LBA82
Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): Additional subgroup analyses from the ph3 RASolute 302 study
https://esmocongress.esmo.org
ESMO Congress 2026
October 23–27, 2026 · Madrid · 2949 items
daraxonrasib
★★★Late-breaking31 people · 34 posts · 1 abstract
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Deep dive
Daraxonrasib (RMC-6236) is an oral, non-covalent RAS(ON) multi-selective tri-complex inhibitor that blocks downstream signaling by forming a tri-complex with the intracellular chaperone CypA and the active, GTP-bound RAS [1]. Its evidence base is anchored by the published phase 3 RASolute 302 trial: 500 patients with previously treated mPDAC were randomized, 91.8% harboring RAS G12 mutations, with OS and PFS in the G12 population as dual primary endpoints [2]; the earlier phase 1-2 study in 168 previously treated RAS-mutated PDAC patients established 300 mg as the phase 3 dose, with treatment-related adverse events of any grade in 96% and grade 3 or higher in 30% [6]. On resistance, paired-sample analysis identified recurrent acquired alterations such as RAS Y64, Y71 and kinase-dead/hypoactive BRAF in 18 of 40 patients [5].
At ESMO26 (October 23), Zev Wainberg presented subgroup analyses of RASolute 302: OS 13.2 vs 6.7 months (HR 0.40), with OS HRs of 0.49, 0.32 and 0.61 for G12D, G12V and G12R respectively, PFS HR 0.55 by BICR, and ORR 32% vs 11%; the OS benefit extended to patients with no identified tumor RAS mutation, and commentators acknowledged consistent benefit across subgroups while cautioning about statistical power in small subgroups. A parallel storyline was the Tango Therapeutics combination: daraxonrasib plus vopimetostat showed a confirmed ORR of 81.8% (18/22) in advanced pancreatic cancer — 85.7% (6/7) in 2L and 84.6% (11/13) in 3L — with 100% disease control and 9-month PFS estimated at 88.4%, using a lower daraxonrasib dose; the on-site zoldonrasib plus vopimetostat data showed a confirmed ORR of 54.2% (19/35), including one CR.
Two steps forward versus existing knowledge. First, while the NEJM primary paper established phase 3 evidence on dual primary endpoints in the G12 population [2], the subgroup analyses refine the benefit down to each genotype and even to patients without identified mutations, echoing the trial design in which the overall population included patients with no RAS mutation identified [2], though small samples warrant caution. Second, the Tango combination follows the preclinical logic that combined blockade of downstream, upstream and orthogonal pathways can prevent RAS inhibitor resistance and yield durable regressions [4], consistent with evidence that RAS(ON) multi-selective inhibition reshapes the tumor immune microenvironment and creates room for combinations [3]. Against the FDA exploratory monotherapy ORRs of 50% in G12V, 24% in G12D and 7% in G12R, the 81.8% is striking, but attribution is debated: the daraxonrasib cohort was predominantly G12V/G12R with no G12D, vopimetostat raised exposure approximately 1.5–2.4-fold, and the all-treated recalculation of 62.1% (18/29) is not a formal ITT/mITT figure.
The limitations are equally clear: subgroups are small with limited statistical power; the 81.8% pools two dose levels while the proposed phase 3 regimen uses the lower dose, whose confirmed ORR and durability are undisclosed; the 7 PDAC patients excluded by the 14-week evaluability rule have no reported follow-up update; at the proposed phase 3 dose there was no grade 3 rash but grade 3 treatment-related adverse events reached 40%, leaving open whether toxicity is genuinely reduced or redistributed. Outside the hall, a Spanish post claimed the EU has already approved daraxonrasib and urged faster national access, underscoring access and reimbursement tensions beyond the data.
References
- 1.Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers · J Med Chem 2025
- 2.Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer · N Engl J Med 2026
- 3.T-cell Dependency of Tumor Regressions and Complete Responses with RAS(ON) Multi-selective Inhibition in Preclinical Models of Pancreatic Ductal Adenocarcinoma · Cancer Discov 2025
- 4.A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance · Proc Natl Acad Sci U S A 2025
- 5.Disrupted molecular glue complex drives RAS inhibitor resistance · Cell 2026
- 6.Daraxonrasib in Previously Treated Advanced <i>RAS</i>-Mutated Pancreatic Cancer · N Engl J Med 2026
Evidence
Floor
Nature Can pancreatic cancer be stopped in its tracks? Radical tactic raises hopes
The FDA's August approval of the pancreatic cancer drug daraxonrasib (Rasonque) has drawn attention to cancer interception, treating precancerous lesions before they turn malignant, in pancreatic cancer. At the AACR meeting, Simeone said combining early detection with interception could raise five-year survival from 13.7% to 50%; her PRECEDE study has enrolled 12,000 people, with more than 50 diagnosed pancreatic cancers, mostly early-stage.
