The China NMPA Approves TYVYT® (sintilimab injection) in Combination with Bevacizumab and Chemotherapy in Patients with EGFR-mutated Non-squamous NSCLC who Progressed after EGFR-TKI Therapy

ROCKVILLIE, Md. and SUZHOU, China, May 9, 2023 /PRNewswire/ -- 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), jointly announced that the National Medical Products Administration (NMPA) of China has approved the supplemental New Drug Application (sNDA) for TYVYT® (sintilimab injection) in combination with bevacizumab and chemotherapy (pemetrexed and cisplatin) in patients with epidermal growth factor receptor (EGFR)-mutated non-squamous non-small cell lung cancer (NSCLC) who progressed after EGFR tyrosine kinase inhibitor (TKI) therapy. It makes TYVYT® (sintilimab injection) globally the first PD-1 inhibitor approved for patients with EGFR-mutated non-squamous NSCLC that progressed after EGFR-TKI therapy, which is a breakthrough in the field of immunotherapy.

This is the seventh NMPA-approved indication of TYVYT® (sintilimab injection). The first six indications of TYVYT® (sintilimab injection) are included in the National Reimbursement Drug List (NRDL), making TYVYT® (sintilimab injection) the only PD-1 inhibitor for the first-line treatment of five high-incidence cancer types in the NRDL – including non-squamous NSCLC, squamous NSCLC, hepatocellular carcinoma, esophageal squamous cell carcinoma, and gastric cancer. TYVYT® (sintilimab injection) is also the first and the only immunotherapy medicine for gastric cancer in the NRDL. This is also the eighth NMPA-approved indication of BYVASDA® (bevacizumab injection).

This new approval in China was based on the results of a randomized, double-blind, multi-center, prospective Phase 3 clinical trial (ORIENT-31, NCT03802240) evaluating TYVYT® (sintilimab injection) ± BYVASDA® (bevacizumab injection) + chemotherapy (pemetrexed and cisplatin) for the treatment of patients with EGFR-mutated non-squamous NSCLC who progressed after EGFR-TKI therapy.

In the second interim analysis (data cutoff date: March 31^st, 2022), in the intent-to-treat (ITT) population, based on the assessment by the Independent Radiographic Review Committee (IRRC), significant and clinically meaningful PFS benefit was sustained with sintilimab plus bevacizumab plus chemotherapy compared with chemotherapy alone (median PFS: 7.2 months vs. 4.3 months; HR=0.51, p<0.0001). Additionally, the key secondary endpoints of objective response rate (ORR) and duration of response (DOR) were improved with sintilimab plus bevacizumab plus chemotherapy, compared with chemotherapy alone.

As of data cutoff date July 4^th, 2022, a trend towards overall survival (OS) benefit with sintilimab plus bevacizumab and chemotherapy was observed although the median OS for chemotherapy was prolonged due to crossover after progression in chemotherapy group. The median OS for sintilimab plus bevacizumab plus chemotherapy and chemotherapy alone were 21.1 months vs 19.2 months, HR=0.98. After adjusting for crossover, the OS HR ranged from 0.79 to 0.84. In the exploratory analyses of quality of life, compared with the chemotherapy alone, sintilimab plus bevacizumab and chemotherapy showed longer median time-to-deterioration of the Global Health Status Dimension Score of EORTC Quality of Life Questionnaire Core 30 (QLQ-C30). The safety profile of this study was consistent with that observed in previously reported studies of sintilimab and bevacizumab, without new or unexpected safety signals.

The first interim analysis results of ORIENT-31 were published in The Lancet Oncology on July 28, 2022^[i]. The second interim analysis results were published in The Lancet Respiratory Medicine on May 5, 2023^[ii].

