR, a 10% complete response rate (CR), and 1-year overall survival of 50%, said Dr. Elizabeth Plimack from the Fox Chase Cancer Center, Philadelphia.
“I would say we are so far past the end of the old era of cytotoxic, nonselected trials, that we can’t even see it in the rearview mirror anymore,” said Dr. Noah M. Hahn from the Johns Hopkins Medical Institutions, Baltimore, commenting on the immunotherapy abstracts. Dr. Hahn was the invited discussant.
But at the same oral abstract session, results of a phase II/III double-blind, randomized trial comparing maintenance lapatinib (Tykerb) with placebo following chemotherapy for metastatic HER1/HER2-positive bladder cancer showed absolutely no benefit from the drug, no matter how the data were sliced, dissected, or rearranged, reported Dr. Thomas Powles from the Barts Cancer Institute at Queen Mary University of London.
“We desperately need new drugs here,” Dr. Powles said.
Atezolizumab trial
“Metastatic urothelial bladder cancer [UBC] is associated with poor outcomes. There are no FDA-approved therapies for patients who relapse after platinum-based therapy, and the overall survival is approximately 5-7 months. Urothelial bladder cancer has a high mutational load, due to tobacco and environmental carcinogen exposures. In other cancers, high somatic nonsynonomous mutational burden has been associated with durable clinical benefit of PD-L1/PD-1-directed therapy, thus the justification for examining this in urothelial bladder cancer,” Dr. Petrylak said.
He presented data on a cohort of 92 patients with metastatic UBC who were enrolled in a larger trial of atezolizumab against UBC and other cancers. The cohort originally included patients with high levels of PD-L1 expression on immunochemical staining (IC 2/3), but was later expanded to include all comers, the majority of whom had low or no detectable levels of PD-L1 expression (IC 0/1).
The patients received atezolizumab via intravenous administration every 3 weeks at either 15 mg/kg of body weight, or in a 1200-mg flat dose.
Responses to atezolizumab among 87 patients evaluable for efficacy correlated with PD-L1 expression, with the 12 patients in the highest quartile (IC 3) having an ORR of 67%, and 34 patients with IC2 having an ORR of 44%, for a combined ORR of 50%. This included 9 patients with a complete response, and 14 with a partial response.
In contrast, the combined ORR for patients with IC 1 or IC 0 was 17%, with no complete responses, and 7 partial responses.
Among 80 patients with postbaseline tumor assessments, 44 had a reduction in tumor burden. There was also a decrease in circulation C-reactive protein, an inflammatory marker, as well as in the tumor markers carcinoembryonic antigen and cancer antigen 19-9 among patients who had responses to atezolizumab.
Patients generally tolerated the treatment well at a median safety follow-up of 16 weeks, with no treatment-related deaths, and only one discontinuation due to a treatment-related adverse event. Grade 3 or 4 immune-mediated events occurred in 5% of patients, and included an increase in aspartate aminotransferase, increased blood bilirubin, and hypophysitis.
Pembrolizumab trial
Dr. Plimack presented updated results and a biomarker analysis from the KEYNOTE 012 study, a phase I study of pembrolizumab in patients with urothelial tract cancers as well as triple-negative breast cancer, head and neck cancer, and gastric cancer.
In the urothelial cohort, 33 patients with recurrent or metastatic cancer of the renal pelvis, ureter, bladder, or urethra received pembrolizumab 10 mg/kg IV every other week until either complete response, after which therapy could be discontinued if desired; partial response or stable disease, which could be followed by 24 months of additional therapy or until disease progression or intolerable toxicity; or confirmed disease progression, whereupon treatment would stop.
Among 29 patients evaluable for response, 8 (27.6%) had a response, including 3 complete responses, and 5 partial responses. There were 3 cases with stable disease, and 14 with disease progression. Four patients did not have a response assessment due to early discontinuation.
Of the eight responders, all had a more than 30% decrease in the size of target lesions.
The patients tolerated the therapy well, with 85% having either grade 1 or 2 adverse events, or none, and no new safety signals were seen. Grade 3 or 4 adverse events occurred in five patients, with no event occurring more than once, but some occurring concurrently in more than one patient. These events included AST elevation, dehydration, hypercalcemia, myalgia, myositis, neuromyopathy, maculopapular and pruritic rashes, rhabdomyolysis, thrombocytopenia, and toxic encephalopathy.
The atezolizumab study was sponsored by Genentech. The pembrolizumab study was supported by Merck. Dr. Petrylak disclosed research funding and travel honoraria from Genentech. Dr. Plimack is an advisory board member for Merck and receives institutional research funding from the company. Dr. Hahn is a consultant/advisor to Genentech and Merck, and receives institutional research funds from the companies.
CHICAGO – Immunotherapies showed their mettle against advanced urothelial cancers in two clinical trials presented at the annual meeting of the American Society of Clinical Oncology, but the targeted agent lapatinib was a total bust as maintenance therapy following chemotherapy in patients with HER1/HER2-positive metastatic bladder cancers.
In a phase Ia trial of an investigational monoclonal antibody (atezolizumab; MPDL3280A)) targeted against the programmed death ligand 1 (PD-L1, also targeted by pembrolizumab [Keytruda]), the overall response rate (ORR) among patients with heavily pretreated urothelial bladder cancer whose tumors had high levels of PD-L1 expression was 50%, and the 1-year overall survival (OS) rate was 57%, reported Dr. Daniel P. Petrylak from the Yale Cancer Center in New Haven, Conn.
In a separate trial, also in a heavily pretreated population, pembrolizumab, which blocks both PD-L1 and PD-L2, was associated with a 28% ORR, a 10% complete response rate (CR), and 1-year overall survival of 50%, said Dr. Elizabeth Plimack from the Fox Chase Cancer Center, Philadelphia.
“I would say we are so far past the end of the old era of cytotoxic, nonselected trials, that we can’t even see it in the rearview mirror anymore,” said Dr. Noah M. Hahn from the Johns Hopkins Medical Institutions, Baltimore, commenting on the immunotherapy abstracts. Dr. Hahn was the invited discussant.
But at the same oral abstract session, results of a phase II/III double-blind, randomized trial comparing maintenance lapatinib (Tykerb) with placebo following chemotherapy for metastatic HER1/HER2-positive bladder cancer showed absolutely no benefit from the drug, no matter how the data were sliced, dissected, or rearranged, reported Dr. Thomas Powles from the Barts Cancer Institute at Queen Mary University of London.
“We desperately need new drugs here,” Dr. Powles said.
Atezolizumab trial
“Metastatic urothelial bladder cancer [UBC] is associated with poor outcomes. There are no FDA-approved therapies for patients who relapse after platinum-based therapy, and the overall survival is approximately 5-7 months. Urothelial bladder cancer has a high mutational load, due to tobacco and environmental carcinogen exposures. In other cancers, high somatic nonsynonomous mutational burden has been associated with durable clinical benefit of PD-L1/PD-1-directed therapy, thus the justification for examining this in urothelial bladder cancer,” Dr. Petrylak said.
He presented data on a cohort of 92 patients with metastatic UBC who were enrolled in a larger trial of atezolizumab against UBC and other cancers. The cohort originally included patients with high levels of PD-L1 expression on immunochemical staining (IC 2/3), but was later expanded to include all comers, the majority of whom had low or no detectable levels of PD-L1 expression (IC 0/1).
The patients received atezolizumab via intravenous administration every 3 weeks at either 15 mg/kg of body weight, or in a 1200-mg flat dose.
Responses to atezolizumab among 87 patients evaluable for efficacy correlated with PD-L1 expression, with the 12 patients in the highest quartile (IC 3) having an ORR of 67%, and 34 patients with IC2 having an ORR of 44%, for a combined ORR of 50%. This included 9 patients with a complete response, and 14 with a partial response.
In contrast, the combined ORR for patients with IC 1 or IC 0 was 17%, with no complete responses, and 7 partial responses.
Among 80 patients with postbaseline tumor assessments, 44 had a reduction in tumor burden. There was also a decrease in circulation C-reactive protein, an inflammatory marker, as well as in the tumor markers carcinoembryonic antigen and cancer antigen 19-9 among patients who had responses to atezolizumab.
Patients generally tolerated the treatment well at a median safety follow-up of 16 weeks, with no treatment-related deaths, and only one discontinuation due to a treatment-related adverse event. Grade 3 or 4 immune-mediated events occurred in 5% of patients, and included an increase in aspartate aminotransferase, increased blood bilirubin, and hypophysitis.
Pembrolizumab trial
Dr. Plimack presented updated results and a biomarker analysis from the KEYNOTE 012 study, a phase I study of pembrolizumab in patients with urothelial tract cancers as well as triple-negative breast cancer, head and neck cancer, and gastric cancer.
In the urothelial cohort, 33 patients with recurrent or metastatic cancer of the renal pelvis, ureter, bladder, or urethra received pembrolizumab 10 mg/kg IV every other week until either complete response, after which therapy could be discontinued if desired; partial response or stable disease, which could be followed by 24 months of additional therapy or until disease progression or intolerable toxicity; or confirmed disease progression, whereupon treatment would stop.
Among 29 patients evaluable for response, 8 (27.6%) had a response, including 3 complete responses, and 5 partial responses. There were 3 cases with stable disease, and 14 with disease progression. Four patients did not have a response assessment due to early discontinuation.
