Induction FOLFIRINOX and SBRT for borderline/locally advanced pancreatic cancer.

782 Background: FOLFIRINOX is a preferred regimen for borderline and locally advanced pancreatic ductal adenocarcinomas (PDAC). Stereotactic body radiotherapy (SBRT) is promising for local disease control, and predictive markers are needed to define when FOLFIRINOX followed by SBRT is of clinical benefit. Methods: Two single-arm, phase 2 trials for borderline resectable PDAC (BRPC) and locally advanced PDAC (LAPC), were conducted at the Yale Smilow Cancer Hospital from 8/2017 – 1/2019 (NCT03099265) and 9/2019 – 9/2023 (NCT03991962). Patients received 8-12 cycles of FOLFIRINOX followed by SBRT (33 Gy in 5 fractions). Radiographic and biochemical responses (CA19-9) were assessed by a multi-disciplinary team for surgical eligibility. Endoscopic ultrasound strain elastography with core biopsies were performed pre-treatment, post-FOLFIRINOX, and post-SBRT to determine the strain ratio (tumor stiffness) and PDAC molecular subtype, respectively. The primary endpoint was 9-month progression-free survival (PFS). Additional endpoints included median PFS, median overall survival (OS), patterns of recurrence, tumor stiffness (assessed by elastography strain ratio), and PDAC molecular subtype (assessed by K17 IHC test). Results: Twenty patients (10F, 10M, median age 64) were enrolled. Thirteen had BRPC and seven had LAPC. Twelve (60%) patients received FOLFIRINOX + SBRT and three (15%) underwent surgery on protocol. Nine-month PFS was 36% (95% CI, 19-68%, expected was 50% based on LAP07). Median PFS was 8 months (95% CI, 5.8-32.4), and median OS was 13.2 months (95% CI, 9-59). The median follow-up was 72.5 months. Overall response rate was 25% with 5 partial responses. Locoregional-only recurrences were rare (10%), with most recurrences occurring at distant sites (40%) or locoregional sites (20%), indicating favorable local disease control. One patient died of oxaliplatin-related pneumonitis. Pre-treatment tumor stiffness was higher in BRPC vs. LAPC (30.5 vs. 11.4, p = 0.04), and stiffer tumors were mainly basal-like molecular subtype ( p = 0.06). Higher pre-treatment tumor stiffness had a non-significant increased risk of death (adjusted for stage, HR 3.85, 95% CI 0.79–18.84, p = 0.09), such that BRPC with higher pre-treatment stiffness exhibited survival outcomes comparable to that of locally advanced tumors. In contrast, among CA19-9 responders, tumors that became stiffer with chemotherapy had a non-statistical improved overall survival relative to tumors that became softer (HR 0.39, 95% CI 0.07-2.04, p = 0.26). Conclusions: FOLFIRINOX followed by SBRT achieved local disease control in PDAC. Tumor stiffness and molecular subtype emerged as potential biomarkers of response and prognosis, warranting validation in larger studies. Early trial closure from the COVID-19 pandemic and censoring of exceptional responders prior to SBRT likely contributed to the inferior observed outcomes. Clinical trial information: NCT03099265 , NCT03991962 .