Daraxonrasib Demonstrates First-Line Activity With/Without Chemotherapy in Metastatic PDAC

First-line treatment with daraxonrasib (RMC-6236) as either monotherapy or in combination with chemotherapy demonstrated antitumor activity and disease control in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), with both regimens producing outcomes that numerically exceed historical benchmarks observed with standard chemotherapy in this setting.^1,2

Two phase 1/2 datasets (NCT05379985; NCT06445062) evaluating the oral, potent, RAS(ON) multi-selective inhibitor as first-line therapy for metastatic PDAC were presented at the 2026 AACR Annual Meeting. Together, they offer the first comprehensive look at the agent's activity in the treatment-naive setting.

In the monotherapy study, presented by Eileen M. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, daraxonrasib produced an overall response rate (ORR) of 47% (95% CI, 31%-64%) and a disease control rate (DCR) of 92% (95% CI, 79%-98%) in efficacy-evaluable patients with RAS-mutant metastatic PDAC (n = 38).¹ In the all-RAS-mutant population (n = 40), the Kaplan-Meier–estimated 6-month progression-free survival (PFS) rate was 71% (95% CI, 53%-83%), and the 6-month overall survival (OS) rate was 83% (95% CI, 67%-92%). Of note, PFS and OS data remained immature at the data cutoff.

In the GI-102 Platform Study, presented by Brian M. Wolpin, MD, MPH, of Dana-Farber Cancer Institute in Boston, Massachusetts, daraxonrasib plus 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), with respective 6-month PFS and OS rates of 84% (95% CI, 68%-93%) and 90% (95% CI, 76%-96%).²

The safety profiles of both regimens were deemed manageable and consistent with prior data.^1,2

“When we compare these results with [that of] chemotherapy, they look better. [With monotherapy], we’re seeing something [a bit] lower than what we’re seeing with the combination,” Wolpin shared in an exclusive interview with OncLive®. “[However], we have to understand that the patient numbers at this point are relatively small, so there’s still work to do to evaluate the stability of these estimates."

Wolpin serves as director of both the Gastrointestinal Cancer Center and Hale Family Center for Pancreatic Cancer Research, the Robert T. and Judith B. Hale Chair in Pancreatic Cancer, and a physician at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School in Boston, Massachusetts.

What was the rationale for evaluating daraxonrasib in the first-line setting?

Metastatic PDAC is a RAS-driven malignancy associated with a 5-year survival rate of approximately 3%. Standard first-line chemotherapy carries substantial toxicity and limited benefit, with reported ORRs of 23% to 43%, 6-month PFS rates of 44% to 56%, 6-month OS rates of 55% to 76%, and a median OS of 8.5 to 11.7 months.

"Chemotherapy does have quite a bit of [toxicity], and it doesn’t work as well as we would like," Wolpin said. "It has been known for some time that over 90% of pancreatic cancers have a mutation in a single gene, KRAS — there are a variety of different mutations, but it is always within that same gene. More recently, there has been substantial work…to design new drugs that can bind to and block KRAS signaling, and one of those drugs is daraxonrasib.”

“Most of the mutations in pancreatic cancer, although they’re in KRAS, are not the mutation that the currently approved drugs work for,” Wolpin added. Daraxonrasib, however, is notable for targeting both GTP-bound mutant and wild-type RAS, including mutations at G12, G13, and Q61. Mechanistically, it operates as what Wolpin described as a "molecular glue."

Daraxonrasib previously demonstrated manageable safety and preliminary efficacy at 300 mg once daily in patients with second-line RAS-mutant metastatic PDAC in a phase 1/2 study; the monotherapy dataset presented at AACR was focused on the treatment-naive first-line population within that study.

How was the monotherapy study designed?