Of the eight responders, all had a more than 30% decrease in the size of target lesions.
The patients tolerated the therapy well, with 85% having either grade 1 or 2 adverse events, or none, and no new safety signals were seen. Grade 3 or 4 adverse events occurred in five patients, with no event occurring more than once, but some occurring concurrently in more than one patient. These events included AST elevation, dehydration, hypercalcemia, myalgia, myositis, neuromyopathy, maculopapular and pruritic rashes, rhabdomyolysis, thrombocytopenia, and toxic encephalopathy.
The atezolizumab study was sponsored by Genentech. The pembrolizumab study was supported by Merck. Dr. Petrylak disclosed research funding and travel honoraria from Genentech. Dr. Plimack is an advisory board member for Merck and receives institutional research funding from the company. Dr. Hahn is a consultant/advisor to Genentech and Merck, and receives institutional research funds from the companies.
Key clinical point: Anti PD-L1 immunotherapies were effective in early clinical trials against advanced urothelial cancers.
Major finding: The overall response rate to atezolizumab among patients with higher levels of PD-L1 expression was 50%. The ORR to pembrolizumab was 27.6%. No benefit was found from lapatinib following chemotherapy for metastatic HER1/HER2-positive bladder cancer.
Data source: Open label, multiple cohort, dose-finding studies in 92 patients (atezolizumab) and 33 patients (pembrolizumab) with urothelial cancers. A phase II/III double-blind, randomized trial comparing maintenance lapatinib (Tykerb) with placebo.
Disclosures: The atezolizumab study was sponsored by Genentech. The pembrolizumab study was supported by Merck. Dr. Petrylak discloses research funding and travel honoraria from Genentech. Dr. Plimack is an advisory board member for Merck and receives institutional research funding from the company. Dr. Hahn is a consultant/adviser to Genentech and Merck, and receives institutional research funds from the companies.
CAR produces high CR rate in adults with rel/ref ALL
the 2015 ASCO Annual Meeting
© ASCO/Max Gersh
CHICAGO—A CD19-targeted chimeric antigen receptor (CAR) T-cell therapy can provide durable complete responses (CRs) or a bridge to allogeneic transplant in adults with relapsed or refractory acute lymphoblastic leukemia (ALL), updated results of a phase 1 study suggest.
The therapy, JCAR015, produced a CR rate of 87%, and 33% of these patients went on to transplant.
The median duration of response or relapse-free survival was 5.3 months. The median overall survival was 8.5 months.
Nearly a quarter of patients developed severe cytokine release syndrome (CRS), and nearly 30% experienced neurological toxicities. But researchers said these effects were largely treatable and reversible.
This study was temporarily placed on clinical hold last year, after 2 patients died from complications related to CRS. But the hold was soon lifted and enrollment and dosing criteria were changed in an attempt to prevent severe CRS.
Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented updated results of this trial (NCT01044069) at the 2015 ASCO Annual Meeting (abstract 7010*). The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.
Results from this trial have previously been reported in Science Translational Medicine (Davila et al 2014; Brentjens et al 2013), at AACR 2014, and at ASH 2014.
At ASCO, Dr Park presented results in 39 patients with relapsed/refractory, CD19+ ALL. All of them were evaluable for toxicity assessment, and 38 were evaluable for response with at least 1 month of follow-up.
There were 29 males, and the patients’ median age was 45 (range, 22-74). Thirty-three percent had Ph+ ALL, and 11% had the T315I mutation.
Forty-nine percent of patients had received 2 prior therapies, 23% had received 3, and 28% had received 4 or more. Thirty-six percent of patients had a prior allogeneic hematopoietic stem cell transplant (HSCT).
For this study, patients first underwent leukapheresis. While their T cells were being manufactured, they were allowed to receive salvage chemotherapy. Patients underwent repeat bone marrow biopsy to assess their disease status immediately prior to T-cell infusion.
Fifty-four percent of patients (n=21) had morphologic disease (>5% blasts in the bone marrow, median 52%) immediately prior to JCAR015 infusion, and the remaining patients (n=18) had minimal residual disease (MRD).
Two days after conditioning with cyclophosphamide, patients received an infusion of 1-3 x 106 CAR T cells/kg. At day 28, the researchers assessed patients’ disease with a repeat bone marrow biopsy.
Treatment results
The median follow-up was 5.6 months (1 to >38 months). Six patients had more than a year of follow-up.
The CR rate was 87% (33/38), and 81% of evaluable patients (26/32) were MRD-negative. The median time to CR was 23 days, and the median duration of response or relapse-free survival was 5.3 months.
“We examined the CR rates by different subgroup,” Dr Park noted. “We looked at whether patients had a pre-T-cell disease burden: morphologic disease vs minimal residual disease, whether they had an allogeneic bone marrow transplant prior to CAR T-cell infusion, their Ph+ status, age at infusion, and prior lines of therapy. And there was no [significant] difference between these groups for CRs and MRD-negative CR rate.”
At the time of presentation, 14 patients were disease-free, 10 of whom had not gone on to HSCT. In all, 11 patients went on to allogeneic HSCT.
Fourteen patients relapsed during follow-up, 3 after HSCT. Two of these patients had CD19-negative bone marrow blasts.
The median overall survival was 8.5 months in all patients and 10.8 months in patients who were MRD-negative. The median overall survival was 9.9 months in patients who underwent allogeneic HSCT and 8.5 months in patients who did not.
Dr Park said key adverse events were CRS—clinically manifested by fever, hypotension, and respiratory insufficiency—and neurological changes such as delirium, global encephalopathy, aphasia, and seizures.
Twenty-three percent of patients (n=9) developed severe CRS, 28% (n=11) had grade 3/4 neurotoxicity, and 8% (n=3) had grade 5 toxicity. The patients with grade 5 toxicities died of ventricular arrhythmia, sepsis, and an unknown cause (although this patient suffered a seizure).
The severity of CRS correlated with disease burden, and CRS was managed with an IL-6R inhibitor (n=4), a steroid (n=2), or both (n=9). Neurological symptoms were reversible and could occur independently of CRS, Dr Park said.
*Information in the abstract differs from that presented at the meeting.
the 2015 ASCO Annual Meeting
© ASCO/Max Gersh
CHICAGO—A CD19-targeted chimeric antigen receptor (CAR) T-cell therapy can provide durable complete responses (CRs) or a bridge to allogeneic transplant in adults with relapsed or refractory acute lymphoblastic leukemia (ALL), updated results of a phase 1 study suggest.
The therapy, JCAR015, produced a CR rate of 87%, and 33% of these patients went on to transplant.
The median duration of response or relapse-free survival was 5.3 months. The median overall survival was 8.5 months.
Nearly a quarter of patients developed severe cytokine release syndrome (CRS), and nearly 30% experienced neurological toxicities. But researchers said these effects were largely treatable and reversible.
This study was temporarily placed on clinical hold last year, after 2 patients died from complications related to CRS. But the hold was soon lifted and enrollment and dosing criteria were changed in an attempt to prevent severe CRS.
Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented updated results of this trial (NCT01044069) at the 2015 ASCO Annual Meeting (abstract 7010*). The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.
Results from this trial have previously been reported in Science Translational Medicine (Davila et al 2014; Brentjens et al 2013), at AACR 2014, and at ASH 2014.
At ASCO, Dr Park presented results in 39 patients with relapsed/refractory, CD19+ ALL. All of them were evaluable for toxicity assessment, and 38 were evaluable for response with at least 1 month of follow-up.
There were 29 males, and the patients’ median age was 45 (range, 22-74). Thirty-three percent had Ph+ ALL, and 11% had the T315I mutation.
Forty-nine percent of patients had received 2 prior therapies, 23% had received 3, and 28% had received 4 or more. Thirty-six percent of patients had a prior allogeneic hematopoietic stem cell transplant (HSCT).
For this study, patients first underwent leukapheresis. While their T cells were being manufactured, they were allowed to receive salvage chemotherapy. Patients underwent repeat bone marrow biopsy to assess their disease status immediately prior to T-cell infusion.
Fifty-four percent of patients (n=21) had morphologic disease (>5% blasts in the bone marrow, median 52%) immediately prior to JCAR015 infusion, and the remaining patients (n=18) had minimal residual disease (MRD).
Two days after conditioning with cyclophosphamide, patients received an infusion of 1-3 x 106 CAR T cells/kg. At day 28, the researchers assessed patients’ disease with a repeat bone marrow biopsy.
Treatment results
The median follow-up was 5.6 months (1 to >38 months). Six patients had more than a year of follow-up.
The CR rate was 87% (33/38), and 81% of evaluable patients (26/32) were MRD-negative. The median time to CR was 23 days, and the median duration of response or relapse-free survival was 5.3 months.
“We examined the CR rates by different subgroup,” Dr Park noted. “We looked at whether patients had a pre-T-cell disease burden: morphologic disease vs minimal residual disease, whether they had an allogeneic bone marrow transplant prior to CAR T-cell infusion, their Ph+ status, age at infusion, and prior lines of therapy. And there was no [significant] difference between these groups for CRs and MRD-negative CR rate.”
At the time of presentation, 14 patients were disease-free, 10 of whom had not gone on to HSCT. In all, 11 patients went on to allogeneic HSCT.
