olomorasib (LY3537982)

P1, N=15, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

P1/2, N=60, Recruiting, Janssen Research & Development, LLC | Trial completion date: Nov 2028 --> Apr 2029

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.

P3, N=1264, Recruiting, Eli Lilly and Company | Trial completion date: Oct 2029 --> Jan 2031 | Trial primary completion date: Oct 2026 --> Nov 2027

Adagrasib monotherapy yielded a median PFS of 4.4-5.6 months, an OS of 10-19.8 months, and an ORR of 19-23%, while its combination with cetuximab reported a PFS of 6.9 months, an OS of 13.4-15.9 months and an ORR of 34-46%...When combined with panitumumab, 960 mg sotorasib demonstrated better results with a PFS of 5.6-5.7 months, OS of 15.2 months and an ORR of 12.5-30%. Similarly, divarasib monotherapy led to a PFS of 5.6-6.9 months and an ORR of 20%, while its combination with cetuximab resulted in a PFS of 8.1 months and an ORR of 62.5%. Combination therapy of olomorasib and MK-1084, which are new-generation KRAS p.G12C (c.34G > T) inhibitors, with cetuximab also demonstrated highly promising efficacy with ORR of 38-44% and 50%, respectively...Initial results of KRAS-G12C inhibitors appear highly promising when they are combined with anti-EGFR therapy compared to historical therapeutic agents indicated for patients with chemotherapy-refractory CRC. Encouraging benefits warrant frontline trials with these novel therapeutics.

P1, N=15, Not yet recruiting, Eli Lilly and Company

This article examines the clinical and translational application of specific next-generation blood-brain barrier penetrant KRASG12C inhibitors, such as sotorasib, adagrasib, olomorasib, RMC-6236, and D3S-001, and their rational integration with radiation therapy, targeted therapies, and immunotherapies to overcome therapeutic resistance in patients with NSCLC brain metastases. This review summarizes recent advances aimed at enhancing intracranial tumor control and overall survival in patients with NSCLC brain metastases through the use of next-generation KRASG12C inhibitors and multimodal therapies.

P1, N=191, Completed, Eli Lilly and Company | Recruiting --> Completed

P1/2, N=60, Recruiting, Janssen Research & Development, LLC | Not yet recruiting --> Recruiting

Olomorasib + pembrolizumab demonstrated manageable safety and promising antitumor activity in patients with KRAS G12C-mutant advanced NSCLC across PD-L1 expression levels, especially in the high PD-L1 first-line setting.

P1, N=188, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

P1/2, N=60, Not yet recruiting, Janssen Research & Development, LLC