KRAS G12C inhibitors: the competitive landscape.

KRAS G12C was the first oncogenic RAS variant made druggable. Genentech puts the mutation in roughly 14% of NSCLC cases. Two covalent inhibitors reached the US market inside eighteen months of each other, both under accelerated approval, and the interesting part of the field has since moved twice: once to next-generation covalent inhibitors, and once again to a class that inhibits RAS in its active state rather than the G12C mutant specifically.

This page is a permanent reference on that field. It states what has been approved and on what evidence, what is on the registry, and where the evidence is contested — with the analyst reading kept in clearly marked blocks so it can never be mistaken for the record.

The field, at a glance

The two approved first-generation drugs

Sotorasib (Lumakras, Amgen)

The FDA granted accelerated approval on 28 May 2021 for KRAS G12C-mutated locally advanced or metastatic NSCLC after at least one prior systemic therapy, at 960 mg once daily. The basis was CodeBreaK 100 (NCT03600883): 124 patients evaluated, objective response rate 36% (95% CI 28–45), median duration of response 10 months. The agency required a post-marketing trial to test whether a lower dose gives the same effect.

On 16 January 2025 the FDA approved sotorasib with panitumumab in KRAS G12C-mutated metastatic colorectal cancer after fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy. In CodeBreaK 300 (NCT05198934, 160 patients), median PFS was 5.6 months versus 2.0 for standard of care, hazard ratio 0.48 (95% CI 0.30–0.78), two-sided p = 0.005; ORR was 26% versus 0. The FDA states the trial was not powered for overall survival and that the final OS analysis was not statistically significant.

Adagrasib (Krazati, Mirati, now Bristol Myers Squibb)

Accelerated approval on 12 December 2022 in previously treated KRAS G12C NSCLC at 600 mg twice daily, on KRYSTAL-1 (NCT03785249): 112 patients evaluated, ORR 43% (95% CI 34–53), median duration of response 8.5 months. Accelerated approval with cetuximab in colorectal cancer on 21 June 2024, on a 94-patient KRYSTAL-1 expansion cohort: ORR 34% (95% CI 25–45), median duration of response 5.8 months, all responses partial.

Bristol Myers Squibb announced on 28 March 2024 that the confirmatory Phase 3 KRYSTAL-12 (NCT04685135, 453 patients) met its primary PFS endpoint and the key secondary ORR endpoint against chemotherapy. As of the 2026 US label, both adagrasib indications remain under accelerated approval.

Divarasib — the head-to-head

Krascendo 1 (NCT06497556) is the only registered trial in which a KRAS G12C inhibitor is compared directly with the approved ones: Phase 3, open-label, 338 patients, divarasib versus sotorasib or adagrasib in previously treated KRAS G12C NSCLC, with blinded-central-review PFS as the primary endpoint. Genentech announced on 1 July 2026 that the study met both its primary PFS endpoint and the key secondary overall survival endpoint at interim analysis, with no new safety findings. The detailed results were stated to be going to a medical meeting and to health authorities; at the review date the full dataset was not yet public, so no effect size is quoted here.

The rest of the divarasib programme is registered and running: Krascendo 2 (NCT06793215, 600 patients) tests a chemotherapy-free divarasib plus pembrolizumab combination in first line, and Krascendo 3 (NCT07541170, 400 patients) moves into resected stage II–III disease. Genentech states divarasib holds FDA Breakthrough Therapy designation from 2022 and Orphan Drug designation for KRAS G12C NSCLC from 2026.

Olomorasib — the first-line immunotherapy bet

Lilly's olomorasib is being developed primarily as a combination partner for checkpoint inhibitors rather than as a second-line monotherapy. The FDA granted it Breakthrough Therapy designation on 4 September 2025 in combination with pembrolizumab for first-line unresectable advanced or metastatic KRAS G12C NSCLC with PD-L1 expression ≥ 50%, on data from the Phase 1/2 LOXO-RAS-20001 study (NCT04956640) and the dose-optimisation portion of SUNRAY-01. Lilly describes preliminary evidence of central nervous system activity.

SUNRAY-01 (NCT06119581) is the largest trial in the entire field at 1,264 planned patients; SUNRAY-02 (NCT06890598, 700 patients) extends into resected and unresectable disease.

Fulzerasib and opnurasib — one market, one wind-down

Fulzerasib (Dupert, Innovent with GenFleet) became China's first approved KRAS G12C inhibitor when the NMPA cleared it on 21 August 2024 for advanced NSCLC after at least one prior systemic therapy. The registrational Phase 2 (NCT05005234) reported, in 116 evaluable patients at a 13 December 2023 cutoff, a confirmed ORR of 49.1% (95% CI 39.7–58.6), disease control rate 90.5% and median PFS of 9.7 months, with median duration of response and median OS not reached.

Novartis's opnurasib (JDQ443) is the counter-example. Its Phase 3 KontRASt-02 (NCT05132075) versus docetaxel is recorded as active but not recruiting, with 95 patients enrolled, and Novartis has opened NCT07468071 (KontRASt-R), a rollover study whose stated purpose is to allow continued access for participants still benefiting.

The RAS(ON) generation — a different target

Revolution Medicines' daraxonrasib inhibits RAS in its active, GTP-bound (ON) state across multiple variants rather than binding the G12C cysteine. It is the first of that class to be approved: the FDA cleared it on 26 August 2026 as RASONQUE, 300 mg once daily, for metastatic pancreatic adenocarcinoma after at least one prior systemic therapy, or for patients who are not candidates for multi-agent therapy.

The evidence is RASolute 302 (NCT06625320), 500 patients randomised 1:1 against physician's choice chemotherapy. In the overall population the FDA records median overall survival of 13.2 months versus 6.7, hazard ratio 0.40 (95% CI 0.30–0.53), p < 0.0001; median PFS 7.2 versus 3.6 months, hazard ratio 0.49 (95% CI 0.38–0.64); ORR 30% versus 11%. The application was reviewed under the Commissioner's National Priority Voucher pilot, and results were presented at the ASCO 2026 plenary with simultaneous publication in the New England Journal of Medicine.

In lung, RASolve 301 (NCT06881784, 590 patients) tests daraxonrasib against docetaxel in previously treated RAS-mutant NSCLC — a broader population than G12C. The G12C-selective RAS(ON) inhibitor elironrasib (RMC-6291) is in Phase 1/2 alone and combined with daraxonrasib (NCT06128551, 534 patients).

Every registered late-stage trial

What we could not confirm

Stated plainly rather than filled in: the Krascendo 1 effect sizes are not public at the review date, only the statement that both endpoints were met. No published Novartis notice of discontinuation for opnurasib was found. Conversion of either first-generation lung indication from accelerated to full approval was not confirmed at a primary FDA record. Those gaps stay open on this page until a primary source closes them.

Landscape last reviewed 1 September 2026. This page is a permanent reference on KRAS G12C and RAS(ON) inhibitors, maintained continuously as registries, regulatory actions and congress disclosures change; it is not a news briefing and does not claim to be exhaustive. Every fact links to the primary record behind it, and trial figures are read from the registry itself on the review date rather than from a release describing it. Enrolment figures are planned targets unless the record states otherwise. No claim of superiority or inferiority is made about any programme: the differences described are structural. Prognyx has no affiliation with any company named here and holds no position in their securities. Names and trademarks belong to their owners. Nothing here is medical or investment advice. Found an error? Write to hello@prognyx.com and it will be corrected.