LY3537982

Shows activity

Also known as:

Olomorasib

Cancer types include:

colon cancer non-small cell lung cancer ovarian cancer pancreas cancer rectal cancer

TrialFetch AI Analysis

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Overview

Olomorasib (LY3537982) is an oral, investigational, next-generation KRAS G12C inhibitor being studied in KRAS G12C-mutant solid tumors. Clinical development includes monotherapy and combinations with pembrolizumab, cetuximab and chemotherapy. The recommended phase 2 monotherapy dose is 150 mg twice daily; 100 mg twice daily has generally been selected for combination regimens. Evidence remains preliminary because the available studies are predominantly early-phase, single-arm trials. (nature.com)

Mechanism of action

Olomorasib is a potent, selective covalent inhibitor that binds mutant KRAS G12C in its inactive, GDP-bound state. This traps KRAS in an inactive configuration, reducing RAS signaling and downstream ERK phosphorylation. Preclinical work indicates high target occupancy at relatively low systemic exposure, selectivity over wild-type KRAS and activity against some KRAS G12C second-site resistance mutations. (nature.com)

Efficacy

In the phase 1/2 LOXO-RAS-20001 study, 168 heavily pretreated patients receiving olomorasib monotherapy at doses of at least 100 mg twice daily were efficacy-evaluable:

Non-colorectal solid tumors: objective response rate (ORR) 37.4%, disease-control rate 89.5%, median progression-free survival (PFS) 6.9 months and median response duration 8.2 months.
Colorectal cancer: ORR 10.3%, disease-control rate 82.8%, median PFS 4.2 months and median response duration 10.4 months.
Previously treated with another KRAS G12C inhibitor: among 38 patients with NSCLC, ORR was 42% and median PFS was 8.2 months.
Brain metastases: more than 30% intracranial tumor shrinkage was observed in 6 of 9 evaluable patients with active, untreated NSCLC brain metastases. (nature.com)

In a phase 1/2 study of olomorasib plus pembrolizumab in advanced NSCLC, ORR was 57.1% among 91 evaluable patients, 73.9% in previously untreated patients and 90% in the first-line subgroup with PD-L1 expression of at least 50%. These subgroup results are based on relatively small, nonrandomized cohorts. (pubmed.ncbi.nlm.nih.gov)

For previously treated KRAS G12C-mutant colorectal cancer, olomorasib plus cetuximab produced an ORR of 42% in 93 patients, with median response duration of 7.6 months and median PFS of 7.5 months in a conference report. (asco.org)

Safety

Among 195 monotherapy recipients, 66% experienced a treatment-related adverse event. The most frequent were diarrhea (22%), nausea (11%) and fatigue (11%), generally grade 1–2. Grade 3 treatment-related events occurred in 7%; no grade 4 or 5 treatment-related events were reported. Dose reductions and treatment discontinuations due to treatment-related events occurred in 6% and 1%, respectively. (nature.com)

With pembrolizumab, 81.7% of patients treated at the principal combination doses experienced treatment-related events, most commonly diarrhea (34.4%) and increased ALT or AST (24.7% and 22.6%). Grade 3 or higher treatment-related events occurred in 33.3%, and 6.5% discontinued both drugs because of toxicity. (pubmed.ncbi.nlm.nih.gov)

With cetuximab, common treatment-related events included acneiform dermatitis, diarrhea, dry skin, paronychia, hypomagnesemia and rash; 24% experienced grade 3 or higher events. (asco.org)

Active trials using LY3537982

Found 3 active trials using this drug:

A Phase 1/2 Study Evaluating the Safety and Efficacy of Amivantamab and Olomorasib Combination Therapy in Metastatic Non-small Cell Lung Cancer

Sponsor: Janssen Research & Development, LLC (industry) Phase: 1/2 Start date: Nov. 12, 2025

TrialFetch AI summary: Patients with metastatic KRAS G12C-mutant NSCLC who have progressed after or cannot tolerate platinum chemotherapy and PD-L1–targeted immunotherapy receive amivantamab, an EGFR/MET bispecific antibody, plus olomorasib, an investigational KRAS G12C inhibitor. Prior KRAS inhibitor treatment is excluded.

ClinicalTrials.gov ID: NCT07227025

SUNRAY-01, A Global Pivotal Study in Participants With KRAS G12C-Mutant, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Comparing First-Line Treatment of LY3537982 and Pembrolizumab vs Placebo and Pembrolizumab in Those With PD-L1 Expression ≥50% or LY3537982 and Pembrolizumab, Pemetrexed, Platinum vs Placebo and Pembrolizumab, Pemetrexed, Platinum Regardless of PD-L1 Expression

Sponsor: Eli Lilly and Company (industry) Phase: 3 Start date: Dec. 21, 2023

TrialFetch AI summary: For patients with previously untreated, unresectable stage IIIB–IIIC or metastatic KRAS G12C-mutant NSCLC, this trial compares the selective KRAS G12C inhibitor olomorasib versus placebo added to first-line pembrolizumab-based therapy. Patients with PD-L1 expression ≥50% receive pembrolizumab alone as the backbone; those in the predominantly nonsquamous cohort receive pembrolizumab, pemetrexed, and platinum chemotherapy regardless of PD-L1 expression.

ClinicalTrials.gov ID: NCT06119581

A Phase 1/2 Study of LY3537982 in Patients With KRAS G12C-Mutant Advanced Solid Tumors

Sponsor: Eli Lilly and Company (industry) Phase: 1/2 Start date: July 19, 2021

TrialFetch AI summary: This trial enrolls patients with unresectable or metastatic KRAS G12C-mutant solid tumors, including NSCLC, colorectal cancer, and pancreatic cancer, generally after standard therapy; a cohort includes previously untreated advanced NSCLC. Patients receive olomorasib, an oral inhibitor that binds inactive KRAS G12C, alone or with pembrolizumab, cetuximab, or pembrolizumab plus pemetrexed and platinum chemotherapy, depending on cohort.

ClinicalTrials.gov ID: NCT04956640