PASS-01 Trial: Modified FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel for Advanced PDAC

Despite both modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel being standard first-line options for advanced pancreatic adenocarcinoma (PDAC), a head-to-head comparison in North American patients is lacking. Additionally, reliable biomarkers to guide therapy selection are needed. The multicenter, randomized phase 2 PASS-01 trial aimed to address these issues by incorporating comprehensive molecular profiling and patient-derived organoid (PDO) drug sensitivity testing. Early results from the trial were presented at the 2024 American Society of Clinical Oncology Annual Meeting by lead author Jennifer J. Knox, MD, of the Princess Margaret Cancer Centre, University of Toronto, in Ontario, Canada.

PASS-01 enrolled treatment-naive patients with de novo metastatic PDAC, Eastern Cooperative Oncology Group performance status of 0-1, and no germline BRCA1/2 or PALB2 mutations. Baseline tumor biopsies underwent whole genome and RNA sequencing for mutational landscape analysis. Viability for PDO generation was assessed, and successful PDOs were subjected to drug sensitivity testing with standard and novel agents. Patients were randomized 1:1 to receive either mFFX or gemcitabine/nab-paclitaxel as first-line therapy. The primary end point was progression-free survival (PFS) by intention-to-treat (ITT) analysis. Secondary end points included objective response rate, safety, overall survival (OS), and the effects of RNA signatures and GATA6 expression on outcomes. A molecular tumor board reviewed each patient’s case after the first 8 weeks to recommend personalized second-line therapy upon disease progression.

The trial enrolled 160 patients (45% from Canada, 55% from the United States), with 140 eligible for PFS analysis (data cutoff, March 1, 2024). Median PFS (ITT) was 5.1 months for gemcitabine/nab-paclitaxel and 4.0 months for mFFX (P=.14). Best overall response (PR/SD) favored gemcitabine/nab-paclitaxel (29%/45%) compared with mFFX (24%/35%). Treatment-related serious adverse events were low (3% for gemcitabine/nab-paclitaxel; 13% for mFFX). Median OS (ITT) was 9.7 months for gemcitabine/nab-paclitaxel and 8.4 months for mFFX (P=.04). Notably, 43% of patients did not receive second-line therapy. Of those who progressed (n=113, ITT), 64 (57%) received further treatment, with a correlative-guided approach used in 50% (21 [66%] received chemotherapy, 11 [34%] received targeted or immunotherapy). Correlative analyses of molecular data and treatment response are ongoing. Whole-genome sequencing was successful in over 80% of patients, and RNA signatures were generated in over 72%. The ITT population included 9% KRAS wild-type and 21% Basal-like PDAC subtypes. PDO drug sensitivity models were established in 50% of patients.

PASS-01 demonstrates the feasibility of integrating multiomic profiling and PDO drug testing into a randomized trial for advanced PDAC. While gemcitabine/nab-paclitaxel showed a trend toward improved PFS and OS in this BRCA mutation-negative cohort, the benefit of current first-line chemotherapy regimens remains low, with a significant proportion of patients unable to receive second-line therapy. These findings highlight the urgent need for biomarker-driven treatment strategies in advanced PDAC.