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Fulzerasib plus cetuximab in first-line KRAS^G12C-mutated non-small-cell lung cancer (KROCUS): a single-arm,

Vanesa Gregorc¹, Margarita Majem², Giuseppe Lo Russo³

¹Istituto di Candiolo Fondazione del Piemonte per l'Oncologia IRCCS, Candiolo, Italy.

The Lancet. Oncology

|April 2, 2026

Abstract

Background:

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.

Methods:

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.

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^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.

Funding:

Zhejiang GenFleet Therapeutics.

Insights

Fulzerasib combined with cetuximab shows promising results in previously untreated KRAS G12C-mutated non-small-cell lung cancer (NSCLC). This combination therapy demonstrated significant objective response rates with a manageable safety profile.

Area of Science:

Oncology
Pharmacology

Background:

Fulzerasib is a KRAS G12C inhibitor with demonstrated clinical activity in non-small-cell lung cancer (NSCLC).
Previous studies suggest combining KRAS G12C inhibitors with anti-EGFR antibodies is effective in colorectal cancer, but its efficacy in NSCLC requires further investigation.

Purpose of the Study:

To evaluate the efficacy and safety of fulzerasib plus cetuximab in treatment-naive patients with KRAS G12C-mutated NSCLC.

Main Methods:

A single-arm, phase 1b/2 trial conducted across 30 centers in Spain, Italy, and Greece.
Eligible patients had KRAS G12C-mutated NSCLC, no prior systemic therapy for advanced disease, ECOG performance status 0-1, and measurable lesions.
Patients received oral fulzerasib 600 mg twice daily plus intravenous cetuximab 500 mg/m² every 2 weeks.

Main Results:

47 patients received treatment, with a median follow-up of 12.8 months.
The confirmed objective response rate was 69% (90% CI 56-80).
Treatment-related adverse events (TRAEs) occurred in 87% of patients, with 15% experiencing grade 3 TRAEs. No grade 4 or 5 TRAEs were observed, and only 6% discontinued treatment due to TRAEs.

Conclusions:

Fulzerasib plus cetuximab exhibits encouraging anti-tumour activity and a favorable safety profile in treatment-naive KRAS G12C-mutated NSCLC.
A phase 3 study investigating this combination is currently being planned.

Read full analysis

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