Eli Lilly and Company announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to olomorasib, in combination with anti-PD-1 therapy Keytruda (pembrolizumab), for the first-line treatment of patients with unresectable advanced or metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation and PD-L1 expression = 50%, as determined by FDA approved tests. Olomorasib is a potent and highly selective second-generation inhibitor of KRAS G12C with preliminary evidence of central nervous system (CNS) activity.
Breakthrough Therapy designation aims to expedite the development and review of drugs that are intended to treat a serious condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over already available therapies that have received full FDA approval.
"The Breakthrough Therapy designation recognizes the potential for olomorasib to be a meaningful treatment advance and highlights the continued unmet need for improved options for patients with KRAS G12C-mutant NSCLC, particularly in the first-line setting in combination with standard-of-care immunotherapy," said David Hyman, M.D., Lilly chief medical officer. "We look forward to presenting updated data from the olomorasib development program in significantly more patients and with longer follow-up at WCLC and continuing to investigate olomorasib in combination with immunotherapy-based regimens in a variety of treatment settings across the phase 3 SUNRAY-01 and SUNRAY-02 studies."
The FDA Breakthrough Therapy designation is based on encouraging results from the phase 1/2 LOXO-RAS-20001 trial and the dose optimization portion of the phase 3 SUNRAY-01 trial. Updated results from an integrated analysis from these studies will be presented at the 2025 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer (IASLC), taking place September 6 - 9 in Barcelona, Spain.
In an oral presentation (Abstract #MA02.06), Lilly will report on an integrated analysis of efficacy and safety results in patients with KRAS G12C-mutant NSCLC who received olomorasib plus pembrolizumab as first-line treatment in the dose optimization cohorts of the phase 1/2 LOXO-RAS-20001 study and phase 3 SUNRAY-01 study. These data will be shared in an oral presentation during the New Treatment Strategies in Other Than EGFR-Positive Tumours session on Sunday, Sept. 7, 2025, from 12-1:15 p.m. Central European Summer Time (CEST).
In a second oral presentation (Abstract #OA08.02), Lilly will report results of an integrated analysis in patients with KRAS G12C-mutant advanced or metastatic NSCLC who received olomorasib in combination with chemoimmunotherapy (pembrolizumab, pemetrexed and platinum) as a first-line treatment in the phase 1/2 LOXO-RAS-20001 trial and safety lead-in for the phase 3 SUNRAY-01 trial. These data will be shared in an oral presentation during the Improving Outcomes in EGFR and KRAS Mutant Tumours, More is Better session on Monday, Sept. 8, 2025, from 12-1:15 p.m. CEST.
The submitted abstracts for both presentations utilized a January 15, 2025 data cut-off date, and the oral presentations will utilize a June 6, 2025 data cut-off date.
LOXO-RAS-20001 is an open-label, multicenter, phase 1/2 study evaluating the safety, tolerability and preliminary efficacy of olomorasib in patients with KRAS G12C-mutant advanced solid tumors (NCT04956640). The study includes a Phase 1a dose escalation phase of olomorasib monotherapy in KRAS G12C-mutant solid tumours and a Phase 1b dose expansion and optimization phase which are evaluating olomorasib as a monotherapy and in combination with other treatments.
SUNRAY-01 is a randomized, double-blind, placebo-controlled, global phase 3 study evaluating the efficacy and safety of olomorasib in combination with pembrolizumab with or without chemotherapy as a first-line treatment for patients with KRAS G12C-mutant metastatic non-small cell lung cancer (NSCLC). The trial is designed to compare olomorasib plus standard-of-care therapies versus placebo plus standard-of-care therapies, with the goal of determining whether the addition of olomorasib can improve clinical outcomes in this patient population. SUNRAY-01 is part of Lilly's broader clinical development program investigating olomorasib across multiple stages and settings of KRAS G12C-mutant NSCLC (NCT06890598).
Olomorasib (LY3537982) is an investigational, oral, potent, and highly selective second-generation inhibitor of the KRAS G12C protein. KRAS is the most common oncogene across all tumour types, and KRAS G12C mutations occur in 13% of patients with non-small cell lung cancer (NSCLC), and 1-3% of patients with other solid tumors. Olomorasib is a highly potent covalent inhibitor with potential for greater than 90% target occupancy, which may allow for safer combinations with less toxicity.
Olomorasib is currently being studied in KRAS G12C-mutated cancers in combination with pembrolizumab with or without chemotherapy for first-line treatment of advanced NSCLC, in combination with immunotherapy for the treatment of resected and unresectable NSCLC, and as monotherapy and in combinations in other advanced solid tumours, including: NCT06119581, NCT06890598, and NCT04956640.
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