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‘Unprecedented’ Responses to Cisplatin/Gemcitabine in BRCA-Mutated Advanced Pancreatic Cancer


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As first-line treatment of patients with pancreatic ductal adenocarcinoma and a germline BRCA/PALB2 mutation, cisplatin plus gemcitabine yielded high response rates and encouraging survival, establishing this doublet as a standard approach in this subset of patients, according to Eileen M. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center, who presented the findings at the 2020 Gastrointestinal Cancers Symposium.1 The findings were simultaneously reported in the Journal of Clinical Oncology.2

Eileen M. O’Reilly, MD

Eileen M. O’Reilly, MD

The study’s aim was to evaluate cisplatin/gemcitabine alone and with veliparib, an inhibitor of poly (ADP-ribose) polymerase (PARP). The response rate to cisplatin/gemcitabine was 65.2%. With the addition of veliparib, the response rate was 74.1%. The study evaluated the arms separately and did compare them.

“Both arms (cisplatin/gemcitabine and cisplatin/gemcitabine/veliparib) were very active, significantly exceeding the prespecified response rate. We also saw encouraging 2-year survival (31%) and 3-year survival (18%),” Dr. O’Reilly said. The investigators noted in the publication that “this represents the longest reported [survival] in any randomized trial in advanced pancreatic ductal adenocarcinoma.”2

“The doublet is the recommendation moving forward,” Dr. O’Reilly said. “We believe these data define a reference regimen for germline BRCA-mutated and PALB2-mutated pancreatic cancer.”

Richard L. Schilsky, MD, FACP, FASCO, Chief Medical Officer and Executive Vice President of ASCO, was impressed with the findings. “Seeing response rates of 60% to 70% in patients with metastatic pancreatic cancer is kind of unprecedented and rather remarkable. The overall survival and progression-free survival data are also far better than we customarily see in metastatic pancreatic cancer,” Dr. Schilsky, a gastrointestinal cancer specialist and former Chief of Hematology/Oncology at the University of Chicago Comprehensive Cancer Center, told The ASCO Post.

Richard L. Schilsky, MD, FACP, FASCO

Richard L. Schilsky, MD, FACP, FASCO

“What the data are telling us is that it’s very important to find those patients with BRCA mutations. Those mutations are clearly important in conferring sensitivity to platinum-based chemotherapy,” Dr. Schilsky said.

Study Also Evaluated Veliparib

The open-label, multicenter phase II study randomly assigned patients with untreated germline BRCA/PALB2-positive pancreatic ductal adenocarcinoma and measurable stage III/IV disease. Patients received cisplatin/gemcitabine or the same plus veliparib. The phase III POLO trial had established proof of principle for the use of a PARP inhibitor as maintenance therapy for germline BRCA-mutated metastatic pancreatic cancer,3 and a phase I trial, led by Dr. O’Reilly, demonstrated a 78% response rate with veliparib/cisplatin/gemcitabine and a median overall survival of 23 months.4

In the current, randomized, phase II study, treatment in arm A consisted of cisplatin at 25 mg/m2 and gemcitabine at 600 mg/m2 on days 3 and 10 plus veliparib at 80 mg orally twice daily on days 1 to 12, given every 3 weeks, with the option for veliparib maintenance. Patients in arm B received the same cisplatin/gemcitabine regimen but no veliparib. The primary endpoint was response rate of arm A and arm B evaluated separately. The modified intent-to-treat analysis included 50 patients.

“Both arms (cisplatin plus gemcitabine and cisplatin, gemcitabine, and veliparib) were very active, significantly exceeding the prespecified response rate.”
— Eileen M. O’Reilly, MD

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High Response Rates in Both Arms

“Response rates were very high in both arms,” Dr. O’Reilly announced. The response rate was 74.1% in arm A and 65.2% in arm B (P = .55). “Both arm A, the triplet, and arm B substantially exceeded the prespecified activity threshold of 30%.”

For the combined arms, ie, the whole cohort, 2-year overall survival was 31% and 3-year survival was 18%. Other outcomes for arm A (cisplatin/gemcitabine/veliparib) and arm B (cisplatin/gemcitabine), respectively, follow:

  • Disease control rate: 100% and 78.3% (P = .02)
  • Median progression-free survival: 10.1 months and 9.7 months (P = .74)
  • Median overall survival: 15.5 months and 16.4 months (P = .61).

