Abstract A002: A phase II study of peri-operative modified FOLFIRINOX in localized pancreatic ductal adenocarcinoma (PDAC)
Authors: Cecchini Michael , Salem Ronald , Robert Marie , Czerniak Suzanne , Rajaei Moein , Townsend Jeffrey , Blaha Ondrej , Zelterman Daniel , Thumar Jaykumar , Kortmansky Jeremy , Zaheer Wajih , Fischbach Neal , Persico Justin , Stein Stacey , Khan Sajid , Cha Charles , Billingsley Kevin , Kunstman John , Chowdhury Sumedha , Tseng Robert , Mauricio Carlos , Yugawa Deanne , Escobar-Hoyos Luisa , Johung Kimberly , Wiess Christina , Spickard Erik , Aushev Vasily N. , Laliotis George , Jurdi Adham , Liu Minetta C. , Lacy Jill 
Published: January 2024

Abstract
Introduction: Advances in adjuvant chemotherapy with 5-fluorouracil, irinotecan, and oxaliplatin (FFX) have improved survival for patients (pts) with resectable PDAC yet few are cured by the current standard of care. Neoadjuvant FFX may lead to early control of micrometastasis and enhance cure rates for this aggressive malignancy. Methods: We performed a single-arm phase-2 clinical trial for resectable PDAC evaluating 6 months of perioperative modified (m) FFX (NCT02047474). Patients underwent baseline pancreatic protocol CT and were reviewed for resectability by a multidisciplinary panel. Enrolled pts received 6 cycles of neoadjuvant mFFX followed by surgery and 6 cycles of adjuvant mFFX. The primary endpoint was a ≥ 66% 12-month progression-free survival (PFS). Additional endpoints included overall survival (OS), circulating tumor DNA (ctDNA), tumor molecular features and tumor Keratin 17 levels. Whole blood was prospectively collected and processed to stored plasma (median volume 5.4 mL, range: 2.6 – 10.2) for retrospective ctDNA analysis using a personalized, tumor-informed ctDNA assay (SignateraTM). Survival rates were estimated by Kaplan-Meier. Results: Forty-six pts enrolled with 63 months median follow up, median age of 65 [R 46–80], 36 (78%) were ECOG 0, 30 (65%) had an endobiliary stent and no pts had staging laparoscopy. All pts started mFFX, and 37 pts (80%) completed all 6 preop cycles. Thirty-three pts (72%) underwent surgery with 3 pts developing investigator-assessed progression during neoadjuvant mFFX. Six pts were unresectable intraoperatively, and 27 pts (59%) underwent resection per protocol (25 R0, 2 R1). Ten additional pts underwent surgery off protocol. The 12-month PFS was 78% (95% CI: 64.2–94.4), median PFS and OS were 36.5 months (95% CI: 16.6–74.5) and 37.2 months (95% CI 17.5–not reached), respectively. Two-year OS was 59% (95% CI: 45.8–74.7). Baseline ctDNA was detected in 16/22 (73%) pts, and after 6 cycles of mFFX ctDNA was detected in 3/17 (18%) of pts. Patients with a positive ctDNA test 4 weeks post-resection had worsened PFS (HR 34.0, 95% CI: 2.6-4758.6; P = 0.006) and OS (HR: 11.7, 95% CI: 1.5–129.9; P = 0.021) compared to ctDNA negative. Mutational signature analysis revealed predominant signatures to be COSMIC signatures SBS1 and SBS5 (age related), and SBS15 (mismatch repair deficiency associated) which was associated with improved OS. Using Keratin 17 as a biomarker of the basal molecular subtype, either in diagnostic needle aspirates or surgical specimens, we found that high K17 expression was associated with worse survival. Conclusion: The perioperative mFFX clinical trial for resectable PDAC met its primary endpoint with a promising survival rate, and R0 resection rate of 93%. These findings warrant further evaluation in a randomized clinical trial. Most pts with detectable ctDNA at baseline experience ctDNA clearance after 6 cycles of neoadjuvant mFFX. In the post-operative setting, ctDNA positivity was strongly associated with recurrence. Signature SBS15 and low K17 were associated with improved OS.
Citation Format: Michael Cecchini, Ronald Salem, Marie Robert, Suzanne Czerniak, Moein Rajaei, Jeffrey Townsend, Ondrej Blaha, Daniel Zelterman, Jaykumar Thumar, Jeremy Kortmansky, Wajih Zaheer, Neal Fischbach, Justin Persico, Stacey Stein, Sajid Khan, Charles Cha, Kevin Billingsley, John Kunstman, Sumedha Chowdhury, Robert Tseng, Carlos Mauricio, Deanne Yugawa, Luisa Escobar-Hoyos, Kimberly Johung, Christina Wiess, Erik Spickard, Vasily N. Aushev, George Laliotis, Adham Jurdi, Minetta C. Liu, Jill Lacy. A phase II study of peri-operative modified FOLFIRINOX in localized pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A002.