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
Lorenza Rimassa@LorenzaRimassa x.com@ 📣 #AACR26 HIGHLIGHTS 📌 ¡Ya disponible el nuevo episodio de #TooMoreGi by @DrAngelaLamarca!
Same topic daraxonrasib · 68 peoplepaclitaxel#TOOMOREGI#DARAXONRASIB#MKRAS#PDAC#ASCO26#ONCOLOG#FORMACI52 views4 likes1 repost0 repliesSally Church@MaverickNY mercedes cerezo@mrcoceres The Innovation | Medicine@Innov_Medicine x.com@ This is what makes Daraxonrasib more effective in pancreatic cancer than what we seen for decades.
x.com@ M. Elisabeth@ChildrenNeedUs_ Check out this Daraxonrasib data.
M. Elisabeth@ChildrenNeedUs_ Daniele Banfi@danielebanfi83 ScienceLink@sciencelinkonco #ScienceLink #Madrid2026 #ESMO26 #RASolute302 #Daraxonrasib
Same topic daraxonrasib · 31 people#SCIENCELINK#MADRID2026#RASOLUTE302#DARAXONRASIB76 views0 likes0 reposts0 repliesMeDucation@MeDucationai BioSpace ESMO 2026: Tango trips on sinking response rates in pancreatic cancer but will move to Phase 3
Same topic daraxonrasib · 81 peopleNo engagement yetSTAT News One family’s story of a life-extending medicine for pancreatic cancer
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick Imprecise Label in the Precision Medicine Era: FDA Approval of Daraxonrasib
The FDA has approved the pan-RAS inhibitor daraxonrasib for previously treated metastatic pancreatic adenocarcinoma. The RASolute 302 trial showed a median overall survival of 13.2 months (HR 0.40), but the label's extension to patients "not suitable for multi-drug systemic therapy" has drawn controversy.
Why it matters: The article analyzes the daraxonrasib label controversy, arguing the vague wording is regulatory wisdom to cover real-world frail patients.
Same topic daraxonrasib · 68 peopleNo engagement yetNEJM Daraxonrasib in Previously Treated Metastatic Pancreatic Cancer
NEJM published a brief piece on daraxonrasib in previously treated metastatic pancreatic cancer on October 22, 2026 (Volume 395, Issue 16, pp. 1661-1662). The material provided contains only the journal citation and no specific trial results or conclusions.
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biocentury.comPick EMA’s CHMP backs RevMed’s first-in-class pancreatic cancer therapy
At its October meeting, EMA's Committee for Medicinal Products for Human Use (CHMP) recommended Rasonque (daraxonrasib), a first-in-class pan-RAS(ON) inhibitor from Revolution Medicines, for patients with metastatic pancreatic ductal adenocarcinoma who have received at least one prior line of therapy.
Why it matters: The CHMP opinion specifies the indication and prior therapy lines, enabling timeline comparison with the same drug approved by FDA via a priority review voucher.
Same topic daraxonrasib · 81 peopleNo engagement yetmp.weixin.qq.com CHMP Backs EU Approval of Revolution Medicines' Daraxonrasib for Metastatic Pancreatic Cancer
The EU's CHMP has issued a positive opinion recommending approval of Revolution Medicines' RASONQUE (daraxonrasib, RMC-6236) for metastatic pancreatic ductal adenocarcinoma. If the European Commission follows the recommendation, daraxonrasib would be approved across the EU for this indication. The opinion is dated 16 October 2026.
mp.weixin.qq.com VS-7375 posts 67% six-month progression-free survival in metastatic pancreatic cancer as daraxonrasib comparison sharpens
Verastem reported early data for its KRAS-targeted drug VS-7375 in metastatic pancreatic ductal adenocarcinoma: among 22 evaluable patients at 900 mg once daily, 16 remained on treatment at month 6, 6-month progression-free survival was 67% and overall survival 80%. Confirmed objective response rate was 41% (9/22), including 50% (4/8) in second-line patients. The numbers invite comparison with Revolution Medicines' daraxonrasib (RMC-6236), approved as RASONQUE on August 26, 2026, after FDA-disclosed data showed weak performance in a large subgroup that VS-7375's population resembles.
mp.weixin.qq.comPick Broad-Spectrum RAS Inhibitor Daraxonrasib Wins FDA Approval in Metastatic Pancreatic Cancer
The broad-spectrum RAS inhibitor daraxonrasib received FDA approval on August 26 for metastatic pancreatic cancer in adults who have received at least one prior systemic therapy or are not suitable for multi-drug combination systemic therapy. Unlike KRAS G12C inhibitors, it covers mutations including G12V, G12D, G13 and Q61, and the article also notes strong efficacy in lung cancer.
Why it matters: First approval extending RAS inhibition beyond KRAS G12C to multiple RAS mutations in pancreatic cancer.
mp.weixin.qq.comPick FDA Approves Revolution Medicines' Daraxonrasib for Metastatic Pancreatic Cancer
On August 26, 2026, the FDA approved daraxonrasib (brand name RASONQUE), developed by Revolution Medicines, for adults with metastatic pancreatic ductal adenocarcinoma who have received at least one prior systemic therapy or are unsuitable for multi-drug combination systemic therapy. It is the first FDA-approved RAS(ON) inhibitor worldwide, extending direct RAS inhibition beyond a single mutation subtype to a broader molecular population.
Why it matters: First FDA approval of a RAS(ON) inhibitor shifts direct RAS targeting to a broader patient population.
