A real-world, propensity-matched analysis of second-line (2L) FOLFIRI-Ram versus Ram-Pac in advanced upper gastrointestinal cancers.

4058 Background: Given historically poor outcomes for advanced upper gastrointestinal (UGI) cancers, there is an urgent need for effective 2L treatments. Since the phase III RAINBOW trial, combination ramucirumab and paclitaxel (Ram-Pac) has filled this role; however, this regimen is plagued by dose-limiting toxicities, specifically neuropathy. The phase II RAMIRIS trial demonstrated the efficacy and tolerability of FOLFIRI-Ram as an alternative 2L, even if it did not improve survival over Ram-Pac. Real-world data to support its use, however, are lacking. Methods: The nationwide Flatiron Health electronic health record-derived de-identified database, which includes treatment data from around 280 cancer clinics across the United States, was queried for patients treated for unresectable or metastatic UGI cancers with 2L Ram-Pac or FOLFIRI-Ram from January 2011-June 2024. Demographics and lab values at time of treatment were extracted. Study cohorts were derived using a greedy match based on a logit model to predict propensity scores from key clinical and laboratory characteristics; patients were matched 1:6 (FOLFIRI-Ram:Ram-Pac) given expected imbalances in sample size. The endpoints of interest were overall survival (OS) and real-world time to treatment discontinuation (rwTTD), determined via Kaplan-Meier method, log-rank test, and Cox proportional hazards model. A hybrid approach was used to construct a multivariate Cox model. Results: Of 15,908 UGI cancer patients identified, 631 received 2L Ram-Pac and 40 received 2L FOLFIRI-Ram. After matching, 40 FOLFIRI-Ram and 240 Ram-Pac patients were included. Median OS from initiation of 2L therapy was 9.7 months with FOLFIRI-Ram (95% CI 6.9-12.3) and 7.7 months with Ram-Pac (95% CI 6.2-8.8), with a hazard ratio (HR) for death of 0.74 with FOLFIRI-Ram versus Ram-Pac (95% CI 0.50-1.11, p = 0.14). Similar results were seen in the multivariate model (HR 0.72, 95% CI 0.49-1.08, p = 0.114) after adjustment for albumin, neutrophil:lymphocyte ratio, and alkaline phosphatase. The median rwTTD with FOLFIRI-Ram was 5.2 months (95% CI 4.1-6.2), compared to 3.7 months with Ram-Pac (95% CI 3.2-4.3). The HR for treatment discontinuation was 0.70 with FOLFIRI-Ram versus Ram-Pac (95% CI 0.48-1.00, p = 0.048). The reduced hazard for treatment discontinuation with FOLFIRI-Ram persisted in the multivariate model (HR 0.67, 95% CI 0.46-0.97, p = 0.033) after adjustment for ECOG status, history of prior surgery, PDL1, albumin, and neutrophil:lymphocyte ratio. Conclusions: In a real-world propensity-score matched analysis, no survival difference was noted with the combination of FOLFIRI-Ram compared to Ram-Pac, however FOLFIRI-Ram was associated with a significantly longer rwTTD. Altogether, these data suggest FOLFIRI-Ram is a viable and tolerable alternative for 2L treatment of UGI cancers.