Fourteen patients relapsed during follow-up, 3 after HSCT. Two of these patients had CD19-negative bone marrow blasts.
The median overall survival was 8.5 months in all patients and 10.8 months in patients who were MRD-negative. The median overall survival was 9.9 months in patients who underwent allogeneic HSCT and 8.5 months in patients who did not.
Dr Park said key adverse events were CRS—clinically manifested by fever, hypotension, and respiratory insufficiency—and neurological changes such as delirium, global encephalopathy, aphasia, and seizures.
Twenty-three percent of patients (n=9) developed severe CRS, 28% (n=11) had grade 3/4 neurotoxicity, and 8% (n=3) had grade 5 toxicity. The patients with grade 5 toxicities died of ventricular arrhythmia, sepsis, and an unknown cause (although this patient suffered a seizure).
The severity of CRS correlated with disease burden, and CRS was managed with an IL-6R inhibitor (n=4), a steroid (n=2), or both (n=9). Neurological symptoms were reversible and could occur independently of CRS, Dr Park said.
*Information in the abstract differs from that presented at the meeting.
the 2015 ASCO Annual Meeting
© ASCO/Max Gersh
CHICAGO—A CD19-targeted chimeric antigen receptor (CAR) T-cell therapy can provide durable complete responses (CRs) or a bridge to allogeneic transplant in adults with relapsed or refractory acute lymphoblastic leukemia (ALL), updated results of a phase 1 study suggest.
The therapy, JCAR015, produced a CR rate of 87%, and 33% of these patients went on to transplant.
The median duration of response or relapse-free survival was 5.3 months. The median overall survival was 8.5 months.
Nearly a quarter of patients developed severe cytokine release syndrome (CRS), and nearly 30% experienced neurological toxicities. But researchers said these effects were largely treatable and reversible.
This study was temporarily placed on clinical hold last year, after 2 patients died from complications related to CRS. But the hold was soon lifted and enrollment and dosing criteria were changed in an attempt to prevent severe CRS.
Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented updated results of this trial (NCT01044069) at the 2015 ASCO Annual Meeting (abstract 7010*). The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.
Results from this trial have previously been reported in Science Translational Medicine (Davila et al 2014; Brentjens et al 2013), at AACR 2014, and at ASH 2014.
At ASCO, Dr Park presented results in 39 patients with relapsed/refractory, CD19+ ALL. All of them were evaluable for toxicity assessment, and 38 were evaluable for response with at least 1 month of follow-up.
There were 29 males, and the patients’ median age was 45 (range, 22-74). Thirty-three percent had Ph+ ALL, and 11% had the T315I mutation.
Forty-nine percent of patients had received 2 prior therapies, 23% had received 3, and 28% had received 4 or more. Thirty-six percent of patients had a prior allogeneic hematopoietic stem cell transplant (HSCT).
For this study, patients first underwent leukapheresis. While their T cells were being manufactured, they were allowed to receive salvage chemotherapy. Patients underwent repeat bone marrow biopsy to assess their disease status immediately prior to T-cell infusion.
Fifty-four percent of patients (n=21) had morphologic disease (>5% blasts in the bone marrow, median 52%) immediately prior to JCAR015 infusion, and the remaining patients (n=18) had minimal residual disease (MRD).
Two days after conditioning with cyclophosphamide, patients received an infusion of 1-3 x 106 CAR T cells/kg. At day 28, the researchers assessed patients’ disease with a repeat bone marrow biopsy.
Treatment results
The median follow-up was 5.6 months (1 to >38 months). Six patients had more than a year of follow-up.
The CR rate was 87% (33/38), and 81% of evaluable patients (26/32) were MRD-negative. The median time to CR was 23 days, and the median duration of response or relapse-free survival was 5.3 months.
“We examined the CR rates by different subgroup,” Dr Park noted. “We looked at whether patients had a pre-T-cell disease burden: morphologic disease vs minimal residual disease, whether they had an allogeneic bone marrow transplant prior to CAR T-cell infusion, their Ph+ status, age at infusion, and prior lines of therapy. And there was no [significant] difference between these groups for CRs and MRD-negative CR rate.”
At the time of presentation, 14 patients were disease-free, 10 of whom had not gone on to HSCT. In all, 11 patients went on to allogeneic HSCT.
Fourteen patients relapsed during follow-up, 3 after HSCT. Two of these patients had CD19-negative bone marrow blasts.
The median overall survival was 8.5 months in all patients and 10.8 months in patients who were MRD-negative. The median overall survival was 9.9 months in patients who underwent allogeneic HSCT and 8.5 months in patients who did not.
Dr Park said key adverse events were CRS—clinically manifested by fever, hypotension, and respiratory insufficiency—and neurological changes such as delirium, global encephalopathy, aphasia, and seizures.
Twenty-three percent of patients (n=9) developed severe CRS, 28% (n=11) had grade 3/4 neurotoxicity, and 8% (n=3) had grade 5 toxicity. The patients with grade 5 toxicities died of ventricular arrhythmia, sepsis, and an unknown cause (although this patient suffered a seizure).
The severity of CRS correlated with disease burden, and CRS was managed with an IL-6R inhibitor (n=4), a steroid (n=2), or both (n=9). Neurological symptoms were reversible and could occur independently of CRS, Dr Park said.
*Information in the abstract differs from that presented at the meeting.
ASCO: Ascites may salvage trebananib in recurrent ovarian cancer
CHICAGO – Disappointing topline overall survival results from TRINOVA-1 reported late last year dashed enthusiasm for trebananib in recurrent ovarian cancer, but a subgroup analysis suggests the anti-angiopoietin therapy may yet have a use.
In patients with ascites at baseline, adding trebananib to paclitaxel provided a nearly 30% survival advantage, increasing median overall survival from 12.3 months to 14.5 months (hazard ratio, 0.72; P = .011), Dr. Bradley Monk reported at the annual meeting of the American Society of Clinical Oncology.
There was no overall survival benefit in the full intent-to-treat population. Median overall survival was 18.3 months for single-agent paclitaxel and 19.3 months for the combination (HR, 0.95; P = .52).
Presence of ascites at baseline was a prespecified subgroup, stressed Dr. Monk, director of gynecologic oncology at St. Joseph’s Hospital, Phoenix, who noted that 32% of women fell into this subgroup (295/919 patients).
Women with and without ascites at baseline had the same age, primary tumor type, number of prior lines of therapy, and prior antiangiogenic therapy, although more patients with ascites had a platinum-free interval of less than 6 months (58% vs. 49%).
“So they were a poor prognosis group not only because of the ascites, but they had more platinum-resistant disease,” he said.
The TRINOVA-1 trial previously demonstrated a significant increase in the primary endpoint of median progression-free survival (PFS) from 5.4 months to 7.2 months when adding weekly trebananib to weekly paclitaxel (HR, 0.66; P < .001).
At baseline, about 40% of patients had received one or two prior lines of prior therapy and roughly a fourth received three prior lines. Patients received an average of 2.2 lines of additional anticancer therapy after progression on study.
An exploratory analysis of PFS after subsequent therapy revealed a median PFS of 12.5 months in the trebananib group vs. 10.9 months in the paclitaxel group (HR, 0.85; P = .024), Dr. Monk said.
Discussant Dr. Don Dizon, with Massachusetts General Hospital in Boston, said the results provide a strong signal of benefit in women with recurrent ovarian cancer and ascites, but can’t be considered definitive without further study.
Both men observed that treatment with trebananib plus paclitaxel was associated with an increase in adverse events. Trebananib was associated with 32% more localized edema of any grade (59% vs. 27%), but most of these events were grade 1 or 2, Dr. Monk said. The paclitaxel and trebananib groups had similar grade 3 (56% vs. 60%) and grade 4 events (12% vs. 12%) and patient-reported Functional Assessment of Cancer Therapy-Ovarian (FACT-O) scores at week 25.
Amgen funded the study. Dr. Monk reported having no conflicts of interest. Dr. Dizon reported employment and an advisory or consulting role with UpToDate and institutional research funding from Aeterna Zentaris and GlaxoSmithKline.
On Twitter @pwendl
CHICAGO – Disappointing topline overall survival results from TRINOVA-1 reported late last year dashed enthusiasm for trebananib in recurrent ovarian cancer, but a subgroup analysis suggests the anti-angiopoietin therapy may yet have a use.
In patients with ascites at baseline, adding trebananib to paclitaxel provided a nearly 30% survival advantage, increasing median overall survival from 12.3 months to 14.5 months (hazard ratio, 0.72; P = .011), Dr. Bradley Monk reported at the annual meeting of the American Society of Clinical Oncology.
There was no overall survival benefit in the full intent-to-treat population. Median overall survival was 18.3 months for single-agent paclitaxel and 19.3 months for the combination (HR, 0.95; P = .52).
Presence of ascites at baseline was a prespecified subgroup, stressed Dr. Monk, director of gynecologic oncology at St. Joseph’s Hospital, Phoenix, who noted that 32% of women fell into this subgroup (295/919 patients).
Women with and without ascites at baseline had the same age, primary tumor type, number of prior lines of therapy, and prior antiangiogenic therapy, although more patients with ascites had a platinum-free interval of less than 6 months (58% vs. 49%).
“So they were a poor prognosis group not only because of the ascites, but they had more platinum-resistant disease,” he said.
