Abstract IA012: A New Perspective: Clinical Trials in the Era of RAS Inhibitors

Abstract

The demonstration of an overall survival benefit for RAS(ON) multi-selective inhibition in previously treated metastatic pancreatic ductal adenocarcinoma (RASolute 302) establishes the first randomised evidence for RAS-directed therapy in this disease. Previously, biomarker-directed treatment in PDAC reached a minority of patients and was derived largely from tumour-agnostic approvals, with germline BRCA1/2 constituting the only ESCAT tier I-A alteration. RAS mutations, present in more than 90% of tumours, now satisfy tier I-A criteria, extending biomarker-defined treatment to most patients. More than forty RAS-directed agents across eight mechanistic classes are in clinical development, at least nine of them in phase 3 and sponsored by multiple organisations. These trials differ in eligible population, comparator and chemotherapy backbone, and share few common design elements. Reported response rates range from 33% to 82%, a spread determined predominantly by treatment line, allele selection and backbone rather than by pharmacological activity; within a single study, investigator-selected backbones yielded divergent response rates in cohorts differing substantially at baseline. ESMO-MCBS v2.0 grades single-arm data to a maximum of grade 3, leaving the grades that denote substantial benefit unattainable without a comparator. This presentation examines the methodological consequences: the limited discriminatory capacity of objective response rate where disease control approaches 90%; the case for qualifying ctDNA molecular response as an early efficacy endpoint; the promotion of patient-reported outcomes and sustained relative dose intensity to co-primary status; master-protocol architectures with shared control arms and pre-specified randomisation at progression; and prospective characterisation of resistance.