Fulzerasib plus cetuximab in first-line KRAS^G12C-mutated non-small-cell lung cancer (KROCUS): a single-arm, multicentre, phase 1b/2 trial.

Abstract

Fulzerasib, a KRAS^G12C inhibitor, has shown clinical activity in previously treated non-small-cell lung cancer (NSCLC). Clinical studies indicate that combining a KRAS^G12C inhibitor with an anti-EGFR antibody is effective in colorectal cancer; however, its benefit in NSCLC remains to be explored. This single-arm, phase 1b/2 trial enrolled patients at 30 medical centres in Spain, Italy, and Greece. Eligible patients had KRAS^G12C-mutated NSCLC with no previous systemic anti-tumour therapy for advanced or metastatic disease and were aged 18 years and older; had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1; had an Eastern Cooperative Oncology Group performance status of 0 or 1; and had a life expectancy of 3 months or more. Enrolled patients received 600 mg oral fulzerasib twice daily plus 500 mg/m² intravenous cetuximab every 2 weeks. The primary endpoint was investigator-assessed objective response rate per RECIST 1.1 assessed in the full response analysis set. The study was registered with ClinicalTrials.gov (NCT05756153) and is complete. Between April 23, 2023, and April 15, 2024, a total of 60 patients were screened, and 47 patients (78%) received treatment. The median age was 68 years (IQR 59-72); 25 patients (53%) were male and 22 (47%) were female. 45 (95%) patients were current or former smokers. As of Jan 14, 2025, the median follow-up time and treatment duration were 12·8 months (90% CI 11·6-14·6) and 10·1 months (IQR 6·3-13·0) months, respectively. The confirmed objective response rate was 69% (90% CI 56-80). Treatment-related adverse events (TRAEs) occurred in 41 (87%) of the 47 patients (grade 3 in seven [15%]). No grade 4 or 5 TRAEs were observed. TRAEs led to drug discontinuation in three (6%) patients, with only cetuximab being discontinued. In treatment-naive KRAS^G12C-mutated NSCLC, fulzerasib plus cetuximab showed encouraging activity with a favourable safety profile. The combination is currently being planned for investigation in a phase 3 study. Zhejiang GenFleet Therapeutics.