The TRINOVA-1 trial previously demonstrated a significant increase in the primary endpoint of median progression-free survival (PFS) from 5.4 months to 7.2 months when adding weekly trebananib to weekly paclitaxel (HR, 0.66; P < .001).
At baseline, about 40% of patients had received one or two prior lines of prior therapy and roughly a fourth received three prior lines. Patients received an average of 2.2 lines of additional anticancer therapy after progression on study.
An exploratory analysis of PFS after subsequent therapy revealed a median PFS of 12.5 months in the trebananib group vs. 10.9 months in the paclitaxel group (HR, 0.85; P = .024), Dr. Monk said.
Discussant Dr. Don Dizon, with Massachusetts General Hospital in Boston, said the results provide a strong signal of benefit in women with recurrent ovarian cancer and ascites, but can’t be considered definitive without further study.
Both men observed that treatment with trebananib plus paclitaxel was associated with an increase in adverse events. Trebananib was associated with 32% more localized edema of any grade (59% vs. 27%), but most of these events were grade 1 or 2, Dr. Monk said. The paclitaxel and trebananib groups had similar grade 3 (56% vs. 60%) and grade 4 events (12% vs. 12%) and patient-reported Functional Assessment of Cancer Therapy-Ovarian (FACT-O) scores at week 25.
Amgen funded the study. Dr. Monk reported having no conflicts of interest. Dr. Dizon reported employment and an advisory or consulting role with UpToDate and institutional research funding from Aeterna Zentaris and GlaxoSmithKline.
On Twitter @pwendl
CHICAGO – Disappointing topline overall survival results from TRINOVA-1 reported late last year dashed enthusiasm for trebananib in recurrent ovarian cancer, but a subgroup analysis suggests the anti-angiopoietin therapy may yet have a use.
In patients with ascites at baseline, adding trebananib to paclitaxel provided a nearly 30% survival advantage, increasing median overall survival from 12.3 months to 14.5 months (hazard ratio, 0.72; P = .011), Dr. Bradley Monk reported at the annual meeting of the American Society of Clinical Oncology.
There was no overall survival benefit in the full intent-to-treat population. Median overall survival was 18.3 months for single-agent paclitaxel and 19.3 months for the combination (HR, 0.95; P = .52).
Presence of ascites at baseline was a prespecified subgroup, stressed Dr. Monk, director of gynecologic oncology at St. Joseph’s Hospital, Phoenix, who noted that 32% of women fell into this subgroup (295/919 patients).
Women with and without ascites at baseline had the same age, primary tumor type, number of prior lines of therapy, and prior antiangiogenic therapy, although more patients with ascites had a platinum-free interval of less than 6 months (58% vs. 49%).
“So they were a poor prognosis group not only because of the ascites, but they had more platinum-resistant disease,” he said.
The TRINOVA-1 trial previously demonstrated a significant increase in the primary endpoint of median progression-free survival (PFS) from 5.4 months to 7.2 months when adding weekly trebananib to weekly paclitaxel (HR, 0.66; P < .001).
At baseline, about 40% of patients had received one or two prior lines of prior therapy and roughly a fourth received three prior lines. Patients received an average of 2.2 lines of additional anticancer therapy after progression on study.
An exploratory analysis of PFS after subsequent therapy revealed a median PFS of 12.5 months in the trebananib group vs. 10.9 months in the paclitaxel group (HR, 0.85; P = .024), Dr. Monk said.
Discussant Dr. Don Dizon, with Massachusetts General Hospital in Boston, said the results provide a strong signal of benefit in women with recurrent ovarian cancer and ascites, but can’t be considered definitive without further study.
Both men observed that treatment with trebananib plus paclitaxel was associated with an increase in adverse events. Trebananib was associated with 32% more localized edema of any grade (59% vs. 27%), but most of these events were grade 1 or 2, Dr. Monk said. The paclitaxel and trebananib groups had similar grade 3 (56% vs. 60%) and grade 4 events (12% vs. 12%) and patient-reported Functional Assessment of Cancer Therapy-Ovarian (FACT-O) scores at week 25.
Amgen funded the study. Dr. Monk reported having no conflicts of interest. Dr. Dizon reported employment and an advisory or consulting role with UpToDate and institutional research funding from Aeterna Zentaris and GlaxoSmithKline.
On Twitter @pwendl
AT THE 2015 ASCO ANNUAL MEETING
Key clinical point: The combination of paclitaxel plus trebananib may be useful in women with recurrent ovarian cancer and ascites.
Major finding: Median overall survival in women with ascites was 12.3 months for paclitaxel vs. 14.5 months for paclitaxel plus trebananib (HR, 0.72; P = .011).
Data source: Phase III study of 919 women with recurrent ovarian cancer.
Disclosures: Amgen funded the study. Dr. Monk reported having no conflicts of interest. Dr. Dizon reported employment and an advisory or consulting role with UpToDate and institutional research funding from Aeterna Zentaris and GlaxoSmithKline.
ASCO: PERSIST-1 – pacritinib tops best available therapy in myelofibrosis
CHICAGO – Pacritinib, an investigational oral inhibitor of Janus kinase 2 (JAK2), reduced splenomegaly and alleviated other symptoms in patients with myelofibrosis, in a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.
After 24 weeks of treatment, patients in the pacritinib arm were about four times more likely to have a sizable reduction in spleen volume than peers in the best available therapy arm, reported lead study author Dr. Ruben A. Mesa, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona.
Of special note, the drug was not associated with increased anemia or thrombocytopenia. In fact, it was safe in the subset of patients who had thrombocytopenia at baseline, a group currently having an unmet need for treatments because they cannot receive ruxolitinib (Jakafi), a dual JAK1 and JAK2 inhibitor that is associated with thrombocytopenia.
“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have impact on the disease course,” Dr. Mesa commented. Additionally, the findings warrant studies of combination therapy with other potentially disease-modifying agents in myeloproliferative neoplasms.
“I think pacritinib for myelofibrosis represents an advance in our field,” commented invited discussant Dr. Lloyd E. Damon, a professor of medicine and director of hematologic malignancies and bone marrow transplant at the University of California, San Francisco.
The trial’s findings have a number of implications going forward, he said. “There are several avenues yet to explore with these types of agents; for instance, what is the role of JAK inhibitors in those who are actually JAK2 mutated, and for that matter, those who are actually calreticulin mutated, and for that matter, those for whom there is no known mutation? The JAK inhibitors so far are directed against wild type,” he noted. “And should we be seeking to develop agents which are very specific against JAK gene products that are mutated or calreticulin gene products that are mutated vis-a-vis what we are seeing in the FLT3 inhibitors?”
Session attendee Dr. Harry Erba, a professor of medicine and director of the hematologic malignancy program, University of Alabama at Birmingham, commented, “With ruxolitinib, I’d always assumed that the improvement in quality of life was due to the JAK1 inhibition and decreasing of inflammatory cytokine signaling. In this study, the benefit in terms of the total symptom score was maybe a little bit less robust, comparing two very different studies – only 20% or 25%.”
“I think when it comes to the mechanism of symptom improvement, JAK2 probably still remains a key piece. As we look at the entire portfolio of JAK inhibitors that have been tested, we see improvement in symptoms whether they hit JAK1 or not,” Dr. Mesa replied.
“Was there a difference in the responses between the spleen-related and the more inflammatory-related symptoms?” Dr. Erba further asked. “Also, the other thing I was struck by, with ruxolitinib, it seems to be such a quick response in terms of quality of life and symptoms, and here there just seemed to be a more gradual improvement in time.”
“We did not see a strong difference between spleen- and non–spleen-related improvements,” Dr. Mesa replied, and the majority of responses seen with pacritinib were still “fairly rapid,” occurring within 4-8 weeks.
The CTI-funded trial – known as PERSIST-1 (A Randomized Controlled Phase 3 Study of Oral Pacritinib Versus Best Available Therapy in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post–Essential Thrombocythemia Myelofibrosis) – was unique in allowing patients to enroll regardless of platelet count, Dr. Mesa noted.
The patients were randomized in 2:1 ratio to receive pacritinib or best available therapy. The latter typically consisted of off-label agents such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea; ruxolitinib was not permitted. Crossover was allowed, and 79% of patients in the best available therapy arm eventually did go on to receive pacritinib.
Median follow-up was 8.4 months. In intention-to-treat analyses, at 24 weeks, 19.1% of patients in the pacritinib arm had a reduction of at least 35% in spleen volume, compared with only 4.7% in the best available therapy arm (P = .0003). The findings were similar in the subsets with a platelet count of less than 50,000 per microliter (22.9% vs. 0%) and less than 100,000 per microliter (16.7% vs. 0%).
Patients in the pacritinib arm were less likely to die if they had a spleen volume reduction of at least 20%, but longer follow-up is needed to determine if the drug improves survival, according to Dr. Mesa, who disclosed that he receives honoraria from and has a consulting or advisory role with Novartis, and receives research funding from Celgene, CTI, Incyte, and Gilead Sciences.
The proportion of patients having at least a one-half reduction in Total Symptom Score was 24.5% with pacritinib and 6.5% with best available therapy (P < .0001).