The principal investigator of the ORIENT-31 Study, Prof. Shun Lu from the Oncology Department of Shanghai Chest Hospital, stated, "Different from the western population, about half of the Chinese patients with NSCLC have EGFR mutations. EGFR-TKI targeted therapy is the first line treatment choice in NSCLC patients with EGFR sensitive mutation. However, almost all patients will eventually develop TKI-resistance and progression of disease and there are no good treatment options for EGFR-TKI failed NSCLC population^[iii]. The ORIENT-31 study is globally the first prospective, randomized and double-blind Phase 3 study that demonstrated that PD-1 inhibitor ± bevacizumab combined with chemotherapy can significantly prolong PFS in EGFR-mutant non-squamous NSCLC population who have failed EGFR-TKI treatment. In addition, compared with standard platinum-based chemotherapy, sintilimab and bevacizumab combined with chemotherapy improved the ORR and DOR, showing survival benefit trend as well as improvement in quality of life. The approval of this indication brings a new treatment option for EGFR-mutated non-squamous NSCLC patients who have failed EGFR-TKI treatment, benefiting more Chinese patients."

Dr. Michael Yu, Founder, Chairman and CEO of Innovent, stated, "Despite proven efficacy in broad types of cancer, immunotherapy has rarely made breakthroughs in the treatment of driver gene-positive non-squamous NSCLC patients. We are excited about the results of ORIENT-31 study and this new approval marks the first immunotherapy combination therapy approved for patients with driver gene-positive non-squamous NSCLC in China, and making TYVYT® the first PD-1 inhibitor approved for driver gene-positive non-squamous NSCLC globally. Innovent will continue our commitment to innovation and contribute to the 'Healthy China 2030' strategy."

Dr. Hui Zhou, Senior Vice President of Innovent, stated, "Lung cancer is a malignant tumor with the highest mortality rate and incidence in China, representing a large unmet medical need^[iv]. The new approval of TYVYT® is another important clinical development milestone, bringing new hope to the broader lung cancer patients with EGFR mutation. Innovent will continue to develop more novel therapies to address unmet clinical needs and bring more effective treatment options to patients in China and globally. "

Mr. Ben Basil, President and General Manager of Lilly China, stated, "Since its debut in 2018, TYVYT® has been approved consecutively six indications including lymphoma, lung cancer, liver cancer, esophageal cancer to gastric cancer, and all six indications have been included in the National Reimbursement Drug List (NRDL), benefiting millions of Chinese patients. I am very excited to see another indication approved today, bringing a brand new treatment option to NSCLC patients who have failed EGFR-TKI treatment in China. TYVYT® sets a great example for our partnership with Innovent. We will continually work with our local partners in bringing more innovative drugs to Chinese patients, continuously making contributions to the 'Healthy China 2030' blueprint."

Dr. Li Wang, Lilly Corporate Senior Vice President, Head of China Drug Development & Medical Affairs Center, stated, "The ORIENT-31 study is globally the first study in immunotherapy to confirm benefits in EGFR positive lung cancer patients who have failed EGFR-TKI treatment. The two interim analyses have demonstrated encouraging clinical results, breaking the dilemma of EGFR-TKI resistance. With the newly approved indication, TYVYT® provides a new treatment option and brings new hope to patients with EGFR-mutated non-squamous NSCLC who progressed after EGFR-TKI therapy in China."

About the ORIENT-31 Study

ORIENT-31 is a randomized, double-blind, multi-center Phase 3 clinical study conducted in China evaluating sintilimab, with or without bevacizumab, combined with chemotherapy (pemetrexed and cisplatin) in patients with EGFR-mutated locally advanced or metastatic nsqNSCLC who have progressed following EGFR TKI treatment (ClinicalTrials.gov, NCT03802240). The primary endpoint is PFS as assessed by IRRC based on RECIST v1.1. The secondary endpoints include overall survival (OS), PFS as assessed by investigators, ORR and safety.

About Sintilimab

Sintilimab, marketed as TYVYT® (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibody co-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^[v]. 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 seven indications and included in the National Reimbursement Drug List (NRDL) for six indications. The updated NRDL reimbursement scope of TYVYT® (sintilimab injection) include:

• For the treatment of unresectable locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma;
• For the treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma;
• For the treatment of unresectable locally advanced or metastatic non-squamous non-small cell lung cancer lacking EGFR or ALK driver gene mutations;
• For the treatment of unresectable locally advanced or metastatic squamous non-small cell lung cancer;
• For the treatment of unresectable or metastatic hepatocellular carcinoma with no prior systematic treatment;
• For the treatment of relapsed or refractory classic Hodgkin's lymphoma after two lines or later of systemic chemotherapy.