This phase 1/2, open-label, multicenter study evaluated daraxonrasib in patients with RAS-mutant solid tumors.¹ In the PDAC cohort, eligible patients were 18 years of age or older with an ECOG performance status (PS) of 0 or 1, measurable disease per RECIST 1.1 criteria, and adequate organ function. Patients with primary central nervous system (CNS) tumors, active brain metastases, or impaired gastrointestinal (GI) function were excluded. Patients with metastatic recurrence following prior treatment for localized disease were permitted to enroll, provided the diagnosis occurred more than 6 months after the last dose of systemic therapy.

Upon enrollment, patients received daraxonrasib at 300 mg orally once daily in 21-day cycles.

The study’s primary end point was safety and tolerability; secondary end points included ORR, DOR, DCR, and PFS per RECIST 1.1 criteria. Plasma samples at baseline and on-treatment were analyzed for changes in RAS variant allele frequency (VAF) in circulating tumor DNA (ctDNA).

What was the design of the combination study?

The GI-102 Platform Study is a phase 1/2, open-label, multicenter study of RAS(ON) inhibitors in patients with RAS-mutant GI tumors.² The current report features results from subprotocol C, evaluating daraxonrasib plus gemcitabine and nab-paclitaxel in patients with previously untreated metastatic PDAC who were 18 years of age or older, had an ECOG PS of 0 or 1, measurable disease per RECIST 1.1 criteria, and adequate organ function.

In the dose escalation phase, patients in Dose Level 1A received daraxonrasib at 200 mg orally once daily plus gemcitabine/nab-paclitaxel on days 1, 8, and 15; patients in Dose Level 1B received daraxonrasib at 200 mg orally once daily plus gemcitabine/nab-paclitaxel on days 1 and 15. Dose Level 1B was carried forward into dose expansion at the recommended phase 2 dose.

The primary end points were safety and tolerability; antitumor activity served as a key secondary end point; and ctDNA response was an exploratory objective.

What were the baseline characteristics in the monotherapy and combination studies?

The data cutoff for both studies was December 1, 2025.^1,2 At this time, 40 patients each were evaluable in the daraxonrasib monotherapy and combination cohorts, with a median follow-up of 13.7 months in the monotherapy study and 9.7 months (range, 5.7-13.8 months) in the combination cohort; patients in the combination arm had at least 18 weeks of follow-up.

In the monotherapy dataset, the median age was 69 years (range, 34-83); the median age was 69 years (range, 34-83) in the combination cohort. Across both datasets, the majority of patients were male (monotherapy = 63%; combination = 65%), with an ECOG PS of 1 reported in 50% and 48% of patients, respectively. Liver metastases were present in 70% and 68% of patients at enrollment, and 50% and 48% were metastatic at diagnosis, with 95% having stage IV disease at study entry in the monotherapy cohort.

Prior anticancer therapy in the non-metastatic setting was reported in 48% and 38% of patients, including 45% who received adjuvant or neoadjuvant therapy and 3% with locally advanced disease in the combination cohort; 28% of patients received FOLFIRINOX, and 10% received gemcitabine plus nab-paclitaxel in the monotherapy cohort. Pancreatic resection was performed in 43% and 33% of patients, respectively.

By RAS genotype (n = 40), KRAS G12D was the most common mutation (50%; 53%), followed by KRAS G12V (25%; 23%) and KRAS G12R (18%; 20%), and other RAS mutations (8%; 5%). Overall, 95% of tumors harbored KRAS G12 alterations in the monotherapy cohort.

What additional ctDNA data were presented in both datasets?

Of 36 patients with paired plasma samples in the monotherapy study, 28 had a detectable RAS mutant allele in ctDNA at baseline and were evaluable for ctDNA response (n = 28). All evaluable patients achieved a greater than 50% decrease in RAS VAF on treatment. Complete and early on-treatment ctDNA clearance, defined as 100% RAS VAF decrease from pre-treatment, was observed in 57% of patients.

Of the 37 patients who had paired plasma samples in the combination study, 28 had a detectable RAS mutant allele in ctDNA at baseline and were evaluable for ctDNA response. Of those patients, 96% had a greater than 50% decrease in RAS VAF on treatment. Complete and early on-treatment ctDNA clearance was observed in 61% of patients.

