Published regulatory strategy

Daraxonrasib (RASONQUE): FDA Development, Meetings and Approval - NDA 220910 - RASONQUE (daraxonrasib, RMC-6236) - Adults with metastatic pancreatic adenocarcinoma after at least one prior systemic therapy or not candidates for multiagent systemic therapy

RASONQUE (daraxonrasib, RMC-6236) · Adults with metastatic pancreatic adenocarcinoma after at least one prior systemic therapy or not candidates for multiagent systemic therapy (US label, 2026-08-26)

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Claims and evidence 28

Intended claim

Evidence gaps

Discovery and medicinal chemistry of RMC-6236Structure-guided optimization identified the noncovalent RAS(ON) multi-selective cyclophilin A recruiting tri-complex inhibitor daraxonrasib (RMC-6236). The 2025 medicinal chemistry paper documents the discovery program.Strong preclinical evidence · https://pubmed.ncbi.nlm.nih.gov/40056080/
Mechanism: cyclophilin A-dependent RAS(ON) tri-complexDaraxonrasib binds cyclophilin A (reported KD 47.6 nM); the complex binds GTP-bound KRAS, NRAS and HRAS wild-type and mutant proteins, disrupts RAF effector association, and suppresses RAS signaling. FDA discussed crystallography, biochemical binding, CypA-dependent cell activity and promoted GTP hydrolysis.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Biochemical and cellular pharmacology across RAS variantsIn cell-free RAS-BRAF interaction assays, reported IC50 values spanned 32.1-230 nM across tested RAS isoforms and variants. Cellular ERK-phosphorylation inhibition in mutant-RAS cell lines had IC50 0.417-3.55 nM. Oncogenic RAS-dependent cancer cell lines exhibited growth inhibition and apoptosis; CypA knockout attenuated activity. Values depend on assay and system.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Mutant KRAS PDAC in-vivo antitumor modelsOral daily daraxonrasib led to tumor regression in pancreatic xenografts: Capan-2 KRAS G12V showed 13% and 53% mean regression at 10 and 25 mg/kg; HPAC KRAS G12D showed 93% regression at 25 mg/kg. Tumor DUSP6 mRNA and pERK suppression supported target engagement.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Wild-type RAS PDAC translational modelsFour KRAS wild-type patient-derived PDAC xenografts were studied at 25 mg/kg once daily. Two showed tumor regression (15% and 35%) and two showed tumor-growth inhibition (67% and 29%). These models helped contextualize exploratory wild-type RAS clinical data but do not replace clinical evidence.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Immune-competent models and combination biologySyngeneic KRAS-mutant tumor models showed antitumor immune activity. In a KRAS G12D pancreatic syngeneic model, single-agent daraxonrasib reduced tumor growth and anti-PD-1 combination increased durable complete regressions from 1/10 to 4/10; preclinical, not a basis for the monotherapy label.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Nonclinical absorption, distribution, metabolism and excretionOral bioavailability 23.7-33.1% in tested animal species; high human plasma protein binding (97.7%); blood-cell partitioning relevant to assay selection; predominantly fecal excretion (~75%); M6, M7 and M4 metabolites investigated, with M6 pharmacologically active but lower potency than parent.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Four- and 13-week GLP repeat-dose toxicologyGLP repeat-dose programs in mouse and cynomolgus monkey supported the advanced-cancer indication. Dose-related hematopoietic/lymphoid, gastrointestinal and other findings were documented. Mouse 4-week study required dose reductions and terminated the highest dose group; 13-week studies informed reversibility and labeling, including bone remodeling.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Cardiovascular, CNS and respiratory safety pharmacologyA standalone GLP monkey cardiovascular study reported reversible changes in heart rate and blood pressure with QT/QTc effects; repeat-dose toxicology had no consistent cardiovascular findings at selected exposures. In vitro hERG evaluation and integrated clinical concentration-QTc analyses supported risk assessment.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Ames, in-vitro micronucleus and in-vivo micronucleus batteryIn 2024 FDA specifically required an in-vivo genotoxicity assay to complete the standard battery. The approved NDA included negative bacterial reverse mutation, human lymphocyte micronucleus and mouse in-vivo micronucleus studies; FDA concluded no genotoxicity signal.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Embryo-fetal toxicology and reproduction riskMouse embryo-fetal development study found increased post-implantation loss and malformations at >=50 mg/kg/day; supported embryo-fetal toxicity labeling. Separate carcinogenicity and fertility studies were not conducted for the advanced-cancer indication, consistent with ICH S9 approach.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Phototoxicity follow-upPositive signal in the GLP BALB/c 3T3 neutral red uptake assay prompted an in-vivo hairless-mouse phototoxicity assessment. The in-vivo GLP study was negative through 100 mg/kg/day, supporting the overall conclusion that daraxonrasib was not phototoxic.Strong preclinical evidence · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
May 2026 FDA clarification / exploratory subgroup requestAt a May 1, 2026 DO3 teleconference, FDA requested exploratory efficacy analyses separated by RAS G12D, G12V, G12R, G13, Q61, and wild-type. Sponsor stated those analyses had been submitted to IND 173046 (SN0098) on May 11, 2026 and would appear in the NDA.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000AdminCorres.pdf
RASolute 302 protocol and statistical analysis revisionsProtocol amendment 1 (2024-08-15) revised washout/cardiac eligibility; amendment 2 (2025-04-11) revised multiplicity testing and eligibility; statistical analysis plan v1 2025-04-23 was revised to v2 2025-11-17 (submitted to IND 2025-11-24); amendment 3 (2026-05-01) permitted crossover from chemotherapy after positive interim results and treatment beyond progression.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
