Phase IIb randomized trial of FOLFIRINOX plus ibrilatazar (ABTL0812) versus placebo as first-line treatment in metastatic pancreatic cancer: An analysis from the PanC-ASAP study.

Abstract

4218 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has poor prognosis and limited first-line treatment options. Ibrilatazar (ABTL0812) is a first-in-class oral agent that induces cytotoxic autophagy selectively in cancer cells. Favorable safety and tolerability of the combination with FOLFIRINOX were established in a Phase I study. D.S. and T.M. are equal contributors. Methods: PanC-ASAP is a Phase IIb double-blind, randomized, placebo-controlled (1:1) study evaluating the efficacy and safety of ibrilatazar (1300 mg TID) plus FOLFIRINOX versus placebo plus FOLFIRINOX as first-line therapy in mPDAC, conducted across 23 sites in the US, Spain, France, and Israel. Eligible patients had histologically confirmed mPDAC, ECOG PS 0–1, and no prior systemic treatment for metastatic disease. Treatment continued until disease progression or intolerable toxicity. Primary endpoint was progression-free survival (PFS), defined as time from randomization to radiographic disease progression or death, assessed by blinded independent central review in the intention-to-treat (ITT) population. Overall survival (OS) was a key secondary endpoint. Safety was assessed in all treated patients. Pre-specified stratification analysis revealed an imbalance in ECOG between arms (ECOG 0/1: 40%/60% ibrilatazar vs 54%/46% placebo), prompting an exploratory efficacy analysis by ECOG PS subgroup. Time-to-event endpoints were analyzed using Kaplan–Meier methods and log-rank tests. Results: In the ITT population (n = 140), median PFS for ibrilatazar vs placebo was 9.4 vs 7.9 mths (HR 0.95; 90% CI, 0.69-1.33; p = 0.814). An exploratory analysis by ECOG showed that, among patients with ECOG 0 (n = 66; ibrilatazar, n = 28; placebo, n = 38), median PFS of 11.1 vs 6.5 mths (HR 0.60; 95% CI, 0.34–1.08; p = 0.089), and median OS of 19.3 vs 12.0 mths (HR 0.57; 95% CI, 0.31–1.05; p = 0.072). Consistent trends favoring ibrilatazar were observed across efficacy endpoints, including objective response rate and duration of treatment. Safety profile of ibrilatazar plus FOLFIRINOX was consistent with the known FOLFIRINOX toxicities. The most common grade ≥3 treatment-emergent adverse events in the ibrilatazar vs placebo were neutropenia (21% vs 22%), diarrhea (21% vs 16%), and neurotoxicity (0% vs 14%). Conclusions: Although primary PFS endpoint was not met in the ITT population, exploratory analysis showed clinically meaningful and consistent efficacy improvements among ECOG 0 patients treated with ibrilatazar plus FOLFIRINOX, with 60% and 70% increases in median OS and median PFS respectively. These findings support further investigation in selected mPDAC populations and suggest ECOG may modify treatment benefit. Clinical trial information: NCT04431258 .