Targeted therapy (TT) in patients with KRAS wildtype (WT) pancreatic ductal adenocarcinoma (PDAC) produces durable response.

Abstract

596 Background: Genomic alterations (GA) that drive cancer development and predict therapeutic response remain elusive in patients (pts) with KRAS WT PDAC. We interrogated our institutional database to identify actionable GAs in pts with metastatic, KRAS WT PDAC and analyzed the therapeutic impact of matched TT. Methods: We reviewed electronic medical records of KRAS WT PDAC pts (n=24) who underwent comprehensive genomic profiling (CGP) utilizing Foundation One CDx (25.0%) or Tempus (75.0%) between 2015-2021. Duration of response (DOR) was calculated from date of treatment (Tx) initiation to Tx discontinuation. Overall survival (OS) was measured from the date of the diagnosis (Dx) of advanced disease (AD) to death or last follow-up. OS was estimated using the Kaplan-Meier method, with at-risk periods left-truncated at the time of CGP. The effect of covariates on survival was evaluated using Cox proportional hazards regression. Results: Of the 24 KRAS WT pts, 14 (58%) had AD: 8 (57%) pts had metastatic disease at or shortly after Dx, 6 (43%) pts developed metachronous recurrence. Median age at Dx for pts with AD was 65, and 57% were female. Seven of 14 pts with AD (50%) had highly actionable GA (HAGA), (Table). Pts with HAGA demonstrated durable responses to TT (Table) with manageable toxicities. Pts with HAGA had a median OS of 28 mo compared to 5.9 mo for those without (Hazard Ratio = 0.47, p = 0.33). Conclusions: The sustained therapeutic benefit noted with TT matched to HAGA in pts with KRAS WT PDAC underscores the need for systematic interrogation of the somatic genome in PDAC pts. Optimal sequencing of cytotoxic therapy with TT and its impact on modulating clonal selection pressure in pts with KRAS WT PDAC merits prospective evaluation.[Table: see text]