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick FDA Approves Daraxonrasib as First Oral RAS-Targeted Drug for Pancreatic Cancer
The FDA approved Rasonque (daraxonrasib) on August 26, 2026 for metastatic pancreatic adenocarcinoma in patients previously treated with at least one systemic therapy. It is the first direct RAS-targeted oral drug approved in pancreatic cancer, a disease where more than 90% of patients carry KRAS mutations. The approval comes 44 years after RAS was identified as the first human oncogene in 1982.
Why it matters: First direct RAS-targeted oral approval in pancreatic cancer, an indication with heavy unmet need.
Same topic daraxonrasib · 68 peopleNo engagement yetBMJ Daraxonrasib: How soon could the new drug for pancreatic cancer be available in the UK?
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick Tam-Peli Extends Survival in Recurrent SCLC; Daraxonrasib Active in RAS-Mutant NSCLC
At the World Conference on Lung Cancer in Seoul, the B7-H3 antibody-drug conjugate Tam-Peli prolonged survival in recurrent small cell lung cancer, with median overall survival of 13.3 months versus 9.4 months (HR 0.46, P<0.001), results published simultaneously in NEJM. The RAS(ON) inhibitor daraxonrasib also showed activity in RAS-mutant non-small cell lung cancer.
Why it matters: Reports survival benefit and new drug activity data from WCLC with simultaneous NEJM publication.
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick FDA Approves Revolution Medicines' Daraxonrasib for Metastatic Pancreatic Cancer
On August 26, 2026, the FDA approved Revolution Medicines' Rasonque (daraxonrasib, formerly RMC-6236) for adults with metastatic pancreatic adenocarcinoma who have received at least one prior line of systemic therapy. It is the first FDA-approved targeted therapy aimed at the active-state RAS(ON) protein family. The RAS(ON) molecular glue approval marks one of the biggest clinical advances in pancreatic cancer in nearly a decade.
Why it matters: First FDA approval of a RAS(ON)-targeted therapy sets a new mechanism class in pancreatic cancer.
Same topic daraxonrasib · 68 peopleNo engagement yetstatnews.com STAT+: We’re reading about an Ultragenyx failure, RevMed for lung cancer, and more
Ultragenyx's gene therapy GTX-102 for Angelman syndrome failed to show benefit versus sham control in a Phase 3 trial, and the company announced plans for "significant expense reductions." Revolution Medicines' daraxonrasib (Rasonque) shrank tumors in more than 30% of patients in a small trial in previously treated NSCLC with RAS mutations; a larger randomized study is underway.
mp.weixin.qq.comPick FDA Approves Revolution's RAS(ON) Inhibitor Daraxonrasib for Metastatic Pancreatic Cancer
The FDA approved Revolution's RASONQUE (daraxonrasib), a once-daily oral tablet, for adults with metastatic pancreatic ductal adenocarcinoma who have received at least one prior systemic therapy or are not candidates for multi-drug combination systemic therapy. The approval on 26 August 2026 came about 6.5 months ahead of the original FDA target date. Daraxonrasib is the first approved RAS(ON) multi-selective inhibitor and the first RAS-targeted drug for metastatic PDAC that broadly inhibits multiple RAS mutations.
Why it matters: First RAS(ON) inhibitor approval covers a metastatic pancreatic cancer population with unmet need, ahead of schedule.
Same topic daraxonrasib · 68 peopleNo engagement yetN Engl J MedPick Daraxonrasib for Previously Treated RAS-Mutant Non-Small-Cell Lung Cancer.
Daraxonrasib (RMC-6236), an oral RAS(ON) multiselective inhibitor, showed antitumor activity in 136 previously treated patients with advanced RAS-mutant NSCLC: objective response occurred in 31% at doses of 120 mg or less, 34% at 160 to 220 mg, and 37% at 300 mg once daily. Adverse events of grade 3 or higher occurred in 54%, including four grade 5 events, with rash, diarrhea, nausea, vomiting, and mucositis or stomatitis each affecting at least 30% of patients.
Why it matters: First safety and efficacy data for a pan-RAS inhibitor across multiple doses in previously treated RAS-mutant NSCLC.
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick FDA Approves Revolution Medicines' RASONQUE (daraxonrasib) for Metastatic Pancreatic Cancer
The FDA approved Revolution Medicines' RASONQUE (daraxonrasib) on August 26 for metastatic pancreatic cancer. It is the first approved drug worldwide to directly target RAS. The approval marks a first for the RAS-targeting class in pancreatic cancer.
Why it matters: First globally approved direct RAS-targeting drug, relevant to oncology drug development readers.
