Daraxonrasib Monotherapy Elicits Meaningful Responses in Previously Treated, RAS-Mutated Pancreatic Cancer

Daraxonrasib (RMC-6236) demonstrated antitumor activity and a manageable safety profile across a diverse set of RAS mutations and dose levels in patients with previously treated, RAS-mutated pancreatic ductal adenocarcinoma (PDAC), according to findings from the phase 1/2 RMC-6236-001 trial (NCT05379985) published in the New England Journal of Medicine.^1,2

In a subgroup of patients with RAS G12-mutated PDAC receiving daraxonrasib at the 300-mg dose level as second-line therapy (n = 26), the objective response rate (ORR) was 35% (95% CI, 17%-56%). The median duration of response (DOR) in this group was 8.2 months (95% CI, 3.8-not evaluable [NE]), and the median progression-free survival (PFS) and overall survival (OS) were 8.5 months (95% CI, 6.7-10.5) and 13.1 months (95% CI, 10.9-NE), respectively.

Among patients with any RAS mutation (G12, G13, or Q61) treated with 300 mg as second-line therapy (n = 38), the ORR was 29% (95% CI, 15%-46%), the disease control rate (DCR) was 95% (95% CI, 82%-99%), the median PFS was 8.1 months (95% CI, 5.9-10.1), and the median OS was 15.6 months (95% CI, 10.9-NE).

For patients with any RAS mutation treated with the 300-mg dose in the third-line setting or later (n = 45), the ORR was 20% (95% CI, 10%-35%), the DCR was 84% (95% CI, 71%-94%), and the median DOR was 3.3 months (95% CI, 2.8-NE).

“RAS mutations are a central driver of disease across multiple solid tumors, including particularly PDAC. There is significant room for improvement in outcomes over the current standard of care: cytotoxic chemotherapies that are not targeted to these underlying RAS cancer drivers,” Alan Sandler, MD, chief development officer of Revolution Medicines, stated in a news release regarding the publication.² “These results, along with those from our phase 3 trial, RASolute 302 [NCT06625320], strengthen our confidence in daraxonrasib’s potential to establish an important new treatment option for patients with pancreatic cancer and other RAS-[mutated] cancers.”

What is the mechanism of action for daraxonrasib?

Daraxonrasib is a first-in-class, noncovalent tri-complex inhibitor designed to target the active, GTP-bound "ON" state of both mutant and wild-type RAS proteins, including KRAS, HRAS, and NRAS.¹ By forming a complex with cyclophilin A and RAS(ON), the agent sterically blocks RAS effector binding, thereby suppressing downstream oncogenic signaling. This differentiates daraxonrasib from earlier RAS(OFF) inhibitors, which are often limited by incomplete inhibition or resistance in PDAC, where RAS mutations primarily drive constitutive signaling in the GTP-bound state.

How was RMC-6236-001 designed?

This phase 1/2, open-label, multicenter study enrolled patients 18 years of age or older with solid tumors harboring KRAS, NRAS or HRAS mutations across 16 sites in the United States.^1,3 In the PDAC cohort, eligible patients had experienced disease progression or unacceptable toxicity after the treatment with fluoropyrimidine- or gemcitabine-based chemotherapy; had an ECOG performance status (PS) of 0 or 1; and had measurable disease per RECIST 1.1 criteria. Exclusion criteria included primary central nervous system (CNS) tumors, active brain metastases, or impaired gastrointestinal (GI) function.³

Upon enrollment, patients received daraxonrasib at 300 mg orally once daily in 21-day cycles; this was established as the recommended phase 3 dose.^1,3

The study’s primary end point was safety and tolerability; secondary end points included ORR, DOR, DCR, and PFS per RECIST 1.1 criteria. Plasma samples at baseline and on-treatment were analyzed for changes in RAS variant allele frequency (VAF) in circulating tumor DNA (ctDNA).

The current report focused on 168 patients with previously treated RAS-mutated PDAC who received daily oral doses of daraxonrasib at 300 mg or less.¹ Baseline characteristics in this population were as follows:

• Median age: 65 years (range, 30-86)
• Male: 55%; Female: 45%
• ECOG PS: 0 (32%), 1 (68%)
• Stage IV at diagnosis: 52%
• Median prior lines of systemic therapy: 2 (range, 1-6)
• Prior gemcitabine plus nab-paclitaxel: 60%
• Prior FOLFIRINOX: 43%
• RAS mutation types: KRAS G12D (39%), KRAS G12V (31%), KRAS G12R (17%), other RAS G12 (2%), and non-RAS G12 (11%)

What should be known about the safety profile of daraxonrasib in this study?

Treatment-related adverse effects (TRAEs) occurred in 96% of safety-evaluable patients in the PDAC cohort (n = 168). Grade 3 or higher TRAEs were reported in 30% of the total population and 34% of those receiving the 300-mg dose (n = 83).

Common TRAEs (>10%) at the 300-mg dose included rash (any-grade, 90%; grade 3 or higher, 7%), stomatitis or mucositis (54%; 4%), diarrhea (52%; 4%), and nausea (39%; 36%). Serious TRAEs occurred in 6% of the total population. No treatment-related deaths were reported, and no patients in the 300-mg cohort discontinued treatment due to TRAEs, although 48% required dose modifications.

