Cracking the KRAS Code: How Daraxonrasib Is Reshaping Pancreatic Cancer and Beyond

Few malignancies have resisted therapeutic innovation in recent memory as much as pancreatic ductal adenocarcinoma (PDAC).¹ Despite incremental advances with multidrug chemotherapy regimens, outcomes for patients with metastatic disease have remained poor, with median overall survival (OS) rarely exceeding 1 year in the frontline setting and historically only 6 to 7 months after progression on first-line therapy. Nearly 90% of PDACs harbor activating KRAS mutations, yet for decades the oncogenic driver underlying most pancreatic cancers remained one of oncology’s most difficult therapeutic targets.

Earlier generations of KRAS inhibitors focused primarily on the inactive, GDP-bound—or "OFF"—state of the protein or on individual allelic variants such as KRAS G12C. Although these approaches transformed treatment for select patients with lung cancer, they offered limited applicability in PDAC, where KRAS G12D, G12V, and G12R mutations predominate and signaling occurs primarily through the active, GTP-bound state.

Daraxonrasib (RMC-6236) was designed with that challenge in mind. Rather than selectively targeting a single KRAS allele, the first-in-class oral RAS(ON) multi-selective inhibitor forms a tri-complex with cyclophilin A and the active, GTP-bound form of RAS, sterically blocking downstream effector interactions across mutant and wild-type KRAS, NRAS, and HRAS proteins. By targeting the activated state of RAS signaling, daraxonrasib offers the potential to inhibit the broad spectrum of KRAS alterations encountered in PDAC while overcoming biologic limitations associated with earlier RAS-directed therapies.

At the 2026 ASCO Annual Meeting (ASCO 2026), investigators presented data from the landmark phase 3 RASolute 302 trial (NCT06625320), demonstrating unprecedented improvements in survival with daraxonrasib compared with standard chemotherapy in patients with previously treated metastatic PDAC.² The findings earned a standing ovation during the plenary session and, for many investigators, marked a turning point not only for pancreatic cancer but also for decades of efforts to successfully drug RAS across tumor types.

For Vincent Picozzi, MD, a medical oncologist at Virginia Mason Medical Center in Seattle, Washington, the study represents a fundamental shift in expectations for patient outcomes. "This really begins a new chapter of treatment for pancreatic cancer. For years we’ve talked about moving the needle in pancreatic cancer, but often that meant improving survival by a matter of weeks,” he said in an interview with OncLive®. “Seeing [a survival benefit] of this magnitude is something we simply haven’t experienced in this disease. It changes the conversation with patients and changes our expectations for what targeted therapy can accomplish.”

How has daraxonrasib progressed from proof of concept to practice-changing therapy?

Prior early-phase clinical data suggested that the use of daraxonrasib alone or in combination with chemotherapy could translate into meaningful patient benefit.^1,3,4 In the phase 1/2 RMC-6236-001 study (NCT05379985), daraxonrasib demonstrated encouraging activity across previously treated RAS-mutant PDAC.¹ Among patients with second-line KRAS G12-mutated disease treated at the recommended phase 3 dose of 300-mg daily (n = 26), the objective response rate (ORR) was 35% (95% CI, 17%-56%), with a median progression-free survival (PFS) of 8.5 months (95% CI, 6.7-10.5) and a median OS of 13.1 months (95% CI, 10.9-not evaluable [NE]). Among patients with any RAS mutation (G12, G13, or Q61) treated in the second-line setting (n = 38), the disease control rate (DCR) was 95% (95% CI, 82%-99%) and the ORR was 29% (95% CI, 15%-46%). Moreover, 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%) and the DCR was 84% (95% CI, 71%-94%).

The safety profile also reinforced daraxonrasib’s potential as a long-term therapeutic platform. Although treatment-related adverse effects (TRAEs) occurred in 96% of patients, the majority were low-grade dermatologic or gastrointestinal (GI) toxicities, including rash, stomatitis, diarrhea, and nausea, which proved manageable with supportive care and dose modifications.

