Revolution Medicines Conference: CEO Details Daraxonrasib Phase III Timeline, First-Line PDAC Push
by Scott Moore · The Cerbat GemRevolution Medicines (NASDAQ:RVMD) CEO Mark Goldsmith outlined the company’s late-stage plans for its RAS(ON) inhibitor daraxonrasib, discussed expansion into first-line pancreatic cancer, and offered updates on colorectal cancer and earlier-stage pipeline efforts during a conversation with Guggenheim Senior Biotech Analyst Michael Schmidt.
Phase III RASolute 302: OS event-driven readout expected in 1H 2026
Goldsmith said top-line data from the company’s first fully randomized Phase III study of daraxonrasib—RASolute 302 in second-line pancreatic ductal adenocarcinoma (PDAC)—is guided for the first half of 2026. He emphasized that while the trial has dual primary endpoints of progression-free survival (PFS) and overall survival (OS), the FDA has “made it pretty clear publicly” that it is seeking OS as the primary driver.
As a result, Goldsmith said RASolute 302 was designed as an OS event-driven program, with the readout triggered by a prespecified number of deaths based on company modeling. Because the trial is powered for OS, he said it is “effectively…overpowered for PFS.”
Goldsmith described three potential outcomes at the interim analysis: failing to meet statistical significance on both endpoints, succeeding on both, or achieving statistical significance on PFS but not yet on OS. In the latter case, he indicated the trial would remain an interim analysis rather than a final analysis.
Patient selection and control arm expectations
On the question of reproducibility relative to earlier-phase data, Goldsmith said the company has kept eligibility criteria consistent from the Phase I/II study into the Phase III trial and has compared those criteria with other Phase III studies. He said the company feels “pretty confident” the patient population should be similar, while acknowledging that results sometimes “discount” from Phase I to Phase III.
For the chemotherapy control arm, Goldsmith pointed to multiple historic Phase III trials showing fairly consistent outcomes in previously treated pancreatic cancer, citing PFS of roughly three to four months and OS in the six to seven month range. He said he sees no reason to expect a sudden change in that backdrop by 2026, while noting there can be variation across trials.
Handling RAS wild-type patients and the nested trial design
Schmidt raised the inclusion of RAS wild-type patients in RASolute 302 and how that could affect an intent-to-treat (ITT) analysis. Goldsmith argued pancreatic cancer appears highly RAS-driven, calling it “biologically a RAS-addicted disease,” and said that even some cases without a detectable RAS point mutation may carry other alterations in the RAS pathway (for example, upstream receptor tyrosine kinase mutations or fusions, or downstream Class I BRAF mutations).
Goldsmith said the company has not reported clinical data in patients with “wild-type” RAS, but noted that pancreatic cancer cell lines without a RAS mutation “tend to still be sensitive” to daraxonrasib. He also cautioned that “wild-type” may reflect limitations of testing, citing false negatives due to biopsy sampling or insufficient tumor DNA in liquid biopsy.
He described a “nested trial design” in which the core analysis focuses on patients with G12 mutations, which he said represent about 85% of pancreatic cancer and constitute the subset with the most supporting data. Patients with other mutations (G13, Q61) or no detectable mutation are included in a broader population analyzed as secondary.
On regulatory review, Goldsmith said FDA can analyze the data in many ways but generally will not seek statistical significance in small subgroups. He said the agency may perform sensitivity analyses and look for concerning signals such as hazard ratios meaningfully greater than one that could indicate potential harm.
Disclosure plans, NDA timing, and first-line PDAC expansion
Asked what the company would disclose if the interim analysis is positive, Goldsmith suggested a press release would likely focus on top-line results, with more rigorous detail presented at a medical meeting.
On timing for an NDA submission, he did not provide specifics but said the company intends to move “swiftly” after unblinding, while noting there are “built-in inefficiencies” in assembling and processing the information required for FDA review and for the agency’s decision to accept a filing.
Goldsmith also discussed the company’s push into first-line metastatic PDAC and said the three-arm RASolute 303 trial is open for enrollment. He said the company expects strong engagement from patients and investigators, citing encouraging single-arm data in later lines and stating that interest in access has been high. He added that investigators who have treated patients with daraxonrasib often want further access to the drug and to enroll patients in first-line studies.
Goldsmith addressed crossover and post-progression access as potential complications for OS interpretation, acknowledging tension between rapid availability for patients and the global regulatory preference for OS outcomes. He said the company’s approach is to move as quickly as possible across development efforts, noting that ex-U.S. approvals typically lag U.S. approval, which could provide some additional time before broad post-progression access impacts trial interpretation internationally.
Portfolio breadth: zoldonrasib, colorectal cancer, and RM-055
Goldsmith discussed physician decision-making in first line between daraxonrasib monotherapy and combination regimens, arguing that offering multiple options can address differing patient needs. He cited some patients’ inability or unwillingness to take chemotherapy and described the value of an oral, once-daily treatment that can be taken at home.
Schmidt also asked about two newly announced Phase III studies in first-line PDAC for zoldonrasib, including one in combination with chemotherapy and another in combination with daraxonrasib. Goldsmith said the company does not yet know whether one regimen will be superior, and expects it could take years to establish a rank order, supporting a strategy of multiple concurrent options. He described zoldonrasib as being reported by investigators and patients as “extremely well tolerated,” and said the company sees “very little” in the way of safety signals, which he believes makes it attractive to combine with more difficult regimens such as GNP or FOLFIRINOX.
On combining a mutant-selective inhibitor with a multi-inhibitor, Goldsmith said the company has observed improved efficacy in experiments pairing two RAS(ON) inhibitors—one multi-inhibitor and one mutant-selective—and suggested the combination may provide additive effects and could support a “chemo-free regimen” that pushes chemotherapy to later lines.
In colorectal cancer, Goldsmith said the company is active in patients and highlighted the complexity of the disease versus pancreatic cancer. He noted that while about 50% of colorectal cancer patients have a RAS mutation, tumors are often genetically and biochemically heterogeneous, which he believes will require combination regimens. He said the company expects to share additional data and provide more visibility into its path toward registration in colorectal cancer sometime this year.
Finally, Goldsmith briefly addressed RM-055, which he described as a new, innovative class of inhibitors with a profile “dramatically different” from other RAS inhibitors. He said additional mechanistic information is expected at an upcoming scientific meeting and that the company anticipates initiating a clinical trial with the first compound in the class by the end of this year, which would become its fifth compound in the clinic.
Goldsmith also reiterated confidence in the company’s decision to pursue a global commercialization build rather than an ex-U.S. partnership approach, saying he believes the company made the right decision and that he does not currently see what would cause a reassessment.
About Revolution Medicines (NASDAQ:RVMD)
Revolution Medicines is a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapies to treat RAS-dependent cancers and other diseases driven by the RAS/MAPK pathway. The company’s research efforts target historically “undruggable” proteins, aiming to inhibit critical nodes in cell signaling that promote tumor growth and therapeutic resistance.
The lead pipeline includes RMC-4630, a SHP2 inhibitor; RMC-6291, a selective KRAS G12C inhibitor; and RMC-6236, a pan-RAS inhibitor designed to address multiple RAS mutations.