What additional data have we seen with daraxonrasib in previously treated PDAC?

Topline results from the first interim analysis of the phase 3 RASolute 302 trial showed that daraxonrasib generated statistically significant and clinically meaningful PFS and OS improvements vs standard chemotherapy in patients with previously-treated metastatic PDAC; these data were consistent with outcomes from the phase 1/2 monotherapy study.^2,4 In the intention-to-treat (ITT) population, daraxonrasib produced a median OS of 13.2 months compared with 6.7 months with chemotherapy (HR, 0.40; P < .0001). Regarding safety, daraxonrasib was generally well tolerated.

Data from the primary, and final, analysis of RASolute 302 will be shared in a presentation at the 2026 ASCO Annual Meeting on May 31, 2026.⁵

What early-phase data have been reported with daraxonrasib?

Two phase 1/2 datasets evaluating daraxonrasib as first-line therapy for metastatic PDAC were presented at the 2026 AACR Annual Meeting. In the GI-102 platform study (NCT06445062), daraxonrasib in combination with gemcitabine and nab-paclitaxel (Abraxane) produced an overall response rate (ORR) of 58% (95% CI, 41%-73%) and a disease control rate (DCR) of 90% (95% CI, 76%-97%) in treated patients (n = 40).⁶ At the 6-month landmark analysis, the PFS rate was 84% (95% CI, 68%-93%), and the OS rate was 90% (95% CI, 76%-96%).

Among efficacy-evaluable patients with RAS-mutant metastatic PDAC in RMC-6236-001 (n = 38), the ORR was 47% (95% CI, 31%-64%) and the DCR was 92% (95% CI, 79%-98%).³ In the all-RAS patient population (n = 40), the Kaplan-Meier estimates for the 6-month PFS and OS rates were 71% (95% CI, 53%-83%) and 83% (95% CI, 67%-92%), respectively. PFS and OS data remained immature at the data cutoff.

Toxicity profiles for both regimens were manageable and consistent with prior reports.^3,6

Where is daraxonrasib in the development pipeline?

On April 13, 2026, Revolution Medicines shared its intention to submit a new drug application for daraxonrasib under the Commissioner’s National Priority Voucher pilot program.⁷ The FDA previously granted a national priority voucher to the agent in October 2025.

More recently, the FDA issued a “safe to proceed” letter permitting the initiation of an expanded access treatment protocol (EAP) for daraxonrasib (RMC-6236) in previously treated metastatic pancreatic ductal adenocarcinoma on May 1, 2026. The program allows certain patients with RAS-mutated pancreatic cancer who cannot participate in clinical trials to access the investigational drug.

Of note, daraxonrasib received prior FDA breakthrough therapy and orphan drug designations for patients with previously treated metastatic PDAC harboring KRAS G12 mutations.

In addition to RASolute 302, daraxonrasib is being evaluated in three other phase 3 registrational trials, including RASolute 303 (NCT07491445).^2,8 This global, 3-arm, randomized, open-label study is evaluating daraxonrasib with or without chemotherapy vs chemotherapy alone as first-line treatment for patients with metastatic PDAC.

References

1. Wolpin B, 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. Revolution Medicines announces publication in New England Journal of Medicine of phase 1/2 clinical data on daraxonrasib in pancreatic cancer. News release. May 6, 2026. May 7, 2026. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-publication-new-england-journal
3. O'Reilly EM, Wolpin B, Pant S, et al. Daraxonrasib monotherapy as first-line (1L) treatment for patients with metastatic pancreatic adenocarcinoma (mPDAC). Presented at: 2026 AACR Annual Meeting; April 17–22, 2026; San Diego, CA. Abstract LB337.
4. Daraxonrasib demonstrates unprecedented overall survival benefit in pivotal Phase 3 RASolute 302 clinical trial in patients with metastatic pancreatic cancer. News release. Revolution Medicines. April 13, 2026. Accessed May 7, 2026. https://ir.revmed.com/news-releases/news-release-details/daraxonrasib-demonstrates-unprecedented-overall-survival-benefit
5. RAS(ON) inhibitor daraxonrasib shows promising results in advanced pancreatic cancer phase 1/2 study. News release. Dana-Farber Cancer Institute. May 6, 2026. Accessed May 7, 2026. https://www.dana-farber.org/newsroom/news-releases/2026/rason-inhibitor-daraxonrasib-shows-promising-results-in-advanced-pancreatic-cancer-phase-12-study
6. Wolpin BM, Musher BL, Manji GA, et al. Daraxonrasib plus chemotherapy (CT) as first line (1L) treatment for patients (Pts) with metastatic pancreatic adenocarcinoma (mPDAC). Presented at: 2026 AACR Annual Meeting; April 17–22, 2026; San Diego, CA. Abstract LB407.
7. FDA permits expanded access for investigational pancreatic cancer drug. FDA. May 1, 2026. Accessed May 7, 2026. https://www.fda.gov/news-events/press-announcements/fda-permits-expanded-access-investigational-pancreatic-cancer-drug
8. Study of daraxonrasib and daraxonrasib + GnP as first-line treatment in patients with metastatic pancreatic adenocarcinoma (RASolute 303). ClinicalTrials.gov Updated April 4, 2026. Accessed May 7, 2026. https://clinicaltrials.gov/study/NCT07491445