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick FDA Grants Early Approval to Daraxonrasib, World's First RAS(ON) Inhibitor, for Pancreatic Cancer
The FDA has granted early approval to Daraxonrasib, the first RAS(ON) inhibitor cleared anywhere in the world, for pancreatic cancer. The decision gives patients with KRAS-mutation-driven pancreatic cancer, a disease with a 5-year relative survival rate of just 3%, a targeted therapy option after years when no targeted drug was available. The approval moves pancreatic cancer treatment from a chemotherapy-dominated approach toward precision targeting.
Why it matters: First global approval of a RAS(ON) inhibitor for pancreatic cancer ends the lack of targeted options in KRAS-driven disease.
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick FDA Approves Revolution Medicines' Pan-RAS Inhibitor Rasonque for Metastatic Pancreatic Cancer
The US FDA has approved Revolution Medicines' oral pan-RAS inhibitor Rasonque (daraxonrasib) for adults with metastatic pancreatic adenocarcinoma who have received at least one prior systemic therapy or are not suited to multi-drug combination systemic therapy. The approval follows overall survival benefit shown in a phase 3 trial. Rasonque works through a molecular-glue ternary complex strategy targeting RAS, a target once considered undruggable.
Why it matters: First approval of a pan-RAS inhibitor for previously treated metastatic pancreatic cancer, a hard-to-treat indication.
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick FDA Approves Revolution Medicines' Daraxonrasib for Metastatic Pancreatic Cancer Ahead of Schedule
The FDA approved Revolution Medicines' daraxonrasib (RMC-6236, brand name Rasonque) on August 26 for patients with metastatic pancreatic cancer who have received at least one prior systemic therapy or are not suited to multiple systemic therapies. The oral RAS(ON) multi-selective non-covalent inhibitor blocks interactions between wild-type and mutant RAS(ON) proteins and downstream effectors, and the FDA said the approval came 6.5 months ahead of schedule.
Why it matters: First RAS(ON) inhibitor approval worldwide, granted early for a hard-to-treat cancer.
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick FDA Approves Daraxonrasib, First RAS(ON) Inhibitor, for Pretreated Metastatic Pancreatic Cancer
The US FDA has approved Revolution Medicines' pan-RAS inhibitor daraxonrasib, brand name Rasonque, for previously treated metastatic pancreatic cancer (PDAC). The drug, the company's lead pipeline asset and the first RAS(ON) inhibitor approved worldwide, is active against G12, G13, Q61 and wild-type RAS. Late-stage trials are already underway in first-line, second-line and adjuvant pancreatic cancer settings.
Why it matters: First global approval of a RAS(ON) inhibitor class covers a hard-to-treat pancreatic cancer population.
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick FDA Grants Early Approval to Revolution Medicines' RAS(ON) Inhibitor Daraxonrasib for Pancreatic Cancer
The FDA approved Revolution Medicines' Rasonque (daraxonrasib), the first RAS(ON) inhibitor to reach the market, on August 26, months ahead of expectation. The once-daily tablet targets multiple forms of RAS protein, a key driver of tumor growth in most pancreatic cancer patients, and offers a new treatment option for the most common form of advanced pancreatic cancer, which arises from cells lining the pancreatic ducts.
Why it matters: First-ever RAS(ON) inhibitor approval, ahead of schedule, for a common pancreatic cancer setting.
Same topic daraxonrasib · 68 peopleNo engagement yetnature.comPick RevMed’s RAS inhibitor gains landmark FDA approval for pancreatic cancer
The US FDA has approved Revolution Medicines' daraxonrasib (Rasonque) for pancreatic adenocarcinoma patients who have received at least one prior systemic therapy or are not eligible for multiagent systemic therapy. It is the first broadly active RAS-targeted inhibitor to reach market, unlike the KRAS G12C-specific inhibitors sotorasib (Lumakras) and adagrasib (Krazati), which are approved only in NSCLC and colorectal cancer subsets.
Why it matters: First approval of a broadly active RAS inhibitor, in a hard-to-treat pancreatic cancer setting.
Same topic daraxonrasib · 68 peopleNo engagement yetbiocentury.comPick RevMed’s first-in-class pancreatic therapy among fastest CNPV approvals
FDA approved Revolution Medicines' daraxonrasib (Rasonque) for pancreatic ductal adenocarcinoma, making it the first targeted therapy in the new RAS(ON) inhibitor class and the first new cancer drug cleared under the commissioner's national priority review voucher initiative. Revolution Medicines (NASDAQ:RVMD) is launching the drug immediately at a WAC of $39,800 for a 30-day supply.
Why it matters: First approval in a new drug class and first under FDA's new priority voucher programme, priced at launch.
