daraxonrasib

Daraxonrasib (formerly RMC-6236) is Revolution Medicines' lead RAS(ON) multi-selective inhibitor - the most clinically advanced drug designed to hit mutant RAS in its active state, rather than waiting for it to be turned off. As of late May 2026, the program has crossed a structural inflection: the pivotal RASolute 302 trial in second-line metastatic pancreatic ductal adenocarcinoma (PDAC) reported a statistically significant overall survival benefit (median OS 13.2 vs 6.7 months, HR 0.40, p<0.0001), the first targeted therapy ever to extend survival broadly in RAS-mutant PDAC [1][2]. Three additional Phase 3 trials continue across non-small cell lung cancer (NSCLC) and PDAC, and FDA has granted Orphan Drug Designation, Breakthrough Therapy Designation, and a Commissioner's National Priority Voucher (CNPV) - a 2025 pilot program providing 1-2 month review on filing [3][14]. RVMD's market cap (~$19B as of May 27, 2026) was repriced on this readout. Filing is the next catalyst; subsequent Phase 3 readouts (1L PDAC, NSCLC, adjuvant PDAC) determine whether daraxonrasib becomes a multi-billion-dollar franchise or a single-indication oncology drug.

Novel small molecule, oral 300 mg once daily; first regulatory filing imminent in second-line (2L - patients who failed one prior therapy) RAS-mutant metastatic PDAC. RASolute 302 (NCT06625320, n=500) randomized previously treated metastatic PDAC patients 1:1 to oral daraxonrasib 300 mg daily vs investigator's choice chemotherapy [1][13]. The trial hit both primary endpoints - progression-free survival (PFS - time from treatment to tumor progression) by Blinded Independent Central Review (BICR - a third-party read of scans that prevents investigator bias) and overall survival (OS - how long patients live) - in the RAS G12-mutant population. Reported median OS was 13.2 months vs 6.7 months (HR 0.40, 95% CI 0.30-0.54, p<0.0001), a 60% reduction in the risk of death [1]. RASolve 301 (NCT06881784, n=590) is recruiting patients with previously treated RAS-mutant NSCLC, with PFS per BICR in the RAS G12X-excluding-G12C population as primary endpoint [4]. RASolute 303 (NCT07491445, n=900) is recruiting first-line (1L - initial treatment) metastatic PDAC patients: daraxonrasib monotherapy and daraxonrasib + gemcitabine/nab-paclitaxel against gem/nab-paclitaxel alone [5]. RASolute 304 (NCT07252232, n=500) is the adjuvant PDAC swing in resected patients, with disease-free survival (DFS - time from surgery to recurrence) as primary endpoint [6]. The Phase 1/2 dataset published in NEJM 2026 - ORR 35% (95% CI 17-56%) in 26 evaluable 2L RAS G12 patients at 300 mg, broader ORR 47% (95% CI 31-64%) with disease control rate 92% across 38 efficacy-evaluable RAS-mutant PDAC patients, and 6-month PFS/OS rates of 71%/83% - justified the full Phase 3 build-out and is now corroborated by the registrational readout [7]. Accelerated approval pathway in 2L PDAC is now the base case.

KRAS is a molecular on/off switch sitting just inside the cell membrane. When growth signals come in, KRAS binds GTP and turns 'on' - telling the cell to grow and divide. Normally it hydrolyzes GTP back to GDP and shuts off. Mutant KRAS (G12D, G12V, G13D, Q61, and others) gets stuck 'on' [8]. About 30% of all solid tumors carry a RAS mutation; PDAC is ~90% KRAS-mutant, and most of those are G12D or G12V - not G12C, which is the only mutation sotorasib and adagrasib hit [8][9]. Daraxonrasib is a tri-complex inhibitor that grabs an intracellular chaperone protein called cyclophilin A and forces it to clamp onto active, GTP-bound RAS, sterically blocking RAS from engaging its downstream effector RAF [10]. Crucially it works against KRAS, NRAS, and HRAS in their active state, and across multiple mutations (G12D, G12V, G13D, G12X non-C) [10]. That's the whole point: one drug, most of the RAS-mutant universe. Validation is genetic - RAS mutations are causal drivers, not bystanders - and pharmacological, because G12C-selective drugs already proved that blocking mutant RAS shrinks tumors in humans. The open question of whether multi-RAS inhibition can be safely dosed at levels that suppress signaling in non-G12C tumors was first answered by the NEJM Phase 1/2 data and is now confirmed by the RASolute 302 OS readout [1][7].

