At the 2026 American Society of Clinical Oncology Annual Meeting, one of the most memorable moments came from pancreatic cancer, a disease where major drug development success has long been rare.
The late-breaking plenary presentation of RASolute 302, presented by Brian M. Wolpin, quickly became one of the defining stories of the meeting. As the first Kaplan-Meier curve for overall survival appeared on the screen, the room reacted. What followed was not just applause, but a standing ovation from physicians and researchers who understood the weight of the result.
Following ASCO, OncoDaily conducted an exclusive interview hosted by Shushan Hovsepyan with Dr. Alan Sandler, Chief Development Officer at Revolution Medicines, to discuss the story behind this moment, the scientific risk of targeting RAS, the path from early clinical development to phase 3 success, and what may come next for patients with RAS-addicted cancers.
What is Daraxonrasib?
Daraxonrasib, also known as RMC-6236, is an investigational oral RAS(ON) multi-selective inhibitor developed by Revolution Medicines. It is designed to inhibit active RAS signaling across multiple RAS mutation subtypes.
RAS has long been one of the most important but difficult targets in oncology. Activating mutations in KRAS, NRAS, and HRAS are found across several solid tumors, including pancreatic ductal adenocarcinoma, colorectal cancer, and subsets of non-small cell lung cancer.
Although KRAS G12C inhibitors helped validate RAS as a druggable target, many RAS-mutant cancers, including most pancreatic cancers, are driven by non-G12C alterations.
Daraxonrasib is designed to target the active, GTP-bound RAS(ON) state through a tri-complex mechanism. Instead of binding RAS directly in the conventional way, daraxonrasib binds cyclophilin A, a chaperone protein. This binary complex then binds RAS, forming a tri-complex that sterically inhibits downstream RAS signaling.
This broader RAS(ON) approach is particularly relevant in pancreatic cancer, where more than 90% of tumors harbor RAS mutations.
Read more about Daraxonrasib (RMC-6236) on OncoDaily.
From an Unexpected Beginning to RAS-Addicted Cancers
Dr. Sandler traced the story back to the early history of Revolution Medicines, before the company became focused on oncology and RAS-driven tumors.
The company was initially exploring antifungal drug development, including efforts to improve upon amphotericin. The shift toward oncology, and eventually toward RAS-addicted cancers, became one of the defining turns in its history. This direction was also linked to the acquisition of Warp Drive Bio, which helped shape the company’s tri-complex inhibitor platform.
“I think you can go all the way back to the establishment of Revolution Medicines, which initially was going to be looking at an antifungal company, looking to try and improve upon amphotericin. Maybe the best thing that happened is that didn’t work out and they turned toward oncology and ultimately, specifically, toward RAS-addicted cancers.”
Daraxonrasib became the first of the company’s RAS(ON) programs to enter clinical development. The program moved quickly from first-in-human testing in 2022 to a positive phase 3 trial in 2026.
“So we’ve gone pretty rapidly from first in human testing in 2022 to a positive phase three trial in 2026, which is, you know, pretty rapid all along the way.”
Early clinical activity in previously treated pancreatic cancer helped support the decision to move quickly. Rather than following a conventional phase 2 pathway, the program moved from an expanded phase 1 experience into a global randomized phase 3 study.
“We had patients with response rates in sort of the mid to upper 30 percent range in this setting and moved very quickly from that phase one approach into the phase three study.”
Why Pancreatic Cancer Was the Right Scientific Challenge
Pancreatic cancer remains one of the most difficult malignancies in oncology drug development. For daraxonrasib, the disease represented both a major unmet need and a biologically compelling setting.
Pancreatic cancer is strongly driven by RAS biology, making it a logical disease in which to test broad RAS inhibition.
“Pancreatic cancer is driven by RAS. Over 90 percent of patients will have some form of a RAS mutation.”
Most of these alterations involve G12, with G13 also represented. This made RAS an important therapeutic target, but also a historically difficult one. For decades, RAS was viewed as one of oncology’s most challenging targets.
“The challenge had been that RAS was felt to be undruggable.”
RAS was discovered decades ago, but the absence of obvious binding pockets made it difficult to inhibit with small molecules. The ability to target active RAS therefore represented a major shift in the field.
“This idea of being able to target RAS was monumental.”
This was also one of the central risks of the program. RAS is not only a cancer driver; it is also part of normal cellular biology. For daraxonrasib, the key distinction was the RAS(ON) state: the drug is designed to target active RAS signaling, which is characteristic of malignant cells, while RAS is typically inactive in normal cells.
“The good news was it attacks the on portion. And for normal cells, RAS is typically off, whereas in the malignant cells, RAS is typically on.”
The ASCO Moment
The ASCO plenary presentation became one of the most discussed parts of the RASolute 302 story. During the presentation, the first survival Kaplan-Meier curve triggered an immediate reaction from the audience.
“There was a murmur through the audience and suddenly some clapping and cheering. And as you know, there was a standing ovation.”
For Dr. Sandler, the reaction reflected more than a positive trial. It reflected the difficulty of pancreatic cancer and the magnitude of the result.
Pancreatic cancer has historically been one of the hardest settings for drug development, particularly in the previously treated metastatic setting. RASolute 302 showed a survival benefit that stood out against that background.
“But that was a monumental moment.”
He described the clinical effect as a doubling of median survival, with a hazard ratio of 0.40, representing a 60% reduction in the risk of death.
“You had a doubling of the median survival in patients going from around 6.6 months to 13.2 months.”
The chemotherapy arm performed in the expected range for previously treated metastatic pancreatic cancer, while the 13.2-month median survival with daraxonrasib stood out as unusually high for this disease setting.
