FDA Grants Breakthrough Therapy Designation to Olomorasib With Pembrolizumab for NSCLC

The FDA has granted breakthrough therapy designation to olomorasib (Eli Lilly and Company) in combination with pembrolizumab (Keytruda; Merck), an anti-PD-1 therapy, 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 greater than 50%.¹

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"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," David Hyman, MD, Lilly chief medical officer, said in a news release.¹

Olomorasib’s Role in NSCLC Treatment

NSCLC is the most common type of lung cancer, accounting for approximately 80% to 85% of all lung cancer cases. This form of cancer causes normal cells in the lungs to become abnormal cells and multiply. While NSCLC grows slowly compared to small cell lung cancer (SCLC), it can spread to other parts of the body before symptoms develop. Symptoms of NSCLC include chest pain, chronic cough, coughing up blood, hoarseness, loss of appetite, shortness of breath, tiredness, and wheezing. If in the metastatic stage, NSCLC commonly spreads to the adrenal glands, bones, brain, liver, lymph nodes, and skin.²

KRAS is the most common oncogene across all tumor types, as KRAS G12C mutations occur in about 13% of patients with NSCLC. As an investigational, oral, potent, and highly selective second-generation inhibitor of the KRAS G12C protein, olomorasib could offer further treatment for individuals with NSCLC, potentially offering greater than 90% target occupancy, which could lead to safer combinations with less toxicity.¹

Currently, olomorasib is being investigated as a combination treatment 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 a monotherapy and in combination in other advanced solid tumors.¹

Clinical Trial Results Supporting Designation for Olomorasib

The breakthrough therapy designation is based on data from the open-label, multicenter, phase 1/2 LOXO-RAS-20001 clinical trial (NCT04956640) and the dose optimization portion of the randomized, double-blind, placebo-controlled, global, phase 3 SUNRAY-01 clinical trial (NCT06890598).^1,3,4

LOXO-RAS-20001

In the study, researchers evaluated the safety, tolerability, and preliminary efficacy of olomorasib in patients with KRAS G12C-mutant advanced solid tumors. The study was divided into 2 phases—phase 1a and phase 1b. Phase 1a was a dose escalation that assessed olomorasib as a single treatment for patients with advanced KRAS G12C-mutant solid tumors to determine the optimal dose. In phase 1b, researchers further evaluated olomorasib alone and in combination with other therapies to identify its effectiveness.¹

SUNRAY-01

Researchers aimed to evaluate the efficacy and safety of olomorasib in combination with pembrolizumab with or without chemotherapy as first-line treatment for patients with KRAS G12C-mutant metastatic NSCLC. The study aimed to compare olomorasib plus standard-of-care therapies with placebo plus standard-of-care to determine if olomorasib can advance clinical outcomes for patients with NSCLC.¹

"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." Hyman said in the news release.¹

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. Eli Lilly and Company. News release. September 4, 2025. Accessed September 5, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-olomorasib-receives-us-fdas-breakthrough-therapy

2. Non-Small Cell Lung Cancer. Cleveland Clinic. News release. Updated January 16, 2025. Accessed September 5, 2025. https://my.clevelandclinic.org/health/diseases/6203-non-small-cell-lung-cancer

3. Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C). National Library of Medicine. Updated March 7, 2025. Accessed September 5, 2025. https://clinicaltrials.gov/study/NCT04956640

4. 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) National Library of Medicine. Updated August 24, 2025. Accessed September 5, 2025. https://clinicaltrials.gov/study/NCT06890598