On June 26, 2022 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of cancer, autoimmune, metabolic, ophthalmology and other major diseases, and Eli Lilly and Company ("Lilly",NYSE: LLY), reported that the National Medical Products Administration (NMPA) of China has approved the supplemental New Drug Application (sNDA) for TYVYT (sintilimab injection) in combination with fluorouracil and platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma (Press release, Innovent Biologics, JUN 26, 2022, View Source [SID1234616257]).
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This is the sixth NMPA-approved indication of TYVYT. TYVYT is the first domestic PD-1 inhibitor approved for the first-line treatment of gastric cancer and is currently approved for the first-line treatment in five major types of cancers. In China, TYVYT was approved for the treatment of relapsed or refractory classical Hodgkin’s lymphoma in December 2018, first-line treatment of nonsquamous non-small cell lung cancer (NSCLC) in February 2021, first-line treatment of squamous NSCLC, and the first-line treatment of hepatocellular carcinoma in June 2021; and the first-line treatment of esophageal squamous cell carcinoma in June 2022.
The approval in China was based on the results of a randomized, double-blind, multicenter Phase III clinical trial (ORIENT-16, NCT03745170) evaluating sintilimab in combination with chemotherapy (oxaliplatin and capecitabine), compared to placebo in combination with chemotherapy, for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma. Based on the interim analysis by Independent Data Monitoring Committee (iDMC), sintilimab in combination with chemotherapy demonstrated superior overall survival (OS), compared to placebo plus chemotherapy, with a 34.0% reduction in the risk of death (HR 0.660，95%CI 0.505-0.864，p=0.0023) and a 5.5-month improvement in median OS (mOS 18.4 months vs. 12.9 months) in patients with combined positive score (CPS) ≥5, and 23.4% reduction in the risk of death (HR 0.766, 95%CI 0.626-0.936，p=0.0090）and a 2.9-month improvement in mOS (15.2 months vs. 12.3 months) in all patients regardless of PD-L1 expression. The safety profile of sintilimab in this study was consistent with that observed in previously reported studies of sintilimab, and no additional safety signals were identified for the combination of sintilimab and chemotherapy. The results of ORIENT-16 study were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021[1].
Prof. Jianming Xu, The Fifth Medical Center of People’s Liberation Army General Hospital stated: "Gastric cancer ranks fifth for global cancer incidence and is the third leading cause of cancer mortality worldwide[2]. Nearly half of global gastric cancer incidence cases and mortality cases occur in China annually[2]. The ORIENT-16 study demonstrated that sintilimab in combination with chemotherapy significantly prolonged overall survival of patients with gastric cancer[1]. We are encouraged by the approval of sintilimab, the first domestic anti-PD-1 monoclonal antibody approved for the treatment of gastric cancer, bringing a new and effective treatment option to be provided to patients with gastric cancer in China."
Dr. Yongjun Liu, President of Innovent, stated: "We are grateful for the recognition received from the Chinese regulatory authorities for TYVYT (sintilimab injection). This is the second sNDA approval this year, following the first one of ESCC, and enabling TYVYT (sintilimab injection) to be the domestically first innovative PD-1 inhibitor for the first-line treatment of five major type of cancers. We look forward to bringing TYVYT (sintilimab injection) as a new standard first-line treatment option for patients with advanced gastric cancer, and opening a new chapter of immunotherapy for gastric cancer. Innovent will uphold our mission of ‘to develop, manufacture and commercialize high-quality biopharmaceutical products that are affordable to ordinary people’ and make continuous contributions to the ‘Healthy China 2030’ implementation."
Dr. Hui Zhou, Senior Vice President of Innovent, stated, "The approval of TYVYT by the NMPA for the treatment of gastric cancer represents an important step forward for Innovent to further expand market coverage and is an important milestone for product development and commercial strategy. Data from the ORIENT-16 study demonstrated significant improvement in overall survival in patients with advanced gastric cancer and safety profile was consistent with that observed in previously reported studies of sintilimab. Survival benefit and reduction in the risk of death were observed, regardless of PD-L1 expression[1]. Gastric cancer is one of the most common malignancies in China and has different disease characteristics when compared with Western population. Innovent will continue to focus on these unmet medical needs and conduct additional clinical trials to untap the potential of our innovative molecules. We hope to bring more safe and efficacious treatment options to cancer patients both in China and worldwide."
