GenFleet Therapeutics, a commercial-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, today announced the latest phase II data of KROCUS study, fulzerasib (GFH925, KRAS G12C inhibitor) in combination with cetuximab for first-line non-small cell lung cancer (NSCLC) treatment，in a late-breaking abstract at the mini oral presentation of the 2025 European Lung Cancer Conference (ELCC) annual meeting.
Spearheaded by GenFleet in collaboration with top-tier European lung cancer experts, the KROCUS study delivered impressive efficacy across all trial participants and particularly exceptional tumor response among brain-metastatic patients. Additionally, the regimen demonstrated better safety/tolerability over fulzerasib monotherapy in second-line and above NSCLC treatment; KROCUS also indicated superior therapeutic potential over current standard-of-care (SOC) including immunotherapy in first-line KRAS-mutant NSCLC treatment. As a pioneering combination of a KRAS G12C inhibitor (fulzerasib) and an anti-EGFR antibody (cetuximab) in first-line lung cancer treatment, this innovative approach holds the potential to establish the next-generation SOC for first-line NSCLC therapy.
The KROCUS study, led by renowned lung cancer expert Dr. Rafael Rosell, is a European multi-center phase Ib/II trial initiated in March 2023. As of Jan. 14 in 2025, a total of 47 patients were enrolled and 45 of them received at least one post-treatment tumor assessment: the objective response rate (ORR) reached 80% and the disease control rate (DCR) reached 100%. The post-treatment evaluation revealed 3 patients achieved complete response; 33 others reached partial response, including one with 100% tumor shrinkage; 57.8% of patients exhibited ≥50% tumor shrinkage. As data cut-off date, the median follow-up time was 12.8 months, and the median progression-free survival was 12.5 months.
34% of enrolled patients had baseline brain metastasis, and the ORR was 71.4% per RECIST 1.1 among brain-metastatic patients who received at least one post-treatment tumor assessment; all non-target lesions of brain-metastatic patients disappeared or remained stable in the course, and brain target lesions of 5 patients exhibited shrinkage.
The data also showcased the combination therapy’s superior therapeutic potential over immunotherapy or chemo-immunotherapy in first-line KRAS-mutant NSCLC treatment: consistent response rates were observed in KROCUS study across subgroups with varied PD-L1 expressions; since STK11 and KEAP1 have been identified as associated with a lower response to immunotherapy and with poor prognosis for first-line NSCLC SOC, it’s noteworthy that similar responses were discovered in KROCUS study between STK11 or KEAP1 wild-type patients and those with STK11 or KEAP1 co-mutations.
The combination therapy displayed a highly favorable safety/tolerability profile, with a lower incidence of treatment-related adverse events (TRAEs) than that of fulzerasib monotherapy for second-line and above NSCLC treatment; grade 3 or higher TRAEs occurred at a considerably lower rate than that of fulzerasib monotherapy (no grade 4 or 5 TRAEs in KROCUS study). The mini oral presentation at ELCC was finished by Dr. Margarita Majem from Hospital de laSanta Creu i Sant Pau, Barcelona.
“I am delighted to participate in this innovative study on first-line NSCLC treatment. The encouraging efficacy data from phase II trial validated investigators’ initial understanding of the study design. The trial findings also underscored the potential of this regimen, designed according to the KRAS-EGFR synergistic mechanism of the RAS pathway, to become a novel SOC for first-line NSCLC treatment. We are pleased that most brain-metastatic patients, without receiving anti-tumor radiotherapy prior to enrollment, were observed with notable tumor response in the trial. Moreover, the impressive safety/tolerability data bolstered our confidence in exploring KRAS-targeted therapies in first-line lung cancer treatment.”stated Dr. Rafael RosellPrincipal Investigator of KROCUS study.
“Two therapies combining KRAS inhibitors with anti-EGFR antibodies have been approved for late-line colorectal cancer treatment. We have integrated the validated mechanism of dual-target synergy with an innovative first-line setting to treat NSCLC, the tumor type with the highest prevalence of G12C mutation. This regimen is well-positioned to mitigate overlapped toxicities while effectively postponing the onset of potential resistance through the mechanistic synergy. This chemo- and immune-free combination represents a potential novel first-line SOC and leaves space for later-line immunotherapy to extend patients’ overall survival. Fulzerasib is the first KRAS G12C inhibitor launched in China and the third globally; we hope the KROCUS study will move fulzerasib forward to front-line treatment, bringing this promising combo therapy to global patients.”stated Yu Wang, M.D.,Ph.D.Chief Medical Officer of GenFleet.
First-line (1L) fulzerasib + cetuximab in KRAS G12Cm advanced NSCLC: updated efficacy and safety from KROCUS study
Presenter: Dr. Margarita Majem
Abstract No. : LBA1
A total of 47 previously untreated advanced KRAS G12C-mutant NSCLC patients were treated with fulzerasib in combination with cetuximab (fulzerasib 600mg BID + cetuximab 500 mg/m2 Q2W) as of Jan 14, 2025.
Efficacy: As of data cutoff date, among the 45 patients who received at least one post-treatment tumor assessment, the ORR was 80% and DCR was 100%; 57.8% had ≥ 50% tumor shrinkage. 16 patients (34%) had brain metastasis; among the 14 brain-metastatic patients that received at least one post-treatment tumor assessment, the ORR per RECIST 1.1 was 71.4%. The median duration of response (DoR) was not reached yet, and 24 patients were still on treatment with a median follow-up of 10.1 months. The mPFS was 12.5 months and the mOS was not reached.
Safety: As of data cutoff date, the combination therapy presented a favorable safety/tolerability profile. TRAEs occurred in 87.2% of patients and the majority of the TRAEs were graded 1-2; 14.9% of patients experienced at least one grade 3 TRAEs; no grade 4-5 TRAEs. 2 patients had treatment-related serious adverse events (TRSAE) and the TRSAEs were assessed to be merely related with cetuximab; 3 patients experienced TRAEs, unrelated to fulzerasib, leading to dose discontinuation. KROCUS demonstrated a relatively low occurrence of dose discontinuation or reduction among different first-line G12C-mutant NSLCL combo studies. No new safety signals were identified compared with fulzerasib or cetuximab as single agent.
About KROCUS Study The multi-center study of fulzerasib in combination with cetuximab started in scores of clinical research centers worldwide from March 2023 and sets its objectives to evaluate the safety/tolerance, efficacy and the pharmacokinetic characteristics of the combination in advanced NSCLC patients harboring KRAS G12C mutation.
Fulzerasib the first China-developed KRAS G12C inhibitor that has its NDA submission accepted and granted with Priority Review Designation by NMPA. Fulzerasib also received Breakthrough Therapy Designations this year for treating advanced KRAS G12C-mutant NSCLC patients that have received at least one systemic therapy and CRC patients who have received at least two systemic therapies.RAS protein family can be divided into KRAS, HRAS and NRAS categories. KRAS mutations are detected in nearly 90% of pancreatic cancer, 30-40% of colon cancer, and 15-20% lung cancer patients. The occurrence of KRAS G12C mutation subset is more frequently observed than those with ALK, ROS1, RET and TRK 1/2/3 mutations combined. GFH925 is a novel, orally active, potent KRAS G12C inhibitor designed to effectively target the GTP/GDP exchange, an essential step in pathway activation, by modifying the cysteine residue of KRAS G12C protein covalently and irreversibly. Preclinical cysteine selectivity studies demonstrated high selectivity of fulzerasib towards G12C. Subsequently, fulzerasib effectively inhibits the downstream signal pathway to induce tumor cells’apoptosis and cell cycle arrest.
