The treatment landscape for advanced pancreatic cancer is shifting. The common RAS mutation is now targetable and the race for the most effective inhibitor is heating up.
In mid-April, Revolution Medicines announced positive results from its phase III RASolute 302 clinical trial of daraxonrasib, an oral multiselective, noncovalent GTP-bound inhibitor that targets RAS G12 mutations (G12, G13, Q61) and wild-type RAS in pancreatic ductal adenocarcinoma. In previously treated patients receiving 300 mg once-daily, single-agent daraxonrasib doubled overall survival over conventional chemotherapy. As stated in a company news release, median overall survival was 13.2 months for this arm, compared to 6.7 months with investigator’s choice of chemotherapy (hazard ratio [HR], 0.40; P < .0001).1 The primary and final analysis will be presented during the Plenary Session of the 2026 ASCO Annual Meeting.
Brian Wolpin, MD, MPH
Principal investigator, Brian Wolpin, MD, MPH, Director of the Hale Family Center for Pancreatic Cancer Research and Gastrointestinal Cancer Center, at Dana-Farber Cancer Institute, and Professor of Medicine, Harvard Medical School, in an interview with The ASCO Post commented on the unprecedented benefit succintly: “A median survival of more than a year in the second-line setting really does get your attention.”
As for what this fairly stunning outcome represents, “It’s been very difficult to treat pancreatic cancer…But with more than 90% of patients having a KRAS mutation and now having drugs that can allow us to block that signaling, we are really poised to radically change how we treat pancreatic cancer,” Dr. Wolpin said. “Many people have been working hard for many years to realize this, and hopefully this is the first step to doing so.”
The U.S. Food and Drug Administration (FDA) granted daraxonrasib Breakthrough Therapy Designation and Orphan Drug Designation for patients with previously treated metastatic pancreatic ductal adenocarcinoma harboring RAS mutations.
In addition, daraxonrasib was selected for the FDA Commissioner’s National Priority Voucher pilot program, which is intended to accelerate the development and review of therapies aligned with U.S. national health priorities.
Daraxonrasib works by suppressing RAS signaling through inhibition of the interaction between both wild-type and mutant RAS(ON) proteins and their downstream effectors.
The ultimate aim, as with all effective novel therapeutics, is to employ treatment in earlier-stage disease. To this end, daraxonrasib has been evaluated in the first-line setting, both as a single agent and in combination with chemotherapy. Results from these two first-line studies were presented as late-breaking abstracts at the 2026 American Association for Cancer Research Annual Meeting and are reported below.2,3
AACR Study: Daraxonrasib/Chemotherapy in the First-Line Setting
Dr. Wolpin presented findings in 40 previously untreated patients (all with metastatic disease; 70% with liver metastases) who received daraxonrasib 200 mg/day plus gemcitabine/nab-paclitaxel in 28-day cycles in the GI-102 platform study.1The regimen was designed to sustain suppression of RAS signaling by maintaining sufficient dose intensity of daraxonrasib and to safely leverage the antitumor activity of the chemotherapy, he said.
“The combination demonstrated compelling preliminary anti-tumor activity and also demonstrated an encouraging early trend in durability,” Dr. Wolpin said.
At a median follow-up of 9.7 months, in the intention-to-treat analysis the objective response rate was 58% and the disease control rate was 90%. At 6 months, 84% of patients were progression-free and 90% were alive; the data were premature for analyses of the medians.
Of 40 patients with paired plasma samples, 28 had detectable RAS mutant alleles in circulating tumor DNA (ctDNA) at baseline and were evaluable for ctDNA response. The assay showed that 96% achieved a greater than 50% reduction in RAS variant allele frequency (VAF) and 61% achieved RAS VAF clearance.
Safety Profile of Combination
The safety profile of the daraxonrasib plus gemcitabine/nab-paclitaxel combination was consistent with the known toxicities of each component. All-grade treatment-related adverse events included rash (90%), diarrhea (75%), fatigue (70%), nausea (68%), vomiting (55%), anemia (50%), stomatitis/mucositis (45%), peripheral edema (43%), decreased neutrophil count (43%), peripheral neuropathy (38%), alopecia (33%), and increased aspartate aminotransferase (AST) (30%).
Grade ≥ 3 toxicities were observed in 73%, and mostly included anemia (33%), decreased neutrophil count (20%), fatigue (18%), rash (15%), diarrhea (15%), and stomatitis/mucositis (10%). There were no grade 5 treatment-related events.
There has been some focus on the occurrence of rash and stomatitis with RAS inhibitors. Dr. Wolpin acknowledged this, noting, “We have been learning how to manage these [toxicities] as we go…We had never given a drug like this before, and I think we are getting better at this now. It is important to also note that with daraxonrasib we don’t see the other toxicities we commonly see with chemotherapy, such as suppression of blood counts, peripheral neuropathy, or liver function abnormalities.”
Mean dose intensity was 82% for daraxonrasib and 80% for chemotherapy; medians were 87% and 81%, respectively. Chemotherapy was responsible for more dose reductions (58% vs 35%) and treatment discontinuations (15% vs 5%) than daraxonrasib, he pointed out.
