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Abstract Background: Combinations of chemotherapy and checkpoint inhibitors have failed to show improvements in pancreas cancer (PC) but all studies reported to date have been in the metastatic setting. Perioperative strategies of PD1 inhibitor combinations have shown promise in many malignancies. The A021501 trial established modified FOLFIRINOX (mFFX) as a reference neoadjuvant regimen for patients (pts) with borderline resectable pancreas cancer (BRPC). Here, we present clinical and pathologic results from a phase 1/2 investigator-initiated study investigating the safety and efficacy of mFFX and Nivolumab in pts with BRPC. Methods: Pts with ECOG PS 0-1 and BRPC confirmed by qualified surgeons were treated with a maximum of 6 cycles of mFFX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours) on days 1 and 15 of a 28-day cycle and Nivolumab (480 mg Iv q 4 weeks). The primary endpoint was safety (including post-operative fistula formation) and pathologic response to neoadjuvant therapy. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR) and overall survival (OS). RNA sequencing was performed on 16 post-treatment resected tumors, 5 patient-matched diagnostic pre-treatment biopsies, and 9 resected tumors from non-trial patients treated with mFFX alone. Results: Overall, 28 pts (median age 68, M: 16, F, 12) were enrolled. 26 (93%) pts completed at least 3 cycles of mFFX and Nivo and 24 (86%) pts underwent surgery (23 R0/1R1). There were no grade 2 post-operative fistulas observed and the rates of grade 3 or higher adverse events was 55% with all being related to mFFX and none attributed to nivolumab. At a median follow-up of 24 months, the median PFS was 34. 8 months, and the median OS was 35. 1 months. Among pts who underwent pancreatectomy, the 18-month OS rate was 90%. There were 2 pathologic complete responses and 2 near complete responses. Compared to pre-treatment biopsies, RNA sequencing from resected specimens revealed higher CD8 (P=0. 018) and Granzyme A (P=0. 024) expression. In patients with pathologically node negative disease (n=11), elevated Granzyme A expression was associated with significantly improved PFS (P=0. 046). Adenosine-related gene expression increased in 50% (n=8) of post-treatment samples (P0. 022) and correlated with expression of adenosine-generating CD73 (P=0. 008). Conclusions: Neoadjuvant mFOLFIRINOX and Nivolumab was associated with favorable rates of R0 resection, PFS and OS relative to historical data in patients with BRPC in this pilot trial. The addition of Nivolumab did not increase rates of G3 AE’s and there were no unexpected safety signals. The addition of Nivolumab to neoadjuvant FOLFIRINOX may benefit some patients by enhancing cytolytic T cell function and decreasing immunosuppressive adenosine. This is the first trial reported with a PD1 inhibitor in neoadjuvant pancreas cancer and a Phase II trial is ongoing. Citation Format: Zev A. Wainberg, Jason Link, David Dawson, Lee Rosen, Stephen Kim, Mark Girgis, Jon King, Joe Hines, Saeed Sadeghi, Olga Olevsky, Deborah J. Wong, Harsimran Multani, Jenna Davis, Lisa Yonemoto, Ann Marie Siney, Christine Kivork, Chi-Hong Tseng, Timothy Donahue. A pilot clinical trial of neoadjuvant modified FOLFIRINOX plus nivolumab in borderline resectable pancreas cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT031.
Wainberg et al. (Fri,) studied this question.