RASolute 302 final PFS and first OS interim analysisFebruary 10, 2026 data cutoff. Both primary endpoints and key secondary endpoints met prespecified efficacy thresholds. In all patients, median OS 13.2 vs 6.7 months, HR 0.40; PFS 7.2 vs 3.6, HR 0.49. In 2026 FDA asked for a nominal OS update if feasible but acknowledged prespecified OS efficacy boundary crossed and final efficacy inference achieved.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Breakthrough Therapy clinical evidenceFor prior-treated metastatic PDAC with KRAS G12 tumors, FDA identified Phase 1/1b data (26 second-line patients, ORR 32% [95% CI 14.9-53.5], duration of response 8.2 months [95% CI 3.8 to not estimable]) in support of Breakthrough Therapy Designation. This was not the full final approval dataset.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
Initial first-in-human IND 170304FDA's unredacted administrative material documents IND 170304 as the development application containing RMC-6236-001, but the original IND submission date is redacted or absent from this approval package. Do not infer a submission date from the Phase 1 clinical start.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
CNPV Part 1 pre-submission: drug substance, nonclinical, HV PKQuality drug-substance, nonclinical, selected Module 1, healthy-volunteer PK studies and clinical-site list submitted for pre-review.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000RiskR.pdf
CNPV Part 2 pre-submission: drug product, BIMO and labelingDrug-product quality, 150 mg biowaiver, BIMO components and draft proposed labeling submitted.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000RiskR.pdf
CNPV Part 3 pre-submission: Phase 3 and Phase 1 clinical dataRASolute 302 and RMC-6236-001 clinical datasets, pre-NDA clinical-pharmacology responses and summary biopharmaceutics information submitted.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000RiskR.pdf
FDA clinical/statistical efficacy assessmentFDA accepted OS benefit in the all-patient ITT analysis (HR 0.40; 13.2 vs 6.7 months). Noted 45 randomized patients never dosed (7 vs 38) and pronounced withdrawal of consent in control before first dose. The FDA flagged differential new-therapy censoring in PFS and discordance of BICR versus investigator assessments in the very small RAS wild-type subset (only 16 patients). Full broad indication rested on randomized OS in the overall population, totality of subgroup/biologic evidence, and unmet need.Strong overall efficacy, uncertain wild-type subgroup · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
FDA OSI/BIMO clinical inspections and data-verification conclusionOSI clinical inspection summary signed July 23, 2026. FDA inspected three RASolute 302 investigators (Andrew Hendifar, Zev Wainberg, Eileen O'Reilly), sponsor Revolution Medicines, and imaging contract research organization. At Dr. Wainberg's site, four unreported adverse events in one participant and 11 unreported concomitant medications in four participants were identified; safety review was advised. Overall data were considered verifiable for NDA support.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000OtherR.pdf
RASONQUE proprietary name reviewFDA conditionally accepted the proprietary name on December 9, 2025 and completed a reassessment July 10, 2026. DMEPA, the promotional review office and the oncology division maintained that Rasonque was acceptable from a look-alike/sound-alike name-confusion perspective.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000NameR.pdf
Medication Guide and carton/container labeling reviewDMEPA's August 3 review identified dosage presentation, net quantity, barcode and other potential medication-error issues. The applicant provided revised labels in August and FDA found revised carton/container labels acceptable on August 20. On August 13, the division requested conversion from Patient Package Insert to Medication Guide; OPDP and patient-labeling reviewers reviewed revisions by August 19.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000OtherR.pdf
FDA clinical pharmacology dose and interaction assessmentFDA accepted 300 mg orally once daily with/without food. Clinical DDI evidence and PBPK models underpinned instructions for CYP3A inhibitors and inducers, P-gp inhibitors/substrates and cyclosporine. Mild/moderate hepatic impairment and mild/moderate renal impairment required no adjustments; the effects of severe hepatic impairment were unresolved and a postmarketing clinical PK trial was required. 150 mg marketed strength bridging was evaluated separately by OPQ.https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
FDA safety analysis / Warnings and PrecautionsIn RASolute 302, dermatitis and soft-tissue, oral and GI adverse effects were prominent. FDA labeling specifically addresses dermatologic/soft tissue toxicity, stomatitis/oral disorders, diarrhea, GI perforation, ILD/pneumonitis and embryo-fetal toxicity. Protocol and final label recommend proactive dermatologic prophylaxis, including skin emollients, topical corticosteroids, sun avoidance and consideration of oral tetracyclines.Randomized safety database and integrated exposure · https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000Lbl.pdf
Source provenance and reconstruction limitsPrimary evidence: 2026 FDA approval letter, complete multidisciplinary review, pre-NDA/2024 EOP administrative correspondence, product quality, labeling, REMS, naming, OSI and medication-error reviews; additional FDA approval announcement, ClinicalTrials.gov and primary preclinical publications. Exact historical experimental conduct dates are not imputed; 2025 Type C full questions/responses were not present. FDA-initiated May 2026 comments 8-15 are recorded separately from seven sponsor-initiated questions.Primary-source verified · https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daraxonrasib-metastatic-pancreatic-adenocarcinoma