During the discussion period, Dr. Wolpin elaborated on safety concerns. “I think there are two toxicities specific to daraxonrasib that require proactive management: rash and mucositis. We have learned, with help from our dermatology colleagues, to institute prophylaxis for the rash, and there are opportunities to do that for mucositis as well. With prophylaxis, the intensity of these side effects is less. It’s manageable as long as you’re proactive.”
AACR Study: Daraxonrasib Monotherapy in the First-Line Setting
Eileen O’Reilly, MD, the Winthrop Rockefeller Endowed Chair in Medical Oncology, Section Head of Hepatopancreaticobiliary/Neuroendocrine Cancers and Co-Director for Medical Initiatives at the David M. Rubenstein Center for Pancreatic Cancer at Memorial Sloan Kettering Cancer Center presented findings for daraxonrasib as a single agent in 40 treatment-naïve patients with RAS-mutant pancreatic ductal adenocarcinoma.3 She noted that more than two-thirds of patients had liver metastases at baseline and two-thirds had not undergone surgical resections, both of which are “well recognized as adverse prognostic factors.”
Eileen O’Reilly, MD
“Daraxonrasib demonstrated anti-tumor activity, with the majority of patients experiencing tumor shrinkage,” Dr. O’Reilly reported. At a median follow-up of 13.7 months, the objective response rate was 47% and disease control rate was 92%. Estimated progression-free survival at 6 months (in the all-RAS-mutant population) was 71% and overall survival was 83%, she said.
All 28 evaluable patients achieved a greater than 50% decrease in RAS VAF; complete and early on-treatment clearance of ctDNA was seen in 57% of patients. “This meaningful RAS VAF ctDNA reduction observed in patients with metastatic [pancreatic ductal adenocarcinoma] indicates inhibition of key oncogenic RAS mutations,” Dr. O’Reilly said. “Also,” she added “these data support the potential for single agent targeted therapy in front-line pancreas cancer, a potential major paradigm shift.”
Safety Profile of Single-Agent Daraxonrasib
All-grade treatment-related adverse events included rash (88%), diarrhea (63%), stomatitis/mucositis (63%), nausea (53%), vomiting (50%), fatigue (35%), and paronychia (20%). Grade ≥ 3 toxicities included primarily rash, diarrhea, and stomatitis/mucositis (10% each), with no grade 4/5 toxicities seen. Treatment-related adverse events led to dose modifications in 70% of patients; one patient (3%) discontinued treatment.
Looking Ahead
Dr. Wolpin commented on the relative benefit of giving daraxonrasib paired with chemotherapy vs as a single agent. “At this point, it’s uncertain. We have studies of about 40 patients each, which gives us a basic sense of how the drug is performing, and it’s enough to know it looks promising, but it’s not feasible to compare the two approaches meaningfully. There is rationale to think that adding chemotherapy may be helpful, but at the same time we likely will get more side effects. We are going to have to wait and see what larger trials tell us.”
The question of single-agent vs combination therapy may well be answered by the upcoming global phase III RASolute 303 trial of daraxonrasib with or without gemcitabine/nab-paclitaxel as a first-line treatment for metastatic pancreatic ductal adenocarcinoma, which is currently enrolling. Patients will be randomized to daraxonrasib alone, gemcitabine/nab-paclitaxel alone, or the combination.
“In terms of the mutant-allele-specific vs multiselective inhibitors, that will have to be assessed in the clinic. It’s such an amazing time in pancreas cancer, where we have so many different inhibitors to the same target, KRAS, but they have different specificities, different mechanisms of action. Some are oral, some are intravenous, and so forth,” Dr. Wolpin said. He added, “It’s going to take the body of evidence to understand the pros and cons to each of those approaches, but at this point, we are in an unprecedented time in pancreas cancer, and we greatly hope to see this play out in real time in the clinic to the benefit of our patients.”
DISCLOSURE: Dr. Wolpin had personal financial disclosures for Amgen, AstraZeneca, Eli Lilly, Harbinger Health, Novartis, Revolution Medicines, Agenus, BeiGene, BMS/Mirati, Cancer Panels, Diaceutics, EcoR1 Capital, GRAIL, Immuneering, Ipsen, SystImmune, Takeda, Tango Therapeutics, and Third Rock Ventures. Dr. O’Reilly reported the following disclosure information: Research Funding to Institution: Arcus, Genentech/Roche, BioNTech, Incyte, AstraZeneca, Elicio Therapeutics, Digestive Care, Agenus, Amgen, Revolution Medicines, Tango Therapeutics. Consulting/DSMB (Uncompensated): Arcus, Amgen, Astellas, AstraZeneca, Corcept, Pfizer, Agenus, BioNTech, Ipsen, Ikena, Merck, Immuneering, Moma Therapeutics, Novartis, BMS, Revolution Medicines, Regeneron, Tango Therapeutics. Travel: BioNTech, Arcus, Pfizer, Revolution Medicines. Other: AACR, ASCO, Imedex, Research To Practice, Stand Up To Cancer (SU2C), NIH/NCI, Break Through Cancer Center Support Grant/Core Grant P30 CA008748 NCI/NIH P50 CA257881-01A1.