Same topic daraxonrasib · 68 peopleNo engagement yetCancer Discovery Pan-RAS Inhibitor Shows Activity in Advanced Lung Cancer
The pan-RAS inhibitor daraxonrasib shrank tumors in more than 30% of patients with previously treated RAS-mutant non-small cell lung cancer. The drug recently earned approval in pancreatic cancer, and these findings support an ongoing phase III trial in lung cancer.
Same topic daraxonrasib · 68 peopleNo engagement yetCancer Discovery ctDNA Profiling Identifies Daraxonrasib Resistance Mechanisms
Same topic daraxonrasib · 68 peopleNo engagement yetmedicalxpress.comPick ESMO: New analysis reinforces survival benefits of targeted therapy for advanced pancreatic cancer
At the ESMO Congress, UCLA researchers presented a new subgroup analysis of the phase 3 RASolute 302 trial, showing that the oral RAS inhibitor daraxonrasib (RASONQUE) extended median overall survival in advanced pancreatic cancer from 6.7 months with standard chemotherapy to 13.2 months. The benefit held across all RAS mutation subgroups, including those with no detected mutation, and across different chemotherapy comparators. The FDA approved the drug in August 2026 for metastatic pancreatic adenocarcinoma after at least one prior line of systemic therapy.
Why it matters: The ESMO-presented phase 3 RASolute 302 subgroup analysis is a large RAS-inhibitor study across mutations, showing daraxonrasib extends survival regardless of RAS mutation status or prior chemotherapy regimen.
Same topic daraxonrasib · 68 peopleNo engagement yetmp.weixin.qq.comPick Rasonque (daraxonrasib) wins FDA approval in 40 days under Commissioner's National Priority Voucher
Rasonque (daraxonrasib) received FDA approval for second-line metastatic pancreatic cancer just 40 days after formal acceptance, 203 days ahead of its PDUFA goal date. The review used the Commissioner's National Priority Voucher (CNPV), an accelerated pilot mechanism FDA launched in June 2025 that breaks the traditional review framework used for decades.
Why it matters: The source gives the timeline of the first approval under the CNPV pilot, letting readers compare it with standard priority-review PDUFA timing.
Same topic daraxonrasib · 68 peopleNo engagement yetEMA NewsPick Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 12-15 October 2026
The EMA's CHMP recommended six new medicines at its October 2026 meeting, including Rasonque (daraxonrasib) for previously treated metastatic pancreatic adenocarcinoma and Foundayo (orforglipron), a once-daily oral GLP-1 receptor agonist for weight management and type 2 diabetes in adults. It also backed Yuviwel (navepegritide) for achondroplasia in children, biosimilars of ranibizumab and filgrastim, and Kizfizo (temozolomide) for glioblastoma and malignant glioma. The committee confirmed refusal of Yartemlea (narsoplimab) after re-examination, and companies withdrew indication-extension applications for Ibrance and Truqap.
Why it matters: First EU approval recommendations for daraxonrasib and oral orforglipron plus key withdrawal and refusal decisions affecting patient access.
Same topic daraxonrasib · 81 peopleNo engagement yetEMA NewsPick EMA recommends authorisation of Rasonque for metastatic pancreatic cancer
The EMA's Committee for Medicinal Products for Human Use (CHMP) has recommended EU approval of the oral RAS inhibitor Rasonque (daraxonrasib) for adults with previously treated metastatic pancreatic adenocarcinoma. The applicant is Revolution Medicines. In a phase 3 study of 500 patients, 92% of whom had RAS G12 mutations, Rasonque gave a median overall survival of 12.4 months versus 6.7 months with chemotherapy, and median progression-free survival of 7.2 versus 3.6 months.
Why it matters: The brief gives median OS of 12.4 versus 6.7 months and PFS of 7.2 versus 3.6 months for Rasonque versus chemotherapy, letting readers judge the clinical benefit.
Same topic daraxonrasib · 81 peopleNo engagement yetNature BiotechnologyPick RevMed’s pancreatic cancer drug first
The FDA in August approved Revolution Medicines' RAS inhibitor Rasonque (daraxonrasib) for metastatic pancreatic ductal adenocarcinoma, making it the first RAS-targeting drug for this indication.
Why it matters: The article compares first-in-class pan-RAS inhibitor Rasonque with existing KRAS G12C inhibitors to clarify its place among RAS-pathway drugs.
Same topic daraxonrasib · 81 peopleNo engagement yetFDA Drugs Oncology (Cancer)/Hematologic Malignancies Approval Notifications
The FDA issued a run of oncology and hematology approvals from July 31 to October 2, 2026. They include pirtobrutinib (Jaypirca, Eli Lilly) for previously untreated CLL or SLL without 17p deletion on October 2, belzutifan plus lenvatinib for advanced clear-cell renal cell carcinoma on September 24, lirafugratinib (Lyrfigtu, Elevar) for FGFR2-rearranged cholangiocarcinoma on September 23, imlunestrant plus abemaciclib for ESR1-mutated breast cancer on September 18, and daraxonrasib (RASONQUE, Revolution Medicines) for metastatic pancreatic adenocarcinoma on August 26. Accelerated approvals in the batch cover sevabertinib for HER2-mutated NSCLC, camizestrant for ESR1-mutated breast cancer, iberdomide for multiple myeloma, and vusolimogene oderparepvec plus nivolumab for melanoma.
Same topic daraxonrasib · 68 peopleNo engagement yet