On June 1, 2023 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of oncology, autoimmune, metabolic, ophthalmology and other major diseases, reported that it has entered into a clinical trial collaboration and supply agreement with Merck KGaA, Darmstadt, Germany for the combination therapy of IBI351 (GFH925) with cetuximab (ERBITUX) as a potential frontline treatment for NSCLC patients harboring KRASG12C mutation in a Phase 1b clinical trial in China (Press release, Innovent Biologics, JUN 1, 2023, View Source [SID1234632363]).
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Under the agreement, Innovent will conduct a Phase 1b study to evaluate the anti-tumor activity and safety of the combination therapy of IBI351(GFH925) with cetuximab in Chinese patients with advanced or metastatic NSCLC harboring KRASG12C mutation. Merck KGaA, Darmstadt, Germany will provide clinical drug supplies of cetuximab in this multi-center trial in China. Cetuximab as a monotherapy or as a combination therapy has not been approved in any country for patients with advanced NSCLC.
Currently, Innovent is conducting a single-arm registrational trial of IBI351(GFH925) monotherapy in previously-treated advanced non-small cell lung cancer patients with KRASG12C mutation in China, with expected NDA filing by the end of 2023. A Phase 1b study of IBI351(GFH925) in combination with sintilimab for previously untreated advanced NSCLC patients with KRASG12C mutation is also under exploration. Latest data of a Phase 1 study of IBI351(GFH925) monotherapy in 67 previously-treated NSCLC patients with KRASG12C mutation were presented at the 2023 American Association for Cancer Research (AACR) (Free AACR Whitepaper)(AACR) Annual Meeting [Link].
Dr. Hui Zhou, Senior Vice President of Innovent, stated: "We are pleased to collaborate with Merck KGaA, Darmstadt, Germany to further explore the potential of IBI351 and cetuximab combination therapy in the early line setting for NSCLC patients harboring KRASG12C mutation, and shed light on next-step clinical development. The combination of a KRASG12C inhibitor and an EGFR inhibitor has shown efficacy in heavily pre-treated patients with metastatic colorectal cancer [1],[2],[3]. Preclinical studies of IBI351 and cetuximab combination therapy also demonstrated potential anti-tumour activity in NSCLC. Innovent has observed favorable safety and promising antitumor activity of IBI351 monotherapy in previously-treated advanced NSCLC harboring KRASG12C mutation, and we are actively expanding treatment lines, hoping to provide better treatment options for more cancer patients. "
About IBI351/GFH925 (KRASG12C Inhibitor)
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 TRK 1/2/3 mutations combined.
Discovered by GenFleet Therapeutics, GFH925 (Innovent R&D code: IBI351) is a novel, orally active, potent KRASG12C inhibitor designed to effectively target the GTP/GDP exchange, an essential step in pathway activation, by modifying the cysteine residue of KRASG12C protein covalently and irreversibly. Preclinical cysteine selectivity studies demonstrated high selectivity of IBI351 towards G12C. Subsequently, IBI351 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 IBI351 in China (including mainland China, 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 IBI351 for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring KRASG12C mutation who have received at least one systemic therapy. In May 2023, the CDE of China’s NMPA granted another BTD for IBI351 for the treatment of previously treated advanced colorectal carcinoma (CRC) patients with KRASG12C mutation.
About Cetuximab (ERBITUX)
Cetixumab (ERBITUX) is an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of action of cetuximab is distinct from standard non-selective chemotherapy treatments in that it specifically targets and binds to the EGFR. This binding inhibits the activation of the receptor and the subsequent signal-transduction pathway, which results in reducing both the invasion of normal tissues by tumor cells and the spread of tumors to new sites. It is also believed to inhibit the ability of tumor cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumors, which appears to lead to an overall suppression of tumor growth. Based on in vitro evidence, cetuximab also targets cytotoxic immune effector cells towards EGFR-expressing tumor cells (antibody-dependent cell-mediated cytotoxicity [ADCC]).
ERBITUX has already obtained market authorization in over 100 countries worldwide for the treatment of RAS wild-type metastatic colorectal cancer and for the treatment of squamous cell carcinoma of the head and neck. Merck licensed the right to market ERBITUX, a registered trademark of ImClone LLC, outside the U.S. and Canada from ImClone LLC, a wholly owned subsidiary of Eli Lilly and Company, in 1998.