Daraxonasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer | Brian M. Wolpin et al. | ResearchPod

Transcript: Daraxonasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer

Alex: Welcome to another episode of ResearchPod. Today we're looking at a study in the New England Journal of Medicine on a new therapeutic approach for pancreatic ductal adenocarcinoma — PDAC.

Sam: For decades, the RAS gene family has been considered essentially undruggable, despite driving over 90% of pancreatic cancers. This study evaluates daraxonasib, a drug that attempts to change that by selectively targeting RAS in its active state.

Alex: So the paper is asking whether we can finally hit these mutations directly, rather than working around them downstream?

Sam: Exactly. And the mechanistic distinction matters here. Previous inhibitors — including the approved G12C-specific agents — worked by locking RAS in its inactive, GDP-bound 'OFF' state. The problem in PDAC is that the protein is constitutively stuck in the active, GTP-bound 'ON' state. It's constantly signalling cell division, and earlier drugs couldn't get a foothold there.

Alex: So what does daraxonasib actually do differently?

Sam: It forms a tri-complex — the drug, the GTP-bound RAS protein, and a chaperone called cyclophilin A. That complex physically occludes the surface RAS uses to recruit downstream effectors like RAF. You're not waiting for the protein to cycle into an inactive state. You're capping it while it's active. And critically, that mechanism works regardless of which specific mutation is driving the activation — G12, G13, Q61 — all of which are far more prevalent in PDAC than the G12C variant that earlier allele-specific inhibitors were built around.

Alex: So the mutation-agnostic targeting is the key design advantage. How does that translate into clinical outcomes, particularly for patients who've already failed FOLFIRINOX or gemcitabine-based regimens?

Sam: The headline number is an objective response rate of around 35% in previously treated patients with G12 mutations. The historical benchmark for second-line therapy in PDAC sits below 10%, so that's a meaningful gap — roughly a threefold difference. That's the load-bearing finding the paper's central claim rests on.

Alex: And the toxicity profile?

Sam: About 30% of patients experienced grade 3 or higher adverse events — primarily rash, diarrhea, and stomatitis. That's not trivial in a population that's already been through heavy prior treatment, and clinical management of those effects is going to be a real part of deploying this drug.

Alex: What about the pharmacokinetics? The paper apparently had something to say about dosing thresholds.

Sam: Yes, and this is where the translational modeling becomes relevant. The authors used PK/PD modeling to predict that sustained 90% pathway inhibition required reaching a 300-milligram dose. The clinical results appear to validate that prediction — patients who hit those exposure targets showed consistent antitumor activity. The preferential intratumoral accumulation the model predicted seems to be doing real work in the observed efficacy.

Daraxonasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer

Brian M. Wolpin, Wungki Park, Ignacio Garrido-Laguna, Alexander Spira, Alexander Starodub, David Sommerhalder, Salman R. Punekar, Minal Barve, Meredith Pelster, Benjamin Herzberg, Nilofer S. Azad, Joel Randolph Hecht

May 6, 2026·4:26·doi·Original Paper

Pancreatic ductal adenocarcinoma (PDAC)Daraxonasib (RMC-6236)RAS mutationsPhase 1-2 clinical trialPancreatic Ductal Adenocarcinoma (PDAC)RAS Mutations

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4 min

Briefing

Research Question

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, with limited treatment options for patients whose disease progresses after initial chemotherapy. Because over 90% of PDAC tumors harbor activating RAS mutations, researchers investigated whether daraxonasib (RMC-6236)—a novel, oral, multiselective inhibitor that targets the active, GTP-bound state of mutant and wild-type RAS—could provide a meaningful clinical benefit in this previously treated population.

Approach

This phase 1-2, open-label, multicenter study enrolled 168 patients with advanced, previously treated RAS-mutated PDAC. Patients received daily oral doses of daraxonasib ranging from 10 mg to 400 mg. The primary endpoint was safety, with secondary endpoints including pharmacokinetics and antitumor activity. The researchers focused on evaluating the 300 mg dose, which was selected for further development based on dose-optimization data. Efficacy was assessed using RECIST criteria, with specific subgroup analyses for patients with RAS G12 mutations.

Main Findings

Daraxonasib showed consistent antitumor activity across diverse RAS mutations. In the subgroup of 26 patients with RAS G12 mutations treated with 300 mg as second-line therapy, the objective response rate was 35%, with a disease control rate of 92%. The median duration of response was 8.2 months, with a median progression-free survival of 8.5 months and a median overall survival of 13.1 months. Among all 38 patients with any RAS mutation (G12, G13, or Q61) treated with 300 mg as second-line therapy, the objective response rate was 29%, with a median overall survival of 15.6 months.

Regarding safety, 96% of patients experienced treatment-related adverse events, most commonly rash, diarrhea, and nausea. Grade 3 or higher treatment-related adverse events occurred in 30% of patients. While these toxicities often required dose modifications, they were generally manageable with clinical interventions, and no patients discontinued treatment due to these events.

Why It Matters

These results suggest that daraxonasib may offer a new therapeutic strategy for a patient population that historically faces very poor outcomes with standard second-line chemotherapy. By targeting the active, GTP-bound state of multiple RAS isoforms, the drug overcomes the limitations of allele-specific inhibitors that only target inactive RAS. The findings support the ongoing phase 3 clinical trials comparing daraxonasib to standard chemotherapy.

Key Terms and Definitions

Daraxonasib (RMC-6236) — An orally bioavailable, noncovalent inhibitor that targets the active, GTP-bound state of mutant and wild-type KRAS, HRAS, and NRAS proteins.
RAS(ON) Inhibitor — A therapeutic agent that binds to and inhibits the active, GTP-bound form of the RAS protein, which is the state responsible for driving oncogenic signaling in many cancers.
Objective Response — A clinical measurement defined in this study as a confirmed complete or partial reduction in tumor burden according to RECIST version 1.1 criteria.
Disease Control — A composite clinical endpoint defined as the sum of patients who achieved a complete response, a partial response, or stable disease.
PDAC — Pancreatic ductal adenocarcinoma, a highly aggressive form of pancreatic cancer characterized by a high prevalence of RAS mutations.

Abstract

BACKGROUND: mutations occur in more than 90% of PDAC tumors. Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate-bound mutant and wild-type RAS. METHODS: -mutated PDAC. RESULTS: G12, G13, or Q61 mutations, 29% (95% CI, 15 to 46) had an objective response. The median duration of response was 8.2 months (95% CI, 3.8 to 8.8), with median values of 8.1 months for progression-free survival and 15.6 months for overall survival. CONCLUSIONS: -mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

Daraxonasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer: Research Paper Podcast