On June 20, 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 Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has approved the supplemental New Drug Application (sNDA) for TYVYT (sintilimab injection) in combination with cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil chemotherapy for the first-line treatment of unresectable, locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) (Press release, Innovent Biologics, JUN 20, 2022, View Source [SID1234616109]).
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This is the fifth NMPA-approved indication of TYVYT. In China, TYVYT was approved for: the treatment of relapsed or refractory classical Hodgkin’s lymphoma in December 2018; the first-line treatment of non-squamous non-small cell lung cancer (NSCLC) in February 2021; and the first-line treatment of squamous NSCLC as well as the first-line treatment of hepatocellular carcinoma in June 2021.
The new approval was based on the interim analysis of ORIENT-15, a global randomized, double-blind, multi-center Phase 3 clinical trial – which evaluated sintilimab in combination with chemotherapy compared to placebo in combination with chemotherapy as first-line therapy for ESCC. Based on the interim analysis conducted by the Independent Data Monitoring Committee (IDMC), sintilimab in combination with chemotherapy demonstrated a statistically significant improvement in the primary endpoint of overall survival (OS) compared to placebo in combination with chemotherapy regardless of PD-L1 expression status, meeting the pre-defined superior efficacy criteria. Safety profile was consistent with that observed in previously reported studies of sintilimab without new or unexpected safety signals. The results of ORIENT-15 were published in British Medical Journal on April 19, 2022[1].
Prof. Shen Lin, Principal Investigator of ORIENT-15 Study, Peking University Cancer Hospital and Institute, stated," Esophageal cancer is one of the most common cancers in China ranking fifth in cancer prevalence and the fourth in mortality cases, with squamous cell carcinoma as most predominant histologic type[2]. In the past, median OS was approximately 10 months for chemotherapy as the first-line standard of care[3]. The results of ORIENT-15 demonstrated that sintilimab plus chemotherapy as the first-line treatment for ESCC significantly improved overall survival (OS) and progression-free survival (PFS) compared to placebo plus chemotherapy, with median OS of 16.7 months（vs. 12.5 months, HR=0.63） and median PFS of 7.2 months（vs. 5.7months,HR=0.56） for sintilimab plus chemotherapy. In addition, the results showed the general applicability of sintilimab with two different chemotherapy regimens[1]. The approval of sintilimab in combination with chemotherapy as a first-line treatment for ESCC is exciting news and will provide an effective and affordable treatment option for patients living with ESCC in China."
Dr. Yongjun Liu, President of Innovent, stated," TYVYT (sintilimab injection) is the only innovative PD-1 inhibitor with positive Phase 3 studies results as a first-line treatment for five major types of cancer, including the squamous/non-squamous non-small cell lung cancer, liver cancer, gastric cancer and now esophageal cancer. We are encouraged by the results of the ORIENT-15 study, a global multi-center phase 3 trial demonstrating sintilimab as a high quality treatment option with great clinical value for people living with esophageal cancer. Innovent is committed to our mission of developing high-quality biopharmaceuticals that are affordable and contribute to the ‘Healthy China 2030’ Plan for cancer prevention and treatment."
Dr. Hui Zhou, Senior Vice President of Innovent, stated, "There is a huge unmet clinical need for the first-line treatment of advanced or metastatic ESCC. The results of ORIENT-15 demonstrated that sintilimab can bring significant clinical benefit to the treatment of ESCC. Today, the NMPA of China approval marks another important milestone for sintilimab, and we believe the positive study results will soon translate into superior clinical benefits for ESCC patients. We believe the approval of this new indication will further strengthen the leadership position of TYVYT (sintilimab injection) and bring hopes to more Chinese cancer patients in broader market."
Mr. Julio Gay-Ger, President and General Manager of Lilly China, stated, "From Hodgkin’s lymphoma, lung cancer, liver cancer, and now to esophageal squamous cell carcinoma (ESCC), we are excited to see another indication of TYVYT (sintilimab injection) approved in China in a short of time, bringing new options to Chinese esophageal cancer patients. With our commitment to oncology, Lilly strives to bring high-quality and affordable innovative drugs to Chinese cancer patients through both independent R&D and local partnerships. TYVYT (sintilimab injection) sets a great example for our partnership with Innovent, and the new approval will further benefit more Chinese cancer patients."
Dr. Li Wang, Senior Vice President of Lilly China and Head of Lilly China Drug Development and Medical Affairs Center, stated, "The approval of TYVYT (sintilimab injection) for the first-line indication of esophageal squamous cell carcinoma (ESCC) demonstrated the clinical value of combined immunotherapy in this field. The number of new cases and deaths of esophageal cancer in China accounts for more than half of the world’s total[2]. The ORIENT-15 study, starting from the Chinese ESCC population while having a global perspective, achieved promising results of benefiting the entire population, bringing new options and new hope for the treatment of ESCC patients[1]."
About the ORIENT-15 Study
ORIENT-15 is a global randomized, double-blind, multicenter Phase 3 clinical study evaluating sintilimab in combination with chemotherapy (cisplatin plus paclitaxel or 5-fluorouracil [5-FU]), compared to placebo in combination with chemotherapy, for the first-line treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ClinicalTrials.gov, NCT03748134). At the time of interim analysis, a total of 659 eligible patients (of the planned 676 estimated participants) were enrolled and randomly assigned into the experimental group or control group in a 1:1 ratio. The primary endpoints were overall survival (OS) in all randomized patients and OS in PD-L1 positive (defined as CPS ≥10) patients[1].
Based on the interim analysis conducted by the Independent Data Monitoring Committee (IDMC), sintilimab in combination with chemotherapy demonstrated a statistically significant improvement in the primary endpoint of overall survival (OS) compared to placebo in combination with chemotherapy, regardless of PD-L1 expression status, meeting the pre-defined superior efficacy criteria. Safety analyses revealed no new safety signals. The results of ORIENT-15 were published in British Medical Journal on April 19, 2022[1].
About Esophageal Squamous Cell Carcinoma (ESCC)
Esophageal cancer (EC) is one of the most common malignant tumors worldwide that begins in the inner layer (mucosa) of the esophagus, which connects the throat to the stomach. Based on GLOBOCAN 2020 estimates, approximately 600,000 new cases of esophageal cancer are diagnosed and approximately 540,000 deaths result from the disease worldwide each year[4]. Esophageal cancer is the seventh most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide[4]. More than half of new and fatal cases of esophageal cancer in the world occur in China[2]. In China, it is estimated there were approximately 320,000 new cases of esophageal cancer diagnosed and approximately 300,000 deaths resulting from the disease in 2020[2]. Esophageal cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of death from cancer in China, where it has a five-year survival rate of only 30%[2].
The two main types of esophageal cancer are squamous cell carcinoma (SCC) and adenocarcinoma. In China, SCC is the predominant histologic type, accounting for more than 90% of all esophageal cancer[5]. In the past, first-line standard systemic therapy was chemotherapy based on platinum drugs for unresectable locally advanced, recurrent or metastatic ESCC, which calls for more effective first-line treatment options. Several PD-1 inhibitors have been approved as first-line treatment in combination with chemotherapy[6],[7] .
About Sintilimab
Sintilimab, marketed as TYVYT (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibodyjointly 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[8]. 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 and included in the National Reimbursement Drug List (NRDL) for four indications, and recently approved for one additional indication 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.
Additionally, Innovent currently has two regulatory submissions under review in the China’s NMPA for sintilimab:
In combination with chemotherapy for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma;
In combination with bevacizumab biosimilar and chemotherapy for EGFR-mutated non-squamous NSCLC following EGFR-TKI treatment.
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.