REFERENCES
1. Revolution Medicines: Daraxonrasib demonstrates unprecedented overall survival benefit in pivotal phase 3 RASolute 302 clinical trial in patients with metastatic pancreatic cancer. https://ir.revmed.com/news-releases/news-release-details/daraxonrasib-demonstrates-unprecedented-overall-survival-benefit. Accessed April 22, 2026.
2. Wolpin BM, Musher BL, Manji GA, et al: Daraxonrasib plus chemotherapy as first-line treatment for patients with metastatic pancreatic adenocarcinoma. 2026 AACR Annual Meeting. Abstract LB407/7. Presented April 21, 2026.
3. O’Reilly EM, Wolpin B, Pant S, et al: Daraxonrasib monotherapy as first-line treatment for patients with metastatic pancreatic adenocarcinoma. 2026 AACR Annual Meeting. Abstract LB337/18. Presented April 21, 2026.
EXPERT POINT OF VIEW
Colin Weekes, MD, PhD, Associate Professor of Medicine at Mass General Brigham Cancer Institute, commented on the latest findings for daraxonrasib in an interview with The ASCO Post. Dr. Weekes co-moderated the AACR’s Late-Breaking Minisymposium during which Dr. Brian Wolpin presented the results of a trial combining daraxonrasib with gemcitabine and nab-paclitaxel in the first-line setting of pancreatic ductal adenocarcinoma.1
Colin Weekes, MD, PhD
“With daraxonrasib and other drugs like it, we now have the capacity to target RAS in pancreas ductal adenocarcinoma, and this is a game-changing situation. The studies are mostly early, but it’s promising to think about using these compounds in ways we haven’t thought about in the past. It’s a new day for pancreas cancer,” Dr. Weekes commented.
Referring to results that made headlines recently—the RASolute 302 study showing a doubling in overall survival with daraxonrasib in previously treated patients, Dr. Weekes pointed out that with conventional chemotherapy administered in the first-line setting, median overall survival barely approaches 1 year. Median overall survival exceeding 1 year in the second-line setting is unprecedented, he said.
“But there is a price to pay for this success, and that is the potential for toxicity, at least with daraxonrasib,” he cautioned. “It has incredible benefit for patients, but it’s not a benign drug. The toxicity can be challenging and it does have to be managed.”
In particular, Dr. Weekes noted, the rash and stomatitis can be problematic for some patients. “It’s different from the rash we’ve seen with, for example, the EGFR [epidermal growth factor receptor]-targeted therapies. I think it will require a dedicated treatment or prophylaxis plan, especially for patients outside of academic centers who may not have access to the supportive care that is needed to manage these toxicities,” he said, adding that diarrhea can also be an issue. “So even though this drug represents a great opportunity for patients, it’s one that must be taken with some consideration.”
Daraxonrasib is a multiselective inhibitor of mutant KRAS whereas some other investigational inhibitors are allele-specific. For example, at the 2026 ASCO Gastrointestinal Cancers Symposium, promising early results were presented for the KRAS G12D inhibitor INCB161734.2 At a median follow-up of about 5 months, the median duration of response and progression-free survival had not been reached with single-agent INCB161734 in heavily pretreated patients.
“I think we will see that these mutation-specific inhibitors have a toxicity profile that favors combinations with FOLFIRINOX [5-FU, leucovorin, irinotecan, oxaliplatin],” Dr. Weekes predicted. In fact, clinical trials of this combination are now opening to patient accrual.
The emerging mutant RAS-targeted treatment approach not only means new drugs and new supportive care measures but also new additional steps in the diagnostic work-up, he continued. “Clinicians will have to know the patient’s mutation status,” he said, indicating that outside of academic centers this is not commonly performed. “There will need to be an evolution in clinical practice in terms of being able to order these tests, get the results back in a timely manner, get insurance coverage, and then move on the results.”
And, he added, mutation-targeted therapy will not be limited to RAS—for example, there are a new class of drugs in development called PRMT5 inhibitors targeting tumors with biallelic MTAP deletions. “Pancreas cancer is a genetically driven cancer, the application of molecular therapy is now an actionable concept, and pancreas cancer care will evolve. It’s an exciting time.”
DISCLOSURE: Dr. Weekes has received research support from Novartis, Elicio, Bristol Myers Squibb, Revolution Medicine and Actuate Therapeutics and has served on the advisory boards of Novartis, Bristol Myers Squibb and Ipsen.
REFERENCES
1. Wolpin BM, Musher BL, Manji GA, et al. Daraxonrasib plus chemotherapy as first-line treatment for patients with metastatic pancreatic adenocarcinoma. 2026 AACR Annual Meeting. Abstract LB407/7. Presented April 21, 2026.
2. Wainberg ZA, Henry JT, Park H, et al: Preliminary phase I results of INCB161734 as monotherapy or in combination with chemotherapy for advanced/metastatic pancreatic duct adenocarcinoma. 2026 ASCO Gastrointestinal Cancers Symposium. Abstract 654. Presented January 9, 2026.
