Daraxonrasib Combo Receives FDA Breakthrough Status in First-Line PDAC

Daraxonrasib (Rasonque) in combination with gemcitabine and nab-paclitaxel (GnP) has received breakthrough therapy designation (BTD) from the FDA for the first-line treatment of patients with metastatic pancreatic adenocarcinoma (PDAC).¹

BTD is a regulatory designation intended to expedite the development and review of therapies for serious conditions that address significant unmet medical needs. To qualify, a therapy must have preliminary clinical evidence indicating substantial improvement over available therapies on a clinically significant end point.

The designation is based on preliminary findings from the phase 1/2 RMC-GI-102 trial (NCT06445062), which is evaluating the combination in patients with treatment-naive, RAS-mutant metastatic PDAC. Here, treatment with the daraxonrasib combination demonstrated preliminary antitumor activity and a manageable safety profile, with toxicities described as consistent with the known safety profiles of daraxonrasib and the chemotherapy regimen.

“This [BTD] underscores the significant unmet need among patients with previously untreated metastatic [PDAC] and recognizes the importance of advancing new treatment options earlier in their treatment journey,” Alan Sandler, MD, chief development officer of Revolution Medicines, stated in a news release.¹

About Daraxonrasib

Daraxonrasib is an oral, RAS(ON) multi-selective, noncovalent, tri-complex inhibitor that recently received FDA approval as monotherapy in the previously treated setting in August 2026.² It is specifically indicated for treatment of adult patients with metastatic PDAC who have received at least 1 prior systemic therapy or who are not candidates for multiagent systemic therapy.

The approval, considered under the Commissioner’s National Priority Voucher pilot program, was based on positive results from the phase 3 RASolute 302 trial (NCT06625320) in which daraxonrasib reduced the risk of death by 60% vs chemotherapy.

In clinical trials supporting the current indication, dermatologic toxicity occurred in 86% of patients receiving daraxonrasib, including grade 3 events in 10%. Stomatitis occurred in 57% of patients, including grade 3 events in 9%, while diarrhea occurred in 63%, including grade 3 events in 6%. Less common but clinically important toxicities included gastrointestinal perforation and interstitial lung disease or pneumonitis.

Ongoing Evaluation in the Untreated Setting

RMC-GI-102 is an open-label, multicenter phase 1/2 trial evaluating RAS(ON) inhibitors in patients with gastrointestinal solid tumors, including a cohort of patients with treatment-naive, RAS-mutant metastatic PDAC receiving daraxonrasib in combination with GnP.³

The findings from RMC-GI-102 have informed the design of RASolute 303 (NCT07491445), an ongoing global, randomized, open-label phase 3 trial evaluating daraxonrasib as monotherapy and in combination with GnP compared with GnP alone in previously untreated metastatic PDAC.⁴ Unlike the earlier RMC-GI-102 cohort, RASolute 303 is evaluating patients regardless of tumor RAS genotype.

The BTD represents a regulatory step toward evaluating daraxonrasib earlier in the treatment course for metastatic PDAC. Results from RASolute 303 will be needed to determine whether the preliminary activity observed in RMC-GI-102 translates into a clinically meaningful benefit compared with GnP alone.

“[Daraxonrasib] monotherapy demonstrated compelling clinical benefit in the RASolute 302 trial, leading to FDA approval for patients with previously treated metastatic pancreatic adenocarcinoma or those who are not candidates for multiagent systemic therapy,” Sandler added in the news release.¹ “Data from the RMC-GI-102 study have now shown the therapeutic potential of [daraxonrasib] in combination with GnP, a commonly used multiagent systemic therapy, in treatment-naive patients. Together with our other ongoing studies, these findings reflect our deep commitment to advancing a broad RAS(ON) approach for patients with some of the most difficult-to-treat cancers.”

Dr Pant Discusses Next Steps in Daraxonrasib Development for Pancreatic Cancer

REFERENCES

1. Revolution Medicines Announces U.S. FDA Breakthrough Therapy Designation for RASONQUE™ (daraxonrasib) in Combination with Chemotherapy for First Line Metastatic Pancreatic Cancer. News release. Revolution Medicines. September 14, 2026. Accessed September 15, 2026. https://tinyurl.com/mv9854bj

2. FDA Approves First in Class Targeted Therapy for Metastatic Pancreatic Cancer. News release. US FDA. August 26, 2026. Accessed September 15, 2026. https://tinyurl.com/cd5nkk9a

3. Study of RAS(ON) Inhibitors in Patients With Gastrointestinal Solid Tumors. ClinicalTrials.gov. Updated July 29, 2026. Accessed September 15, 2026. https://clinicaltrials.gov/study/NCT06445062

4. Study of Daraxonrasib and Daraxonrasib + GnP as First-line Treatment in Patients With Metastatic Pancreatic Adenocarcinoma (RASolute 303). ClinicalTrials.gov. Updated September 14, 2026. Accessed September 15, 2026. https://clinicaltrials.gov/study/NCT07491445