Investigators characterized this RAS VAF ctDNA reduction as indicative of the agent’s inhibition of key oncogenic RAS mutations, as well as the on-target activity of daraxonrasib when combined with chemotherapy.

What was the safety profile of daraxonrasib monotherapy?

The median duration of treatment with daraxonsarib was 7.7 months (range, 0.03-15). All-grade treatment-related adverse effects (TRAEs) occurred in 38 patients (95%), and grade 3 or higher TRAEs were observed in 38%) of patients.¹ No grade 4 or 5 TRAEs were reported. TRAEs occurring in 15% or more of patients were as follows: (any grade; grade ≥3):

• Rash (bundled term): 88%; 10%
• Diarrhea: 63%; 10%
• Stomatitis: 63%; 10%
• Nausea: 53%; 3%
• Vomiting: 50%; 5%
• Fatigue: 35%; 3%
• Paronychia: 20%; 0%
• Decreased appetite: 18%; 0%
• Constipation: 15%; 0%

Serious TRAEs occurred in 10% of patients, with 8% being grade 3 or higher. TRAEs led to dose modifications (70%), interruption (60%) and reduction (40%). Rash was the most common TRAE leading to dose modification. Only 1 patient (3%) discontinued treatment due to a TRAE. The mean dose intensity was 84% and the median dose intensity was 88%.

How did the safety profile of daraxonrasib plus chemotherapy compare?

Any-grade TRAEs occurred in all 40 patients treated with the combination, and grade 3 or higher TRAEs were observed in 73% of patients. Serious TRAEs occurred in 28% of patients, 25% of which were grade 3 or higher.^,2 No grade 5 TRAEs occurred. Rash was the most common TRAE and was predominantly grade 1 or 2. TRAEs occurring in 30% or more of patients were as follows (any grade; grade ≥3):

• Rash (bundled term): 90%; 15%
• Diarrhea: 75%; 15%
• Fatigue: 70%; 18%
• Nausea: 68%; 5%
• Vomiting: 55%; 0%
• Anemia: 50%; 33%
• Stomatitis/mucositis: 45%; 10%
• Peripheral edema: 43%; 0%
• Neutrophil count decreased: 43%; 20%
• Peripheral neuropathy: 38%; 0%
• Platelet count decreased: 38%; 8%
• Alopecia: 33%; 0%
• Increased Aspartate Aminotransferase Level: 30%; 3%

Daraxonrasib-related dose modifications, interruptions, and reductions were necessary in 60%, 60%, and 35% of patients, respectively. Two patients discontinued daraxonrasib due to grade 3 acute pancreatitis (n = 1) and grade 3 nausea and grade 2 vomiting (n = 1). Dose modifications, interruptions, and reductions due to chemotherapy-related TRAEs occurred in 75%, 53%, and 58% of patients, respectively. Six patients discontinued chemotherapy due to TRAEs. The mean dose intensity was 82% for daraxonrasib and 80% for chemotherapy; the respective median dose intensities were 87% and 81%.

"In both the combination study and when given alone, the safety profile of daraxonrasib was quite similar to what we’ve seen before," Wolpin reiterated. "We’ve now treated a reasonably large number of patients with this [agent], so we have a pretty good sense of what the AEs are, and they were really quite similar [between] these studies. When we [administer daraxonrasib] together with chemotherapy, we get the AEs that chemotherapy brings. But really nothing new or different came up."

What’s next for daraxonrasib in pancreatic cancer?