“We did not see any significant drug-emergent thrombocytopenia,” Dr. Mesa reported. In fact, among patients who entered the trial with a platelet count of less than 50,000 per microliter, those in the pacritinib arm had a significant, steady improvement in platelet count. “This could be multifactorial, from reduced splenic sequestration amongst other beneficial features,” he proposed
Among patients who were red cell transfusion dependent at baseline, 25.7% in the pacritinib arm achieved transfusion independence, compared with none in the control arm (P = .04).
The most common nonhematologic grade 3 or 4 adverse event with pacritinib was diarrhea (5% vs. 0%), while the most common hematologic grade 3 or 4 adverse event was anemia (16.8% vs. 15.1%).
Dr. Mesa noted that an ongoing sister trial, PERSIST-2, is still open to accrual. “This is a trial exclusively for patients with thrombocytopenia and allows individuals who have previously received JAK inhibitor therapy, with patients being randomized to the dose tested in the PERSIST-1 study or a b.i.d. dosing with similar goals and endpoints,” he elaborated.
CHICAGO – Pacritinib, an investigational oral inhibitor of Janus kinase 2 (JAK2), reduced splenomegaly and alleviated other symptoms in patients with myelofibrosis, in a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.
After 24 weeks of treatment, patients in the pacritinib arm were about four times more likely to have a sizable reduction in spleen volume than peers in the best available therapy arm, reported lead study author Dr. Ruben A. Mesa, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona.
Of special note, the drug was not associated with increased anemia or thrombocytopenia. In fact, it was safe in the subset of patients who had thrombocytopenia at baseline, a group currently having an unmet need for treatments because they cannot receive ruxolitinib (Jakafi), a dual JAK1 and JAK2 inhibitor that is associated with thrombocytopenia.
“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have impact on the disease course,” Dr. Mesa commented. Additionally, the findings warrant studies of combination therapy with other potentially disease-modifying agents in myeloproliferative neoplasms.
“I think pacritinib for myelofibrosis represents an advance in our field,” commented invited discussant Dr. Lloyd E. Damon, a professor of medicine and director of hematologic malignancies and bone marrow transplant at the University of California, San Francisco.
The trial’s findings have a number of implications going forward, he said. “There are several avenues yet to explore with these types of agents; for instance, what is the role of JAK inhibitors in those who are actually JAK2 mutated, and for that matter, those who are actually calreticulin mutated, and for that matter, those for whom there is no known mutation? The JAK inhibitors so far are directed against wild type,” he noted. “And should we be seeking to develop agents which are very specific against JAK gene products that are mutated or calreticulin gene products that are mutated vis-a-vis what we are seeing in the FLT3 inhibitors?”
Session attendee Dr. Harry Erba, a professor of medicine and director of the hematologic malignancy program, University of Alabama at Birmingham, commented, “With ruxolitinib, I’d always assumed that the improvement in quality of life was due to the JAK1 inhibition and decreasing of inflammatory cytokine signaling. In this study, the benefit in terms of the total symptom score was maybe a little bit less robust, comparing two very different studies – only 20% or 25%.”
“I think when it comes to the mechanism of symptom improvement, JAK2 probably still remains a key piece. As we look at the entire portfolio of JAK inhibitors that have been tested, we see improvement in symptoms whether they hit JAK1 or not,” Dr. Mesa replied.
“Was there a difference in the responses between the spleen-related and the more inflammatory-related symptoms?” Dr. Erba further asked. “Also, the other thing I was struck by, with ruxolitinib, it seems to be such a quick response in terms of quality of life and symptoms, and here there just seemed to be a more gradual improvement in time.”
“We did not see a strong difference between spleen- and non–spleen-related improvements,” Dr. Mesa replied, and the majority of responses seen with pacritinib were still “fairly rapid,” occurring within 4-8 weeks.
The CTI-funded trial – known as PERSIST-1 (A Randomized Controlled Phase 3 Study of Oral Pacritinib Versus Best Available Therapy in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post–Essential Thrombocythemia Myelofibrosis) – was unique in allowing patients to enroll regardless of platelet count, Dr. Mesa noted.
The patients were randomized in 2:1 ratio to receive pacritinib or best available therapy. The latter typically consisted of off-label agents such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea; ruxolitinib was not permitted. Crossover was allowed, and 79% of patients in the best available therapy arm eventually did go on to receive pacritinib.
Median follow-up was 8.4 months. In intention-to-treat analyses, at 24 weeks, 19.1% of patients in the pacritinib arm had a reduction of at least 35% in spleen volume, compared with only 4.7% in the best available therapy arm (P = .0003). The findings were similar in the subsets with a platelet count of less than 50,000 per microliter (22.9% vs. 0%) and less than 100,000 per microliter (16.7% vs. 0%).
Patients in the pacritinib arm were less likely to die if they had a spleen volume reduction of at least 20%, but longer follow-up is needed to determine if the drug improves survival, according to Dr. Mesa, who disclosed that he receives honoraria from and has a consulting or advisory role with Novartis, and receives research funding from Celgene, CTI, Incyte, and Gilead Sciences.
The proportion of patients having at least a one-half reduction in Total Symptom Score was 24.5% with pacritinib and 6.5% with best available therapy (P < .0001).
“We did not see any significant drug-emergent thrombocytopenia,” Dr. Mesa reported. In fact, among patients who entered the trial with a platelet count of less than 50,000 per microliter, those in the pacritinib arm had a significant, steady improvement in platelet count. “This could be multifactorial, from reduced splenic sequestration amongst other beneficial features,” he proposed
Among patients who were red cell transfusion dependent at baseline, 25.7% in the pacritinib arm achieved transfusion independence, compared with none in the control arm (P = .04).
The most common nonhematologic grade 3 or 4 adverse event with pacritinib was diarrhea (5% vs. 0%), while the most common hematologic grade 3 or 4 adverse event was anemia (16.8% vs. 15.1%).
Dr. Mesa noted that an ongoing sister trial, PERSIST-2, is still open to accrual. “This is a trial exclusively for patients with thrombocytopenia and allows individuals who have previously received JAK inhibitor therapy, with patients being randomized to the dose tested in the PERSIST-1 study or a b.i.d. dosing with similar goals and endpoints,” he elaborated.
CHICAGO – Pacritinib, an investigational oral inhibitor of Janus kinase 2 (JAK2), reduced splenomegaly and alleviated other symptoms in patients with myelofibrosis, in a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.
After 24 weeks of treatment, patients in the pacritinib arm were about four times more likely to have a sizable reduction in spleen volume than peers in the best available therapy arm, reported lead study author Dr. Ruben A. Mesa, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona.
Of special note, the drug was not associated with increased anemia or thrombocytopenia. In fact, it was safe in the subset of patients who had thrombocytopenia at baseline, a group currently having an unmet need for treatments because they cannot receive ruxolitinib (Jakafi), a dual JAK1 and JAK2 inhibitor that is associated with thrombocytopenia.
“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have impact on the disease course,” Dr. Mesa commented. Additionally, the findings warrant studies of combination therapy with other potentially disease-modifying agents in myeloproliferative neoplasms.
“I think pacritinib for myelofibrosis represents an advance in our field,” commented invited discussant Dr. Lloyd E. Damon, a professor of medicine and director of hematologic malignancies and bone marrow transplant at the University of California, San Francisco.
The trial’s findings have a number of implications going forward, he said. “There are several avenues yet to explore with these types of agents; for instance, what is the role of JAK inhibitors in those who are actually JAK2 mutated, and for that matter, those who are actually calreticulin mutated, and for that matter, those for whom there is no known mutation? The JAK inhibitors so far are directed against wild type,” he noted. “And should we be seeking to develop agents which are very specific against JAK gene products that are mutated or calreticulin gene products that are mutated vis-a-vis what we are seeing in the FLT3 inhibitors?”
Session attendee Dr. Harry Erba, a professor of medicine and director of the hematologic malignancy program, University of Alabama at Birmingham, commented, “With ruxolitinib, I’d always assumed that the improvement in quality of life was due to the JAK1 inhibition and decreasing of inflammatory cytokine signaling. In this study, the benefit in terms of the total symptom score was maybe a little bit less robust, comparing two very different studies – only 20% or 25%.”
“I think when it comes to the mechanism of symptom improvement, JAK2 probably still remains a key piece. As we look at the entire portfolio of JAK inhibitors that have been tested, we see improvement in symptoms whether they hit JAK1 or not,” Dr. Mesa replied.
“Was there a difference in the responses between the spleen-related and the more inflammatory-related symptoms?” Dr. Erba further asked. “Also, the other thing I was struck by, with ruxolitinib, it seems to be such a quick response in terms of quality of life and symptoms, and here there just seemed to be a more gradual improvement in time.”
“We did not see a strong difference between spleen- and non–spleen-related improvements,” Dr. Mesa replied, and the majority of responses seen with pacritinib were still “fairly rapid,” occurring within 4-8 weeks.
The CTI-funded trial – known as PERSIST-1 (A Randomized Controlled Phase 3 Study of Oral Pacritinib Versus Best Available Therapy in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post–Essential Thrombocythemia Myelofibrosis) – was unique in allowing patients to enroll regardless of platelet count, Dr. Mesa noted.
The patients were randomized in 2:1 ratio to receive pacritinib or best available therapy. The latter typically consisted of off-label agents such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea; ruxolitinib was not permitted. Crossover was allowed, and 79% of patients in the best available therapy arm eventually did go on to receive pacritinib.
