Updated data from the phase 2 KROCUS study presented at the 2025 European Lung Cancer Congress has revealed promising efficacy and safety for the combination of fulzerasib (GFH925) and cetuximab (Erbitux) as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS G12C mutations.
The doublet therapy demonstrated an objective response rate (ORR) of 80.0% among 47 evaluable patients, with a confirmed ORR of 68.9%. Notably, 57.8% of patients experienced tumor shrinkage of at least 50%, and the disease control rate reached 100%. The combination also showed efficacy in patients with brain metastases, with 10 of 14 such patients achieving systemic response (71.4%).
At a median follow-up of 12.8 months, the median duration of response had not been reached, and the median progression-free survival was 12.5 months. The median overall survival was also not reached, suggesting durable benefits from the treatment.
"The combination shows the potential to provide a chemotherapy-free option in the first-line setting," said Dr. Margarita Majem of Hospital de la Santa Creu i Sant Pau in Barcelona, Spain, who presented the data. "A phase 3 study in the population of patients with a PD-L1 under 50% is being planned."
Study Design and Patient Characteristics
KROCUS is a single-arm, open-label, phase 2 trial that enrolled patients with pathologically confirmed advanced NSCLC with KRAS G12C mutations who had not previously received systemic treatment for advanced or metastatic disease. Patients received 600 mg of fulzerasib twice daily plus 500 mg/m² of cetuximab every 2 weeks until disease progression, intolerable toxicity, or other withdrawal criteria were met.
The study population included 47 evaluable patients with a median age of 68 years. Most patients were White (95.7%), former smokers (72.3%), and had adenocarcinoma (97.9%). Notably, 34.0% of patients had brain metastases, 23.4% had bone metastases, and 19.1% had adrenal gland metastases.
"KROCUS is the first study to explore the efficacy and safety of a KRAS G12C inhibitor and an anti-EGFR antibody in the first-line treatment of NSCLC," Dr. Majem noted.
Efficacy Across Biomarker Subgroups
The investigators observed comparable response rates across PD-L1 expression subgroups. The confirmed ORRs in patients with baseline PD-L1 tumor proportion scores (TPS) of less than 1%, 1% to 49%, and 50% or higher were 57.1%, 62.5%, and 75.0%, respectively.
Similarly, no correlation was found between response to the doublet and EGFR expression levels. Patients with baseline EGFR H scores under 200 had a confirmed ORR of 68.4%, while those with scores of 200 or higher had a confirmed ORR of 76.9%.
The combination also demonstrated efficacy in patients with challenging co-mutations. Those with PD-L1 TPS of less than 1% and STK11 co-mutations achieved a confirmed ORR of 62.5%, while patients with KEAP1 co-mutations also showed responses regardless of EGFR expression levels.
Safety Profile
The fulzerasib-cetuximab combination demonstrated a manageable safety profile. Treatment-related adverse effects (TRAEs) occurred in 87.2% of patients, with grade 3 events reported in 14.9%. Serious TRAEs were experienced by 4.3% of patients, though none were related to fulzerasib.
The most common TRAEs included rash (53%), pruritus (32%), asthenia (26%), nausea (26%), and dermatitis acneiform (19%). Most adverse events were grade 1 or 2 in severity.
"[The regimen had a] good safety profile," Dr. Majem said. "Most TRAEs were grade 1 or 2 with no new safety signals."
Comparison with Other KRAS G12C-Targeted Approaches
The fulzerasib-cetuximab combination adds to the growing landscape of therapies targeting KRAS G12C mutations in NSCLC. Another approach being investigated is the combination of adagrasib (Krazati) with pembrolizumab (Keytruda), which has shown an ORR of 59% and a median PFS of 27.7 months in patients with KRAS G12C-mutated NSCLC and PD-L1 TPS ≥50%, according to 2-year follow-up data from the phase 2 KRYSTAL-7 trial also presented at the 2025 European Lung Cancer Congress.
The adagrasib-pembrolizumab combination demonstrated durable responses with a median duration of response of 26.3 months, though it had a different safety profile with grade 3-4 TRAEs occurring in 69% of patients.
Clinical Implications
The emergence of effective targeted combinations for KRAS G12C-mutated NSCLC represents a significant advancement in precision medicine for lung cancer. KRAS mutations have historically been considered "undruggable," but recent developments with KRAS G12C inhibitors are changing this paradigm.
The fulzerasib-cetuximab combination, if confirmed in larger studies, could provide a chemotherapy-free first-line option for patients with KRAS G12C-mutated NSCLC. This would be particularly valuable for patients who may not tolerate or prefer to avoid chemotherapy.
The planned phase 3 study focusing on patients with PD-L1 expression under 50% will be crucial to determine whether this combination can become a standard of care option for this specific patient population.
Future Directions
As research into KRAS-targeted therapies continues to evolve, several questions remain to be addressed:
- How will these combinations compare with standard first-line options like chemotherapy plus immunotherapy?
- Can biomarkers beyond KRAS G12C mutation status help identify patients most likely to benefit from these targeted approaches?
- What are the optimal strategies for managing resistance that inevitably develops to KRAS G12C inhibitors?
The ongoing development of fulzerasib-cetuximab and other KRAS-targeted combinations represents an important step forward in expanding treatment options for patients with KRAS G12C-mutated NSCLC, a population with historically limited targeted therapy options.