Studies and FDA questions 14

Studies and endpoints

RMC-6236-001: first-in-human dose escalation / expansionNCT05379985; first dosed May 2022. Multicenter open-label Phase 1/1b program exploring escalating daily oral doses 10 to 400 mg, PK, tolerability, food/formulation and tumor activity in RAS-mutated advanced solid tumors, including PDAC. At July 21, 2025 data cutoff, 534 enrolled; 300 mg selected for the pivotal program. Exploratory PDAC activity supported Breakthrough Therapy Designation.Phase 1/1b · Ongoing at NDA review
RASolute 302: randomized pivotal Phase 3 trialNCT06625320. Global open-label randomized (1:1) comparison of daraxonrasib 300 mg daily versus investigator-selected mFOLFIRINOX, FOLFOX, gemcitabine+nab-paclitaxel, or nanoliposomal irinotecan+5-FU/leucovorin after one prior line. 500 patients (248/252), including 459 with RAS G12. February 10, 2026 cutoff was final PFS and first OS interim analysis; achieved primary and key secondary endpoints. 92% had KRAS G12 alterations, with very small non-G12 and wild-type subgroups. Protocol version 4 (May 1, 2026) subsequently enabled crossover.Phase 3 · Ongoing follow-up; registrational interim analysis positive
RMC-6236-507: Relative bioavailability and food effectRandomized four-period crossover in healthy adults; 200 mg single-dose comparison of non-BHT and commercial BHT tablet, fasted/low-fat/high-fat food conditions; bioavailability and food effectPhase 1 · Completed for NDA
RMC-6236-502: Radiolabeled mass balance / ADMESingle-dose 14C-daraxonrasib 220 mg solution in healthy males; mass balance, recovery of parent/metabolites, elimination pathways; FDA queried formulation discrepancy and extrapolation to marketed dosePhase 1 · Completed for NDA
RMC-6236-506: Hepatic impairment pharmacokinetics40 mg tablet study comparing 12 participants with mild/moderate hepatic impairment and six healthy controls; limited severe impairment information, contributing to PMR 5049-2Phase 1 · Completed for NDA
RMC-6236-501: Acid-reducing agent interactionFixed-sequence crossover 220 mg tablet alone versus esomeprazole exposure to assess acid-reducing agent effectPhase 1 · Completed for NDA
RMC-6236-503: Effects on CYP3A and transporter probesFixed-sequence DDI study of 200 mg daraxonrasib on CYP3A and transporter probe substrates including midazolam, dabigatran, rosuvastatin and pravastatin; FDA assessed timing and potential underestimation at 300 mgPhase 1 · Completed for NDA
RMC-6236-504: Strong CYP3A inhibitor interaction40 mg daraxonrasib with/without itraconazole; approximate five-fold AUC elevation prompted risk mitigation and interaction dose restrictions in the final labelPhase 1 · Completed for NDA
RMC-6236-505: Inducer and P-gp inhibitor interactionTwo-part fixed-sequence DDI study, phenytoin induction at 200 mg daraxonrasib and quinidine P-gp inhibition at 40 mg; informed dose adjustments for CYP3A inducers and P-gp inhibitorsPhase 1 · Completed for NDA
PMR 5049-1: pediatric relapsed/refractory solid tumorsPediatric Research Equity Act deferred study in children age >=1 to <17 years: assess daraxonrasib dosing, PK, safety and preliminary antitumor activity in relapsed/refractory solid tumors. FDA waived study below age 1. Draft protocol June 2027; final September 2027; study completion January 2032; final report August 2032.Postmarketing · Required; pending at 2026-08-26
PMR 5049-2: severe hepatic impairment pharmacokineticsFDA 505(o)(3) required clinical trial to characterize serious potential increased toxicity, PK and appropriate daraxonrasib dosing in severe hepatic impairment, addressing a preapproval study gap. Final protocol due October 2026, completion March 2027 and final report September 2027.Postmarketing · Required; pending at 2026-08-26