Median follow-up was 8.4 months. In intention-to-treat analyses, at 24 weeks, 19.1% of patients in the pacritinib arm had a reduction of at least 35% in spleen volume, compared with only 4.7% in the best available therapy arm (P = .0003). The findings were similar in the subsets with a platelet count of less than 50,000 per microliter (22.9% vs. 0%) and less than 100,000 per microliter (16.7% vs. 0%).
Patients in the pacritinib arm were less likely to die if they had a spleen volume reduction of at least 20%, but longer follow-up is needed to determine if the drug improves survival, according to Dr. Mesa, who disclosed that he receives honoraria from and has a consulting or advisory role with Novartis, and receives research funding from Celgene, CTI, Incyte, and Gilead Sciences.
The proportion of patients having at least a one-half reduction in Total Symptom Score was 24.5% with pacritinib and 6.5% with best available therapy (P < .0001).
“We did not see any significant drug-emergent thrombocytopenia,” Dr. Mesa reported. In fact, among patients who entered the trial with a platelet count of less than 50,000 per microliter, those in the pacritinib arm had a significant, steady improvement in platelet count. “This could be multifactorial, from reduced splenic sequestration amongst other beneficial features,” he proposed
Among patients who were red cell transfusion dependent at baseline, 25.7% in the pacritinib arm achieved transfusion independence, compared with none in the control arm (P = .04).
The most common nonhematologic grade 3 or 4 adverse event with pacritinib was diarrhea (5% vs. 0%), while the most common hematologic grade 3 or 4 adverse event was anemia (16.8% vs. 15.1%).
Dr. Mesa noted that an ongoing sister trial, PERSIST-2, is still open to accrual. “This is a trial exclusively for patients with thrombocytopenia and allows individuals who have previously received JAK inhibitor therapy, with patients being randomized to the dose tested in the PERSIST-1 study or a b.i.d. dosing with similar goals and endpoints,” he elaborated.
AT THE 2015 ASCO ANNUAL MEETING
Key clinical point: Pacritinib is superior to best available therapy for alleviating splenomegaly and other symptoms of myelofibrosis.
Major finding: Patients were more likely to have a 35% or greater reduction in spleen volume with pacritinib (19.1% vs. 4.7%).
Data source: A randomized phase III trial in 327 patients with myelofibrosis or similar neoplasias.
Disclosures: Dr. Mesa disclosed that he receives honoraria from and has a consulting or advisory role with Novartis, and receives research funding from Celgene, CTI, Incyte, and Gilead Sciences. The trial was funded by CTI.
No survival difference with allo- or auto-SCT in PTCL
© ASCO/Max Gersh
CHICAGO—Allogeneic and autologous transplants produce similar survival rates when used as first-line therapy in younger patients with peripheral
T-cell lymphoma (PTCL), according to interim results of the AATT trial.
The study also showed that deaths among patients who received autologous stem cell transplants (auto-SCTs) were a result of relapse and salvage treatment, while deaths among allogeneic SCT (allo-SCT) recipients were transplant-related.
Norbert Schmitz, MD, PhD, of Asklepios Hospital St. Georg in Hamburg, Germany, presented these findings at the 2015 ASCO Annual Meeting (abstract 8507*).
Dr Schmitz noted that only previous study comparing auto-SCT with allo-SCT as first-line therapy in PTCL was not designed or powered to evaluate the differences between the transplant types.
So he and his colleagues conducted the AATT trial to determine the differences. The team hypothesized that allo-SCT would improve 3-year event-free survival from 35% to 60%, given an α of 5% and a power of 80%. They needed 140 patients to prove or disprove this theory.
Ultimately, the investigators enrolled 104 patients and performed an interim analysis when 58 patients were evaluable for response.
Of the 58 patients, 30 were randomized to the auto-SCT arm and 28 to the allo-SCT arm. Baseline characteristics were similar between the arms, including patients’ median ages (49 and 50, respectively), the proportion of patients with stage III/IV disease (87% and 93%), and the proportion with ECOG status greater than 1 (23% and 18%).
Most patients in both arms had PTCL not otherwise specified (36% in the auto-SCT arm and 50% in the allo-SCT arm). Other subtypes included angioimmunoblastic T-cell lymphoma (23% and 32%, respectively), ALK-negative anaplastic large-cell lymphoma (20% and 4%), and “other” PTCLs (20% and 8%). The other PTCLs were NK/T-cell lymphoma, intestinal T/NK-cell lymphoma, hepatosplenic γδ lymphoma, and subcutaneous panniculitis-like PTCL.
Treatment characteristics
Before undergoing transplant, patients in both arms received treatment with CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone) on days 1, 15, 29, and 43. If they experienced a complete response (CR), partial response, or no change, patients received DHAP (dexamethasone, cytarabine, and cisplatin) on day 64.
Patients in the auto-SCT arm received BEAM (carmustine, etoposide, cytarabine, and melphalan) prior to transplant. And patients in the allo-SCT arm received FBC (fludarabine, busulfan, and cyclophosphamide).
Overall, 36 patients (62%) completed treatment per protocol, 19 in the auto-SCT arm and 17 in the allo-SCT arm. Thirty-eight percent of all patients could not proceed to transplant per protocol, mostly because of early lymphoma progression.
Response and survival
The researchers observed CRs/unconfirmed CRs (CRus) in 33% (n=10) of patients in the auto-SCT arm and 39% (n=11) in the allo-SCT arm. CR/CRus and progressive disease within 2 months occurred in 3% (n=1) and 4% (n=1) of patients, respectively.
Partial responses were seen in 17% (n=5) of patients in the auto-SCT arm and 7% (n=2) in the allo-SCT arm. There was no change in 7% (n=2) and 0% of patients, respectively. And responses were unknown in 7% (n=2) of patients in the auto-SCT arm.
Progressive disease occurred in 33% (n=10) of patients in the auto-SCT arm and 36% (n=10) in the allo-SCT arm. And treatment-related death occurred in 0% (n=0) and 14% (n=4), respectively.
At the interim analysis, there was no significant difference between the treatment arms with regard to event-free survival (P=0.963) or overall survival (P=0.174).
“At that time, the decision was made to stop the study,” Dr Schmitz said.
He explained that a conditional power analysis showed a low probability that the primary endpoint—a 25% improvement in event-free survival with allo-SCT—could still be met. So the data safety monitoring board decided to stop enrollment.
An updated analysis, performed at a median observation time of 26 months, showed there was still no significant difference in overall survival between the treatment arms (P=0.362).
Cause of death
In the intent-to-treat population—30 patients in the auto-SCT arm and 28 in the allo-SCT arm—there were 16 lymphoma-related deaths, 10 in the auto-SCT arm and 6 in the allo-SCT arm.
There were 6 deaths related to study treatment (4 early and 2 late), all in the allo-SCT arm. One patient in the allo-SCT arm died of post-transplant lymphoproliferative disorder, and 1 patient in the same arm died of hemorrhage after salvage. One patient in each arm died as a result of salvage treatment.
Dr Schmitz and his colleagues also looked at the cause of death among patients who received a transplant—19 in the auto-SCT arm and 17 in the allo-SCT arm.
After SCT, there were 7 deaths in each arm. In the auto-SCT arm, there were 6 lymphoma-related deaths and 1 death related to salvage treatment. In the allo-SCT arm, there were 7 cases of non-relapse-related mortality, including 1 patient with post-transplant lymphoproliferative disorder.
“There certainly seems to be a [graft-vs-lymphoma] effect of allo-transplant in T-cell lymphoma that is, unfortunately, in some way, counterbalanced by high transplant-related mortality,” Dr Schmitz said.
He added that results of a final analysis of the 104 patients enrolled on this study should be available in 2017.
*Information in the abstract differs from that presented at the meeting.
© ASCO/Max Gersh
CHICAGO—Allogeneic and autologous transplants produce similar survival rates when used as first-line therapy in younger patients with peripheral
T-cell lymphoma (PTCL), according to interim results of the AATT trial.
The study also showed that deaths among patients who received autologous stem cell transplants (auto-SCTs) were a result of relapse and salvage treatment, while deaths among allogeneic SCT (allo-SCT) recipients were transplant-related.
Norbert Schmitz, MD, PhD, of Asklepios Hospital St. Georg in Hamburg, Germany, presented these findings at the 2015 ASCO Annual Meeting (abstract 8507*).
Dr Schmitz noted that only previous study comparing auto-SCT with allo-SCT as first-line therapy in PTCL was not designed or powered to evaluate the differences between the transplant types.
So he and his colleagues conducted the AATT trial to determine the differences. The team hypothesized that allo-SCT would improve 3-year event-free survival from 35% to 60%, given an α of 5% and a power of 80%. They needed 140 patients to prove or disprove this theory.
Ultimately, the investigators enrolled 104 patients and performed an interim analysis when 58 patients were evaluable for response.
Of the 58 patients, 30 were randomized to the auto-SCT arm and 28 to the allo-SCT arm. Baseline characteristics were similar between the arms, including patients’ median ages (49 and 50, respectively), the proportion of patients with stage III/IV disease (87% and 93%), and the proportion with ECOG status greater than 1 (23% and 18%).
