Benchmarking survival outcomes of quemliclustat in first-line metastatic pancreatic ductal adenocarcinoma: Insights from ARC-8 and implications for PRISM-1.

Abstract

e16396 Background: Outcomes in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) remain poor, with gemcitabine plus nab-paclitaxel (GnP) yielding median overall survival (OS) < 11 months in contemporary trials. ARC-8, a phase I/Ib randomized study, evaluated the CD73 inhibitor quemliclustat combined with GnP ± the PD-1 inhibitor zimberelimab and demonstrated encouraging survival outcomes. We conducted a trial-in-context benchmark analysis to assess whether the ARC-8 OS signal exceeds contemporary first-line expectations after accounting for cross-trial differences. Methods: Published ARC-8 efficacy data were synthesized for treatment-naïve mPDAC patients receiving 100-mg quemliclustat-based regimens (quemliclustat + GnP or quemliclustat + zimberelimab + GnP). As ARC-8 lacked a control arm, a matched synthetic control arm (SCA) was derived from historical GnP-treated patients using key baseline characteristics. Contemporary phase III GnP benchmarks from MPACT and NAPOLI-3 control arms were included. Cross-trial differences in OS, progression-free survival (PFS), and overall response rate (ORR) were qualitatively assessed for potential directional bias. Results: Across benchmarking approaches, pooled ARC-8 quemliclustat-based regimens were associated with a median OS of 15.7 months, exceeding contemporary first-line GnP benchmarks. In the matched SCA comparison, OS remained improved (HR for death 0.63), despite baseline characteristics expected to bias against ARC-8. PFS and ORR were broadly similar to GnP benchmarks. No new safety signals or toxicity were observed. Conclusions: In a trial-in-context benchmark analysis, quemliclustat-based regimens in ARC-8 were associated with a consistent OS advantage compared with contemporary GnP benchmarks despite similar PFS and ORR, suggesting a clinically meaningful survival signal and supporting the clinical and biologic rationale for the ongoing phase III PRISM-1 trial. OS, PFS and ORR for ARC-8 Quemliclustat regimens v/s GnP benchmarks. Population/ comparator Median OS, months (95% CI) 12-moOS (%) Median PFS, months ORR (%) ARC-8 Q100 ± Z + GnP (n=122) 15.7 (12.7 63 6.3 (5.4-7.7) 39 Synthetic control GnP (matched, n=515) 9.5 (8.8-10.5) 39.7 5.6 37.3 Contemporary phase III GnP benchmarks 9.2 (8.3-10.6) 40 5.6 (5.3-5.8) 36 Q=quemliclustat; Z=zimberelimab; GnP=gemcitabine+nab-paclitaxel.