Additionally, 2 phase 1/2 data sets evaluating daraxonrasib for metastatic PDAC were presented at the 2026 AACR Annual Meeting. Among efficacy-evaluable patients with RAS-mutant metastatic PDAC in the RMC-6236-001 trial (NCT05379985; n = 38), the ORR was 47% (95% CI, 31%-64%) and the DCR was 92% (95% CI, 79%-98%).³ In this all-RAS population, 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.

The second presentation, which included data from the GI-102 platform study (NCT06445062), showed that daraxonrasib in combination with gemcitabine and nab-paclitaxel (Abraxane) produced an ORR of 58% (95% CI, 41%-73%) and a DCR of 90% (95% CI, 76%-97%) in treated patients (n = 40).⁴ These results offered proof of principle that pan-RAS inhibition could produce clinically meaningful responses in a disease defined by limited therapeutic progress.^1,3,4

What were the practice-changing findings from RASolute 302?

Against this backdrop, RASolute 302 trial generated results that many investigators described as unprecedented for the second-line setting.² Data presented in a plenary session during ASCO 2026 showed that daraxonrasib produced a statistically significant and clinically meaningful improvement in OS and progression-free survival (PFS) compared with investigator’s choice of chemotherapy in patients with previously treated metastatic PDAC. In the RAS G12–mutant population (daraxonrasib, n = 228; chemotherapy, n = 231), the median OS was 13.2 months (95% CI, 10.0-NE) with daraxonrasib vs 6.6 months (95% CI, 5.4-8.2) with chemotherapy (HR, 0.40; 95% CI, 0.30-0.54; P = 5.9 × 10⁻¹⁰). The 12-month OS rate was 53.3% with daraxonrasib vs 18.7% with chemotherapy. The median PFS was 7.3 months (95% CI, 6.3-8.1) vs 3.5 months (95% CI, 2.9-3.8; HR, 0.45; 95% CI, 0.34-0.59; P < .0001). The respective ORRs were 33.2% with daraxonrasib (n = 217) vs 11.8% with chemotherapy (n = 221; P < .0001).

In the intention-to-treat (ITT) population, the median PFS was 7.2 months (95% CI, 5.7-7.5) with daraxonrasib vs 3.6 months (95% CI, 2.9-4.2; HR, 0.49; 95% CI, 0.38-0.64; P = 5.2×10⁻⁸), and the median OS was 13.2 months (95% CI, 10.0-NE) vs 6.7 months (95% CI, 5.8-8.0; HR, 0.40; 95% CI, 0.30-0.53; P < .0001). The ORR was 31.6% with daraxonrasib (n = 237) vs 11.2% with chemotherapy (n = 241; P < .0001).

“As a physician who started their training and scientific journey in pancreatic cancer and KRAS before moving to lung [cancer], I truly consider it a historic moment in time to have a targeted therapy that more than doubles the median OS for patients with pancreatic cancer,” said Ferdinandos Skoulidis, MD, PhD, MRCP, an associate professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

“The fact that we can double OS in a disease that historically has had very few treatment options proves a few things,” Benjamin Herzberg, MD, an assistant professor of medicine at the Columbia University Herbert Irving Comprehensive Cancer Center, in New York, New York, added. “It proves that if we hit the right target, the drugs work. And if we choose the right target and we hit it well, we will help patients with the disease; we don’t need complex explanations for why certain things work and certain things don’t.”

The agent’s safety profile and quality of life (QOL) benefits were just as notable as these efficacy outcomes. In RASolute 302, daraxonrasib delayed deterioration in patient-reported pain and global QOL vs chemotherapy. The safety profile was also manageable with no new signals; 42% of patients in the daraxonrasib arm remained on treatment at the data cutoff vs 14% in the chemotherapy arm. Any-grade treatment-emergent adverse effects (TEAEs) occurred in all patients receiving daraxonrasib and 97.7% receiving chemotherapy. Any-grade treatment-related AEs (TRAEs) were reported in 97.9% and 93.5% of patients, respectively. The most common TRAEs leading to dose reduction with daraxonrasib were rash (17.4%) and stomatitis (6.6%).

How do these findings influence the future of RAS-targeted therapy in PDAC and beyond?