Mr. Julio Gay-Ger, President and General Manager of Lilly China, stated, "China is well-known for gastrointestinal cancers[2]. The approval of TYVYT (sintilimab injection) as first-line treatment for gastric cancer marks another milestone. So far, TYVYT has covered major cancer types including lymphoma, lung cancer, liver cancer, esophageal cancer and gastric cancer, benefiting millions of Chinese patients. With our commitment to oncology, Lilly strives for bringing high-quality and affordable innovative drugs to Chinese cancer patients through both independent R&D and local partnerships. We look forward to continually working with our partner Innovent in bringing more innovative anti-tumor drugs to Chinese patients."
Dr. Li Wang, Senior Vice President of Lilly China and Head of Lilly China Drug Development and Medical Affairs Center, stated, "The ORIENT-16 study, led by Chinese investigators, is the first randomized, double-blind Phase III clinical study in China to demonstrate the significant benefit of immunotherapy combined with chemotherapy for the first-line treatment of advanced gastric cancer[1]. It provided strong evidence for the treatment of advanced gastric cancer in China. The approval of TYVYT (sintilimab injection) as first-line treatment for gastric cancer has provided a new option and fresh perspective for existing treatment, and will further benefit more and more Chinese gastric patients"
About the ORIENT-16 Study
ORIENT-16 is a randomized, double-blind, multi-center Phase 3 clinical study evaluating sintilimab or placebo, in combination with chemotherapy (oxaliplatin and capecitabine), for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (ClinicalTrials.gov, NCT03745170). The primary endpoint was overall survival, in PD-L1 positive (CPS>5) and all randomized patients[1].
As of the cutoff date for the interim analysis, a total of 650 patients were enrolled and randomly assigned with a 1:1 ratio to receive sintilimab or placebo in combination with chemotherapy until disease progression, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first. The study met both primary endpoints and the safety profile of sintilimab in this study was consistent with that observed in previously reported studies of sintilimab, and no additional safety signals were identified for the combination of sintilimab and chemotherapy. The results were published at the ESMO (Free ESMO Whitepaper) Congress 2021.
About Gastric Cancer
Gastric cancer is one of the most common malignant tumor types worldwide. According to GLOBOCAN estimates, there were approximately one million new cases in 2020 and 769,000 new deaths of gastric cancer each year, making it the fifth most common cancer and third leading cause of cancer death globally[2],[3]. About half of all gastric cancer cases occurred in East Asia, mainly in China[2]. The first-line treatment of advanced gastric cancer is still limited. Currently, the 5-year survival rate of advanced or metastatic gastric cancer ranges from 5 to 20 percent. The median survival was about 1 year for patients who received chemotherapy only[4],[5].
About Sintilimab
Sintilimab, marketed as TYVYT (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibody jointly developed by Innovent and Eli Lilly and Company. Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells[6]. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.
In China, sintilimab has been approved for six indications as below, with the first four included in the National Reimbursement Drug List (NRDL), including:
The treatment of relapsed or refractory classic Hodgkin’s lymphoma after two lines or later of systemic chemotherapy;
In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of non-squamous non-small cell lung cancer lacking EGFR or ALK driver mutations;
In combination with gemcitabine and platinum chemotherapy, for the first-line treatment of squamous non-small cell lung cancer;
In combination with BYVASDA (bevacizumab biosimilar injection) for the first-line treatment of unresectable or advanced hepatocellular carcinoma;
In combination with cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil for the first-line treatment of esophageal squamous cell carcinoma;
In combination with fluorouracil and platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma.
Innovent currently has the regulatory submission for sintilimab in combination with bevacizumab biosimilar and chemotherapy for EGFR-mutated non-squamous NSCLC following EGFR-TKI treatment under review in the China’s NMPA.
Additionally, two clinical studies of sintilimab have met their primary endpoints:
Phase 2 study as second-line treatment of esophageal squamous cell carcinoma;
Phase 3 study as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy.