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SAN FRANCISCO – The combination of cisplatin and gemcitabine is highly efficacious as first-line therapy for advanced pancreatic cancer in patients with a germline BRCA1/2 or PALB2 mutation, with no additional benefit seen from concurrent veliparib, a phase 2 randomized controlled trial finds.
Up to 9% of pancreatic ductal adenocarcinomas occur in individuals with one of these germline mutations, which render cells more sensitive to platinum agents and PARP inhibitors because of ineffective DNA repair.
In the trial, nearly two-thirds of patients had a response to cisplatin-gemcitabine alone, according to results reported at the 2020 GI Cancers Symposium and simultaneously published (J Clin Oncol. 2020 Jan 24. doi: 10.1200/JCO.19.02931). Although almost three-quarters had a response when the investigational PARP 1/2 inhibitor veliparib was added, the difference was not statistically significant and toxicity was greater.
“Both arms were very active and substantially exceeded the prespecified thresholds,” said lead investigator Eileen Mary O’Reilly, MD, section head of Hepatopancreaticobilary & Neuroendocrine Cancers at Memorial Sloan Kettering Cancer Center in New York.
“The doublet is our recommendation for moving forward, and we believe these data define a reference regimen for germline BRCA-mutated or PALB2-mutated pancreas cancer,” she stated, noting that the PARP inhibitor olaparib (Lynparza) conferred benefit when used as maintenance therapy in the POLO trial. “I think the strategy that at the current time is best supported by the totality of the data is platinum-based therapy upfront and then sequential use of the PARP inhibitor as a maintenance approach.”
The trial was designed in 2012, before efficacy of the FOLFIRINOX regimen was well established, so an obvious question is which chemotherapy to use, Dr. O’Reilly acknowledged.
“I would say these are the only prospective randomized data we have with platinum-based therapy in germline-mutated pancreas cancer. So it comes with a high level of evidence,” she maintained. “Nonetheless, I think FOLFIRINOX is also an option. The options are good, and it probably will depend on the patient in front of you because there certainly are some lack of toxicity advantages, for the most part, to cisplatin and gemcitabine. This was a well-tolerated regimen.”
Implications for practice
“I wouldn’t say this is a negative study. It’s negative with respect to the veliparib question, but otherwise, it’s a very exciting study,” Richard L. Schilsky, MD, chief medical officer and executive vice president of ASCO, said in an interview. “Seeing response rates of 60% and 70% in patients with metastatic pancreatic cancer is kind of unprecedented, and that’s quite remarkable.”
The reason for the lack of additional benefit from veliparib is unclear, he said. But it may be related to the specific PARP inhibitor or to the smaller sample size or very high response rate seen with chemotherapy alone, which possibly precluded detection of a significant difference.
When choosing between chemotherapy regimens, evidence favors the doublet, according to Dr. Schilsky. “FOLFIRINOX doesn’t have a 70% response rate; it may be 35%. If it was my family member, I would say, get gemcitabine-platinum if you have a BRCA mutation.”
“I think the real take-home message, quite honestly, for most oncologists is that patients with pancreatic cancer should be tested for germline BRCA mutations,” he recommended. “It can not only help inform the therapy choice, but of course, some of these cancers are going to run in families because these are germline mutations and they are going to reveal families that have a high risk of not only pancreatic cancer, but breast, ovarian, and all the other BRCA-associated cancers.”
Study details
The trial was conducted among 52 patients with untreated locally advanced or metastatic pancreatic ductal adenocarcinoma. Fully 94% had a BRCA mutation, while the rest had a PALB2 mutation, according to data reported at the symposium, sponsored by the American Gastroenterological Association, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The response rate – the trial’s primary endpoint – was 65.2% with cisplatin-gemcitabine alone and 74.1% with cisplatin-gemcitabine plus veliparib (P = .55), with both arms far exceeding not only the 10% prespecified as “acceptable,” but also the 30% prespecified as “promising.” The respective disease control rates were 78.3% and 100% (P = .02).
Median progression-free survival was 9.7 months with chemotherapy alone and 10.1 months with chemotherapy plus the PARP inhibitor (P = .73). “If you reference an unselected population, that would be about 5 to 7 months,” Dr. O’Reilly noted. Median overall survival was 16.4 months and 15.5 months, respectively (P = .6). For the entire trial cohort, the 2-year overall survival rate was 30.6% and the 3-year overall survival rate was 17.8%.
“The combination came at the expense of hematologic toxicity,” Dr. O’Reilly said, with patients given veliparib having higher rates of grade 3 or 4 neutropenia (48% vs. 30%), thrombocytopenia (55% vs. 9%), and anemia (52% vs. 35%).
In an exploratory analysis among all patients receiving 4 or more months of chemotherapy and then continuing on or starting a PARP inhibitor as their next therapy, without disease progression, median overall survival was 23.4 months, very similar to what was seen in the POLO trial, she noted.
Dr. O’Reilly disclosed that she has ties with Vesselon, Polaris, and CytomX, and that her institution receives grant/research support from Celgene, Sanofi, Genentech-Roche, AstraZeneca, BMS, Silenseed, MabVax, Halozyme, and Acta Biologica. The trial was funded by the Lustgarten Foundation, the David M. Rubenstein Center for Pancreatic Cancer Research, the Reiss Family Foundation, the National Cancer Institute’s Cancer Therapy Evaluation Program, and NCI grants. Dr. Schilsky disclosed that he has no conflicts of interest.
SOURCE: O’Reilly EM et al. 2020 GI Cancers Symposium. Abstract 639.
SAN FRANCISCO – The combination of cisplatin and gemcitabine is highly efficacious as first-line therapy for advanced pancreatic cancer in patients with a germline BRCA1/2 or PALB2 mutation, with no additional benefit seen from concurrent veliparib, a phase 2 randomized controlled trial finds.
Up to 9% of pancreatic ductal adenocarcinomas occur in individuals with one of these germline mutations, which render cells more sensitive to platinum agents and PARP inhibitors because of ineffective DNA repair.
In the trial, nearly two-thirds of patients had a response to cisplatin-gemcitabine alone, according to results reported at the 2020 GI Cancers Symposium and simultaneously published (J Clin Oncol. 2020 Jan 24. doi: 10.1200/JCO.19.02931). Although almost three-quarters had a response when the investigational PARP 1/2 inhibitor veliparib was added, the difference was not statistically significant and toxicity was greater.
“Both arms were very active and substantially exceeded the prespecified thresholds,” said lead investigator Eileen Mary O’Reilly, MD, section head of Hepatopancreaticobilary & Neuroendocrine Cancers at Memorial Sloan Kettering Cancer Center in New York.
“The doublet is our recommendation for moving forward, and we believe these data define a reference regimen for germline BRCA-mutated or PALB2-mutated pancreas cancer,” she stated, noting that the PARP inhibitor olaparib (Lynparza) conferred benefit when used as maintenance therapy in the POLO trial. “I think the strategy that at the current time is best supported by the totality of the data is platinum-based therapy upfront and then sequential use of the PARP inhibitor as a maintenance approach.”
The trial was designed in 2012, before efficacy of the FOLFIRINOX regimen was well established, so an obvious question is which chemotherapy to use, Dr. O’Reilly acknowledged.
“I would say these are the only prospective randomized data we have with platinum-based therapy in germline-mutated pancreas cancer. So it comes with a high level of evidence,” she maintained. “Nonetheless, I think FOLFIRINOX is also an option. The options are good, and it probably will depend on the patient in front of you because there certainly are some lack of toxicity advantages, for the most part, to cisplatin and gemcitabine. This was a well-tolerated regimen.”
Implications for practice
“I wouldn’t say this is a negative study. It’s negative with respect to the veliparib question, but otherwise, it’s a very exciting study,” Richard L. Schilsky, MD, chief medical officer and executive vice president of ASCO, said in an interview. “Seeing response rates of 60% and 70% in patients with metastatic pancreatic cancer is kind of unprecedented, and that’s quite remarkable.”
The reason for the lack of additional benefit from veliparib is unclear, he said. But it may be related to the specific PARP inhibitor or to the smaller sample size or very high response rate seen with chemotherapy alone, which possibly precluded detection of a significant difference.