Although the implications of RASolute 302 have been felt most profoundly in pancreatic cancer, the study has broader implications for other tumor types. Activating RAS mutations occur in approximately 30% of all human cancers, driving tumorigenesis across malignancies, including colorectal cancer, non–small cell lung cancer (NSCLC), biliary tract cancer, melanoma, and several gynecologic cancers.¹ For decades, these alterations have represented one of oncology’s most compelling—and frustrating—therapeutic targets. The success of daraxonrasib suggests that effective, multiselective inhibition of active RAS signaling may finally be achievable across a much wider range of cancers than previously thought.^1,2

“[RASolute 302] also proves that KRAS is targetable beyond G12C… with newer modalities,” Herzberg added. “That’s proof of principle for a variety of new approaches to KRAS and to targeting cancers generally.”

This possibility is being capitalized on through the agent’s rapidly expanding clinical development program. In addition to RASolute 302, daraxonrasib is being evaluated in 2 other phase 3 registrational trials in PDAC: RASolute 303 (NCT07491445) and RASolute 304 (NCT07252232).⁵ RASolute 303 is a global, multicenter randomized, open-label study evaluating daraxonrasib with or without chemotherapy vs chemotherapy alone as first-line treatment for patients with metastatic PDAC. RASolute 304 is a multicenter, open-label, randomized study evaluating adjuvant daraxonrasib vs observation following completion of neoadjuvant and/or adjuvant chemotherapy in resected PDAC.

Plans for additional registrational studies in other RAS-mutated solid tumors are also underway.⁷ These include the phase 3 RASolve 301 trial (NCT06881784) evaluating the agent in first-, second-, and third-line metastatic NSCLC and a study of daraxonrasib in combination with SOC RAS(ON) inhibitor doublets or investigational agents in RAS-mutated solid tumors.

Targeted combinations containing daraxonrasib have generated similarly encouraging early signals.⁸ Among patients with MTAP-deleted, RAS-mutated pancreatic cancer, the combination of daraxonrasib and the PRMT5 inhibitor vopimetostat produced an ORR of 92% among 12 response-evaluable patients in a phase 1/2 trial (NCT06922591). Although the dataset remains preliminary, it signals that daraxonrasib could serve not only as an effective monotherapy but also as a backbone for future combination regimens, according to Andrew H. Ko, MD, a professor of medicine and codirector of the Pancreas Center at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

“I anticipate [that daraxonrasib will] end up being used in earlier settings,” Ko predicted. “There are studies in the adjuvant and perioperative settings, and…there are going to be other studies of more allele-specific RAS inhibitors that may be as effective with less toxicity. There are combination approaches [under evaluation that] combine RAS [inhibition] with chemotherapy, other targeted therapies like PRMT5 inhibitors for MTAP-deleted tumors, or immunotherapy. The sky’s the limit here… but we’re still at the beginning of this era of RAS inhibitors.”

Daniel H. Ahn, DO, an oncologist, internist, and assistant professor of medicine at Mayo Clinic, agreed with Ko, explaining that, "From the data that we currently have…the next logical question is, does it potentially make sense to use this treatment in other settings? We can evaluate daraxonrasib not only in the adjuvant setting; the next question is, ‘Does…daraxonrasib still have the same benefit if we move it to an earlier setting?’ The reason why that’s important is that, first, we could potentially treat patients who may not be candidates to receive treatment in the refractory setting if they were to progress or experience a decline in their performance status. Second, and just as important: can the clinical benefit, or clinical magnitude, be enhanced if we were to move this treatment to the frontline setting?”

As additional roles for daraxonrasib continue to be explored, resistance to currently available allele-specific KRAS inhibitors also remains a growing clinical challenge that translational analyses will need to address, according to Daniel King, MD, PhD, a GI medical oncologist based at the Monter Cancer Center and Director of Research and Development for Northwell Health in Lake Success, New York. “While this might be a breakthrough, it’s hard to call it a miracle. These are not cures. We now have a challenge to determine what are the reasons that patients are developing resistance to RAS[-targeted] treatments. How can we counteract that resistance—either by doubling down on RAS [targeting] and adding more drugs against it or by thinking about mechanisms of resistance and how we design trials that counteract those?”

