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Gemcitabine-Cisplatin Combination a New Standard in Pancreatic Cancer with Germline BRCA or PALB2 Mutation

JHOP - April 2020 Vol 10, No 2 - Gastrointestinal Cancers

Platinum-based therapy represents a new standard of care in patients with pancreatic cancer and germline BRCA or PALB2 mutation, based on data reported at the 2020 Gastrointestinal Cancers Symposium. The findings were published simultaneously in the Journal of Clinical Oncology (O’Reilly EM, et al. J Clin Oncol. 2020 Jan 24. Epub ahead of print).

In this phase 2 study, patients who were randomized to a 3-drug regimen of gemcitabine, cisplatin, and the investigational drug veliparib had an overall response rate of 74.1%, which was not significantly superior to the 65.1% rate (P = .55) in patients randomized to gemcitabine plus cisplatin without veliparib, said Eileen M. O’Reilly, MD, Section Head, Hepatopancreaticobiliary & Neuroendocrine Cancers, Memorial Sloan Kettering Cancer Center, New York City.

Furthermore, patients who received veliparib had a higher rate of hematologic toxicity. Based on the excellent response rates in both arms but the higher rate of hematologic toxicity in the triplet arm, “The doublet is our recommendation for moving forward, and we believe these data define a reference regimen for germline BRCA-mutated, PALB2-mutated pancreas cancer,” said Dr O’Reilly.

Mutations in the BRCA1/BRCA2 and the PALB2 genes are present in up to 9% of patients with pancreatic ductal adenocarcinoma. These genes code for proteins critical for homologous recombination repair of DNA, she said.

Patients with untreated stage III or IV pancreatic cancer, germline BRCA1/2 or PALB2 mutation, and Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible for the study. A total of 50 patients were randomized to the triplet regimen (N = 27) or to the doublet regimen (N = 23). Overall, 84% of the patients had stage IV disease, 24% had BRCA1 mutation, 70% had BRCA2 mutation, and 6% had PALB2 mutation. Metastasis to the liver was identified in 74%. Patient demographics were well-balanced between the 2 arms.

Patients in the triplet arm received cisplatin 25 mg/m2, gemcitabine 600 mg/m2 on days 3 and 10, and veliparib 80 mg twice daily on days 1 to 12, all given for 3 weeks, with an option for veliparib maintenance. In the doublet arm, cisplatin and gemcitabine were given at the same doses as in the triplet arm, but gemcitabine was administered on days 1 and 8 of the 21-day cycle.

“We saw encouraging progression-­free survival [PFS] in both arms, and if you reference an unselected population, that would be about 5 to 7 months,” said Dr O’Reilly. “The [3-drug] combination came at the expense of more hematologic toxicity, with more anemia, thrombocytopenia, and neutropenia, and more dose reductions and delays, although the dose intensity in both arms was relatively similar over time.”

The median PFS was 10.1 months in patients randomized to the 3-drug regimen versus 9.7 months in those assigned to the doublet, a nonsignificant difference (P = .73). The median overall survival (OS) was also not significantly different (15.5 months vs 16.4 months, respectively; P = .6).

Exploratory analyses across the combined cohorts showed a median PFS of 6.8 months and a median OS of 14 months in patients with germline BRCA1 mutation, and 11.3 months and 20.2 months, respectively, in those with germline BRCA2 mutation.

The 2-year OS in the combined cohort was 31% and the 3-year OS was 18%. These OS rates represent among the longest reported in any randomized clinical trial in pancreatic cancer, said Dr O’Reilly.

In a subset of 10 patients who received ≥4 months of platinum therapy and then a poly (ADP-ribose) polymerase (PARP) inhibitor as an immediate next line of therapy, the median OS combined from both arms was 23.4 months.

Anemia occurred in 52% of the patients in the triplet arm versus 35% in the doublet arm; thrombocytopenia was 55% and 9%, respectively; and neutropenia was 41% and 30%, respectively.

When these data are combined with those from the POLO trial, the use of platinum-based therapy that is followed by sequential maintenance treatment with PARP inhibitors is an optimal first-line treatment approach in patients with pancreatic cancer and a germline BRCA1/2 or PALB2 mutation, the researchers wrote in the published article.

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Last modified: April 27, 2020