Overall survival (OS) with NALIRIFOX (NFX) compared to FOLFIRINOX (FFX) in patients not previously treated for metastatic pancreatic ductal adenocarcinoma (mPDAC): An external control arm study.

e16383 Background: The phase 3 NAPOLI 3 trial (NCT04083235) demonstrated significantly improved OS in patients with mPDAC treated with first-line (1L) NFX (liposomal Irinotecan + 5-fluorouracil/leucovorin + oxaliplatin)compared to 1L gemcitabine + nab-paclitaxel. However, no evidence has been found that directly compares NFX to FFX (irinotecan + 5-fluorouracil/leucovorin + oxaliplatin), another standard-of-care regimen for 1L mPDAC. To evaluate the relative efficacy of NFX versus FFX, this study compared OS between NFX from NAPOLI 3 and external controls treated with FFX from real-world data. Methods: The 1L NFX cohort (n = 383) was derived from the intent-to-treat population in the NAPOLI 3 trial. A trial-aligned FFX cohort was constructed using the Flatiron Health database, that included patients treated with 1L FFX between January 1, 2020 and July 31, 2022 who met the NAPOLI 3 eligibility criteria. Additionally, a subgroup of patients treated with 1L modified FFX (mFFX) was identified. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics between the NFX cohort and the trial-aligned FFX cohorts. Doubly robust, IPTW-weighted Cox regression models were used to compare OS between the cohorts. Results: The trial-aligned FFX cohort included 219 patients, 70% (n = 154) of whom received mFFX. After IPTW, key baseline characteristics were well balanced (Table 1). Median OS (95% confidence interval [CI]) was 11.7 (10.5, 13.0) months for NFX, 9.0 (7.3, 11.1) months for FFX cohort, and 8.0 (6.7, 11.2) months for mFFX. NFX was associated with a statistically significant 21% lower risk of death compared to FFX (HR: 0.79 [95% CI: 0.64-0.96], p = 0.02). Similarly, the subgroup analysis showed NFX was associated with a statistically significant 20% reduction in the risk of death compared to mFFX (HR: 0.80 [95% CI: 0.64-0.99], p = 0.04). Conclusions: In these analyses, NFX demonstrated significantly improved OS compared to both FFX and mFFX. This external control arm analysis provides important insights into the efficacy of NFX in the absence of comparative evidence from randomized clinical trials. NFX cohort vs trial-aligned FFX cohorts after IPTW. Weighted NFX (vs. trial-aligned FFX)N=365 Weighted trial-aligned FFXN=215 Weighted NFX (vs. trial-aligned mFFX)N=366 Weighted trial-aligned mFFXN=153 Baseline characteristics, n (%) Age ≥65 years 179 (49.1) 102 (47.4) 182 (49.8) 71 (46.8) Female 170 (46.7) 102 (47.5) 170 (46.4) 71 (46.6) White 293 (80.3) 164 (76.3) 294 (80.4) 118 (77.2) ECOG score ≥1 199 (54.4) 113 (52.4) 206 (56.1) 80 (52.3) OS Median, months (95% CI) 11.7 (10.5, 13.0) 9.0 (7.3, 11.1) 11.5 (10.3, 12.5) 8.0 (6.7, 11.2) HR (95% CI), p-value Reference 0.79 (0.64, 0.96), 0.02 Reference 0.80 (0.64, 0.99), 0.04