FDA Grants Breakthrough Therapy Designation to Olomorasib in KRAS G12C NSCLC

The FDA has granted breakthrough therapy designation to olomorasib in combination with pembrolizumab (Keytruda) for the treatment of unresectable advanced or metastatic non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation and PD-L1 expression ≥50%.¹

This designation is supported by data from the phase 1/2 LOXO-RAS-20001 trial (NCT04956640) and the dose-optimization portion of the phase 3 SUNRAY-01 trial (NCT06119581). Updated results from these trials were presented at the 2025 IASLC World Conference on Lung Cancer (WCLC).

In an analysis of both studies, the overall response rate (ORR) for patients treated with olomorasib at 100 mg daily was 71% (n = 82) regardless of PD-L1 expression and 85% in patients with PD-L1 expression ≥50%. With a median follow-up of 7.6 months (IQR, 5.5–9.5), the median duration of response (DOR) was not reached, and the 6-month progression-free survival (PFS) rate was 77%.²

"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, MD, chief medical officer at Eli Lilly, in a press release. "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 [NCT06890598] studies."

Breakthrough therapy designation is intended to expedite the development and review of therapies that treat a serious condition and offer a substantial improvement over currently available therapies.³

About the Phase 1/2 LOXO-RAS-20001 Study

LOXO-RAS-20001 is a phase 1/2, open-label, multicenter study of olomorasib in patients with KRAS G12C-mutant solid tumors.⁴ The study consists of dose-escalation, dose-expansion, and dose-optimization parts. The primary end points are to determine the recommended phase 2 dose, assess the safety and tolerability of olomorasib, and determine the optimum dose of olomorasib in combination with pembrolizumab. Secondary end points include ORR, DOR, best overall response, time to response (TTR), disease control rate (DCR), PFS, overall survival (OS), intracranial DOR, and pharmacokinetics.

About SUNRAY-01 and SUNRAY-02

SUNRAY-01 is a global, pivotal study assessing first-line treatment of olomorasib and pembrolizumab vs placebo and pembrolizumab in patients with KRAS G12C-mutated NSCLC with PD-L1 expression ≥50% or olomorasib plus pembrolizumab, pemetrexed, and platinum vs placebo, pembrolizumab, and pemetrexed regardless of PD-L1 expression.⁵

The primary end points are incidence of treatment-emergent adverse events and PFS, and secondary end points include OS, ORR, DOR, DCR, TTR, and patient-reported outcomes.

SUNRAY-02 is a phase 3, double-blind, placebo-controlled study evaluating olomorasib plus standard-of-care immunotherapy in patients with KRAS G12C-mutant NSCLC.⁶ Patients will be randomized to receive olomorasib or placebo plus pembrolizumab or durvalumab (Imfinzi).

The primary end points are disease-free survival and PFS, and secondary end points include OS, change in health-related quality of life, ORR, DOR, DCR, TTR, and patient-reported outcomes.

REFERENCES:

1. Lilly's olomorasib receives U.S. FDA's Breakthrough Therapy designation for the treatment of certain newly diagnosed metastatic KRAS G12C-mutant lung cancers. News release. Eli Lilly and Company. September 4, 2025. Accessed September 9, 2025. https://tinyurl.com/3nkhkdsd

2. Johnson ML, Mateos LL, Yamada T, et al. Efficacy and Safety of 1L Olomorasib Plus Pembrolizumab in KRAS G12C-Mutant NSCLC: Results From LOXO-RAS-20001 and SUNRAY-01. Presented at: IASLC 2025 World Conference on Lung Cancer; September 6–9, 2025; Barcelona, Spain. Abstract MA02.06.

3. Breakthrough Therapy. US FDA. Updated January 4, 2018. Accessed September 9, 2025. https://tinyurl.com/5az23mkb

4. Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C). ClinicalTrials.gov. Updated March 7, 2025. Accessed September 9, 2025. https://clinicaltrials.gov/study/NCT04956640

5. A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer (SUNRAY-01). ClinicalTrials.gov. Updated September 9, 2025. Accessed September 9, 2025. https://clinicaltrials.gov/study/NCT06119581

6. Study of Olomorasib (LY3537982) in Combination With Standard of Care in Participants With Resected or Unresectable KRAS G12C-mutant Non-Small Cell Lung Cancer (SUNRAY-02). ClinicalTrials.gov. Updated September 9, 2025. Accessed September 9, 2025. https://clinicaltrials.gov/study/NCT06890598