The FDA has granted Breakthrough Therapy Designation (BTD) to Eli Lilly’s olomorasib in combination with Merck’s Keytruda (pembrolizumab).

The combination is in development for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation and high PD-L1 expression. BTD was based on data from the Phase Ia/Ib LOXO-RAS-20001 trial (NCT04956640) and Phase III SUNRAY-01 dose optimization trial.¹

What Makes Olomorasib a Promising Option for KRAS G12C-Mutant NSCLC Patients?

"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, Lilly, in a press release.

LOXO-RAS-20001 Trial Design and Endpoints

• The open-label, multicenter LOXO-RAS-20001 trial is evaluating the safety, tolerability, and preliminary efficacy of olomorasib in approximately 540 patients with KRAS G12C-mutant advanced solid tumors.
• The trial consists of a Phase Ia dose-escalation stage assessing olomorasib monotherapy in KRAS G12C-mutant solid tumors, followed by a Phase Ib dose-expansion and optimization stage evaluating the drug as monotherapy and in combination with other treatments.
• Primary endpoints of the trial include determining the recommended Phase II dose of olomorasib (Phase Ia), evaluating safety and tolerability of the drug alone and in combination with other agents (Phase Ib), and establishing the optimal dose in treatment-naïve advanced NSCLC patients when combined with pembrolizumab.²

SUNRAY-01 Trial Design and Endpoints

• The randomized, double-blind, placebo-controlled SUNRAY-01 trial evaluated the efficacy and safety of olomorasib in combination with Keytruda in approximately 700 patients with KRAS G12C-mutant metastatic NSCLC.
• The primary endpoint of part A of the trial is progression-free survival (PFS) as per investigator assessment.
• The primary endpoint of part B is progression-free survival (PFS).
• Key secondary endpoints for both parts include overall survival and change from baseline in health-related quality of life.
• Other secondary endpoints for part B include objective response rate (ORR), duration of response, disease control rate (DCR), time to response, and time to worsening of NSCLC-related symptoms.³

LOXO-RAS-20001 Trial Results

• Results from the LOXO-RAS-20001 trial showed an ORR of 63% and DCR of 93% at a median follow-up of six months, with median PFS not yet reached.
• Responses were observed across PD-L1 subgroups, with an ORR of 75% in patients with PD-L1 ≥50% and 56% in those with PD-L1 <50% or unknown.
• In the first-line setting, ORR reached 78% with a DCR of 100%.
• Common treatment-related adverse events included diarrhea, ALT elevation, AST elevation, fatigue, nausea, and pruritus.
• Toxicities led to olomorasib dose reductions in 14% of patients, dose holds in 27%, and Keytruda dose holds in 18%; 9% discontinued one agent and 9% discontinued both.⁴

Lung Cancer Unmet Needs

• According to the American Cancer Society, approximately 87% of all lung cancers are NSCLC.
• In the United States, lung cancer is considered the leading cause of cancer-related deaths, accounting for approximately 20% of cancer deaths.
• Annually, more people die of lung cancer than of colon, breast, and prostate cancers combined.
• By the end of 2025, it is estimated that there will be around 226,650 new cases of lung cancer in the United States and approximately 124,730 deaths.⁵

"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 III SUNRAY-01 and SUNRAY-02 studies,” concluded Hyman, in the press release.

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. Lilly. September 4, 2025. Accessed September 4, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-olomorasib-receives-us-fdas-breakthrough-therapy
2. Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C). Clinicaltrials.gov. Accessed September 4, 2025. https://clinicaltrials.gov/study/NCT04956640
3. 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. Accessed September 4, 2025. https://clinicaltrials.gov/study/NCT06890598
4. Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC. ASCO. Accessed September 4, 2025. https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.8510?utm_source=chatgpt.com
5. Key Statistics for Lung Cancer. American Cancer Society. Accessed September 4, 2025. https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html