A Phase II Study of Neoadjuvant FOLFIRINOX in Combination with Losartan Followed by Chemoradiotherapy in Locally Advanced Pancreatic Cancer: R0 Resection Rate and Clinical Outcomes

Purpose: To evaluate the margin negative (R0) resection rate of neoadjuvant FOLFIRINOX and losartan followed by chemoradiotherapy for locally-advanced pancreatic cancer (LAPC). Methods: LAPC patients (per NCCN), ECOG PS 0-1 were enrolled in a single-institution NCI-sponsored phase II study. Patients received 8 cycles of FOLFIRINOX/losartan. If the tumor was radiographically resectable after chemotherapy, patients received short-course chemoradiotherapy (CRT) in 5 fractions (protons 25 GyE, capecitabine 825 mg/m2 bid). If the tumor had persistent vascular involvement, patients received CRT to 50.4 Gy with a vascular boost to 58.8 Gy. The primary endpoint was R0 resection rate. Secondary endpoints were tolerability, PFS, OS, and circulating biomarkers. Results: Fifty patients were enrolled from 8/2013 to 7/2017, with 49 patients evaluable (1 patient withdrew consent). Median age was 63y (42-78), median tumor size was 41mm (18-68), and was located in the pancreatic head in 63% of patients. Thirty-nine patients completed 8 cycles of FOLFIRINOX/losartan, while 10 had fewer than 8 cycles due to progression (5), losartan intolerance (3) and toxicity (2). Grade 3 or greater toxicity occurred in 25 (51%) patients. Forty-five (92%) patients received CRT: 7 patients (15%) had short -course, while 38 (85%) had long-course. Forty-two (86%) patients underwent attempted surgery, with 34 (69%) patients resected. R0 resection was achieved in 30 patients (61% of evaluable patients, 88% of resected patients). Median follow-up was 17.1 months. Overall mPFS was 17.5 months and mOS 31.4 months. Among resected patients, mPFS was 21.3 months and mOS was 33.0 months. Conclusions: Neoadjuvant FOLFIRINOX/losartan provides downstaging of LAPC allowing for R0 resection in 61% of patients. These findings are being validated in an ongoing multicenter randomized trial. Clinical Trial Number: ClinicalTrials.gov Identifier: NCT01821729 Funding Statement: This study was funded by NIH Proton Beam NCI/Federal Share Program grant C06 CA059267, and in part by the Cancer Clinical Investigator Team Leadership Award awarded by the National Cancer Institute though a supplement to P30CA006516 (TSH); P01CA080124, U01CA224173, R01CA208205 (RKJ, DGD, YB). DGD is also supported through The Samuel Singer Brown Fund for Pancreatic Ductal Adenocarcinoma Research. Declaration of Interests: Dr. Hong reports Novartis, Astra-Zeneca, Clinical Genomics, Taiho (clinical trial funding), EMD Serono (Advisory board). Dr. Ryan reports MPM Capital (consulting). Dr Faris reports Novartis (active employment), N-of-One and Merrimack Pharmaceuticals (consulting), and Exelixis, Takeda, and Roche (clinical trial funding). Dr. Kwak reports Novartis (active employment). Dr. Jain reports honorarium from Amgen; consultant fees from Merck, Ophthotech, Pfizer, SPARC, SynDevRx, XTuit; owns equity in Enlight, Ophthotech, SynDevRx, XTuit; served on the Board of Directors of XTuit and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund. Neither reagents nor funding from these organizations were used in this study. No other authors reported conflicts of interest. Ethics Approval Statement: Patients with LAPC were prospectively enrolled in this NCI-sponsored clinical trial approved by the institutional review board (NCT01821729).