Early results of the PASS-01 trial: Pancreatic adenocarcinoma signature stratification for treatment-01.
Jennifer J. Knox, Elizabeth M. Jaffee, Grainne M. O’Kane, Daniel A. King, Dan Laheru, Kenneth H. Yu, Kimberly Perez, Amber N. Habowski, Robert C. Grant, Sandra E. Fischer, Andrew J. Aguirre, Raymond Woo-Jun Jang, Craig Devoe, Eileen M. O’Reilly, Anna Dodd, Brian M. Wolpin, Xiang Y. Ye, Faiyaz Notta, Steven Gallinger, David A. Tuveson
Abstract
LBA4004 Background: Over 60% of patients with pancreatic ductal adenocarcinoma (PDAC) present with metastatic disease. Both modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel (GnP) are first-line options in advanced PDAC, however have not been compared prospectively in North American patients. Moreover, biomarkers to guide selection are lacking. Basal-like and Classical subtypes are prognostic, but their predictive impact is unknown. Patient-derived organoids (PDOs) are now feasible to study for drug pharmacotyping. Expedient molecular profiling with additional PDO drug sensitivities could enable better precision choices in PDAC. Methods: PASS-01 is a multi-center randomized phase II trial evaluating the benefit of 1 st line mFFX vs GnP in de novo metastatic PDAC patients with ECOG PS 0-1, (germline BRCA1/2, PALB2 excluded) who have baseline tumor biopsies (bx) for whole genome/transcriptional sequencing (WGTS) and PDO generation/pharmacotyping with standard and novel drugs. The primary endpoint is the PFS of mFFX vs GnP (received at least 1 dose of assigned chemo, per protocol (PP)), 136 patients needed to reach 80% power to detect a difference in median PFS of 7 vs 5 months between mFFX and GnP at significance level of 0.3 in a 2-sided test. Secondary endpoints include: ORR, SAEs, OS, impact of RNA signatures and GATA6 expression on outcomes. Each patient is discussed at a molecular tumor board immediately following their 1 st 8-week CT with the goal of recommending precision 2nd-line treatment options on progression. Results: This trial accrued 160 pts between 09/20 and 01/24, 45% in Canada, 55% in US with 140 eligible for 1 st line PFS, data lock Mar 1/24 (see table). Median PFS (PP) was 5.1 mo for GnP and 4.0 mo for mFFX (p=0.14). Best response PR/SD for GnP: 29/45% and 24/35% for mFFX. SAEs attributed to the study were 3% GnP, 13% mFFX and 0.7% bx. Median OS (ITT) was 9.7 mo with GnP and 8.4 mo with mFFX, p=0.04. Of 113 patients in the PP analysis with progression, 64 (57%) received 2nd-line treatment (GnP, n= 30, mFFX n=34) Of these, a correlate-guided approach was delivered in 32 (50%), including 21 (66%) receiving chemo and 11 (34%) receiving a targeted or immunotherapy regimen. Correlative studies are underway. Preliminary analysis shows >80% successful whole genomes and >72% RNA signatures. PP patients include 9 % KRAS wild-type and 21% Basal-like PDAC. PDO-drug models have been established in 50%. Conclusions: Upfront multi-omic profiling of PDAC can be successfully incorporated into a multicenter randomized trial. While we have observed PP improved PFS and ITT longer OS favouring GnP in this cohort without gBRCA 1/2 or PALB2m, the benefit of chemo for advanced PDAC patients remains poor, with 43% unable to receive 2 nd line, arguing strongly for the development of 1 st -line biomarker selected strategies. Clinical trial information: NCT04469556 . [Table: see text]