RASolute 302: Key Results and Safety
RASolute 302 was a global, randomized phase 3 trial evaluating daraxonrasib monotherapy versus standard-of-care chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma.
Patients were randomized to receive daraxonrasib 300 mg orally once daily or investigator’s choice of standard-of-care cytotoxic chemotherapy.
The trial met its primary and key secondary endpoints. In the RAS G12-mutant population, median overall survival was 13.2 months with daraxonrasib compared with 6.6 months with chemotherapy. In the intent-to-treat population, median overall survival was 13.2 months versus 6.7 months, respectively. The hazard ratio for death was 0.40 in both populations.
Progression-free survival and objective response rate were also improved with daraxonrasib compared with chemotherapy.
The safety profile was manageable. Grade 3 or higher treatment-related adverse events occurred less frequently with daraxonrasib than with chemotherapy, and treatment-related adverse events leading to treatment discontinuation were also lower with daraxonrasib.
Read more about RASolute 302 Trial at ASCO 2026 on OncoDaily.
The Hardest Part of Moving From Concept to Clinic
One of the central challenges in developing daraxonrasib was the biology of RAS itself. RAS is critical in cancer biology, but it also has important roles in normal cellular function.
Because daraxonrasib is a broad RAS(ON) inhibitor, early development had to address whether this approach could be tolerated safely. The phase 1 study started at very low doses because of these concerns. As development continued, the drug showed a tolerability profile that allowed the program to move forward.
Rash, mild diarrhea, and oral mucositis were observed. In general, these toxicities were described as mostly grade 1 or 2, with grade 3 or higher events less common. Over time, the program also developed a preventive approach for rash, using strategies familiar to oncologists from EGFR-directed therapy, including oral antibiotics and topical treatments.
This helped make toxicity management part of the development story, rather than a barrier to continued treatment.
When Did the Team Know the Drug Could Work?
Confidence began during the phase 1 study, when activity was seen as dosing approached therapeutic levels.
Investigators began reporting patients who were feeling better clinically, with responses later confirmed on imaging. These early signals were important because responses were not necessarily expected in previously treated pancreatic cancer.
“There was activity that was seen early in the study as the dose started to get toward therapeutic dose levels.”
Those early observations helped support rapid movement into later-stage development.
“We believe that there is something here and gave us that confidence to move forward as quickly as possible.”
Quality of Life as Part of the Story
Beyond survival, patient-reported outcomes were an important part of the RASolute 302 story.
In metastatic pancreatic cancer, pain, symptoms, and treatment burden can heavily affect daily life. In RASolute 302, daraxonrasib delayed worsening of pain and overall quality of life compared with chemotherapy.
“Quality of life is something that’s obviously extremely important to patients.”
The patient-reported outcome data made the result more meaningful beyond the survival curve.
“Not only are patients living longer, but they’re also feeling better along that time as well and for longer periods of time.”
For Dr. Sandler, this also reflected a broader patient-centered approach in drug development: not only trying to extend survival, but also trying to preserve how patients feel during that time.
Access and Ongoing Development
Daraxonrasib remains investigational and is not yet approved by regulatory authorities.
Revolution Medicines is working with the U.S. Food and Drug Administration on regulatory submission. The company has also established an expanded access program in the United States for eligible patients with previously treated metastatic pancreatic cancer.
In the United States, access depends on patients and physicians requesting participation and on institutions completing the required review process. Outside the United States, access pathways depend on individual country processes.
Clinical trials remain an important route for access globally, and Revolution Medicines has broadened its global clinical trial footprint.
“We do realize the importance of trying to get this drug to patients as quickly as possible.”
The daraxonrasib development program is also moving into earlier treatment settings. A first-line metastatic pancreatic cancer study is evaluating daraxonrasib alone and in combination with gemcitabine plus nab-paclitaxel, compared with standard gemcitabine plus nab-paclitaxel.
Daraxonrasib is also being studied in patients with resected pancreatic cancer after surgery and perioperative therapy, with randomization to daraxonrasib or no further treatment.
The resected-disease study is especially important because of its potential implications beyond disease control.
“That actually has the potential not only extending life, but that may increase the cure rate of patients with resected pancreatic cancer.”
“This Is Just the Beginning”
Looking back at what this moment may represent for oncology drug development, Dr. Sandler summarized the broader meaning of the work in simple terms.
“Something that was thought not to be possible became possible in a very, very dramatic way.”
He also emphasized that daraxonrasib is part of a broader RAS(ON) inhibitor platform.
Revolution Medicines is developing multiple clinical-stage RAS(ON) inhibitors, including daraxonrasib as a multi-selective agent and additional agents directed at specific RAS variants, including elironrasib for G12C, zoldonrasib for G12D, and RMC-5127 for G12V. These agents are being studied across pancreatic cancer, non-small cell lung cancer, colorectal cancer, and other RAS-addicted malignancies.
“So what I like to say is this is, this is just the beginning.”
Using a baseball analogy from Revolution Medicines CEO Mark Goldsmith, Dr. Sandler said the field is still early in understanding how far RAS(ON) inhibition may go.
“We’re only in maybe the second or third inning at this particular point.”
Takeaway
RASolute 302 marked a major moment in pancreatic cancer drug development. In previously treated metastatic pancreatic ductal adenocarcinoma, daraxonrasib improved overall survival, progression-free survival, objective response rate, and patient-reported outcomes compared with chemotherapy.
For patients, the results suggest the possibility of longer survival with better preservation of quality of life. For the field, the ASCO standing ovation reflected something larger than one trial: the possibility that broad RAS(ON) inhibition may become a new therapeutic foundation in one of oncology’s most difficult diseases.
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