Same topic daraxonrasib · 68 peopleNo engagement yetstatnews.comPick STAT+: FDA approves new pancreatic cancer drug expected to usher in new era of treatment
The FDA has approved Revolution Medicines' Rasonque (daraxonrasib) as a second-line treatment for advanced pancreatic cancer, the first drug to target a genetic cause of this cancer. In the pivotal trial supporting approval, the Rasonque arm achieved a median overall survival of 13.2 months versus 6.7 months with standard chemotherapy. Andrew Ko, a gastrointestinal oncology specialist at UCSF, called it the biggest advance in pancreatic cancer treatment in decades.
Why it matters: The brief gives second-line median overall survival of 13.2 versus 6.7 months, letting readers judge the gain over standard chemotherapy.
Same topic daraxonrasib · 68 peopleNo engagement yetFiercePharmaPick FDA greenlights Revolution Medicines' pancreatic cancer gamechanger
The FDA has approved Revolution Medicines' Ras inhibitor daraxonrasib for metastatic pancreatic cancer. The decision follows data presented at the American Society of Clinical Oncology meeting in May. Daraxonrasib targets Ras in a disease setting with limited options.
Why it matters: FDA approval of a new Ras inhibitor for metastatic pancreatic cancer matters to clinicians and industry readers.
Same topic daraxonrasib · 68 peopleNo engagement yetfiercebiotech.comPick FDA greenlights Revolution Medicines' pancreatic cancer gamechanger
FDA has approved Revolution Medicines' Ras inhibitor daraxonrasib for metastatic pancreatic cancer. The approval is based on clinical data that drew a standing ovation at the American Society of Clinical Oncology (ASCO) annual meeting in May.
Why it matters: FDA approval based on standing-ovation data at ASCO in May provides regulatory backing for Ras inhibitors in pancreatic cancer.
Same topic daraxonrasib · 68 peopleNo engagement yetBioCenturyPick Merck turns to China-based SciBrunch for KRAS program, pays $400M up front: Deals Report
Merck & Co. has licensed global rights to SPR2015, a preclinical KRAS G12D molecular glue inhibitor from China-based SciBrunch, paying $400 million up front. The deal follows reported failed M&A negotiations with Revolution Medicines in the $30 billion range, after that company reported in April that daraxonrasib led to a survival benefit in pancreatic cancer patients. Further deal terms for the SciBrunch agreement were not disclosed.
Why it matters: Large upfront licensing payment by Merck for a preclinical KRAS G12D program after failed Revolution Medicines talks.
STAT News Opinion: STAT+: The NIH budget should be $100 billion per year
Reed Jobs argues in a STAT+ opinion piece that the U.S. NIH annual budget should be raised to $100 billion, strengthening rather than weakening investment in research. He cites daraxonrasib, a KRAS-targeting drug from Revolution Medicines, which the FDA approved in late August for previously treated KRAS-mutant pancreatic cancer and which nearly doubled survival rates in a clinical trial.
Same topic daraxonrasib · 68 peopleNo engagement yetbiocentury.com Six first-in-class approvals in August
FDA approved six first-in-class drugs in August. Among them, Revolution Medicines' RAS(ON) inhibitor Rasonque daraxonrasib was approved just 40 days after submission under the Commissioner's National Priority Review Voucher (CNPV) program.
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick FDA Approves Revolution Medicines' RAS Inhibitor Rasonque for Metastatic Pancreatic Cancer
The FDA approved Revolution Medicines' first-in-class RAS inhibitor Rasonque (daraxonrasib) on August 26 for adults with metastatic pancreatic ductal adenocarcinoma who have received at least one prior systemic therapy or are not suited for multi-drug systemic treatment. It is the first RAS-targeted therapy for the most common type of pancreatic cancer. The drug was reviewed under the FDA commissioner's national priority voucher pilot programme, and approval came one month after the application was accepted, 6.5 months ahead of the PDUFA goal date.
Why it matters: First RAS-targeted therapy approved for metastatic pancreatic ductal adenocarcinoma, reviewed 6.5 months early.
Same topic daraxonrasib · 68 peopleNo engagement yetFDA Press ReleasesPick FDA Approves First in Class Targeted Therapy for Metastatic Pancreatic Cancer
The FDA approved Revolution Medicines' Rasonque (daraxonrasib), a once-daily RAS inhibitor, for adults with metastatic pancreatic adenocarcinoma who have had at least one prior systemic therapy or are not candidates for multiagent systemic therapy. In a 500-patient randomized trial, Rasonque improved median overall survival to 13.2 months versus 6.7 months on standard chemotherapy. The approval came 6.5 months ahead of the user fee deadline, under Breakthrough Therapy, Orphan Drug and Priority Review designations and the National Priority Voucher pilot program.
Why it matters: First-in-class RAS inhibitor approval gives a survival benefit in metastatic pancreatic adenocarcinoma, a high-mortality cancer with few options.
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