Four Phase 3 trials, all sponsored by Revolution Medicines. RASolute 302 (NCT06625320, n=500) - the readout that has now occurred - tested oral daraxonrasib 300 mg daily vs investigator's choice IV chemotherapy in 2L metastatic PDAC, with co-primary endpoints PFS by BICR and OS in the RAS G12-mutant population. Reported HR for OS was 0.40 (p<0.0001), median OS 13.2 vs 6.7 months [1]. RASolve 301 (NCT06881784, n=590) tests daraxonrasib vs docetaxel in previously treated RAS-mutant NSCLC, primary endpoint PFS by BICR in the RAS G12X non-C population [4]. The carve-out matters - competitors already own G12C; Revolution is fighting for everything else. RASolute 303 (NCT07491445, n=900) is the franchise-defining trial: 1L metastatic PDAC, daraxonrasib monotherapy and daraxonrasib + gem/nab-pac vs gem/nab-pac alone, PFS primary [5]. The three-arm design is aggressive - it asks two questions (can daraxonrasib replace chemo? can it add to chemo?) and powers both. RASolute 304 (NCT07252232, n=500) takes the drug into adjuvant resected PDAC with DFS as primary [6]. Endpoints are appropriate, comparators are real standards of care, and enrollment in the three remaining trials continues. Concerns: the adjuvant trial DFS readout is years away, and the 1L PDAC three-arm design risks splitting effect size if either daraxonrasib arm underperforms.

Our model puts the chance of this drug eventually getting approved at 23%. It starts from the historical approval rate for Phase 3 drugs in this area, which is about 48%, then adjusts that number based on ten specific facts about the trial and sponsor. The estimate gets a boost from the trial's open-label design and larger-than-typical enrollment, but is pulled down by the sponsor's thin approval track record and weak earlier-phase results. The remaining factors are close to average for this stage, so they don't move the number much either way.

Efficacy: the 2L PDAC readout is clean (OS hit), but RASolute 303 in 1L PDAC carries design risk - the three-arm structure could compress effect size if either daraxonrasib arm underperforms standard-of-care chemo. The G12X-non-C NSCLC population is heterogeneous (G12D, G12V, G13D, Q61), and a single drug may not hit all variants equally hard. Safety: pan-RAS inhibition is, in principle, riskier than G12C-selective inhibition - wild-type RAS matters in normal tissues. The NEJM Phase 1/2 paper reported grade ≥3 treatment-related adverse events in ~34% of patients (rash, stomatitis/mucositis, diarrhea, nausea), 48% required dose modifications, no discontinuations [7]. A 2026 case report flagged ocular surface toxicity in a patient on an investigational KRAS G12C inhibitor; cross-class read-across is uncertain but worth tracking [15]. Resistance is mechanism-based and now mechanistically characterized - disruption of the cyclophilin A/RAS tri-complex drives bypass [12]. Execution: Revolution Medicines is well-funded - Q1 2026 ended with $1.9B cash, supplemented by a $2.1B April 2026 financing for ~$4.0B pro-forma cash, against 2026 GAAP operating expense guidance of $1.7-1.8B [16]. Runway extends through filing and well into RASolute 303 readout. Commercial: PDAC has small patient numbers (~64K US/year, fewer eligible), so pricing has to be high to support development cost. Competitive risk: MRTX1133 (Mirati/BMS, KRAS G12D-selective oral inhibitor) is the most credible direct competitor for 1L PDAC since G12D is the dominant PDAC mutation; Boehringer's BI 1701963 (SOS1::pan-KRAS inhibitor) and multiple China-based G12D-selective programs are also in early clinical development. Second movers may compress pricing or share by 2028+.

Catalyst hit. RASolute 302's OS readout (HR 0.40, median 13.2 vs 6.7 months) is the first targeted therapy ever to extend survival broadly in RAS-mutant PDAC - a category-defining result [1]. Filing is the next concrete catalyst; the National Priority Voucher promises a 1-2 month FDA review post-acceptance [14]. The investor question is no longer 'does daraxonrasib work?' but 'how big is the franchise?' That answer depends on RASolute 303 (1L PDAC) and RASolve 301 (NSCLC). Specific signals to watch: (1) ASCO/ESMO 2026 presentations of full RASolute 302 dataset including subgroups by RAS mutation and prior therapy; (2) FDA filing acceptance and PDUFA date; (3) Updated RASolute 303 enrollment timelines - completion now likely pulled forward given positive 302 read-through; (4) Any disclosed combination strategy addressing the cyclophilin A complex resistance mechanism [12]. Hazard ratio framing for non-technical readers: HR<1.0 means the drug arm progresses or dies more slowly than control; 0.40 means a 60% reduction in the risk of death - exceptionally large for PDAC. Revolution Medicines (RVMD) trades almost entirely on this molecule. ~$19B market cap as of late May 2026 [17], $4.0B pro-forma cash, no revenue, effectively single-asset - but daraxonrasib now has the readout that makes the rest of the pipeline a series of upside options rather than make-or-break bets.