Most patients in both arms had PTCL not otherwise specified (36% in the auto-SCT arm and 50% in the allo-SCT arm). Other subtypes included angioimmunoblastic T-cell lymphoma (23% and 32%, respectively), ALK-negative anaplastic large-cell lymphoma (20% and 4%), and “other” PTCLs (20% and 8%). The other PTCLs were NK/T-cell lymphoma, intestinal T/NK-cell lymphoma, hepatosplenic γδ lymphoma, and subcutaneous panniculitis-like PTCL.
Treatment characteristics
Before undergoing transplant, patients in both arms received treatment with CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone) on days 1, 15, 29, and 43. If they experienced a complete response (CR), partial response, or no change, patients received DHAP (dexamethasone, cytarabine, and cisplatin) on day 64.
Patients in the auto-SCT arm received BEAM (carmustine, etoposide, cytarabine, and melphalan) prior to transplant. And patients in the allo-SCT arm received FBC (fludarabine, busulfan, and cyclophosphamide).
Overall, 36 patients (62%) completed treatment per protocol, 19 in the auto-SCT arm and 17 in the allo-SCT arm. Thirty-eight percent of all patients could not proceed to transplant per protocol, mostly because of early lymphoma progression.
Response and survival
The researchers observed CRs/unconfirmed CRs (CRus) in 33% (n=10) of patients in the auto-SCT arm and 39% (n=11) in the allo-SCT arm. CR/CRus and progressive disease within 2 months occurred in 3% (n=1) and 4% (n=1) of patients, respectively.
Partial responses were seen in 17% (n=5) of patients in the auto-SCT arm and 7% (n=2) in the allo-SCT arm. There was no change in 7% (n=2) and 0% of patients, respectively. And responses were unknown in 7% (n=2) of patients in the auto-SCT arm.
Progressive disease occurred in 33% (n=10) of patients in the auto-SCT arm and 36% (n=10) in the allo-SCT arm. And treatment-related death occurred in 0% (n=0) and 14% (n=4), respectively.
At the interim analysis, there was no significant difference between the treatment arms with regard to event-free survival (P=0.963) or overall survival (P=0.174).
“At that time, the decision was made to stop the study,” Dr Schmitz said.
He explained that a conditional power analysis showed a low probability that the primary endpoint—a 25% improvement in event-free survival with allo-SCT—could still be met. So the data safety monitoring board decided to stop enrollment.
An updated analysis, performed at a median observation time of 26 months, showed there was still no significant difference in overall survival between the treatment arms (P=0.362).
Cause of death
In the intent-to-treat population—30 patients in the auto-SCT arm and 28 in the allo-SCT arm—there were 16 lymphoma-related deaths, 10 in the auto-SCT arm and 6 in the allo-SCT arm.
There were 6 deaths related to study treatment (4 early and 2 late), all in the allo-SCT arm. One patient in the allo-SCT arm died of post-transplant lymphoproliferative disorder, and 1 patient in the same arm died of hemorrhage after salvage. One patient in each arm died as a result of salvage treatment.
Dr Schmitz and his colleagues also looked at the cause of death among patients who received a transplant—19 in the auto-SCT arm and 17 in the allo-SCT arm.
After SCT, there were 7 deaths in each arm. In the auto-SCT arm, there were 6 lymphoma-related deaths and 1 death related to salvage treatment. In the allo-SCT arm, there were 7 cases of non-relapse-related mortality, including 1 patient with post-transplant lymphoproliferative disorder.
“There certainly seems to be a [graft-vs-lymphoma] effect of allo-transplant in T-cell lymphoma that is, unfortunately, in some way, counterbalanced by high transplant-related mortality,” Dr Schmitz said.
He added that results of a final analysis of the 104 patients enrolled on this study should be available in 2017.
*Information in the abstract differs from that presented at the meeting.
© ASCO/Max Gersh
CHICAGO—Allogeneic and autologous transplants produce similar survival rates when used as first-line therapy in younger patients with peripheral
T-cell lymphoma (PTCL), according to interim results of the AATT trial.
The study also showed that deaths among patients who received autologous stem cell transplants (auto-SCTs) were a result of relapse and salvage treatment, while deaths among allogeneic SCT (allo-SCT) recipients were transplant-related.
Norbert Schmitz, MD, PhD, of Asklepios Hospital St. Georg in Hamburg, Germany, presented these findings at the 2015 ASCO Annual Meeting (abstract 8507*).
Dr Schmitz noted that only previous study comparing auto-SCT with allo-SCT as first-line therapy in PTCL was not designed or powered to evaluate the differences between the transplant types.
So he and his colleagues conducted the AATT trial to determine the differences. The team hypothesized that allo-SCT would improve 3-year event-free survival from 35% to 60%, given an α of 5% and a power of 80%. They needed 140 patients to prove or disprove this theory.
Ultimately, the investigators enrolled 104 patients and performed an interim analysis when 58 patients were evaluable for response.
Of the 58 patients, 30 were randomized to the auto-SCT arm and 28 to the allo-SCT arm. Baseline characteristics were similar between the arms, including patients’ median ages (49 and 50, respectively), the proportion of patients with stage III/IV disease (87% and 93%), and the proportion with ECOG status greater than 1 (23% and 18%).
Most patients in both arms had PTCL not otherwise specified (36% in the auto-SCT arm and 50% in the allo-SCT arm). Other subtypes included angioimmunoblastic T-cell lymphoma (23% and 32%, respectively), ALK-negative anaplastic large-cell lymphoma (20% and 4%), and “other” PTCLs (20% and 8%). The other PTCLs were NK/T-cell lymphoma, intestinal T/NK-cell lymphoma, hepatosplenic γδ lymphoma, and subcutaneous panniculitis-like PTCL.
Treatment characteristics
Before undergoing transplant, patients in both arms received treatment with CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone) on days 1, 15, 29, and 43. If they experienced a complete response (CR), partial response, or no change, patients received DHAP (dexamethasone, cytarabine, and cisplatin) on day 64.
Patients in the auto-SCT arm received BEAM (carmustine, etoposide, cytarabine, and melphalan) prior to transplant. And patients in the allo-SCT arm received FBC (fludarabine, busulfan, and cyclophosphamide).
Overall, 36 patients (62%) completed treatment per protocol, 19 in the auto-SCT arm and 17 in the allo-SCT arm. Thirty-eight percent of all patients could not proceed to transplant per protocol, mostly because of early lymphoma progression.
Response and survival
The researchers observed CRs/unconfirmed CRs (CRus) in 33% (n=10) of patients in the auto-SCT arm and 39% (n=11) in the allo-SCT arm. CR/CRus and progressive disease within 2 months occurred in 3% (n=1) and 4% (n=1) of patients, respectively.
Partial responses were seen in 17% (n=5) of patients in the auto-SCT arm and 7% (n=2) in the allo-SCT arm. There was no change in 7% (n=2) and 0% of patients, respectively. And responses were unknown in 7% (n=2) of patients in the auto-SCT arm.
Progressive disease occurred in 33% (n=10) of patients in the auto-SCT arm and 36% (n=10) in the allo-SCT arm. And treatment-related death occurred in 0% (n=0) and 14% (n=4), respectively.
At the interim analysis, there was no significant difference between the treatment arms with regard to event-free survival (P=0.963) or overall survival (P=0.174).
“At that time, the decision was made to stop the study,” Dr Schmitz said.
He explained that a conditional power analysis showed a low probability that the primary endpoint—a 25% improvement in event-free survival with allo-SCT—could still be met. So the data safety monitoring board decided to stop enrollment.
An updated analysis, performed at a median observation time of 26 months, showed there was still no significant difference in overall survival between the treatment arms (P=0.362).
Cause of death
In the intent-to-treat population—30 patients in the auto-SCT arm and 28 in the allo-SCT arm—there were 16 lymphoma-related deaths, 10 in the auto-SCT arm and 6 in the allo-SCT arm.
There were 6 deaths related to study treatment (4 early and 2 late), all in the allo-SCT arm. One patient in the allo-SCT arm died of post-transplant lymphoproliferative disorder, and 1 patient in the same arm died of hemorrhage after salvage. One patient in each arm died as a result of salvage treatment.
Dr Schmitz and his colleagues also looked at the cause of death among patients who received a transplant—19 in the auto-SCT arm and 17 in the allo-SCT arm.
After SCT, there were 7 deaths in each arm. In the auto-SCT arm, there were 6 lymphoma-related deaths and 1 death related to salvage treatment. In the allo-SCT arm, there were 7 cases of non-relapse-related mortality, including 1 patient with post-transplant lymphoproliferative disorder.
“There certainly seems to be a [graft-vs-lymphoma] effect of allo-transplant in T-cell lymphoma that is, unfortunately, in some way, counterbalanced by high transplant-related mortality,” Dr Schmitz said.
He added that results of a final analysis of the 104 patients enrolled on this study should be available in 2017.
*Information in the abstract differs from that presented at the meeting.
Triplet shows early promise for relapsed CLL, NHL
©ASCO/Rodney White
CHICAGO—A 3-drug combination is safe and highly active in certain patients with relapsed B-cell malignancies, according to a speaker at the 2015 ASCO Annual Meeting.
The combination consists of the anti-CD20 monoclonal antibody ublituximab, the PI3Kδ inhibitor TGR-1202, and the BTK inhibitor ibrutinib.
In a small, phase 1 study, the triplet produced an overall response rate of 62%. It was particularly active in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and those with mantle cell lymphoma (MCL).
