KRAS G12C–mutated NSCLC | Image Credit:
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The doublet comprised of fulzerasib (GFH925) and cetuximab (Erbitux) demonstrated efficacy with acceptable safety when utilized as first-line treatment in patients with advanced non–small cell lung cancer (NSCLC) harboring KRAS G12C mutations, according to updated data from the phase 2 KROCUS study (NCT05756153) presented during the 2025 European Lung Cancer Congress.1
At a data cutoff date of January 14, 2025, the combination elicited an objective response rate (ORR) of 80.0% in evaluable patients (n = 47); the confirmed ORR was 68.9%. More than half of patients (57.8%) experienced tumor shrinkage of at least 50%. The disease control rate (DCR) was 100%. Ten of the patients with brain metastases (n = 14), achieved systemic response by RECIST 1.1 (ORR, 71.4%). All non-target lesions either disappeared or became stable. In 5 patients who had brain target lesions, all shrank during the treatment period.
At a median follow-up of 12.8 months (range, 0.16-18.4), the median duration of response (n = 31) was not reached (NR; 95% CI, 10.7-not applicable [NA]). The median progression-free survival (n = 47) was 12.5 months (95% CI, 7.39-NA). The median overall survival was also NR.
“The combination shows the potential to provide a chemotherapy-free option in the first-line setting,” Margarita Majem, MD, PhD, of Hospital de laSanta Creu i Sant Pau, in Barcelona, Spain, said in a late-breaking presentation of the data. “A phase 3 study in the population of patients with a PD-L1 under 50% is being planned.”
A Bird’s Eye View of KROCUS: Background, Design, Previous Data, and More
The single-arm, open-label, phase 2 trial included patients with pathologically confirmed advanced NSCLC with KRAS G12C mutations who had not previously received systemic treatment for advanced or metastatic lesions and who had an ECOG performance status no higher than 1. Patients could not have other known actionable driver mutations or alterations, but those with stable and asymptomatic brain metastases were permitted.
Participants received 600 mg of fulzerasib twice daily plus 500 mg/m2 of cetuximab every 2 weeks. Treatment continued until disease progression, intolerable toxicity, or other withdrawal criteria were met. ORR by RECIST 1.1 served as the trial’s primary end point, and key secondary end points included PFS by RECIST 1.1 and safety. Exploratory end points included analysis of PD-L1 (TPS) and EGFR (H score) expression levels as well as the examination of co-mutations at baseline and end of therapy.
“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,” Majem noted. Prior findings from the study indicated that the doublet induced an ORR of 81.8% and a DCR of 100%.2
Looking at the Current Analysis
In the 47 evaluable patients, the median age was 68 years (range, 46-87) and 53.2% were male. Most patients were White (95.7%), former smokers (72.3%), had an ECOG performance status of 1 (55.3%), and had adenocarcinoma (97.9%). Patients had TNM stage IIIB (4.3%), IVA (53.2%), or VB (42.6%) disease.1 Moreover, 34.0% of patients had brain metastasis, 23.4% had bone metastasis, and 19.1% had adrenal gland metastasis. One patient received prior neoadjuvant therapy and 2 patients previously received chemoradiation.
As of the data cutoff date, 24 patients were still receiving treatment. The median duration of treatment was 10.1 months (range, 0.2-18.4).
When investigators looked at PD-L1 and EGFR expression, they noted comparable response rates across PD-L1 subsets and did not find any correlation between response to the doublet and EGFR expression levels. The confirmed ORRs (cORRs) in those with baseline PD-L1 TPS expression of less than 1% (n = 14), 1% to 49% (n = 8), and 50% or higher (n = 12) were 57.1%, 62.5%, and 75.0%, respectively. The cORRs in those with baseline EGFR H scores of under 200 (n = 19) and 200 or higher (n = 13) were 68.4% and 76.9%, respectively.
Responses were observed in those with STK11 or KEAP1 co-mutations, as well. Those with PD-L1 TPS of less than 1% and a STK11 co-mutation (n = 8) had a cORR of 62.5%; those with a PD-L1 TPS of 1% to 49% and STK11 co-mutation (n = 36) had a cORR of 69.4%. Those with an EGFR H score under 200 and a KEAP1 co-mutation (n = 3) had a cORR of 66.7%; those with an EGFR H score of 200 or higher and a KEAP1 co-mutation (n = 41) had a cORR of 68.3%.
Safety Spotlight
At least 1 treatment-related adverse effect (TRAE) occurred in 87.2% of those who received the doublet, and these effects were grade 3 for 14.9% of patients. At least 1 serious TRAE was experienced by 4.3% of patients but none were related to fulzerasib. At least 1 TRAE led to dose reduction, interruption, or discontinuation for 10.6%, 27.7%, and 6.4% of patients, respectively; they were related to fulzerasib for 8.5%, 14.9%, and 0% of cases, respectively.
The most common TRAEs experienced with the combination were rash (any grade, 53%; grade 3, 2%), pruritus (32%; 0%), asthenia (26%; 2%), nausea (26%; 0%), dermatitis acneiform (19%; 0%), diarrhea (13%; 0%), peripheral edema (9%; 0%), anemia (9%; 0%), dyspnea (4%; 0%), and pyrexia (4%; 0%).
“[The regimen had a] good safety profile,” Majem said. “Most TRAEs were grade 1 or 2 with no new safety signals.”
Disclosures: Dr Majem disclosed receiving speaker fees from Amgen, AstraZeneca, Casen Recordati, Helsinn, Pfizer, Roche, and Takeda. She received advisory board fees from Amgen, AstraZeneca, BMS, Beigene, Casen Recordati, Janssen, Pfizer, Roche, Sanofi, and Takeda. Institutional fees were provided by AstraZeneca, BMS, and Roche. The study was sponsored by Zhejiang GenFleet Therapeutic, Inc.
References
Majem M, Gregorc V, Lo Russo G, et al. First-line (1L) fulzerasib + cetuximab in KRAS G12Cm advanced NSCLC: Updated efficacy and safety from KROCUS study. Presented at: 2025 European Lung Cancer Congress; March 26-29, 2025; Paris, France. Abstract LBA1.
Gregorc V, González-Cao M, Salvagni S, et al. KROCUS: A phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC. J Clin Oncol. 2024;42(suppl 17):LBA8511. doi:10.1200/JCO.2024.42.17_suppl.LBA8511