When choosing between chemotherapy regimens, evidence favors the doublet, according to Dr. Schilsky. “FOLFIRINOX doesn’t have a 70% response rate; it may be 35%. If it was my family member, I would say, get gemcitabine-platinum if you have a BRCA mutation.”
“I think the real take-home message, quite honestly, for most oncologists is that patients with pancreatic cancer should be tested for germline BRCA mutations,” he recommended. “It can not only help inform the therapy choice, but of course, some of these cancers are going to run in families because these are germline mutations and they are going to reveal families that have a high risk of not only pancreatic cancer, but breast, ovarian, and all the other BRCA-associated cancers.”
Study details
The trial was conducted among 52 patients with untreated locally advanced or metastatic pancreatic ductal adenocarcinoma. Fully 94% had a BRCA mutation, while the rest had a PALB2 mutation, according to data reported at the symposium, sponsored by the American Gastroenterological Association, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The response rate – the trial’s primary endpoint – was 65.2% with cisplatin-gemcitabine alone and 74.1% with cisplatin-gemcitabine plus veliparib (P = .55), with both arms far exceeding not only the 10% prespecified as “acceptable,” but also the 30% prespecified as “promising.” The respective disease control rates were 78.3% and 100% (P = .02).
Median progression-free survival was 9.7 months with chemotherapy alone and 10.1 months with chemotherapy plus the PARP inhibitor (P = .73). “If you reference an unselected population, that would be about 5 to 7 months,” Dr. O’Reilly noted. Median overall survival was 16.4 months and 15.5 months, respectively (P = .6). For the entire trial cohort, the 2-year overall survival rate was 30.6% and the 3-year overall survival rate was 17.8%.
“The combination came at the expense of hematologic toxicity,” Dr. O’Reilly said, with patients given veliparib having higher rates of grade 3 or 4 neutropenia (48% vs. 30%), thrombocytopenia (55% vs. 9%), and anemia (52% vs. 35%).
In an exploratory analysis among all patients receiving 4 or more months of chemotherapy and then continuing on or starting a PARP inhibitor as their next therapy, without disease progression, median overall survival was 23.4 months, very similar to what was seen in the POLO trial, she noted.
Dr. O’Reilly disclosed that she has ties with Vesselon, Polaris, and CytomX, and that her institution receives grant/research support from Celgene, Sanofi, Genentech-Roche, AstraZeneca, BMS, Silenseed, MabVax, Halozyme, and Acta Biologica. The trial was funded by the Lustgarten Foundation, the David M. Rubenstein Center for Pancreatic Cancer Research, the Reiss Family Foundation, the National Cancer Institute’s Cancer Therapy Evaluation Program, and NCI grants. Dr. Schilsky disclosed that he has no conflicts of interest.
SOURCE: O’Reilly EM et al. 2020 GI Cancers Symposium. Abstract 639.
SAN FRANCISCO – The combination of cisplatin and gemcitabine is highly efficacious as first-line therapy for advanced pancreatic cancer in patients with a germline BRCA1/2 or PALB2 mutation, with no additional benefit seen from concurrent veliparib, a phase 2 randomized controlled trial finds.
Up to 9% of pancreatic ductal adenocarcinomas occur in individuals with one of these germline mutations, which render cells more sensitive to platinum agents and PARP inhibitors because of ineffective DNA repair.
In the trial, nearly two-thirds of patients had a response to cisplatin-gemcitabine alone, according to results reported at the 2020 GI Cancers Symposium and simultaneously published (J Clin Oncol. 2020 Jan 24. doi: 10.1200/JCO.19.02931). Although almost three-quarters had a response when the investigational PARP 1/2 inhibitor veliparib was added, the difference was not statistically significant and toxicity was greater.
“Both arms were very active and substantially exceeded the prespecified thresholds,” said lead investigator Eileen Mary O’Reilly, MD, section head of Hepatopancreaticobilary & Neuroendocrine Cancers at Memorial Sloan Kettering Cancer Center in New York.
“The doublet is our recommendation for moving forward, and we believe these data define a reference regimen for germline BRCA-mutated or PALB2-mutated pancreas cancer,” she stated, noting that the PARP inhibitor olaparib (Lynparza) conferred benefit when used as maintenance therapy in the POLO trial. “I think the strategy that at the current time is best supported by the totality of the data is platinum-based therapy upfront and then sequential use of the PARP inhibitor as a maintenance approach.”
