LBA1 - First-line (1L) fulzerasib + cetuximab in KRAS G12Cm advanced NSCLC: Updated efficacy and safety from KROCUS study

Background

Upstream activation of epidermal growth factor receptor (EGFR) has been identified as a dominant mechanism underlying resistance to KRAS inhibition. The synergistic effect of KRAS G12C inhibitor and anti-EGFR antibody has been proved in clinical settings. Here we report the updated data of fulzerasib (FUL) plus cetuximab (CETU) from the KROCUS trial (NCT05756153).

Methods

KROCUS is an international, single-arm, multicenter phase 2 study evaluating FUL plus CETU in 1L pts with KRAS G12Cm advanced NSCLC. Pts would receive FUL orally at 600 mg BID and CETU iv 500 mg/m², Q2W. The primary endpoint is objective response rate (ORR) assessed by investigator per RECIST v1.1. Other endpoints include safety, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and exploratory biomarkers.

Results

As of 14 Jan 2025, 47 pts received the combination of FUL and CETU with a median follow-up time 12.8 months (ms, range: 0.16, 18.4). The mPFS was 12.5 ms (95% CI: 7.39, NA). The mDoR and mOS were not reached. The ORR was 80.0% (36/45, cORR 68.9%) among evaluable pts and 57.8% (26/45) had ≥ 50% tumor shrinkages. The systemic ORR in pts with brain metastases was 71.4% (10/14) per RECIST 1.1. Responses were consistent across different PD-L1 TPS levels with cORR 57.1% (8/14), 62.5% (5/8) and 75.0% (9/12) in

Conclusions

The combination of FUL + CETU showed deep and durable response with a favorable safety profile in 1L KRAS G12Cm NSCLC pts, providing a chemo-free treatment option. A phase III randomized trial with control of pembrolizumab plus chemotherapy is being planned to confirm the efficacy and safety of this novel combination in pts with PDL1 TPS < 50% in the 1L.

Clinical trial identification

NCT05756153.

Legal entity responsible for the study

Zhejiang GenFleet Therapeutics Co., Ltd.

Funding

Zhejiang GenFleet Therapeutics Co., Ltd.

Disclosure

M. Majem: Financial Interests, Personal, Advisory Board: Amgen, Roche, AstraZeneca, Takeda, Janssen, Cassen Recordati, BMS, Sanofi, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Roche, AstraZeneca, Pfizer, Takeda, Helsinn, Cassen Recordatti; Financial Interests, Institutional, Funding: BMS, AstraZeneca, Roche; Non-Financial Interests, Personal, Leadership Role, Board Member: Associacio Contra El Cancer Barcelona; Non-Financial Interests, Personal, Leadership Role: Asocacion Para La Investigacion Del Cancer De Pulmon En Mujeres. V. Gregorc: Financial Interests, Personal, Expert Testimony, 2020: Sanofi; Financial Interests, Personal, Advisory Board, 2021: Eli Lilly; Financial Interests, Personal, Advisory Board, 2022: Boehringer Ingelheim; Financial Interests, Personal, Expert Testimony, 2022: Pfizer; Financial Interests, Personal, Invited Speaker, 2023: Novartis; Financial Interests, Personal, Advisory Board, 2024: BMS, Pierre Fabre, Regeneron; Financial Interests, Personal, Invited Speaker, 2024: MSD. G. Lo Russo: Financial Interests, Personal, Advisory Board: MSD, Novartis, AstraZeneca, BMS, Sanofi, Pfizer, Roche, Lilly, GSK, Daiichi Sankyo, Johnson & Johnson, Regeneron, Merck, Pierre Fabre; Financial Interests, Personal, Invited Speaker: Italfarmaco, Merck, BMS, Lilly, Sanofi; Financial Interests, Institutional, Other, Contribute For Meeting Organization: Janssen; Financial Interests, Institutional, Other, Contribute For Meeting Organization: Bayer; Financial Interests, Personal, Other, Travel Accommodation: Amgen, MSD; Financial Interests, Institutional, Other, Contribute to meeting organization: BeiGene; Financial Interests, Institutional, Invited Speaker: MSD, BMS, Roche, GSK, Celgene, Novartis, AstraZeneca, Amgen, Lilly. M. Maio: Financial Interests, Personal, Advisory Board: BMS, Roche, GSK, Sanofi, Alfasigma, Amgen, Sciclone, Eli Lilly, MSD, Incyte, Pierre Fabre, AstraZeneca, Pfizer, Merck Serono; Financial Interests, Personal, Stocks/Shares: Epigen, Theravance. M. Gonzalez Cao: Financial Interests, Personal, Research Grant: Roche, AstraZeneca; Financial Interests, Personal, Other, travel and accommodations reimbursement: Pierre Fabre. A. Koumarianou: Non-Financial Interests, Institutional, Speaker’s Bureau: MSD, Bristol Myers Squibb, AstraZeneca. A. Bearz: Financial Interests, Personal, Invited Speaker: Pfizer, BMS, Novartis; Financial Interests, Personal, Advisory Board: Pfizer, Regeneron, Roche, Pierre Fabre. R. Bernabe Caro: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Lilly, Sanofi, Janssen. S. Viteri: Financial Interests, Personal, Advisory Board: Merck Healthcare KGAA Germany, Bristol Myers Squibb S.A. U, Ipsen, Affimed; Financial Interests, Personal, Invited Speaker: MSD de España SA; Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: Canon Medical, OSE Immunotherapeutics, Nuvalent, AbbVie, Genfleet, Dizal, Taiho, GSK, Anheart Therapeutics; Financial Interests, Personal, Officer: Mi Cancer Center SLP; Financial Interests, Personal, Ownership Interest, Private Healthcare Practice: Mi Cancer Center SLP. M.F. Sanmamed: Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Advisory Board: MSD, Catalym. F. Zagouri: Financial Interests, Personal, Invited Speaker: Roche, Novartis, Gilead, Genesis Pharma, AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, MSD, Pfizer; Non-Financial Interests, Personal, Principal Investigator: Roche, Eli Lilly, Pfizer, MSD. M.T. Moran Bueno: Financial Interests, Personal, Invited Speaker: MSD, Roche; Non-Financial Interests, Personal, Other, Travel expenses: MSD. Y. Zhang, Y. Shan, H. Zhu: Financial Interests, Personal, Full or part-time Employment: GenFleet Therapeutics. All other authors have declared no conflicts of interest.