NeoPancONE: GATA6 expression as a predictor of benefit to peri-operative modified FOLFIRINOX in resectable pancreatic adenocarcinoma (r-PDAC): A multicentre phase II study.

Abstract

4011 Background: Modified FOLFIRINOX (mFFX) is increasingly used in the perioperative setting in r-PDAC and patients (pts) would benefit from a biomarker approach. GATA6 expression enriches for the classical RNA subtype, associated with improved OS in advanced PDAC. Low expression identifies the basal subtype which may predict mFFX resistance. NeoPancONE is a single arm Phase II multicentre study evaluating clinical outcomes and investigating GATA6 as a biomarker of response to perioperative mFFX in r-PDAC. Methods: Pts were enrolled following central radiology review (CRR) and underwent an EUS FNB for GATA6 in-situ hybridization (ISH). Six cycles of mFFX were planned pre and postoperatively. The primary endpoint was 1 yr event-free survival (EFS) according to GATA6 ISH (high vs low). Secondary endpoints include OS, RECIST response, SAEs, R0 resection rates and RNA subtyping by PurIST. Statistical assumptions used a ratio of 3:1 GATA6 high:low, with a 1 yr EFS of 65% for high and 34% for low (HR 2.5, 80% power, 2 sided alpha 0.05). KM method and log-rank test were used. Results: Between Sep-2020– Sep 2023, 146 pts were screened and 84 enrolled (58%) at 8 Canadian centres. CRR deemed 39 (27%) ineligible. Clinical data are summarized (Table). GATA6 ISH was analysed in 74 (88%); 62 (84%) were high, 16% low. At a median follow up of 24.5 mos, the med EFS and OS in the ITT were 16.1 mos (95 CI; 13-21) and 34.2 mos (95 CI; 28-NE). Med OS in the 73 pts who underwent surgery was 35.6 mos (95 CI 33-NE). The 1 yr EFS was 71% in GATA6 high vs 58% in GATA6 low p= 0.53. 1 yr OS was 87% in high vs 75% for low p= 0.29. The proportion progressing within 6 mos of enrollment in the GATA6 low group was significantly higher (42% vs 12% p=0.02). PuriST subtyping was reported in 49 (67%) resections; 14% basal, 86% classical. The 1 yr EFS was 79% in classical vs 43% in the basal subtype p=0.1. The 1 yr OS was 95% in classical vs 57% in basal p=0.034. Conclusions: This is one of the first trials in r-PDAC to identify potential biomarkers to predict perioperative mFFX response. GATA6 by ISH can be assessed on baseline tissue. GATA6 high is a prognostic biomarker, although NS, trends towards improved EFS and an encouraging OS. Disease progression within 6 months of enrollment occurs in nearly 50% of patients with low GATA6 expression. Neoadjuvant mFFX should not be the standard of care in these patients. Basal/Classical subtyping had stronger prognostic value than GATA6 and should be considered at baseline EUS FNB for future perioperative strategies in r-PDAC studies. Clinical trial information: NCT04472910 . Characteristic n=84 Age med. (range) yrs 64 (44, 83) Baseline EUS FNB tissue n (%) 83 (98) Pre-op completed 6 cycles n (%) 62 (74) Pre-op RECIST CR/PR/SD/PD/NE % 1/18/64/11/6 Surgery Completed Y/N n (%) / R0 / R1 n (%) 73 (87) / 11(13) / 62 (85) / 11 (15) Adjuvant Chemotherapy Y / N n (%) 63 (86) / 10 (14) mFFX associated SAE ≥G3 n (%) 13 (15) Pre-op mFFX related deaths 3 (4)