Abstract B122: The timing matters: schedule-dependent optimization of gemcitabine and RAS(ON) inhibition in pancreatic cancer, a call for a new approach to clinical trial design

Abstract

Recent data published from the RASolute 302 trial (NCT06625320), showing that RAS inhibition nearly doubles median survival to 13.2 months compared to 6.7 months with standard-of-care chemotherapy for patients with pancreatic ductal adenocarcinoma (PDAC), received an ovation when presented at the 2026 ASCO Oncology meeting. Despite these advances, most patients develop resistance, indicating that RAS inhibition alone is unlikely to provide durable control and that rational combination strategies will be required. The current phase 3 RASolute 303 clinical trial combines RAS(ON) inhibition with standard-of-care chemotherapeutic regimens using concurrent administration. This approach, based on coordination, has not been evaluated for efficacy and tolerability against alternative scheduling strategies. In fact, in PDAC models, the scheduling of gemcitabine (GEM) before nab-paclitaxel improves therapeutic efficacy compared to concurrent administration. These findings suggest that the timing of treatment is a biological variable to be exploited to enhance patient outcomes. Herein, we assessed whether the timed-sequencing of GEM and RAS(ON) inhibitor daraxonrasib (RMC-6236; hereafter RASi) administration alters therapeutic outcomes in an immunocompetent orthotopic PDAC model. In this study, using a clinically tractable sequencing paradigm, we compared concurrent therapy with sequential regimens in which GEM preceded RASi (GEM→RASi) or vice versa (RASi→GEM). Specifically, we tested six different arms to this pre-clinical trial to assess relevant translational endpoints including: 1) tumor growth kinetics; 2) survival outcomes; 3) tolerability and systemic effects. We show that GEM followed by RAS inhibitor (GEM→RASi) scheduling is associated with improved survival and altered tumor growth dynamics relative to reverse scheduling and monotherapies, and favorable survival trends compared to concurrent treatment, with reduced total agent exposure. These findings identify timed-treatment scheduling as a modifiable variable with direct implications for the clinical integration of RAS(ON) inhibitors. Mechanistically, a strong putative explanation for the observed sequencing effect may lie in gemcitabine-induced cell cycle redistribution. Ongoing studies are evaluating whether GEM arrests surviving cells at the G1/S transition, a phase associated with heightened RAS pathway dependency, during which oncogenic KRAS activity is essential for cell cycle re-entry. RAS inhibitors are currently under clinical evaluation in combination with standard-of-care chemotherapy in PDAC. Our data question the assumption that concurrent administration is optimal, instead suggesting that defined therapeutic sequencing may enhance efficacy, while reducing overall chemotherapy exposure and eventual therapeutic resistance. This is an important consideration given that adverse events to extended regimens are frequently dose-limiting, and the logistical burden of infusion-based therapy represents a meaningful and sometimes prohibitive barrier for patients.