Evaluating the relative treatment efficacy of CD40 agonist mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) using unanchored indirect treatment comparisons (ITCs).

723 Background: Mitazalimab, a human CD40 agonistic IgG1antibody has demonstrated encouraging results in combination with mFOLFIRINOX (mFFX) in the phase 2 single arm trial OPTIMIZE-1 in patients with mPDAC. We conducted unanchored ITCs to assess the relative efficacy of mitazalimab + mFFX vs FOLFIRINOX (FFX) / mFFX and NALIRIFOX (NFX), the most effective therapies to date. Methods: Using data from OPTIMIZE-1 and published data from five RCTs identified via a literature review, matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STC), two commonly used ITC methods for health technology assessment (1) were conducted to balance effect modifiers and prognostic factors between trials. Analysis outcomes were overall survival (OS), objective response rate (ORR), and progression free survival (PFS). Reconstructed survival data from FFX, mFFX, and NFX studies were pooled together for the comparison with FFX/mFFX (Pool #1) and FFX/mFFX/NFX (Pool #2) pooled studies. Results: In the STC analysis mitazalimab + mFFX showed a significantly higher OS versus Pool #1 [hazard ratio (HR): 0.64; 95% CI: 0.46 – 0.87] and #2 [HR: 0.65; 95% CI: 0.47 – 0.87], corresponding to an improvement in median OS by 3.4 and 3.3 months respectively. The OS HRs of study-level pairwise comparisons ranged from 0.57 (95% CI: 0.39 – 0.80) to 0.85 (95% CI: 0.53 – 1.39) with only one non-significant comparison. MAICs showed similar trends, although the comparison with Pool #1 was close to statistical significance (HR: 0.68; 95% CI: 0.45 – 1.02). Results of the PFS and ORR comparisons are shown in the table below. Conclusions: Literature based ITCs show a significantly better efficacy of mitazalimab + mFFX versus the current available therapies in patients with mPDAC. These trends will have to be confirmed in a randomized Phase 3 study. 1. Phillippo DM et al, 2019. Clinical trial information: NCT02829099 . ITC results – HR (for OS and PFS) and odds ratios (for ORR) and their 95% CIs. STC MAIC Comparator study OS PFS ORR OS PFS ORR PRODIGE 4 (FFX) 0.57 (0.39 – 0.80) 0.63 (0.44 – 0.88) 1.62(0.87 – 2.99) 0.60 (0.40 – 0.89) 0.56 (0.37 – 0.82) 1.55(0.84 – 2.87) PANOPTIMOX (FFX) 0.58 (0.39 – 0.84) 0.68 (0.47 – 0.98) 1.17(0.59 – 2.30) 0.60 (0.38 – 0.94) 0.67(0.44 – 1.02) 1.04(0.52 – 2.05) AVENGER500 (FFX) 0.71 (0.50 – 0.98) 1.15(0.82 – 1.60) 1.35(0.75 – 2.42) 0.69(0.46 – 1.03) 1.11(0.76 – 1.62) 1.30(0.72 – 2.34) SWOGS1313 (mFFX) 0.85(0.53 – 1.39) 0.89(0.57 – 1.36) 0.90(0.43 – 1.89) 0.91(0.55 – 1.50) 0.86(0.55 – 1.33) 0.88(0.42 – 1.86) Pool #1 0.64 (0.46 – 0.87) 0.81(0.59 – 1.10) 1.33(0.77 – 2.32) 0.68(0.45 – 1.02) 0.81(0.56 – 1.18) 1.20(0.69 – 2.09) NAPOLI-3 (NFX) 0.68 (0.49 – 0.93) 0.85(0.61 – 1.17) 0.97(0.55 – 1.71) 0.67 (0.46 - 0.97) 0.83(0.58 – 1.20) 0.92(0.52 – 1.62) Pool #2 0.65 (0.47 – 0.87) 0.82(0.60 – 1.11) 1.17(0.68 – 2.02) 0.68 (0.47 – 0.99)