Timothy F. Burns, Natraj Reddy Ammakkanavar, Antoine Hollebecque, Dae Ho Lee, Takafumi Koyama, Philippe A. Cassier, Antoîne Italiano, Ji‐Youn Han, Nimit Singhal, Shinji Takeuchi, Rebecca S. Heist, Dustin A. Deming, Alexander I. Spira, Quincy S. Chu, Adrian G. Sacher, Yutaka Fujiwara, Michael Chisamore, Arthur Xintian You, Samuel McNeely, Aaron Alan Fink, Aaron Chen, Geoffrey R. Oxnard, Melinda D. Willard, Yonina R. Murciano‐Goroff, Konstantin H. Dragnev
INTRODUCTION: Immunotherapy-based regimens are the standard first-line treatment for KRAS G12C-mutant NSCLC, but outcomes remain suboptimal. Prior attempts to combine KRAS G12C inhibitors with immunotherapy have been challenged by toxicity. We report results from LOXO-RAS-20001, a phase 1/2 trial evaluating the combination of olomorasib with pembrolizumab in KRAS G12C-mutant NSCLC, including in first-line setting. METHODS: Patients with advanced KRAS G12C-mutant NSCLC in any treatment line, including prior KRAS G12Ci and immunotherapy were eligible. Any PD-L1 level (0%-100%) was permitted. Three dose levels of olomorasib (50, 100, and 150 mg twice daily) plus pembrolizumab were evaluated, focusing on 50 and 100 mg twice daily for safety and efficacy. RESULTS: A total of 99 enrolled patients had a median age of 68 (range, 42-83) years; 52% of tumors were PD-L1 0% to 49%, 36% were PD-L1 more than or equal to 50%, and 51% were first line. Of 93 patients treated at 50 or 100 mg twice daily, 76 (81.7%) experienced treatment-related adverse event (TRAEs) of any grade, most often, diarrhea (34.4%) and increased alanine aminotransferase/aspartate aminotransferase level (24.7%/22.6%). Grade more than or equal to 3 TRAEs were found in 33.3%. TRAEs led to olomorasib dose reductions in 20.4% and discontinuation of both therapies in 6.5% of patients. Among 91 efficacy-evaluable patients, at a median follow-up of 12.5 months (interquartile range, 6.2-16.9), objective response rate was 57.1% (95% confidence interval [CI], 46.3-67.5) across all PD-L1 expression levels, 73.9% (95% CI, 58.9-85.7) in first line, and 90% (95% CI, 68.3-98.8) in first-line patients with PD-L1 more than or equal to 50%. CONCLUSION: Olomorasib plus pembrolizumab demonstrated manageable safety and promising antitumor activity in patients with KRAS G12C-mutant advanced NSCLC across PD-L1 expression levels, especially in the high PD-L1 first-line setting.