Fulzerasib plus cetuximab shows 69% response in first-line KRAS-mutated NSCLC

BACKGROUND: Fulzerasib, a KRAS inhibitor, has shown clinical activity in previously treated non-small-cell lung cancer (NSCLC). Clinical studies indicate that combining a KRAS inhibitor with an anti-EGFR antibody is effective in colorectal cancer; however, its benefit in NSCLC remains to be explored. METHODS: This single-arm, phase 1b/2 trial enrolled patients at 30 medical centres in Spain, Italy, and Greece. Eligible patients had KRAS-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/m 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. FINDINGS: 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. INTERPRETATION: In treatment-naive KRAS-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. FUNDING: Zhejiang GenFleet Therapeutics.