The investigational RAS inhibitor daraxonrasib has shown early promise in the first-line treatment of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) — though grade 3 or higher adverse events are common, according to a phase 1/2 trial. 

Among 39 patients who received daraxonrasib alongside standard chemotherapy, the objective response rate was 59%, with a disease control rate of 92% at a median of 10 months.

The results offer “compelling initial evidence of activity,” lead investigator Brian M. Wolpin, MD, of Dana-Farber Cancer Institute, Boston, reported at the American Association for Cancer Research (AACR) Annual Meeting 2026.

Historically, he noted, objective response rates with standard multiagent chemotherapy have been in the 30%-40% range.

The findings come on the heels of positive news for daraxonrasib in the second line. On April 13, drugmaker Revolution Medicines announced results of a phase 3 trial showing that daraxonrasib monotherapy doubled overall survival vs standard chemotherapy among patients with previously treated mPDAC. Median survival was 13.2 months with the RAS inhibitor and 6.7 months with chemotherapy.

The company said it intends to submit a new drug application to the FDA under a Commissioner’s National Priority Voucher, which entitles it to faster review.

Daraxonrasib has also been in the news due to former senator Ben Sasse’s experience with taking the drug. Sasse, who announced late last year that he’d been diagnosed with stage IV pancreatic cancer, has recently gone public with the good and the bad of his treatment: tumor shrinkage of 76%, at the cost of a severe skin reaction.

The First-Line Setting

The data Wolpin presented at the AACR meeting come from a phase 1/2 platform study evaluating RAS(ON) inhibitors in gastrointestinal cancers, with the current analysis focused on patients with RAS-mutant mPDAC and no previous systemic therapy.

Patients received 200 mg/d daraxonrasib orally in combination with gemcitabine and nab-paclitaxel. The chemotherapy backbone was administered on days 1 and 15 of a 28-day cycle, a modified schedule selected after dose escalation to improve tolerability while maintaining dose intensity.

The primary endpoints were safety and tolerability. Secondary endpoints included objective response rate, disease control rate, and progression-free survival, with exploratory analyses assessing molecular response via circulating tumor DNA (ctDNA).

At a median follow-up of 9.7 months, 40 patients had received treatment, with 39 evaluable for efficacy. Among those patients, the confirmed objective response rate was 59% (95% CI, 42%-74%), with a disease control rate of 92% (95% CI, 79%-98%).

At 6 months, estimated progression-free survival among all treated patients was 84%, whereas estimated overall survival was 90%. Median progression-free and overall survival data were not mature.

Wolpin noted that the survival findings are encouraging, as 6-month progression-free survival with chemotherapy has been in the 50% range in larger trials.

Among 28 patients evaluable for ctDNA, 96% had at least a 50% reduction in RAS variant allele frequency, while 61% had complete clearance of detectable RAS mutations.

Managing Safety Concerns

Treatment-related adverse events were common and consistent with the known profiles of the individual agents, Wolpin said. 

All patients experienced treatment-related adverse events of any grade — most commonly rash (90%), diarrhea (75%), fatigue (70%), nausea (68%), vomiting (55%), and anemia (50%). 

Nearly three-quarters (73%) experienced grade 3 or higher side effects, including anemia, neutropenia, fatigue, rash, diarrhea, and mucositis.

Just more than one third of patients needed daraxonrasib dose reductions, whereas 58% required chemotherapy dose reductions. Daraxonrasib was discontinued due to treatment-related adverse events in 5% of patients. Rash was the most common reason for dose modification.

While attendees at the presentation expressed enthusiasm for the efficacy findings, they also raised concerns about safety.

An audience member from Ludwig Maximilian University of Munich, Munich, Germany, said the regimen appeared to be a “very toxic combination” that could be particularly difficult for frail or elderly patients. He asked what steps would be taken to mitigate toxicity in the recently launched phase 3 RASolute 303 trial.

That trial is evaluating daraxonrasib as monotherapy or chemotherapy add-on vs standard chemotherapy alone as first-line treatment for patients with mPDAC.

Wolpin replied that there are two main toxicities specific to daraxonrasib — skin reactions and mucositis — that require “proactive” strategies. He said he and his colleagues have learned that rash prophylaxis, similar to measures used to prevent EGFR inhibitor-induced rash, is necessary.

“I would say, having treated patients on the study, I found that these things were manageable as long as we were proactive about the rash and the mucositis [and] used our usual approaches to manage the chemotherapy toxicity,” Wolpin said.

He acknowledged, however, that as with any treatment, decisions would have to be made on a patient-by-patient basis, with consideration of the potential benefits and risks.

The study was funded by Revolution Medicines. Wolpin and his colleagues disclosed financial relationships with Revolution Medicines and several other companies.