What’s next for daraxonrasib in the developmental 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.⁹ 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 for daraxonrasib (RMC-6236) in previously treated metastatic PDAC on May 1, 2026. The program allows select patients with RAS-mutated pancreatic cancer who cannot participate in clinical trials to access the investigational agent. The agent has also received prior FDA breakthrough therapy and orphan drug designations in pretreated metastatic PDAC harboring KRAS G12 mutations.

Whether daraxonrasib becomes a new standard of care will depend on regulatory review and longer-term follow-up from RASolute 302. Nevertheless, as Ko observed, the trial has already altered the trajectory of pancreatic cancer drug development, turning a once “undruggable” pathway into a clinically actionable target.

“These are absolutely transformative data. They had me emotional at the time of initial presentation, not just because the results were so strikingly positive, but because this mechanism of action, in terms of being able to effectively target RAS… is going to be broadly applicable across all settings in the relatively near future. We’re not there yet, in terms of saying that it’s going to replace chemotherapy in the frontline setting, but that time may come.”

Ultimately, rather than asking whether RAS can be successfully targeted, the field has begun asking how best to integrate pan-RAS inhibition throughout the treatment continuum and whether similar strategies can transform outcomes across other RAS-driven malignancies.

“RAS is a target that we’ve been hoping to impact for many years,” Kevin Kalinsky, MD, MS, FASCO, a professor and director in the Division of Medical Oncology in the Department of Hematology and Medical Oncology at the Emory University School of Medicine; as well as the Louisa and Rand Glenn Family Chair in Breast Cancer Research and the director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University in Atlanta, Georgia, concluded. “Just the fact that there’s now a drug that targets that mutation is remarkable, but even beyond that, pancreatic cancer has been so difficult to make advances in for so long. [It is] inspiring to see, because they also herald where other drug development could go for that cancer [as well as] for other [tumor types] that harbor a RAS mutation.”

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. Wolpin BM, Wainberg ZA, Hendifar AE, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): primary and final analysis from the phase 3 RASolute 302 study. J Clin Oncol. 2026;44(suppl 17):LBA4005. doi:10.1200/JCO.2026.44.17_suppl.LBA4005.
3. O’Reilly EM, Wolpin B, Pant S, et al. Daraxonrasib monotherapy as first-line (1L) treatment for patients with metastatic pancreatic adenocarcinoma (mPDAC). Cancer Res. 2026;86(suppl 8):LB337. doi:10.1158/1538-7445.AM2026-LB337
4. 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). Cancer Res. 2026;86(suppl 8):LB407. doi:10.1158/1538-7445.AM2026-LB407
5. Revolution Medicines to present clinical data from RAS(ON) inhibitor combination trials in pancreatic cancer at ESMO Gastrointestinal Cancers Congress 2026. News Release. Revolution Medicines. June 24, 2026. Accessed July 8, 2026. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-present-clinical-data-rason-inhibitor
6. RevMed Pipeline. Revolution Medicines. 2026. Accessed July 8, 2026. https://www.revmed.com/pipeline/
7. Revolution Medicines announces first patient dosed in phase 3 clinical trial evaluating Daraxonrasib in previously treated patients with RAS mutant non-small cell lung cancer. News Release. Revolution Medicines. May 14, 2025. Accessed July 8, 2026. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-first-patient-dosed-phase-3
8. Tango Therapeutics announces combination of vopimetostat and daraxonrasib demonstrated 92% objective response rate in pancreatic cancer. News release. Tango Therapeutics. June 8, 2026. Accessed July 8, 2026. https://www.globenewswire.com/news-release/2026/06/08/3307926/0/en/tango-therapeutics-announces-combination-of-vopimetostat-and-daraxonrasib-demonstrated-92-objective-response-rate-in-pancreatic-cancer.html
9. FDA permits expanded access for investigational pancreatic cancer drug. FDA. May 1, 2026. Accessed July 8, 2026. https://www.fda.gov/news-events/press-announcements/fda-permits-expanded-access-investigational-pancreatic-cancer-drug