Efficacy and Safety of Olomorasib with Pembrolizumab+Chemotherapy as First Line Treatment in Patients with KRAS G12C-Mutant Advanced NSCLC

Olomorasib, a potent, second-generation KRAS G12C inhibitor has demonstrated promising activity in KRAS G12C-mutant non-small cell lung cancer (NSCLC) as monotherapy and in combination with pembrolizumab. Here, we report the first clinical data describing olomorasib in combination with chemo-immunotherapy (chemo – IO).

The phase 1 trial (NCT04956640) enrolled patients (pts) with advanced KRAS G12C-mutant NSCLC into multiple cohorts. Two doses of olomorasib (50 mg and 100 mg, orally BID) in combination with standard chemotherapy (CT) platinum/pemetrexed and pembrolizumab were studied.

Of the 89 pts who received olomorasib+pembrolizumab, a subset of 20 pts received CT. Median age was 68 years; PD-L1 was negative in 11 pts, low in 7, high in 1 and unknown in 1. Prior to enrollment 8 pts received 1 cycle of SOC therapy. Median duration of therapy was 4.2 months and 16 pts remained on study therapy at time of data-cut. All grade TRAEs in>20% of pts were anemia, nausea, decreased appetite, fatigue, and neutrophil count decreased; grade≥3 TRAEs in≥10% of pts were diarrhea and decrease in neutrophil count, WBC count, and platelet count. Grade 3 immune-related AEs included elevated ALT/AST and pneumonitis. TRAEs resulted in olomorasib dose reduction in 2 pts. Hematologic toxicity delayed subsequent cycle of chemo in 3 pts. Among the 18 efficacy-evaluable pts, ORR was 44% (95% CI, 22-69) and disease control rate was 83% (95% CI, 59-96).

Olomorasib in combination with chemo-IO demonstrated a favorable safety profile, consistent with the safety profiles observed with other combinations of CT and targeted therapy. The ORR was lower in this first-line cohort compared to the prior report with olomorasib+pembrolizumab, representative of the higher risk, PD-L1 negative pts enrolled to chemo-IO backbone. A global, registrational study investigating this combination in first-line NSCLC is currently enrolling (SUNRAY-01, NCT06119581).

Publikationsverlauf

Artikel online veröffentlicht:
18. März 2025