Daraxonrasib Shows Anti-Tumor Activity in Pretreated RAS+ Pancreatic Cancer

Findings from the phase 1/2 RMC-6236-001 trial (NCT05379985), published in The New England Journal of Medicine, demonstrated that daraxonrasib (RMC-6236)—an oral, noncovalent, multi-selective RAS(ON) inhibitor—provided antitumor activity and was associated with grade 3 or higher treatment-related adverse events (TRAEs) in a third of patients with previously treated metastatic RAS-mutant pancreatic ductal adenocarcinoma (PDAC).¹ Topline results from the phase 3 RASolute 302 trial (NCT06625320) further confirm the benefit with daraxonrasib, demonstrating a near doubling of median overall survival (OS) compared with standard-of-care chemotherapy in the second-line setting.²

What efficacy findings were observed with daraxonrasib in pancreatic cancer?

In the phase 1/2 trial, daraxonrasib demonstrated an objective response rate (ORR) of 35% (95% CI, 17%-56%) among 26 patients with RAS G12 mutations who received the 300-mg daily dose in the second-line setting. In this population, the median duration of response (DOR) was 8.2 months (95% CI, 3.8-not evaluable [NE]), the median progression-free survival (PFS) was 8.5 months (95% CI, 6.7-10.5), and the median OS reached 13.1 months (95% CI, 10.9-NE).

Among a broader group of 38 patients, including those with any RAS mutation (G12D, G12V, or G12R, or G61H) treated with the 300-mg dose in the second line, the ORR was 29% (95% CI, 15%-46%), with a median DOR of 8.2 months (95% CI, 3.8-8.8), median PFS of 8.1 months (95% CI, 5.9-10.1), and median OS of 15.6 months (95% CI, 10.9-NE).

The phase 3 RASolute 302 trial confirmed these survival data in a larger population.² In the intention-to-treat (ITT) population, daraxonrasib produced a median OS of 13.2 months compared with 6.7 months for patients receiving investigator’s choice of chemotherapy (HR, 0.40; P <.0001).

“Although direct comparisons cannot be made, the results of this study suggest that across PDAC with varied RAS mutations, [PFS] and [OS] estimates exceeded those that have been historically reported with second-line chemotherapy,” wrote lead study author Brian Wolpin, MD, MPH, director of the Gastrointestinal Cancer Center and director of the Hale Family Center for Pancreatic Cancer Research at Dana Farber Cancer Center, and coauthors, in the study.¹

What safety and tolerability results were reported for daraxonrasib?

AEs of any grade occurred in 99% of patients, with the most common being rash (89%), diarrhea (50%), and nausea (47%). Grade 3 or higher AEs occurred in 65% of patients. Treatment-related AEs (TRAEs) of any grade occurred in 96%, the majority of which were grade 1 or 2, and grade 3 or higher TRAEs occurred in 30%. Serious TRAEs occurred 6%, with diarrhea being the most frequent (2%).

Common TRAEs at the 300-mg dose level included rash (90%), stomatitis or mucositis (54%), diarrhea (52%), and nausea (39%). Grade 3 or higher TRAEs occurred in 34% of this cohort, with rash and anemia occurring in 7% each. Dose modifications were required in 48% of patients at the 300-mg dose, and rash and stomatitis or mucositis were events that led to dose modifications in more than 10% of patients.

Reportedly, rash and gastrointestinal events were manageable with routine clinical interventions.

How was the RMC-6236-001 trial of daraxonrasib in PDAC designed?

The RMC-6236-001 study was an open-label, multicenter phase 1/2 trial evaluating daraxonrasib monotherapy in patients with advanced solid tumors harboring activating RAS mutations, such as KRAS, NRAS, and HRAS at codons 12, 13, or 61. Eligible patients with PDAC were required to have documented progression after receipt of fluoropyrimidine- or gemcitabine-based chemotherapy.

The median age of patients was 65 years (range, 30-86), with 55% being male, 77% being White, and 68% having an ECOG performance status of 1. Most patients had stage IV disease at diagnosis (52%), 2 or more prior lines of systemic therapy (58%), liver metastases (67%), and history of Whipple procedure (36%). RAS mutations were G12D (39%), G12V (31%), G12R (17%), other G12 (2%), and non-RAS G12 (11%).

The study assessed various dose levels, with patients receiving 10 to 400 mg of daraxonrasib administered orally once daily. Additional patients with KRAS G12-mutated PDAC were enrolled in expansion cohorts at doses of 120 mg, 200 mg, or 300 mg of daraxonrasib. The primary end point was to evaluate safety and AEs. Secondary end points included preliminary antitumor efficacy and pharmacokinetics.

On May 1, 2026, the FDA issued a “safe to proceed” letter permitting an expanded access program for daraxonrasib in this population, allowing the developer to provide the treatment to eligible patients in a controlled and monitored setting, consistent with FDA regulations governing investigational medicines.³ According to Wolpin, the “widely anticipated results of this study indicate that daraxonrasib provides a clear and highly meaningful step forward for patients with pancreatic cancer who have experienced progression on prior treatment, typically chemotherapy.”²

References

1. Wolpin BM, Park W, Garrido-Laguna I, et al. Daraxonrasib in previously treated advanced RAS-mutated pancreatic cancer. N Engl J Med. 2026;394(18):1790-1802. doi:10.1056/NEJMoa2505783
2. Daraxonrasib demonstrates unprecedented overall survival benefit in pivotal phase 3 RASolute 302 clinical trial in patients with metastatic pancreatic cancer. News release. Revolution Medicines Inc. April 13, 2026. Accessed May 8, 2026. https://tinyurl.com/44t5vh5d
3. FDA permits expanded access for investigational pancreatic cancer drug. News release. FDA. May 1, 2026. Accessed May 8, 2026. https://tinyurl.com/4xbhx3pd