Exceptional sustained responses to ipilimumab/nivolumab (ipi/nivo) in patients (pts) with advanced pancreaticobiliary cancers and germline DNA damage repair (DDR) mutations.

Abstract

e16757 Background: Immune checkpoint inhibitors (ICIs) have not shown meaningful clinical activity in unselected pts with pancreaticobiliary cancer. DDR-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 DDR deficiency may be sensitive to ICIs. Methods: Utilizing the IRB-approved database at the University of Miami, we identified pts with advanced pancreaticobiliary cancer with germline DDR mutations who were treated with dual ICI. Results: Eleven pts were identified (3 BRCA1, 4 BRCA2, 1 RAD51C, 1 RAD51D, 1 ATM, and 1 PALB2). There were two complete responses (CR), one partial response (PR), three stable disease (SD), two progressive disease (PD), and three pending evaluation. Evaluable responses are sustained for 22 months (m), 19m, and 7m, respectively. All pts had microsatellite stable tumors and none had high TMB. Among pts with responses, TMB was 4, 8, and 8 mut/Mb, respectively. One pt with a CR had gBRCA1 with pancreatic adenocarcinoma (PDAC) s/p distal pancreatectomy/splenectomy, adjuvant gemcitabine (gem)/capecitabine, biopsy-proven recurrence in lung and retroperitoneum 12m later, initiated ipi/nivo, and achieved a CR ongoing for 22m on nivo maintenance. Second pt with a CR had gBRCA1 and unresectable cholangiocarcinoma (CC), with disease progression after gem/cisplatin (cis), therapy switched to ipi/nivo. After 4 doses, an incidental cerebellar lesion was found which was biopsy-proven CC, therefore taken off treatment. Pt has been in CR for 19m without further therapy. The pt with a PR had RAD51C and metastatic PDAC s/p FOLFIRINOX for 6m, followed by olaparib for 12m. At progression, disease rapidly progressed through 5-fluorouracil/nanoliposomal irinotecan, gem/nab-paclitaxel/cis, and FOLFIRINOX. Pt was initiated on ipi/nivo with immediate improvement in pain and tumor markers; PR ongoing for 7m with continued clinical and tumor marker improvement on nivo maintenance. Additional correlative studies (RNA sequencing, Hyperion Imaging, mutation allele fraction analysis) among responders vs. nonresponders will be reported at the meeting. Conclusions: In this series, 6 out of 8 evaluable pts with advanced pancreaticobiliary cancers had disease control with ipi/nivo. This series suggests that tumors with germline DDR mutations may be responsive to ICIs. Further evaluation is warranted.