GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies in oncology and immunology, announced China’s National Medical Products Administration has approved Dupert®（fulzerasib, GFH925/IBI351）for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation who have received at least one systemic therapy. Fulzerasib was the first China-developed KRAS G12C inhibitor that had its NDA submission accepted with Priority Review Designation in 2023, and the monotherapy was also granted two Breakthrough Therapy Designations (BTD) for treating advanced KRAS G12C-mutant NSCLC and colorectal cancer (CRC) patients.
The NDA approval is based on the results from a single-arm registrational study (NCT05005234) intended to evaluate the efficacy and safety of fulzerasib monotherapy in advanced NSCLC patients with KRAS G12C mutation who failed or were intolerant to the standard treatment in China. The updated data from this registration study has been published in full manuscript in the Journal of Thoracic Oncology (JTO) .
As of the data cutoff date (Dec 13, 2023), a total of 116 NSCLC subjects were enrolled and evaluable. Fulzerasib was generally well-tolerated and demonstrated encouraging antitumor activity. The confirmed objective response rate (ORR) assessed by the Independent Radiology Review Committee (IRRC) was 49.1% (95% CI: 39.7-58.6). Disease control rate (DCR) was 90.5% (95%CI: 83.7, 95.2). The median duration of response (DoR) was not reached. Median progression-free survival (PFS) was 9.7 months (95%CI: 5.6-11.0), and median overall survival (OS) was not yet reached.
Beyond monotherapy, the combination of KRAS and EGFR inhibitors exhibits a synergistic biological mechanism and thus enables the potential of fulzerasib to serve as a first-line treatment option. In 2023, GenFleet initiated a first-line NSCLC combination study (KROCUS) of fulzerasib and cetuximab in Europe, led by world-renowned Professor Rafael Rosell. The analysis of preliminary phase II data was selected for late-breaking abstract and oral presentation at the ASCO conference in June 2024: as of Apr. 19 2024, a total of 33 subjects had at least one post-treatment tumor assessment. The ORR was 81.8% (95% CI: 64.5, 93) and the DCR was 100% (95% CI: 89.4, 100). The ORR was 70% among those with brain metastases (32.5% of enrolled patients).
Yu Wang, M.D.,Ph.D.
Chief Medical Officer of GenFleet
“Initiated in 2018, the fulzerasib’s development has been moving forward rapidly and yielded positive results. We are delighted at the approval of fulzerasib in China and thankful for the collaborative efforts of Innovent Biologics and the investigators. Given the high G12C prevalence among advanced NSCLC patients in western countries, GenFleet has embarked on the KROCUS study in Europe, a pioneering trial of first-line therapy integrating KRAS and EGFR inhibitors. In specific patient populations, the KROCUS study has demonstrated efficacy and safety potentially comparable or even superior to immunotherapy combined with chemotherapy, positioning the fulzerasib/cetuximab combination as a potentially novel first-line SOC for G12C-mutated NSCLC patients.”
RAS protein family can be divided into KRAS, HRAS and NRAS categories. KRAS mutation 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 NTRK 1/2/3 mutations combined.
Discovered by GenFleet Therapeutics, fulzerasib (GFH925/IBI351) 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 GFH925 towards G12C. Subsequently, GFH925 effectively inhibits the downstream signal pathway to induce tumor cells’ apoptosis and cell cycle arrest.
In September 2021, Innovent and GenFleet Therapeutics entered into an exclusive license agreement for the development and commercialization of GFH925 in China (including the Chinese mainland, Hong Kong, Macau and Taiwan) with additional option-in rights for global development and commercialization.
In January 2023, the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has granted Breakthrough Therapy Designation (BTD) for fulzerasib for the treatment of patients with advanced NSCLC harboring KRAS G12C mutation who have received at least one systemic therapy. In May 2023, the CDE of China’s NMPA granted another BTD for fulzerasib for the treatment of advanced CRC patients with KRAS G12C mutation who have received at least two systemic therapies.
In August 2024, the CDE of NMPA has approved fulzerasib for the treatment of advanced NSCLC patients harboring KRAS G12C mutation who have received at least one systemic therapy.
GenFleet Therapeutics, a clinical-stage biotechnology company focusing on cutting-edge therapies, is dedicated to serving significant global unmet medical needs in oncology and immunology. Based on the deep understanding of disease biology and translational medicine, GenFleet’s proprietary and fully integrated R&D platform highlights multiple cutting-edge products with novel mechanisms and global IP.
Since its inception in 2017, GenFleet has built up industry-leading capabilities and expertise in developing novel drug candidates - both small molecules and biologics. Its pipeline includes over 10 programs, many of which have entered later-stage or pivotal clinical trials across China (including Taiwan), the United States, Europe and Australia. The first-line combination therapy of fulzerasib and cetuximab has entered into phase II study in Europe, marking the world's first treatment integrating KRAS and EGFR inhibitors for first-line non-small cell lung cancer.
With accomplished capabilities in RAS-pathway targeted therapies, GenFleet's also vigorously pursuing the development of other innovative therapies and novel modalities. Furthermore, it's also expanding commercial collaborative network through strategic out-licensing agreements or clinical cooperations with prestigious listed companies including Innovent, Verastem, SELLAS and Merck, BeiGene. GenFleet is expected to progress additional programs into the clinic, as well as transition from a clinical stage biotech company into a commercial stage biopharmaceutical company in the next 3-5 years.
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