Journal Article

Pan-tumor activity of olomorasib, a next-generation KRAS G12C inhibitor in KRAS G12C-mutant advanced solid tumors: a first-in-human study

Burns, Timothy F., Willard, Melinda D., Oxnard, Geoffrey R., Hollebecque, Antoine, Han, Ji-Youn, Chen, Aaron, Patnaik, Amita, Nagasaka, Misako, Tosi, Diego, Gomez-Roca, Carlos, Spira, Alexander, Reddy Ammakkanavar, Natraj, Heist, Rebecca S., You, Arthur Xintian, Murciano-Goroff, Yonina R., Fink, Aaron, Sacher, Adrian, Shimizu, Toshio, Koyama, Takafumi, Cassier, Philippe A., Kim, So Yeon, Peter, Raimund, McNeely, Samuel C., Cosman, Rasha, Sabari, Joshua K., Kuboki, Yasutoshi, Bodor, J. Nicholas

2026

Overview

This multicenter, first-in-human Phase 1 study (NCT04956640) evaluated olomorasib (LY3537982), a next-generation KRAS G12C inhibitor designed to enhance target occupancy at low absolute exposures. In total, data from 195 patients are reported: Phase 1a dose escalation ( n  = 112) assessed olomorasib monotherapy at 50, 100, 150 or 200 mg BID across KRAS G12C-mutant advanced solid tumors; the primary objective was to determine the recommended Phase 2 dose (RP2D) based on dose-limiting toxicities (DLTs). No DLTs occurred, and 150 mg BID was selected as the RP2D. The primary objective for the Phase 1b dose expansion ( n  = 83) was to evaluate the safety and tolerability of olomorasib in specific KRAS G12C-mutant tumor types. Olomorasib was well tolerated, with predominantly grade 1–2 treatment-related adverse events (TRAEs) and infrequent grade 3 TRAEs; no grade 4/5 TRAEs occurred. Secondary objectives evaluated the antitumor activity of olomorasib. Among 168 efficacy-evaluable patients, the ORR and median PFS were both higher in non-CRC solid tumors compared to CRC, including in patients with NSCLC who previously received a KRAS G12C inhibitor. Intracranial responses were observed in patients with untreated, active brain metastases. This may support the potential of next-generation KRAS G12C inhibitors to overcome limitations of earlier agents and justify further investigation of combination therapy. KRAS G12C inhibitors have improved outcomes but mainly in non-small cell lung cancer and colorectal cancer, despite it being a well-established oncogene in a range of cancer types. Here, the authors present a first-in-human phase I/II clinical trial investigating the next-generation KRAS G12C inhibitor, olomorasib, in KRAS G12C-mutant advanced solid tumors.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/154/152 / 631/67/1059 / 692/4028/67/1059 / Adult / Aged / Aged, 80 and over / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - adverse effects / Antineoplastic Agents - therapeutic use / Antitumor activity / Cancer therapies / Colorectal cancer / Diarrhea / FDA approval / Female / Humanities and Social Sciences / Humans / Immunotherapy / Inhibitors / K-Ras protein / Lung cancer / Male / Metastases / Middle Aged / multidisciplinary / Mutants / Mutation / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - pathology / Non-small cell lung carcinoma / Patients / Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors / Proto-Oncogene Proteins p21(ras) - genetics / Science / Science (multidisciplinary) / Small cell lung carcinoma / Solid tumors / Toxicity / Tumors