Olomorasib Showed Promising Antitumor Activity in NSCLC

Patients with KRAS G12C-mutant advanced non–small cell lung cancer (NSCLC) were safely treated with a combination of olomorasib and pembrolizumab in a new study.¹ Safety and activity were maintained across PD-L1 expression levels.

KRAS G12C inhibitors have been used to address patients with KRAS G12C-mutant advanced or metastatic NSCLC who had previously been treated with a systemic therapy, but long-term durability of response is lacking, as most patients will develop acquired resistance.² Immune checkpoint inhibitors (ICIs) and oral targeted therapies are not often taken in combination in those with advanced NSCLC. Olomorasib is an oral KRAS G12C inhibitor that showed growth inhibition and antitumor activity in previous models and was more effective in combination.¹ This study aimed to assess the efficacy of olomorasib with the immunotherapy pembrolizumab as a first-line treatment in patients with KRAS G12C-mutant advanced or metastatic NSCLC.

The LOXO-RAS-20001 study was a phase 1/2 study that took place in multiple centers around the world. The phase 1a portion of the study had all patients receiving olomorasib monotherapy before the phase 1b/2 portion expanded so that some patients received the monotherapy, whereas others received olomorasib as part of a combination. This study focused on the 2 cohorts of phase 1b, where eligible patients needed to have KRAS G12C-mutant advanced or metastatic NSCLC. All patients were enrolled between July 5, 2022, and December 19, 2024; 46 different sites across 6 countries were used to enroll patients.

Patients were eligible if they were aged 18 years or older, had measurable disease, and had advanced or metastatic NSCLC. Participants also needed to be KRAS G12C inhibitor naïve and have an Eastern Cooperative Oncology Group performance status between 0 and 1. Patients with active brain metastases, untreated infections, autoimmune diseases that required treatment, or immune-related toxicity that led to the discontinuation of other immunotherapies were excluded from the study.

There were 99 patients in the study who received olomorasib with pembrolizumab; 27 patients received 50 mg of olomorasib, 66 received 100 mg of olomorasib, and 6 received 150 mg of olomorasib, all while receiving 200 mg of pembrolizumab. The median (range) age of the participants was 68 (42-83) years, and 52% were women.

The efficacy was evaluated, with the 91 patients receiving 50 mg or 100 mg. The median follow-up was 12.5 months. Objective response rate (ORR) was 57.1% (95% CI, 46.3-67.5). Complete response was seen in 1.1% and partial response in 49.5%. Median duration of response (DOR) was 17.2 months, and median time to response was 1.4 months. Median progression-free survival was 11.8 months (95% CI, 7.6-18.3). The 46 patients who used this as a first-line treatment had a progression-free survival rate of 66.7% (95% CI, 40.9-83.2), and the ORR was 73.9% (95% CI, 58.9-85.7) after a median follow-up of 7.9 months. The ORR was 48% (95% CI, 28.7-68.1) in those who had previously been treated; the DOR was 17.2 months.

The researchers found that 94.6% of the 93 patients tested had at least 1 treatment-emergent adverse event (TEAE), with diarrhea, nausea, vomiting, decreased appetite, and constipation being the most common. Increased liver function tests were also common TEAEs reported. A total of 81.7% of the patients reported a treatment-related adverse event (TRAE) of any grade, of which diarrhea was the most common (34.4%). A total of 33.4% of the patients experienced a TRAE that was grade 3 or higher. Grade 4 TRAEs were reported in only 2 instances, where 2 patients reported pneumonitis and neutrophil count decrease, respectively.

PD-L1 expression was determined through clones and scoring methods, which could have affected the subgroup analysis by PD-L1 status. The population was heterogeneous because it included those who had been previously treated, first-line patients, and patients with unknown PD-L1 status. The detection of KRAS G12C could have been limited due to low-shedding tumors.

“Olomorasib, in combination with pembrolizumab, has demonstrated significant efficacy and a manageable safety profile in patients with KRAS G12C-mutant advanced/metastatic NSCLC, including patients who had received prior chemotherapy, chemoimmunotherapy, and/or KRAS G12C inhibitors,” the authors concluded.

References

1. 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. Published online November 28, 2025. doi:10.1016/j.jtho.2025.11.018

2. Liu J, Kang R, Tang D. The KRAS-G12C inhibitor: activity and resistance. Cancer Gene Ther. 2022;29:875-878. doi:10.1038/s41417-021-00383-9