KEY TAKEAWAYS
- The phase 1 & 2 trial aimed to investigate the efficacy and safety of combining fulzerasib, with cetuximab as front-line treatment for patients with NSCLC.
- The primary objective was to evaluate fulzerasib with cetuximab in untreated advanced NSCLC with KRAS G12C mutation.
- Researchers noticed promising efficacy and safety of fulzerasib + cetuximab; further investigation is ongoing.
Fulzerasib (GFH925), a KRAS G12C inhibitor, showed substantial efficacy in previously treated patients with Non–Small Cell Lung Cancer (NSCLC) as monotherapy. Activation of the epidermal growth factor receptor (EGFR) is identified as one of the dominant mechanisms for KRAS inhibition resistance. Preclinical evidence showed synergistic activity in KRAS G12C mutant NSCLC modeling using fulzerasib in combination with cetuximab.
Vanesa Gregorc and the team aimed to report the first results for a KRAS G12C inhibitor combined with an anti-EGFR antibody in patients with NSCLC as front-line treatment.
They performed an inclusive analysis in the KROCUS (NCT05756153) study, an open-label, single-arm, multi-center, Phase II trial. The primary objective was to evaluate the efficacy of fulzerasib in combination with cetuximab in patients with previously untreated advanced NSCLC harboring KRAS G12C mutation. Secondary objectives included assessing safety/tolerability, pharmacokinetics, and biomarkers. Patients were enrolled to receive fulzerasib (oral, 600 mg BID) and cetuximab (intravenous, 500 mg/m2, every two weeks [Q2W]) combination treatment in a 28-day cycle.
About 27 patients (median age: 68 years old; 55.6% female) were treated on Jan. 30, 2024. A total of 11 (40.7%) have baseline brain metastases. Among 20 patients with at least 1 post-treatment tumor assessment, the overall response rate (ORR) was 80.0% (95% CI: 56.3, 94.3, including 1 complete response [CR]), with 8 patients experiencing ≥50% tumor shrinkage in target lesions.
The disease control rate (DCR) was 100% (95% CI: 83.2, 100.0). Notably, 71.4% of patients with brain metastases achieved partial responses (PRs). Of the nine patients with baseline PD-L1 expression tested (6 TPS≥1% and 3 TPS <1%), all achieved PRs.
The overall safety profile of the combination treatment was favorable, with treatment-related adverse events (TRAEs) of any grade occurring in 21 patients (77.8%). About 5 patients (18.5%) experienced Grade 3 (G3) TRAEs, with no G4 or 5 TRAEs reported. Three patients (11.1%) had dose reduction/interruption with fulzerasib due to TRAEs, while 1 patient (3.7%) had dose reduction/interruption, and 3 patients (11.1%) discontinued cetuximab due to TRAEs.
The study concluded that preliminary data from the ongoing KROCUS study indicated promising efficacy and a favorable safety profile for the combination of fulzerasib and cetuximab in the first-line treatment of KRAS G12C mutated NSCLC. Further data generation is anticipated to solidify its potential as a frontline therapy option.
The trial was sponsored by the Zhejiang Genfleet Therapeutics Co., Ltd.
Source: https://meetings.asco.org/abstracts-presentations/232540
Clinical Trial: https://clinicaltrials.gov/study/NCT05756153
Gregorc V, González-Cao M, Salvagni S, et al. (2024). “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.” Presented at ASCO 2024. J Clin Oncol 42, 2024 (suppl 17; abstr LBA8511), 10.1200/JCO.2024.42.17_suppl.LBA8511
