Olomorasib + Pembrolizumab

Olomorasib + pembrolizumab is a promising combination therapy being investigated for the treatment of KRAS G12C-mutant non-small cell lung cancer (NSCLC). This combination pairs olomorasib (LY3537982), a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, with pembrolizumab (Keytruda), an established immunotherapy agent. The combination has shown favorable safety profiles and promising antitumor activity in clinical trials, particularly in first-line treatment settings. In the LOXO-RAS-20001 phase 1/2 study, the combination demonstrated an overall response rate of 77-78% in previously untreated patients with KRAS G12C-mutant advanced NSCLC[1][4][5]. The rationale behind this combination is that while immunotherapy is established as the cornerstone of first-line treatment for KRAS-mutant NSCLC, outcomes remain suboptimal. Adding targeted therapy (olomorasib) to immunotherapy (pembrolizumab) may improve treatment outcomes[1][6]. Based on these promising results, a global registrational trial called SUNRAY-01 (NCT06119581) is currently enrolling patients to further investigate this combination in the first-line metastatic setting[5][7][8]. Clinical Efficacy In the LOXO-RAS-20001 phase 1/2 study: - First-line setting: 77-78% overall response rate with 100% disease control rate[1][4][5] - Previously treated patients: 40% overall response rate[4][5] - Median time to response: 1.4 months[4][5] - Median progression-free survival: Not reached at data cutoff in first-line patients[4][5] - 12-month progression-free survival rate: 72.8%[4] Safety Profile The combination demonstrated a favorable safety profile with manageable adverse events: - Treatment-related adverse events occurred in 70% of patients[5] - Grade 3-4 treatment-related adverse events occurred in 27% of patients[5] - Most common adverse events included diarrhea (23%), alanine transaminase increase (20%), pruritus (19%), aspartate aminotransferase increase (16%), and fatigue (16%)[5] - Treatment-related adverse events led to olomorasib dose holds in 25% of patients and dose reductions in 17%[5] - Discontinuation rates: olomorasib alone (3%), pembrolizumab alone (11%), both drugs (5%)[5] Ongoing Development The SUNRAY-01 trial (NCT06119581) is a pivotal, global, phase 3 study designed to: 1. Optimize the dosing of olomorasib (50mg vs 100mg BID) in combination with first-line standard of care 2. Compare efficacy and safety of olomorasib plus standard of care with placebo plus standard of care[7][8] The study has two main parts: - Part A: 384 participants with PD-L1 expression ≥50% randomized to pembrolizumab plus olomorasib or placebo - Part B: 552 participants randomized to pembrolizumab, pemetrexed, platinum plus olomorasib or placebo regardless of PD-L1 expression[7][8] Another study (NCT06890598) is also investigating olomorasib in combination with standard of care in participants with resected or unresectable KRAS G12C-mutant NSCLC[9].

Brand names

Keytruda (for Pembrolizumab)