The most common adverse events were infusion reactions, gastrointestinal events, rash, and fatigue. Grade 3 neutropenia and leukopenia occurred in 1 patient each.
Nathan Fowler, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the meeting as abstract 8501.*
The trial enrolled 16 patients with CLL/SLL or non-Hodgkin lymphoma (NHL). Four had CLL, 1 had SLL, and 1 had Richter’s transformation. Four patients had follicular lymphoma (FL), 3 had diffuse large B-cell lymphoma (DLBCL), 2 had mantle cell lymphoma (MCL), and 1 had marginal zone lymphoma (MZL).
The patients’ median age was 63, and their median number of prior treatment regimens was 4 (range, 1-5). Fifty percent of patients (n=8) were refractory to prior therapy.
Treatment consisted of 900 mg of ublituximab, ibrutinib at either 420 mg (CLL/SLL) or 560 mg (NHL), and TGR-1202 at 3 different doses: 400 mg, 600 mg, or 800 mg. Ibrutinib and TGR-1202 were given once-daily beginning on day 1 of each cycle. Ublituximab was given on days 1, 8, and 15 of cycles 1 and 2, then on day 1 of cycles 4, 6, 9, and 12.
Safety and efficacy
Sixteen patients were evaluable for safety and 13 for efficacy. One of the patients was removed from the efficacy analysis at the discretion of the investigators, and it was too early to evaluate the other 2 patients.
The median time on study was 4 months (range, 1-9 months). The 5 CLL/SLL patients received TGR-1202 at 400 mg. One of these patients had a dose-limiting toxicity—reactivation of varicella zoster.
Of the NHL patients, 3 received TGR-1202 at 400 mg, 4 received 600 mg, and 4 received 800 mg. There were no dose-limiting toxicities in any of these patients.
Adverse events that were considered possibly related to treatment included infusion reactions (25%), diarrhea (19%), nausea (19%), fatigue (19%), rash (19%), anemia (13%), neutropenia (13%), leukopenia (13%), and insomnia (13%). Grade 3 events included neutropenia and leukopenia (6% each), and there were no grade 4 events.
“The majority of patients have demonstrated a response to the therapy,” Dr Fowler said. “All of the patients that have responded continue on treatment, and the longest [treatment duration] is about 10 months.”
The only complete response occurred in a patient with MCL. Partial responses occurred in all 3 CLL patients, 2 FL patients, the SLL patient, the MZL patient, and 1 MCL patient. One patient with FL, 2 with DLBCL, and 1 with Richter’s transformation did not respond to treatment.
In closing, Dr Fowler said this treatment was well-tolerated and showed significant early activity in this heavily pretreated patient population. Dose-escalation with TGR-1202 continues at 800 mg, and phase 2 studies of the triplet are planned.
*Information in the abstract differs from that presented at the meeting.
©ASCO/Rodney White
CHICAGO—A 3-drug combination is safe and highly active in certain patients with relapsed B-cell malignancies, according to a speaker at the 2015 ASCO Annual Meeting.
The combination consists of the anti-CD20 monoclonal antibody ublituximab, the PI3Kδ inhibitor TGR-1202, and the BTK inhibitor ibrutinib.
In a small, phase 1 study, the triplet produced an overall response rate of 62%. It was particularly active in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and those with mantle cell lymphoma (MCL).
The most common adverse events were infusion reactions, gastrointestinal events, rash, and fatigue. Grade 3 neutropenia and leukopenia occurred in 1 patient each.
Nathan Fowler, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the meeting as abstract 8501.*
The trial enrolled 16 patients with CLL/SLL or non-Hodgkin lymphoma (NHL). Four had CLL, 1 had SLL, and 1 had Richter’s transformation. Four patients had follicular lymphoma (FL), 3 had diffuse large B-cell lymphoma (DLBCL), 2 had mantle cell lymphoma (MCL), and 1 had marginal zone lymphoma (MZL).
The patients’ median age was 63, and their median number of prior treatment regimens was 4 (range, 1-5). Fifty percent of patients (n=8) were refractory to prior therapy.
Treatment consisted of 900 mg of ublituximab, ibrutinib at either 420 mg (CLL/SLL) or 560 mg (NHL), and TGR-1202 at 3 different doses: 400 mg, 600 mg, or 800 mg. Ibrutinib and TGR-1202 were given once-daily beginning on day 1 of each cycle. Ublituximab was given on days 1, 8, and 15 of cycles 1 and 2, then on day 1 of cycles 4, 6, 9, and 12.
Safety and efficacy
Sixteen patients were evaluable for safety and 13 for efficacy. One of the patients was removed from the efficacy analysis at the discretion of the investigators, and it was too early to evaluate the other 2 patients.
The median time on study was 4 months (range, 1-9 months). The 5 CLL/SLL patients received TGR-1202 at 400 mg. One of these patients had a dose-limiting toxicity—reactivation of varicella zoster.
Of the NHL patients, 3 received TGR-1202 at 400 mg, 4 received 600 mg, and 4 received 800 mg. There were no dose-limiting toxicities in any of these patients.
Adverse events that were considered possibly related to treatment included infusion reactions (25%), diarrhea (19%), nausea (19%), fatigue (19%), rash (19%), anemia (13%), neutropenia (13%), leukopenia (13%), and insomnia (13%). Grade 3 events included neutropenia and leukopenia (6% each), and there were no grade 4 events.
“The majority of patients have demonstrated a response to the therapy,” Dr Fowler said. “All of the patients that have responded continue on treatment, and the longest [treatment duration] is about 10 months.”
The only complete response occurred in a patient with MCL. Partial responses occurred in all 3 CLL patients, 2 FL patients, the SLL patient, the MZL patient, and 1 MCL patient. One patient with FL, 2 with DLBCL, and 1 with Richter’s transformation did not respond to treatment.
In closing, Dr Fowler said this treatment was well-tolerated and showed significant early activity in this heavily pretreated patient population. Dose-escalation with TGR-1202 continues at 800 mg, and phase 2 studies of the triplet are planned.
*Information in the abstract differs from that presented at the meeting.
©ASCO/Rodney White
CHICAGO—A 3-drug combination is safe and highly active in certain patients with relapsed B-cell malignancies, according to a speaker at the 2015 ASCO Annual Meeting.
The combination consists of the anti-CD20 monoclonal antibody ublituximab, the PI3Kδ inhibitor TGR-1202, and the BTK inhibitor ibrutinib.
In a small, phase 1 study, the triplet produced an overall response rate of 62%. It was particularly active in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and those with mantle cell lymphoma (MCL).
The most common adverse events were infusion reactions, gastrointestinal events, rash, and fatigue. Grade 3 neutropenia and leukopenia occurred in 1 patient each.
Nathan Fowler, MD, of MD Anderson Cancer Center in Houston, Texas, presented these results at the meeting as abstract 8501.*
The trial enrolled 16 patients with CLL/SLL or non-Hodgkin lymphoma (NHL). Four had CLL, 1 had SLL, and 1 had Richter’s transformation. Four patients had follicular lymphoma (FL), 3 had diffuse large B-cell lymphoma (DLBCL), 2 had mantle cell lymphoma (MCL), and 1 had marginal zone lymphoma (MZL).
The patients’ median age was 63, and their median number of prior treatment regimens was 4 (range, 1-5). Fifty percent of patients (n=8) were refractory to prior therapy.
Treatment consisted of 900 mg of ublituximab, ibrutinib at either 420 mg (CLL/SLL) or 560 mg (NHL), and TGR-1202 at 3 different doses: 400 mg, 600 mg, or 800 mg. Ibrutinib and TGR-1202 were given once-daily beginning on day 1 of each cycle. Ublituximab was given on days 1, 8, and 15 of cycles 1 and 2, then on day 1 of cycles 4, 6, 9, and 12.
Safety and efficacy
Sixteen patients were evaluable for safety and 13 for efficacy. One of the patients was removed from the efficacy analysis at the discretion of the investigators, and it was too early to evaluate the other 2 patients.
The median time on study was 4 months (range, 1-9 months). The 5 CLL/SLL patients received TGR-1202 at 400 mg. One of these patients had a dose-limiting toxicity—reactivation of varicella zoster.
Of the NHL patients, 3 received TGR-1202 at 400 mg, 4 received 600 mg, and 4 received 800 mg. There were no dose-limiting toxicities in any of these patients.
Adverse events that were considered possibly related to treatment included infusion reactions (25%), diarrhea (19%), nausea (19%), fatigue (19%), rash (19%), anemia (13%), neutropenia (13%), leukopenia (13%), and insomnia (13%). Grade 3 events included neutropenia and leukopenia (6% each), and there were no grade 4 events.
“The majority of patients have demonstrated a response to the therapy,” Dr Fowler said. “All of the patients that have responded continue on treatment, and the longest [treatment duration] is about 10 months.”
The only complete response occurred in a patient with MCL. Partial responses occurred in all 3 CLL patients, 2 FL patients, the SLL patient, the MZL patient, and 1 MCL patient. One patient with FL, 2 with DLBCL, and 1 with Richter’s transformation did not respond to treatment.
In closing, Dr Fowler said this treatment was well-tolerated and showed significant early activity in this heavily pretreated patient population. Dose-escalation with TGR-1202 continues at 800 mg, and phase 2 studies of the triplet are planned.
*Information in the abstract differs from that presented at the meeting.