Eli Lilly and Company (NYSE: LLY) announced that the US FDA has granted Breakthrough Therapy Designation (BTD) to olomorasib (LY3537982), an oral next-generation KRAS G12C inhibitor, as monotherapy for adult patients with advanced pancreatic cancer who have received at least one prior systemic therapy and whose tumors harbor a KRAS G12C mutation, as determined by an FDA-approved test. The designation marks the second BTD for olomorasib, extending its regulatory momentum beyond lung cancer into one of oncology's most treatment-resistant diseases.
No approved therapy currently targets KRAS G12C in pancreatic cancer. KRAS mutations are present in approximately 90% of pancreatic cancers overall, with the G12C variant occurring in roughly 1% to 2% of patients — a small but molecularly defined population for whom outcomes are reported to be worse than in patients without the mutation, according to published data cited by Lilly. The five-year survival rate for metastatic pancreatic cancer remains below 5%.
The BTD is based on preliminary results from LOXO-RAS-20001, an open-label, multicenter Phase I/II study evaluating olomorasib in patients with KRAS G12C-mutant advanced solid tumors. The trial includes a Phase Ia dose escalation phase of olomorasib monotherapy and Phase Ib expansion cohorts assessing monotherapy and combination regimens. Lilly has not publicly disclosed pancreatic cancer-specific objective response rate (ORR) or progression-free survival (PFS) figures from this cohort in connection with the BTD announcement.
Broader monotherapy data from the same trial, presented at the 2024 American Society of Clinical Oncology Annual Meeting with a March 18, 2024 data cutoff, reported an ORR of 35% (37/105) across KRAS G12C inhibitor-naïve non-colorectal solid tumors, with a median PFS of 7.1 months (95% CI: 5.5–8.9). Among 184 total patients in the monotherapy dataset, 24 had pancreatic cancer. Treatment-related adverse events were predominantly Grade 1; diarrhea (23%), nausea (11%), and fatigue (10%) were the most common, with treatment discontinuation due to adverse events in 1% of patients.
Olomorasib was designed to achieve greater than 90% sustained KRAS G12C target occupancy, a pharmacokinetic property the company says may support both monotherapy activity and combination tolerability. The molecule covalently binds to the mutant cysteine residue in the GDP-bound inactive state of KRAS G12C, locking the oncoprotein in an inactive conformation.