Additionally, sintilimab has been approved in combination with bevacizumab and chemotherapy (pemetrexed and cisplatin) for the treatment of patients with EGFR-mutated nsqNSCLC who progressed after EGFR-TKI therapy.

Besides, two clinical studies of sintilimab have met their primary endpoints:

• Phase 2 study of sintilimab monotherapy as second-line treatment of esophageal squamous cell carcinoma;
• Phase 3 study of sintilimab monotherapy as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy.

About BYVASDA® (bevacizumab injection)

BYVASDA® is a recombinant humanized anti-VEGF monoclonal antibody drug. Vascular endothelial growth factor (VEGF) is an important factor in angiogenesis that is highly expressed by the endothelial cells in most human tumors. An anti-VEGF antibody binds VEGF-A selectively with high affinity and blocks its binding to VEGF-2 receptors on the surface of vascular endothelial cells, thereby inhibiting signaling pathways such as PI3K-Akt/PKB and Ras-Raf-MEK-ERK. BYVASDA® produces anti-tumor effects by inhibiting the growth, proliferation and migration of vascular endothelial cells, blocking angiogenesis, reducing vascular permeability, blocking blood supply to tumor tissues, inhibiting the proliferation and metastasis of tumor cells and inducing apoptosis in tumor cells^[vi]. In China, BYVASDA® is approved for eight indications including advanced non-small cell lung cancer, metastatic colorectal cancer, adult recurrent glioblastoma, advanced or unresectable hepatocellular carcinoma, epithelial ovarian, fallopian tube, or primary peritoneal cancer and cervical cancer, seven of which are included in the NRDL.

About Innovent

Inspired by the spirit of "Start with Integrity, Succeed through Action," Innovent's mission is to develop, manufacture and commercialize high-quality biopharmaceutical products that are affordable to ordinary people. Established in 2011, Innovent is committed to developing, manufacturing and commercializing high-quality innovative medicines for the treatment of cancer, autoimmune disease, metabolic disorder and other major diseases. On October 31, 2018, Innovent was listed on the Main Board of the Stock Exchange of Hong Kong Limited with the stock code: 01801.HK.

Since its inception, Innovent has developed a fully integrated multi-functional platform which includes R&D, CMC (Chemistry, Manufacturing, and Controls), clinical development and commercialization capabilities. Leveraging the platform, the company has built a robust pipeline of 35 valuable assets in the fields of cancer, metabolic disorder, autoimmune disease and other major therapeutic areas, with 8 approved products on the market. These include: TYVYT® (sintilimab injection), BYVASDA® (bevacizumab biosimilar injection), SULINNO® (adalimumab biosimilar injection), HALPRYZA® (rituximab biosimilar injection) , Pemazyre® (pemigatinib oral inhibitor), olverembatinib (BCR-ABL TKI) , Cyramza® (ramucirumab) and Retsevmo® (selpercatinib). An additional 3 assets are under NMPA NDA review, 6 assets are in Phase 3 or pivotal clinical trials, and 18 more molecules are in clinical studies.

Innovent has built an international team with advanced talent in high-end biological drug development and commercialization, including many global experts. The company has also entered into strategic collaborations with Eli Lilly and Company, Sanofi, Adimab, Incyte, MD Anderson Cancer Center and other international partners. Innovent strives to work with many collaborators to help advance China's biopharmaceutical industry, improve drug availability and enhance the quality of the patients' lives. For more information, please visit: www.innoventbio.com. and www.linkedin.com/company/innovent-biologics/.

About Eli Lilly and Company

Lilly is a global healthcare leader that unites caring with discovery to create medicines to make life better for people around the world.

We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and https://newsroom.lilly.com/social-channels.

