LY3537982

Overview

LY3537982 (olomorasib) is an investigational, oral, second‑generation covalent inhibitor of KRAS G12C being developed for KRAS G12C‑mutant solid tumors. A global phase 3 first‑line NSCLC program (SUNRAY‑01; NCT06119581) is ongoing, and on September 4, 2025, the FDA granted Breakthrough Therapy designation to olomorasib plus pembrolizumab for first‑line KRAS G12C‑mutant NSCLC with PD‑L1 ≥50%. (ascopubs.org)

Mechanism of action

• Target: mutant KRAS G12C.
• Modality: oral covalent inhibitor that binds the inactive GDP‑bound form of KRAS G12C, locking it in the off state and suppressing downstream signaling. Preclinical work reported high potency and >90% sustained target occupancy; kinetic efficiency (kinact/Ki) exceeded first‑generation inhibitors in head‑to‑head assays. (aacrjournals.org)

Efficacy

Evidence to date comes from phase 1/2 LOXO‑RAS‑20001 and conference abstracts across tumor types.

• NSCLC, olomorasib + pembrolizumab (phase 1/2, data cutoff Oct 30, 2023):
• In KRAS G12C inhibitor–naïve patients across lines (n=30 evaluable), ORR 63% and disease control rate (DCR) 93%; median PFS not estimable at ~6 months’ follow‑up.

• In the first‑line subset (n=9), ORR 78% and DCR 100%. Responses observed across PD‑L1 strata. These data supported initiation of the SUNRAY‑01 phase 3 study. (ascopubs.org)

• NSCLC, olomorasib monotherapy (phase 1/2, data cutoff Oct 30, 2023):

• Pan‑tumor update reported ongoing single‑agent activity across multiple cohorts; study design and population details provided in the ASCO abstract (ORR by histology reported in session). (ascopubs.org)

• Gastrointestinal tumors (phase 1; ASCO GI 2024, data cutoff July 24, 2023):

• Monotherapy ORR/DCR by cohort (evaluable): CRC 13%/84% (n=32); pancreatic 33%/92% (n=24); biliary tract 50%/80% (n=10); other GI 50%/100% (n=6).

• Colorectal cancer combination: olomorasib + cetuximab ORR 42% and DCR 95% (n=38 evaluable). (ascopubs.org)

• Program status: The pivotal first‑line NSCLC trial SUNRAY‑01 is enrolling globally; design and endpoints are detailed in the ASCO Trial‑in‑Progress abstract. (ascopubs.org)

Safety

• Monotherapy (phase 1): Treatment‑emergent adverse events (TEAEs) ≥10% included diarrhea (38%), constipation (16%), fatigue (16%), peripheral edema (13%), and nausea (11%), predominantly grade 1; one grade ≥3 treatment‑related neutropenia; no pneumonitis and no grade ≥2 transaminitis in the initial report. (aacrjournals.org)

• Combination with pembrolizumab (phase 1/2): At 50–100 mg BID olomorasib, common treatment‑related AEs (either drug‑related) were diarrhea (30%), ALT increase (20%), AST increase (18%), fatigue (14%), nausea (14%), pruritus (11%); grade 3 diarrhea occurred in 16%; pneumonitis in three patients (grades 2–4). Two of six patients at 150 mg BID had grade ≥3 LFT elevations, and that dose was not pursued. Discontinuations due to TRAEs occurred in 9% for either agent and 9% for both. (ascopubs.org)

• Combination with cetuximab in CRC (phase 1): Class‑typical dermatologic and electrolyte AEs (e.g., dermatitis acneiform 59%, dry skin 44%, hypomagnesemia 33%); one DLT (ALT/AST increase) at 100 mg BID; most events grade 1–2. (ascopubs.org)

Ongoing and planned trials

• LOXO‑RAS‑20001 (NCT04956640): Phase 1/2 dose‑escalation/expansion of olomorasib as monotherapy and in combinations (including pembrolizumab and cetuximab) across KRAS G12C‑mutant solid tumors. (ascopubs.org)
• SUNRAY‑01 (NCT06119581): Global pivotal, randomized, first‑line NSCLC trial of olomorasib + pembrolizumab with or without chemotherapy versus matched placebo regimens; primary endpoint PFS by BICR. (ascopubs.org)

Further reading

• Pan‑tumor phase 1/2 update of olomorasib monotherapy (ASCO 2024 abstract 3007). (ascopubs.org)
• Olomorasib + pembrolizumab in KRAS G12C‑mutant NSCLC (ASCO 2024 abstract 195). (ascopubs.org)
• GI tumor cohort results and CRC + cetuximab combination (ASCO GI 2024 abstract 94). (ascopubs.org)
• First‑in‑human and preclinical characterization of LY3537982 (AACR 2021/2023 abstracts). (aacrjournals.org)
• SUNRAY‑01 phase 3 trial design (ASCO Trial‑in‑Progress). (ascopubs.org)
• FDA Breakthrough Therapy designation announcement for first‑line NSCLC combination (Sept 4, 2025). (investor.lilly.com)

Notes: Efficacy figures above reflect investigator‑assessed responses at the stated data cutoffs from conference abstracts and may include unconfirmed responses pending confirmation at the time of reporting. Larger, randomized data from SUNRAY‑01 are awaited. (ascopubs.org)

Last updated: Oct 2025