Research in Context

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Fulzerasib plus cetuximab explored in first-line KRAS^G12C-mutated NSCLC

KROCUS trial authors caution that randomised validation is still needed, while reporting encouraging anti-tumour activity for this investigational combination, which they describe as holding potential as a chemotherapy-free, immunotherapy-free option.

  • Vanesa Gregorc, MD; Margarita Majem, MD PhD; Giuseppe Lo Russo, MD PhD; Michele Maio, MD; Stephanie Salvagni, MD; Vanesa Gutiérrez-Calderon, MD; et al.

  • April 1, 2026

  • The Lancet Oncology
  • The Lancet Oncology, Volume 27, Issue 4, Pages 432–441
  • 10.1016/S1470-2045(25)00764-8

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Evidence before this study

During the conception of the KROCUS trial in 2022, we searched PubMed for articles published from database inception to June 30, 2022, using the terms “non-small cell lung cancer” OR “NSCLC,” “first-line treatment,” “standard of care,” “KRAS,” AND “epidermal growth factor receptor”. Mutations in KRASG12C occur in approximately 13% of non-small-cell lung cancer (NSCLC) cases in the overall population. KRASG12C inhibitors have showed substantial anti-tumour effects and acceptable safety profiles in the treatment of NSCLC in later-line settings. Although the current standard of care (immunotherapy or immunochemotherapy) provide a response rate of 27·3–61·4% and a progression-free survival of 5·6–11·1 months in the population regardless of PD-L1 expression levels in the first line setting, the benefit is mainly associated with PD-L1 expression. In addition, KRASG12C mutations are often accompanied by mutations in STK11 and KEAP1, with frequencies of 10–28% and 6–23%, respectively. Patients with these co-mutations generally do not respond well to immunotherapy or immunochemotherapy. Furthermore, a broad range of toxicities can arise with immunotherapy or immunochemotherapy, including immune-related adverse events and chemotherapy-related adverse events, which impact patients’ adherence to treatment, overall health-related quality of life, and sequential treatment options.

Added value of this study

Fulzerasib plus cetuximab showed encouraging anti-tumour activity. The median progression-free survival achieved with this combination exceeded the outcomes reported for the current standard of care in the overall population. The safety profile of the combination was favourable compared with immunochemotherapy. No new safety signals were identified compared with data reported for these agents as monotherapy.

Implications of all the available evidence

To the best of our knowledge, the KROCUS trial is the first clinical trial exploring the role of a KRASG12C inhibitor plus an EGFR antibody in the first-line setting of KRASG12C-mutated NSCLC. The combination of fulzerasib and cetuximab holds potential as a chemotherapy-free and immunotherapy-free treatment option, particularly for patients with poor performance status and those ineligible for immunotherapy or immunochemotherapy. Further randomised controlled studies are warranted to validate these findings and establish the optimal role of this combination regimen in the first-line treatment of KRASG12C-mutated NSCLC.

Source: The Lancet Oncology

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