Both datasets support the initiation of the phase 3 RASolute 303 (NCT07491445), a global, 3-arm, randomized, open-label study evaluating daraxonrasib with or without chemotherapy vs chemotherapy alone as first-line treatment for patients with metastatic PDAC.^1-3

"Both of the studies reported at AACR had relatively small numbers of patients so far, at [approximately] 40 patients each," Wolpin acknowledged. "In the second-line setting, where a much larger group of patients have been treated, daraxonrasib does look effective. When we look at the data so far in the first-line setting, daraxonrasib also looks effective, and when you compare it to the SOC, it may improve upon that. However, it is very early days. A larger study [is required] to prove that using daraxonrasib in the first-line setting will help patients."

RASolute 303 is planned to enroll approximately 900 patients with confirmed metastatic PDAC regardless of RAS mutation status, with ECOG PS of 0 or 1 and no prior systemic therapy for metastatic disease. Patients will be randomized 1:1:1 to 300 mg of daraxonrasib as monotherapy; 200 mg of daraxonrasib plus gemcitabine/nab-paclitaxel on days 1 and 15 of a 28-day cycle for up to 6 months followed by daraxonrasib monotherapy at 300 mg; or gemcitabine/nab-paclitaxel alone on days 1, 8, and 15 of a 28-day cycle. RAS mutation status is required for stratification. The study’s coprimary end points are PFS and OS, with secondary end points including ORR, DOR, safety, and patient-reported outcomes.

Wolpin noted that results from the phase 3 RASolute 302 trial (NCT06625320), which contained a much larger dataset and already reported superior outcomes with daraxonrasib vs chemotherapy in the second line, will be presented at the 2026 ASCO Annual Meeting.⁴

"The trial itself will be presented at [this year’s] ASCO [Annual Meeting], and then those data can be used to try to justify to [an FDA approval]," he said. "Based on the data we have so far, the place that it would fit in the armamentarium for pancreatic cancer would be in the second-line setting [for] patients who have received chemotherapy and have had progression of their cancer. The follow-up trials that have now begun are to look at whether it could be useful earlier, but we won’t know those results for some time."

Disclosures: Wolpin reported being an employee of Dana-Farber Cancer Institute; consultant roles with Agenus, BeiGene, BMS/Mirati, Cancer Panels, EcoR1 Capital, GRAIL, Harbinger Health, Immuneering, Ipsen, Lustgarten Foundation, Revolution Medicines, SystImmune, Takeda, Tango Therapeutics, and Third Rock Ventures; grant/research support to institution from Amgen, AstraZeneca, Break Through Cancer, Eli Lilly, Harbinger Health, Lustgarten Foundation, Mark Foundation, NIH/NCI, Novartis, Pancreatic Cancer Action Network, Revolution Medicines, Stand Up to Cancer, and Stephenson Foundation; no stockholdings; and honoraria from EcoR1 Capital, GRAIL, Harbinger Health, Immuneering, Revolution Medicines, SysImmune, Takeda, Tango Therapeutics, and Third Rock Ventures.

Support provided by Revolution Medicines. Content independently published by OncLive.

References

1. O'Reilly EM, Wolpin B, Pant S, et al. Daraxonrasib monotherapy as first-line (1L) treatment for patients with metastatic pancreatic adenocarcinoma (mPDAC). Presented at: 2026 AACR Annual Meeting; April 17–22, 2026; San Diego, CA. Abstract LB337.
2. 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). Presented at: 2026 AACR Annual Meeting; April 17–22, 2026; San Diego, CA. Abstract LB407.
3. Study of daraxonrasib and daraxonrasib + GnP as first-line treatment in patients with metastatic pancreatic adenocarcinoma (RASolute 303). ClinicalTrials.gov. Updated April 4, 2026. Accessed April 22, 2026. https://clinicaltrials.gov/study/NCT07491445?term=NCT07491445
4. Daraxonrasib demonstrates unprecedented overall survival benefit in pivotal phase 3 RASolute 302 clinical trial in patients with metastatic pancreatic cancer. News Release. Revolution Medicines. April 13, 2026. Accessed April 22, 2026. https://ir.revmed.com/news-releases/news-release-details/daraxonrasib-demonstrates-unprecedented-overall-survival-benefit