In light of the emerging data in the field and from the POLO trial, the investigators conducted several exploratory analyses of participants who received 4 or more months of platinum therapy and then continued or received a PARP inhibitor as an immediate next line of therapy in the absence of disease progression. This study group included 10 patients from the two arms combined, 8 of whom had stage IV disease. Their median overall survival was 23.4 months, “referencing similarly to the POLO data,” noted Dr. O’Reilly.

In an exploratory analysis by BRCA status, the median progression-free survival was 6.8 months for BRCA1 and 11.3 months for BRCA2, and the median overall survival was 14 months and 20.2 months, respectively, investigators reported in the publication.2

Toxicity Profile

At least one dose reduction or drug discontinuation as a result of toxicity was observed in 74% of patients in arm A and 26% of patients in arm B. This was a result of hematologic toxicity in 90% and 17%, respectively. Grade 3 or 4 toxicity included anemia in 52% of the veliparib arm and 35% of the doublet arm; thrombocytopenia in 55% and 9%, respectively; and neutropenia in 41% and 30%, respectively.

KEY POINTS

  • An open-label, randomized, phase II trial evaluated a first-line regimen for patients with stage III/IV pancreatic ductal adenocarcinoma and a germline BRCA/PALB2 mutation.
  • Patients received cisplatin plus gemcitabine with or without the PARP inhibitor veliparib.
  • Response rates in both arms were very high: 74.1% in the veliparib arm and 65.2% in the cisplatin/gemcitabine arm.
  • Overall survival in the entire population was 31% at 2 years and 18% at 2 years.
  • The investigators believe that cisplatin/gemcitabine should be a standard-of-care first-line regimen in BRCA-mutated advanced pancreatic ductal adenocarcinoma.

Cisplatin/Gemcitabine as Backbone

In the discussion period, Dr. O’Reilly was asked why cisplatin/gemcitabine was chosen as the backbone chemotherapy in the study. Today, FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) is probably a more commonly used regimen, an audience member pointed out.

“Cisplatin is a very active drug in BRCA-mutated pancreatic cancer, and this study was designed in 2012, before we had much of the information we have now. But this is a practical question: is FOLFIRINOX the preferred approach or is this?” she asked.

“These data are the only prospective randomized data we have for platinum-based therapy in germline BRCA-mutated pancreatic cancer, so I think it comes with a high level of evidence,” explained Dr. O’Reilly. “Nonetheless, FOLFIRINOX is also an option, and in the absence of knowing germline BRCA status, FOLFIRINOX will be preferred. The choice depends on the patient in front of you. There certainly are some advantages for cisplatin/gemcitabine in terms of a relative lack of toxicity. This was a well-tolerated regimen.”

Another listener questioned whether patients may have been underdosed: “In designing the study, the decision was made to try to optimize the platinum at the expense of gemcitabine and to facilitate the addition of veliparib. Based on the activity, this was not underdosing. We saw substantial responses. I think that’s unequivocal,” Dr. O’Reilly stated. “In my mind, being able to deliver the treatment and over a period of time is perhaps more important than the ceiling of the dosing that could be administered in this setting.” 

 

DISCLOSURE: Dr. O’Reilly has served as a consultant for Celgene, Genentech, Ipsen, Sobi, Merck, AstraZeneca, Bayer, BMS, Vessel, Polaris, and CytomX and has received grant or research support from MSK, Celgene, Sanofi, Genentech-Roche, AstraZeneca, BMS, Silenseed, Mabax, Halozyme, and ActaBiologica. Dr. Schilsky has received institutional research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech/Roche, Lilly, Merck, and Pfizer and has been reimbursed for travel, accommodations, or expenses by Varian.

REFERENCES

1. O’Reilly EM, Lee JW, Zalupski M, et al: A randomized, multicenter, phase II trial of gemcitabine, cisplatin ± veliparib in patients with pancreas adenocarcinoma and a known germline BRCA/PALB2 mutation. 2020 Gastrointestinal Cancers Symposium. Abstract 639. Presented January 24, 2020.

2. O’Reilly EM, Lee JW, Zalupski M, et al: Randomized, multicenter, phase II trial of gemcitabine and cisplating with or without veliparib in patients with pancreas adenocarcinoma and a germline BRCA/PALB2 mutation. J Clin Oncol. January 24, 2020 (early release online).

3. Golan T, Hammel P, Reni M, et al: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 381:317-327, 2019.

4. O’Reilly EM, Lee JW, Lowery MA, et al: Phase I trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer 124:1374-1382, 2018.


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