About Eli Lilly and Company's strategic cooperation with Innovent Biologics

Lilly entered into a strategic collaboration with Innovent focused on biological medicine in March 2015 – a groundbreaking partnership between a Chinese pharmaceutical company and a multinational pharmaceutical company. Under the agreement, Lilly and Innovent will co-develop and commercialize oncology medicines, including Tyvyt® (sintilimab injection) in China. In October 2015, the two companies announced the extension of their existing collaboration to include co-development of three additional oncology antibodies targeting oncology indications. In August 2019, Innovent further entered into a licensing agreement with Lilly to develop and commercialize a potentially global best-in-class diabetes medicine in China. Its collaboration with Lilly indicates that Innovent has established a comprehensive level of cooperation between China's innovative pharmaceuticals sector and the international pharmaceuticals sector in fields such as R&D, CMC, clinical development and commercialization. In August 2020, Lilly and Innovent announced a global expansion of their strategic alliance for sintilimab. In March 2022, Lilly and Innovent deepened the strategic partnership in oncology, in which Innovent obtained the sole commercialization rights of CYRAMZA® (ramucirumab) and Retsevmo® (selpercatinib), and a right of first negotiation for potential future commercialization of pirtobrutinib in Mainland China.

Note:

TYVYT® (sintilimab injection) is not an approved product in the United States.
BYVASDA®, SULINNO®, and HALPRYZA® are not approved products in the United States.
TYVYT® (sintilimab injection, Innovent)
BYVASDA® (bevacizumab injection, Innovent)
HALPRYZA® (rituximab injection, Innovent)
SULINNO® (adalimumab injection, Innovent)
Pemazyre® (pemigatinib oral inhibitor, Incyte Corporation). Pemazyre® was discovered by Incyte Corporation and licensed to Innovent for development and commercialization in Mainland China, Hong Kong, Macau and Taiwan.
CYRAMZA® (ramucirumab, Eli Lilly). Cyramza® was discovered by Eli Lilly and licensed to Innovent for commercialization in Mainland China.
Retsevmo® (selpercatinib, Eli Lilly). Retsevmo® was discovered by Eli Lilly and licensed to Innovent for commercialization in Mainland China.

Disclaimer: INNOVENT does not recommend use of any unapproved drugs/indications.

Innovent Biologics, Inc. Forward-Looking Statements

This news release may contain certain forward-looking statements that are, by their nature, subject to significant risks and uncertainties. The words "anticipate", "believe", "estimate", "expect", "intend" and similar expressions, as they relate to Innovent, are intended to identify certain of such forward-looking statements. The Company does not intend to update these forward-looking statements regularly.

These forward-looking statements are based on the existing beliefs, assumptions, expectations, estimates, projections and understandings of the management of the Company with respect to future events at the time these statements are made. These statements are not a guarantee of future developments and are subject to risks, uncertainties and other factors, some of which are beyond the Company's control and are difficult to predict. Consequently, actual results may differ materially from information contained in the forward-looking statements as a result of future changes or developments in our business, the Company's competitive environment and political, economic, legal and social conditions.

The Company, the Directors and the employees of the Company assume (a) no obligation to correct or update the forward-looking statements contained in this site; and (b) no liability in the event that any of the forward-looking statements does not materialise or turn out to be incorrect.

References

[i] Lu S, Wu L, Jian H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022;S1470-2045(22)00382-5. doi:10.1016/S1470-2045(22)00382-5.

[ii] Lu S, Lin, Wu, et al. Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med May 5, 2023. doi:10.1016/S2213-2600(23)00135-2.

[iii] Chen P, Liu Y, Wen Y, et al. Non–small cell lung cancer in China[J]. Cancer Communications, 2022, 42(10): 937-970.

[iv] Zheng R, Zhang S, Wang S, et al. Lung cancer incidence and mortality in China: updated statistics and an overview of temporal trends from 2000 to 2016[J]. Journal of the National Cancer Center, 2022.

[v] Wang J, Fei K, Jing H, et al. Durable blockade of PD-1 signaling links preclinical efficacy of sintilimab to its clinical benefit. mAbs 2019;11(8): 1443-1451.

[vi] International Journal of Nanomedicine 2019:14 7643-7663

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