Exceptional responses to ipilimumab/nivolumab (ipi/nivo) in patients (pts) with refractory pancreatic ductal adenocarcinoma (PDAC) and germline BRCA or RAD51 mutations.

Abstract

754 Background: Immune checkpoint inhibitors (ICI’s) have not shown meaningful clinical activity in unselected pts with PDAC. BRCA-deficient tumors have increased genomic instability, including increased tumor mutation burden (TMB), more tumor-infiltrating immune cells, and enrichment of a T cell-inflamed signature. We hypothesized that pts with mutations in BRCA or other homologous recombination repair genes may be sensitive to ICI’s. Methods: Utilizing the IRB-approved PDAC database at the University of Miami, we identified pts with relapsed/refractory PDAC with pathogenic germline mutations who were treated with combination ICI’s (ipi 1mg/kg and nivo 3mg/kg every 21 days followed by nivo 240mg every 2 weeks). Results: Five pts were identified (1 BRCA1, 2 BRCA2, 1 RAD51C and 1 RAD51D). Among the 3 evaluable pts, there was one complete response (CR), one partial response (PR) and one had progressive disease (PD). The pt with a CR had BRCA1; he had resection followed by adjuvant gem/cape and had a biopsy-proven recurrence in the lung and retroperitoneum 1y after the end of adjuvant therapy. He received ipi/nivo at recurrence and achieved a CR, ongoing for 17m on nivo maintenance. The patient with a PR had RAD51C; he was diagnosed with mPDAC and received FOLFIRINOX for 6m, followed by olaparib on a trial for 12m. Upon PD, the disease quickly progressed on 5FU/liposomal irinotecan, gemcitabine/nab-paclitaxel/cisplatin and FOLFIRINOX. He then started ipi/nivo with immediate improvement in pain and tumor markers. A radiological PR was seen after 2 doses and is ongoing for 3m with continued clinical and tumor marker improvement. The 3rd evaluable pt had BRCA2 and had PD with an exponential rise in tumor markers accompanied by clinical deterioration. Response data on the final two pts were pending at the time of submission and will be presented at the meeting. Conclusions: In this biomarker selected cohort, 2 out of 3 evaluable pts with PDAC had impressive responses to ipi/nivo. PDAC has generally been refractory to ICI therapy but this series suggests that this subgroup may be responsive to ICI’s. Further evaluation is warranted.