Pan-RAS Inhibition with Daraxonrasib Shows Promising Activity in Advanced Pancreatic Cancer | New England Journal of Medicine

Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited survival gains despite advances in systemic therapy. More than 90% of PDAC tumors harbor activating RAS mutations, making RAS signaling a central therapeutic target. However, effective inhibition of the broader spectrum of RAS alterations in pancreatic cancer has remained a major challenge.

Problem Statement

Most currently available targeted therapies address only selected KRAS subtypes, while the majority of RAS-mutated PDAC lacks effective precision treatment options after progression on standard chemotherapy. A therapeutic strategy capable of targeting multiple active RAS variants simultaneously could potentially overcome this limitation and expand the applicability of RAS-directed therapy in pancreatic cancer.

Summary

This phase 1–2 study demonstrates encouraging clinical activity of daraxonrasib, a multiselective RAS(ON) inhibitor, in previously treated RAS-mutated PDAC. Daraxonrasib targets active guanosine triphosphate-bound mutant and wild-type RAS, enabling broader inhibition across multiple RAS mutation subtypes rather than focusing on a single KRAS alteration. In heavily pretreated patients, the drug produced meaningful objective response rates, particularly in tumors harboring RAS G12 mutations, with durable responses and progression-free survival outcomes that compare favorably with existing second-line therapies in PDAC. Importantly, responses were also observed across broader RAS mutation groups, suggesting potential applicability beyond highly selected molecular subsets. Toxicities were common but largely manageable, with gastrointestinal adverse effects, rash and mucosal toxicity representing the dominant treatment-related events. Approximately one-third of patients experienced grade 3 or higher adverse events, indicating that tolerability remains an important consideration in further development. Overall, this study represents one of the most promising advances in broad-spectrum RAS inhibition for pancreatic cancer and supports the emergence of pan-RAS targeting as a potentially transformative therapeutic strategy in RAS-driven solid tumors.