On November 30, 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, metabolic, autoimmune, ophthalmology and other major diseases, reported the publication of updated clinical data of IBI351 (KRAS G12C inhibitor) monotherapy in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) at the European Society for Medical Oncology Asia Congress (ESMO Asia) 2023, held during December 1-3 in Singapore (Press release, Innovent Biologics, NOV 30, 2023, View Source [SID1234638074]). The data from a registrational Phase II study of IBI351 for NSCLC is accepted as a LBA (Late-breaking abstracts) program. The New Drug Application (NDA) for IBI351 monotherapy treating NSCLC was recently accepted by China’s National Medical Products Administration (NMPA) and granted Priority Review Designation.

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Presentation title: Efficacy and safety of IBI351 (GFH925), a selective KRAS G12C inhibitor, monotherapy in advanced non-small cell lung cancer (NSCLC) patients with KRAS G12C mutation: initial results from a registrational phase II study

Abstract #: LBA12

IBI351 (GFH925) is a selective, covalent and irreversible KRAS G12C inhibitor. The data presented was from a single-arm Phase 2 registration clinical study (NCT05005234) in advanced NSCLC patients harbouring KRAS G12C mutation who have received at least one systemic therapy.

As data cutoff date (June 13, 2023), a total of 116 NSCLC subjects were enrolled and evaluable:

IBI351 demonstrated encouraging antitumor activity. The confirmed objective response rate (ORR) assessed by the Independent Imaging Review Committee (IRRC) was 46.6% (95%CI: 37.2-56.0), meeting the primary endpoint. Disease control rate (DCR) was 90.5% (95%CI: 83.7, 95.2). The median duration of response (DoR) was 8.3 months, and 53.7% (29/54) of participants with tumor response were still on treatment. Median progression-free survival (PFS) was 8.3 months (95%CI: 5.6-10.4), and median survival (OS) was not yet reached.
IBI351 was well tolerated in general. As data cutoff, about 90.5% (105/116) of subjects had treatment-related adverse events (TRAEs), most were grade 1-2. The most common TRAEs were anemia, alanine aminotransferase increased, aspartate aminotransferase increased, asthenia and protein urine present. About 40.5% of subjects had grade 3 or higher TRAEs.
Professor Yi-Long Wu, Leading Principal Investigator of the study, from Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, stated: "KRAS mutation as the ‘undruggable’ target for decades has become one of the most popular directions for clinical development recently. Although FDA has approved KRAS G12C targeted drugs overseas, there’s no drug approved in China. IBI351 is China’s first KRAS G12C inhibitor with NDA acceptance. As a selective, covalent and irreversible KRAS G12C inhibitor, IBI351 has demonstrated excellent efficacy and manageable safety in pivotal Phase 2 study. We look forward to the approval of this drug to benefit more NSCLC patients harbouring KRAS G12C mutation who have received at least one systemic therapy."

Presentation title: Efficacy and safety of IBI351(GFH925) monotherapy in metastatic colorectal cancer harboring KRAS G12C mutation: updated results from a pooled analysis of two phase I studies

Abstract #: 106P

IBI351 (GFH925) is a specific selective, covalent and irreversible KRAS G12C inhibitor. The updated data presented is based on the pooled analysis of two ongoing clinical studies (NCT05005234, NCT05497336) with extended follow-up.

As of June 13, 2023, a total of 56 patients with advanced CRC were enrolled (3 in the 700mg QD dose group, 4 in the 450mg BID dose group, 48 in the 600mg BID dose group, and 1 in the 750mg BID dose group).

For 600mg BID patients (n=48), confirmed ORR was 45.8% and DCR was 89.6%. Median DoR was not reached, and the 6 month DoR rate was 65.5%. Median PFS was 7.6 months. Median OS has not yet been reached, with a 6month OS rate of 91.1%.
For 600mg BID patients with at least two lines of prior treatment (n=27), cORR and DCR were 63.0% and 88.9%, respectively.
TRAEs occurred in 94.6% patients while majority of them were grade 1-2. The most common TRAEs were anamia, white blood cell count decreased, blood bilirubin increased, pruritus, neutrophil count decreased, aspartate aminotransferase increased, and gamma-glutamyl transferase increased. Grade 3 TRAEs occurred in 23.2% patients. No grade 4-5 TRAEs or TRAEs leading to treatment discontinuation occurred.
Professor Ying Yuan, Leading Principal Investigator of the study, from the Second Affiliated Hospital of Zhejiang University School of Medicine stated: "Advanced colorectal cancer patients with KRAS G12C mutation have poor prognosis and short survival time with limited existing treatment methods; there is an urgent unmet clinical need. IBI351 as a selective covalent irreversible KRAS G12C inhibitor, its monotherapy has demonstrated outstanding efficacy and manageable safety in advanced colorectal cancer with KRAS G12C mutation. We look forward to more positive results update from this study."

Dr. Hui Zhou, Senior Vice President of Innovent, stated: "We are pleased to present our clinical development updates at the 2023 ESMO (Free ESMO Whitepaper) Asia Congress. Based on the encouraging efficacy and safety data shown in the registrational Phase 2 trial in lung cancer, IBI351 has recently successfully received NDA acceptance by the NMPA of China with the Priority Review designation. We will continue to explore the clinical development of IBI351 monotherapy and combination therapy in the fields of lung cancer, colorectal cancer and other solid tumors to benefit more cancer patients ."

About IBI351 (KRAS G12C 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.

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 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 (GenFleet R&D code: GFH925) 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 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 IBI351 for the treatment of advanced CRC patients with KRAS G12C mutation who have received at least two systemic therapies. In November 2023, the CDE of NMPA accepted and granted Priority Review designation to the NDA for IBI351 for the treatment of advanced NSCLC patients harboring KRAS G12C mutation who have received at least one systemic therapy.