The trial was designed in 2012, before efficacy of the FOLFIRINOX regimen was well established, so an obvious question is which chemotherapy to use, Dr. O’Reilly acknowledged.
“I would say these are the only prospective randomized data we have with platinum-based therapy in germline-mutated pancreas cancer. So it comes with a high level of evidence,” she maintained. “Nonetheless, I think FOLFIRINOX is also an option. The options are good, and it probably will depend on the patient in front of you because there certainly are some lack of toxicity advantages, for the most part, to cisplatin and gemcitabine. This was a well-tolerated regimen.”
Implications for practice
“I wouldn’t say this is a negative study. It’s negative with respect to the veliparib question, but otherwise, it’s a very exciting study,” Richard L. Schilsky, MD, chief medical officer and executive vice president of ASCO, said in an interview. “Seeing response rates of 60% and 70% in patients with metastatic pancreatic cancer is kind of unprecedented, and that’s quite remarkable.”
The reason for the lack of additional benefit from veliparib is unclear, he said. But it may be related to the specific PARP inhibitor or to the smaller sample size or very high response rate seen with chemotherapy alone, which possibly precluded detection of a significant difference.
When choosing between chemotherapy regimens, evidence favors the doublet, according to Dr. Schilsky. “FOLFIRINOX doesn’t have a 70% response rate; it may be 35%. If it was my family member, I would say, get gemcitabine-platinum if you have a BRCA mutation.”
“I think the real take-home message, quite honestly, for most oncologists is that patients with pancreatic cancer should be tested for germline BRCA mutations,” he recommended. “It can not only help inform the therapy choice, but of course, some of these cancers are going to run in families because these are germline mutations and they are going to reveal families that have a high risk of not only pancreatic cancer, but breast, ovarian, and all the other BRCA-associated cancers.”
Study details
The trial was conducted among 52 patients with untreated locally advanced or metastatic pancreatic ductal adenocarcinoma. Fully 94% had a BRCA mutation, while the rest had a PALB2 mutation, according to data reported at the symposium, sponsored by the American Gastroenterological Association, the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
The response rate – the trial’s primary endpoint – was 65.2% with cisplatin-gemcitabine alone and 74.1% with cisplatin-gemcitabine plus veliparib (P = .55), with both arms far exceeding not only the 10% prespecified as “acceptable,” but also the 30% prespecified as “promising.” The respective disease control rates were 78.3% and 100% (P = .02).
Median progression-free survival was 9.7 months with chemotherapy alone and 10.1 months with chemotherapy plus the PARP inhibitor (P = .73). “If you reference an unselected population, that would be about 5 to 7 months,” Dr. O’Reilly noted. Median overall survival was 16.4 months and 15.5 months, respectively (P = .6). For the entire trial cohort, the 2-year overall survival rate was 30.6% and the 3-year overall survival rate was 17.8%.
“The combination came at the expense of hematologic toxicity,” Dr. O’Reilly said, with patients given veliparib having higher rates of grade 3 or 4 neutropenia (48% vs. 30%), thrombocytopenia (55% vs. 9%), and anemia (52% vs. 35%).
In an exploratory analysis among all patients receiving 4 or more months of chemotherapy and then continuing on or starting a PARP inhibitor as their next therapy, without disease progression, median overall survival was 23.4 months, very similar to what was seen in the POLO trial, she noted.
Dr. O’Reilly disclosed that she has ties with Vesselon, Polaris, and CytomX, and that her institution receives grant/research support from Celgene, Sanofi, Genentech-Roche, AstraZeneca, BMS, Silenseed, MabVax, Halozyme, and Acta Biologica. The trial was funded by the Lustgarten Foundation, the David M. Rubenstein Center for Pancreatic Cancer Research, the Reiss Family Foundation, the National Cancer Institute’s Cancer Therapy Evaluation Program, and NCI grants. Dr. Schilsky disclosed that he has no conflicts of interest.
SOURCE: O’Reilly EM et al. 2020 GI Cancers Symposium. Abstract 639.
REPORTING FROM THE 2020 GI CANCERS SYMPOSIUM