FDA meetings

FDA Type B end-of-phase written responsesIND 170304. FDA issued written responses to ten sponsor questions on 300 mg selection, Phase 3 design, patient diversity, clinical pharmacology, QTc, food effect, DDI, metabolites, genotoxicity and proposed NDA content. FDA did not object to 300 mg but urged overall survival as the sole pivotal primary objective, emphasized mutation subgroup evidence and recommended an in-vivo genotoxicity assay.TYPE_B_EOP · 10 FDA questions
FDA Type C NDA content and format (written responses)IND 173046 Type C interaction requested March 3, 2025 with written FDA responses issued May 15, 2025. Public FDA multidisciplinary review summarizes agreement that format/content of clinical and clinical pharmacology/nonclinical packages appeared reasonable and that a companion diagnostic would not be needed if all-comer benefit was demonstrated. The underlying sponsor questions and verbatim answers are not included in the supplied administrative correspondence; no text is reconstructed.TYPE_C · Meeting scope is captured in this strategy.
FDA Type B pre-NDA meetingIND 173046. The FDA agreed topline randomized results were sufficient for submission seeking full approval, but considered the broad all-comer indication a review issue. Whether a companion diagnostic was needed depended on the final biomarker-restricted versus all-comer label. FDA agreed a safety update was not presently necessary, deemed NDA content generally adequate, and warned of compressed CNPV review logistics. Eight further groups of FDA comments (numbered 8-15) included detailed PFS censoring sensitivity analyses, dermatologic toxicity and pharmacology/DDI deficiencies.TYPE_B · 7 FDA questions

Risks and fallback paths 4

Risks

Very small RAS wild-type subgroupRAS wild-type tumors accounted for 16 randomized patients (~3%). BICR PFS hazard ratio 1.92 (95% CI 0.39-9.52) differed from investigator PFS HR 0.62 and OS HR 0.43 (both very imprecise). FDA discussed these uncertainties but concluded benefit-risk favored a broad indication.High · High · Accepted / managed at approval
PFS censoring and control-arm attritionFDA requested analyses addressing imbalance in new anticancer therapy before progression/death (8.1% vs 23.8%) and the large fraction of control-arm patients never dosed (38/252 vs 7/248). OS was the more direct, persuasive measure for benefit-risk.Medium · High · Accepted / managed at approval
Severe hepatic impairment exposure riskThe preapproval PK study did not characterize severe hepatic impairment adequately. FDA specifically required PMR 5049-2 to define dosing and serious potential increased drug toxicity in severe hepatic impairment.Medium · High · Accepted / managed at approval
On-target dermatologic, oral and gastrointestinal toxicityRash, stomatitis and diarrhea were common; other major labeled risks were GI perforation, ILD/pneumonitis and embryo-fetal toxicity. Risk was managed by supportive care, dose modification, Medication Guide and routine pharmacovigilance without a REMS.Medium · High · Accepted / managed at approval

Fallbacks

Sources and related research

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000Approv.pdf
https://pubmed.ncbi.nlm.nih.gov/40056080/
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000MultidisciplineR.pdf
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000AdminCorres.pdf
https://www.fda.gov/news-events/press-announcements/fda-permits-expanded-access-investigational-pancreatic-cancer-drug
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000RiskR.pdf
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000ChemR.pdf
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220910Orig1s000OtherR.pdf

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