FDA Grants Breakthrough Therapy Designation to First-Line Daraxonrasib Plus Chemo in mPDAC

The FDA has granted breakthrough therapy designation to daraxonrasib (Rasonque) in combination with gemcitabine and nab-paclitaxel (Abraxane) for the treatment of patients with treatment-naive metastatic pancreatic ductal adenocarcinoma (mPDAC).¹

The designation was supported by data from patients with treatment-naive RAS-mutant mPDAC who received daraxonrasib plus gemcitabine and nab-paclitaxel in the open-label, multicenter phase 1/2 RMC-GI-102 trial (NCT06445062). The combination demonstrated preliminary antitumor activity in this cohort, along with a manageable safety profile consistent with the known safety profiles of daraxonrasib, gemcitabine, and nab-paclitaxel.

“This breakthrough therapy designation underscores the significant unmet need among patients with previously untreated [mPDAC] 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. “[Daraxonrasib] monotherapy demonstrated compelling clinical benefit in the RASolute 302 trial, leading to FDA approval for patients with previously treated [mPDAC] or those who are not candidates for multi-agent systemic therapy. Data from the RMC-GI-102 study have now shown the therapeutic potential of [daraxonrasib] in combination with gemcitabine and nab-paclitaxel, a commonly used multi-agent 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.”

What data supported the FDA breakthrough therapy designation for daraxonrasib plus chemotherapy in mPDAC?

RMC-GI-102 is evaluating daraxonrasib-based combinations in patients with RAS-mutant gastrointestinal (GI) tumors.²

“[The KRAS] mutation as a driving force in cancer was discovered in the early 1980s, but because of the shape of the protein, it was considered for decades to be an undruggable target,” Kim A. Reiss Binder, MD, said in an interview with OncLive^®. “The KRAS protein is smooth, like a golf ball, with little divots in it, but no deep pockets that you can get something to anchor on. It wasn’t until 2012 that somebody created a molecular glue, a way to stick another protein to the KRAS rather than directly trying to insert something in there. That was an enormous breakthrough. If you can stick something on top of these proteins, you end up with a change in the tertiary structure of the protein, and now that protein is no longer doing the activities that it was doing to drive the malignancy.”

Reiss Binder is the assistant program director of the Hematology/Oncology Fellowship Program and an associate professor of medicine (hematology-oncology) at the Hospital of the University of Pennsylvania in Philadelphia.

The cohort supporting the present designation comprised patients with previously untreated RAS-mutant mPDAC who received daraxonrasib at 200 mg once daily in 28-day cycles plus gemcitabine and nab-paclitaxel administered on days 1 and 15 of each cycle. As of a December 1, 2025, data cutoff, 40 patients had been treated in this first-line cohort and had at least 18 weeks of follow-up. In this population, the combination produced a confirmed objective response rate of 58% (95% CI, 41%-73%), including 1 complete response, as reported in findings presented at the 2026 AACR Annual Meeting. The median progression-free survival (PFS) and overall survival (OS) data were immature at the data cutoff, although the estimated 6-month PFS and OS rates were 84% (95% CI, 68%-93%) and 90% (95% CI, 76%-96%), respectively.

The most frequently observed grade 3 or higher treatment-related adverse effects (TRAEs) were anemia (33%), decreased neutrophil counts (20%), and fatigue (18%). No grade 5 TRAEs occurred. In total, 2 patients discontinued daraxonrasib due to TRAEs, and 6 patients discontinued gemcitabine plus nab-paclitaxel due to TRAEs. The mean dose intensities were 82% for daraxonrasib and 80% for gemcitabine plus nab-paclitaxel.

These data informed the design of the ongoing global phase 3 RASolute 303 trial (NCT07491445), which is evaluating daraxonrasib as monotherapy vs daraxonrasib in combination with gemcitabine and nab-paclitaxel vs gemcitabine and nab-paclitaxel alone in patients with previously untreated mPDAC, independent of tumor RAS genotype.^1,3

What is the approval and development status of daraxonrasib?

Daraxonrasib is an oral, RAS(ON) multiselective, noncovalent, tricomplex inhibitor.¹ In August 2026, the FDA approved daraxonrasib as monotherapy for the treatment of adult patients with mPDAC who have received at least 1 prior systemic therapy or who are not eligible for multi-agent systemic therapy, based on data from the phase 3 RASolute 302 trial (NCT06625320).^1,4 Following the RASolute 302 readout, an ESMO Guidelines Express update recommended the use of daraxonrasib after chemotherapy progression in patients with RAS-mutated mPDAC.⁵

The United States prescribing information for daraxonrasib includes warnings and precautions for dermatologic and soft tissue toxicity, stomatitis and oral disorders, diarrhea, GI perforation, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.¹ Beyond PDAC, the agent is being evaluated in a global phase 3 registrational program that includes metastatic RAS-mutant non–small cell lung cancer.

References

1. Revolution Medicines announces US FDA breakthrough therapy designation for Rasonque (daraxonrasib) in combination with chemotherapy for first-line metastatic pancreatic cancer. News release. Revolution Medicines, Inc. September 14, 2026. Accessed September 15, 2026. https://www.revmed.com/media/news/13431/revolution-medicines-announces-u-s-fda-breakthrough-therapy-designation-for-rasonquetm-daraxonrasib-in-combination-with-chemotherapy-for-first-line-metastatic-pancreatic-cancer
2. Revolution Medicines to present updated phase 1/2 clinical data for daraxonrasib in first-line metastatic pancreatic cancer across monotherapy and combination cohorts at the 2026 AACR Annual Meeting. News release. Revolution Medicines, Inc. April 21, 2026. Accessed September 15, 2026. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-present-updated-phase-12-clinical-data/
3. 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
4. FDA approves first in class targeted therapy for metastatic pancreatic cancer. FDA. August 26, 2026. Accessed September 15, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-class-targeted-therapy-metastatic-pancreatic-cancer?utm_medium=email&utm_source=govdelivery
5. Conroy T, Ducreux M; on behalf of the ESMO Guidelines Committee. ESMO Clinical Practice Guideline Express Update on daraxonrasib in the treatment of metastatic pancreatic cancer. Ann Oncol. Published online 2026. doi:10.1016/j.annonc.2026.08.003