Research Summary:
KRAS G12C mutations occur in a substantial subset of advanced non-small cell lung cancer (NSCLC), and current first-line standards based on immune checkpoint inhibitors (ICIs), with or without chemotherapy, yield suboptimal long-term outcomes. Olomorasib is an orally bioavailable, highly selective KRAS G12C inhibitor designed to achieve high-target occupancy at low systemic exposure, with preclinical data suggesting robust tumor inhibition with other anticancer treatments. The Phase I/II LOXO-RAS-20001 study was developed to characterize safety, tolerability, pharmacokinetics, and preliminary antitumor activity of olomorasib alone and in combination with pembrolizumab in advanced solid tumors harboring KRAS G12C mutations. Burns et al1 analyzed Phase IB cohorts that evaluated olomorasib plus pembrolizumab as first-line treatment in patients with KRAS G12C-mutant advanced or metastatic NSCLC, including individuals previously treated with chemotherapy, chemoimmunotherapy, and prior KRAS G12C inhibitors. Safety endpoints included treatment-emergent adverse events (TEAEs) and treatment-related adverse events (TRAEs), while efficacy endpoints included objective response rate (ORR), best overall response (BOR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS).
Between July 2022 and January 2025, 99 patients with KRAS G12C-mutant advanced or metastatic NSCLC were enrolled and treated with olomorasib in combination with pembrolizumab. Median age was 68 years, 52% were female, 90% of patients were current or former smokers, and 36% had prior brain metastases. Programmed death-ligand 1
(PD-L1) expression was less than 1% in 25% of patients, 1% to 49% in 26%, at least 50% in 36%, and unknown in 12%. Approximately half of the cohort (51%) received first-line metastatic treatment, whereas 49% had received prior systemic therapy; among previously treated patients, 86% had received prior anti-programmed cell death-1/PD-L1 therapy with or without platinum-based chemotherapy, 14% had received platinum-based chemotherapy alone, and 41% had received a prior KRAS G12C inhibitor.
Two of 6 patients treated at 150 mg twice daily experienced Grade 3 liver function test elevations in the safety lead-in, leading to discontinuation of that dose level; subsequent safety and efficacy analyses focused on 93 patients treated at 50 mg (n=27) or 100 mg (n=66) twice daily. In these patients, 94.6% experienced at least one TEAE and 52.7% experienced Grade 3 or higher TEAEs. Common TEAEs of any grade included diarrhea (39.8%), nausea (28.0%), vomiting (20.4%), decreased appetite (20.4%), alanine aminotransferase elevation (28.0%), and aspartate aminotransferase elevation (23.7%).
TRAEs occurred in 81.7% of patients, with Grade 3 or higher TRAEs occurring in 33.3%. The most frequent TRAEs were diarrhea (34.4%), increased alanine aminotransferase (24.7%), and increased aspartate aminotransferase (22.6%), with Grade 3 diarrhea in 11.8% and Grade 3 elevations of alanine aminotransferase and aspartate aminotransferase in 11.8% and 9.7%, respectively. There were two Grade 4 TRAEs (pneumonitis and decreased neutrophil count) and no Grade 5 TRAEs. Grade 3 liver enzyme elevations were asymptomatic, without concomitant bilirubin elevation, and resolved to Grade 1 or baseline with dose modification or corticosteroids; median onset was 52 days, median duration was 7 days, and recurrence after resolution occurred in 2 of 16 patients. Median time to onset of Grade 2 or higher diarrhea was 62 days, with median duration of 7 days and resolution after antidiarrheals, dose adjustment, or corticosteroids. TRAEs led to olomorasib dose reduction in 20.4% of patients, discontinuation of olomorasib in 2.2%, discontinuation of pembrolizumab in 16.1%, and discontinuation of both agents in 6.5%.
Among 91 efficacy-evaluable patients treated at 50 mg or 100 mg twice daily, median follow-up was 12.5 months. ORR was 57.1%, including 1.1% complete response, 49.5% partial response, and 6.6% unconfirmed partial response. DCR was 85.7%. Median DOR was 17.2 months and median time to response was 1.4 months. Median PFS was 11.8 months, with a 12-month PFS rate of 44.8%. In the 46 first-line metastatic patients, median follow-up was 7.9 months. ORR was 73.9%, DCR was 91.3%, and the 12-month PFS rate was 66.7%. Among first-line patients with PD-L1 expression of at least 50% (n=20), ORR was 90.0%, with responses observed across PD-L1-high strata (50–60%, >60–89%, and 90–100%). In 45 previously treated efficacy-evaluable patients, 27 had received at least two prior lines of therapy, and antitumor activity remained notable. Patients who had received prior chemotherapy and/or ICIs had an ORR of 48.1%, median DOR of 17.2 months, and median PFS of 11.7 months, with a 12-month PFS rate of 39.7%. Patients previously treated with chemotherapy and/or ICIs and a KRAS G12C inhibitor (n=18) had an ORR of 27.8%, median DOR of 5.7 months, and median PFS of 4.3 months, with a 12-month PFS rate of 17.7%.
Overall, olomorasib in combination with pembrolizumab demonstrated promising efficacy and a manageable safety profile in patients with KRAS G12C-mutant advanced or metastatic NSCLC across treatment lines and PD-L1 expression levels, with particularly strong activity in the first-line PD-L1-high setting.
References
- Burns TF, Ammakkanavar NR, Hollebecque A, et al. Efficacy and safety of olomorasib in combination with pembrolizumab in treatment of patients with KRAS G12C-mutant advanced NSCLC. J Thorac Oncol. 2025:S1556-0864(25)02936-3.