Pamrevlumab plus nab-paclitaxel/gemcitabine (Pam + GA) as first- and second-line therapy in metastatic pancreatic cancer (mPDAC): Results from Precision Promise (PrP) Bayesian platform trial.

Abstract

673 Background: Pamrevlumab (Pam) is a fully human recombinant monoclonal antibody against connective tissue growth factor. Early clinical data with Pam plus chemotherapy showed a favorable safety profile and potential efficacy in PDAC. In PrP, Pam + GA was tested as first line (Line 1) and second line (Line 2) therapy for mPDAC vs GA. PrP is a phase 2/3, innovative Bayesian adaptive platform trial sponsored by the Pancreatic Cancer Action Network testing multiple experimental arms efficiently against common controls (1). Methods: Randomization is 70% (adaptive amongst experimental arms in stage 1) and 15%:15% amongst two control arms (GA, mFOLFIRINOX). Pam + GA graduates from stage 1 to 2 if the Bayesian predictive power (PP) of eventual success is ≥ 35% for one of the arm’s signatures [Line 1, Line 2 or Line 1 & 2 (All)]. All participants (pts) are followed for 12 months (mos) after last pt randomized and treated in Pam + GA. Stages 1 and 2 are combined for final analysis. Efficacy is defined by overall survival (OS) hazard ratio (HR, experimental vs control), by a Bayesian statistical model. Superiority (HR < 1) is claimed at final analysis if the Bayesian probability of superiority is ≥ 98%. Results: Pam + GA entered PrP in Jun 2021. Between 6/2021 - 1/2023, at 23 US sites, 317 pts were treated and are included in the mITT analysis. 213 pts were treated in the Pam + GA arm (102 Line 1; 111 Line 2), 45 in the GA arm (23 Line 1; 22 Line 2), 31 in the mFOLFIRINOX arm and 28 in other experimental arms. All treated pts before and during Pam + GA enrollment were in the Bayesian model, with outcomes adjusted via a time machine to increase the trial’s statistical power. Baseline characteristics were balanced across the arms. Pam + GA met criteria to graduate to stage 2 in Sep 2022 in the All signature (Line 1 & 2). At final analysis, Pam + GA did not meet the OS primary endpoint [model estimated HR: 1.18 (95% credible interval, 0.88, 1.56), posterior Pr(HR < 1) = 0.14, below specified ≥ 0.98]. No benefit was seen in PFS nor ORR (Table). No new safety signals were seen. Conclusions: PrP, the first Bayesian platform trial in mPDAC, performed as designed; Pam + GA did not improve OS versus GA in Line 1 and Line 2 mPDAC. The novel Bayesian design warrants further study in mPDAC to enhance efficiency of drug development. Future designs should explore different strategies to allocate patients to control arm(s) vs experimental arms and accommodate novel agents intended to benefit subsets of mPDAC. 1. Picozzi, ASCO TPS 4188, 2022. Clinical trial information: NCT04229004 . Line 1 Line 2 GA Pam + GA Hazard Ratio GA Pam + GA Hazard Ratio Model Estimated mOS (mos) 11.3 9.7 1.18(95% CI* 0.88, 1.56) 7.8 6.6 1.18(95% CI* 0.88, 1.56) mPFS (mos) 5.3 5.9 0.64(95% CI^ 0.36, 1.14) 7.0 3.9 1.35(95% CI^ 0.78, 2.33) ORR (%) 26.1 35.3 4.5 9.0 *Credible Interval. ^Confidence Interval.