Olomorasib Earns FDA Breakthrough Therapy in KRAS G12C+ Pancreatic Cancer

The FDA has granted breakthrough therapy designation to olomorasib (LY3537982) as a monotherapy for adult patients with advanced pancreatic cancer harboring a KRAS G12C mutation who have received at least 1 prior systemic therapy, according to a news release from developer Eli Lilly and Company.¹ Patients must be identified by an FDA-approved test. Olomorasib previously received breakthrough therapy designation in combination with pembrolizumab (Keytruda) for the first-line treatment of KRAS G12C–mutant, PD-L1–high non–small cell lung cancer (NSCLC).

“Pancreatic cancer has historically been one of the most difficult-to-treat cancers and people whose tumors harbor a KRAS G12C mutation [have] limited options once their disease progresses,” stated Jacob Van Naarden, executive vice president and president of Lilly Oncology.¹ “This breakthrough therapy designation reflects the early potential we're seeing with olomorasib in this setting and the critical need for new treatment options. With now 2 breakthrough therapy designations across pancreatic and lung cancers, olomorasib continues to demonstrate broad potential clinical evidence across KRAS G12C-driven tumors and reflects our commitment to bringing meaningful new treatment options to patients living with these cancers.”

What supported the breakthrough therapy designation?

The designation is based on preliminary results from the open-label, multicenter, phase 1/2 LOXO-RAS-20001 trial (NCT04956640), which is evaluating olomorasib in patients with KRAS G12C-mutant advanced solid tumors, including those with advanced pancreatic cancer who received at least 1 prior line of systemic therapy. The trial includes a phase 1a dose-escalation portion assessing olomorasib monotherapy and a phase 1b dose-expansion and optimization portion evaluating the agent as monotherapy and in combination with other treatments.

LOXO-RAS-20001 is designed in 4 parts: phase 1a dose escalation, phase 1b dose expansion, phase 1b dose optimization, and phase 2, and is expected to run for up to approximately 4 years.²

Eligible patients must have measurable disease per RECIST v1.1 guidelines and KRAS G12C mutation confirmed in tumor tissue or circulating tumor DNA. Those who received prior adjuvant or neoadjuvant therapy are eligible if the last systemic treatment dose was completed at least 6 months before enrollment.

The trial will enroll patients across tumor types, including NSCLC, colorectal, endometrial, ovarian, pancreatic, and biliary tract cancers. It will evaluate olomorasib alone and in combination with agents including pembrolizumab, cetuximab (Erbitux), pemetrexed, cisplatin, and carboplatin. Primary outcomes center on safety, tolerability, and dose-finding, with preliminary antitumor activity, including objective response rate, assessed as a secondary measure.

Full findings from the pancreatic cancer cohort have not yet been published; Lilly's release characterized the results as encouraging enough to support the designation.

What is olomorasib and how does it work?

Olomorasib is an investigational, oral, potent, and highly selective next-generation inhibitor of KRAS G12C, engineered for high predicted target occupancy and potency as monotherapy or in combination regimens. Beyond LOXO-RAS-20001, the agent is being studied in the pivotal, registrational phase 3 SUNRAY-01 trial (NCT06119581), which is evaluating olomorasib with pembrolizumab, with or without chemotherapy, as first-line treatment for KRAS G12C-mutant advanced NSCLC, and in SUNRAY-02 (NCT06890598), assessing olomorasib with standard-of-care immunotherapy in resected or unresectable KRAS G12C-mutant NSCLC.

How does this fit into the broader RAS-targeted pancreatic cancer landscape?

The designation adds olomorasib to a growing field of RAS-directed agents in pancreatic cancer. CancerNetwork® previously covered the FDA's acceptance of the new drug application for daraxonrasib, a RAS(ON) multiselective inhibitor, in previously treated metastatic pancreatic ductal adenocarcinoma, based on phase 3 RASolute 302 trial (NCT06625320) data showing improvements in overall survival and progression-free survival.³

References

1. Lilly's olomorasib receives U.S. FDA's Breakthrough Therapy designation for the treatment of previously treated KRAS G12C-mutant advanced pancreatic cancer. News release. Eli Lilly and Company. August 3, 2026. Accessed August 4, 2026. https://tinyurl.com/58t92era
2. Study of LY3537982 in cancer patients with a specific genetic mutation (KRAS G12C). ClinicalTrials.gov. Updated May 29, 2026. Accessed August 4, 2026. https://tinyurl.com/u48a824d
3. Revolution Medicines' new drug application for daraxonrasib accepted for review by US FDA for previously treated metastatic pancreatic cancer. News release. Revolution Medicines, Inc. July 22, 2026. Accessed August 4, 2026. https://tinyurl.com/2c3em84c