On December 25, Sino Biopharmaceutical Limited (1177.HK) received a drug registration certificate from the National Medical Products Administration (NMPA) for the tenth indication of its Class 1 innovative drug, Anlotinib Hydrochloride Capsules (Fukewei^®). The new indication is for the first-line treatment of advanced hepatocellular carcinoma in combination with Penpulimab Injection (Annike^®). This also marks the fifth approved indication for Penpulimab. By achieving a "1+1>2" synergistic effect through the combination of immunotherapy and anti-angiogenic therapy, the "An-An combination" will provide a new first-line treatment option for patients with advanced liver cancer in China. 

Primary liver cancer is the sixth most common malignancy worldwide^[1], with hepatocellular carcinoma accounting for 80-85% of cases^[2]. China is a high-incidence region for liver cancer. In 2022, there were 368,000 new cases in China, accounting for 42.5% of the global total, and 317,000 deaths, representing 41.8% of the global total^[3]. In China, about 70% of hepatocellular carcinoma patients were diagnosed at an intermediate or advanced stage^[4], yet treatment options for advanced hepatocellular carcinoma have been limited. The growth of liver cancer depends on its unique immune microenvironment and vascular microenvironment. Studies have shown that combining immune checkpoint inhibitors with anti-angiogenic drugs can not only directly inhibit tumor growth but also improve the tumor microenvironment and enhance the infiltration and activity of immune cells, thereby achieving a synergistic effect. 

The marketing approval of Anlotinib for the first-line treatment of advanced hepatocellular carcinoma is primarily based on the positive "dual-endpoint positive" results from a Phase III clinical study (ALTN-AK105-III-02). The findings of this study have been published in the top international oncology journal, "The Lancet Oncology" (Impact Factor: 41.6). This study was a multi-center, randomized, open-label, parallel-controlled Phase III clinical trial designed to evaluate the efficacy and safety of Anlotinib combined with Penpulimab versus Sorafenib as a first-line treatment for advanced hepatocellular carcinoma. 

A total of 649 patients with advanced liver cancer were enrolled in the study. Among them, 40.9% of subjects had major vascular invasion, and 49.2% of patients had an alpha-fetoprotein (AFP) level of ≥400 ng/mL. The study results^[5] showed that the median progression-free survival (mPFS) was 6.9 months in the experimental group versus 2.8 months in the control group, with a significant 47% reduction in the risk of disease progression or death. The median overall survival (mOS) was 16.5 months in the experimental group versus 13.2 months in the control group, with a significant 31% reduction in the risk of death. Based on these results, the Independent Data Monitoring Committee (IDMC) determined that the primary endpoints of PFS and OS both met the pre-specified superiority criteria of the protocol. 

To date, Anlotinib has been successfully approved for 10 indications in China, including third-line non-small cell lung cancer, third-line small cell lung cancer, first-line extensive-stage small cell lung cancer, soft tissue sarcoma, thyroid cancer, renal cell carcinoma, and endometrial cancer. Six of these indications have been included in the National Reimbursement Drug List. In addition, the "De-Fu combination"—Anlotinib combined with Benmelstobart Injection (Andewei^®)—is currently under review for marketing approval for two indications: consolidation therapy for locally advanced/unresectable non-small cell lung cancer, and for the treatment of advanced or unresectable alveolar soft part sarcoma. 

Penpulimab has been approved for five indications in China, covering nasopharyngeal carcinoma, squamous non-small cell lung cancer, Hodgkin's lymphoma, and the newly approved hepatocellular carcinoma. Four of these indications have been included in the National Reimbursement Drug List. With the approval of more indications, Sino Biopharmaceutical Limited will provide more diverse and precise treatment options for a greater number of cancer patients. 

References:
[1] BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263.
[2] Siegel RL, Miller KD, Fuchs HE, Jemal A: Cancer Statistics, 2021. CA Cancer J Clin 2021, 71(1): 7-33.
[3] "Cancer incidence and mortality in China, 2022". National Cancer Center. 
[4] Chinese Association of Liver Cancer of Chinese Medical Doctor Association. Chinese Expert Consensus on the Whole-Course Management of Hepatocellular Carcinoma (2023 Edition) [J]. Chinese Journal of Digestive Surgery, 2023, 22(7): 824-842. 
[5] Jian Z,et al. Primary results from the phase Ⅲ ALTN-AK105-Ⅲ-02 study: Anlotinib plus penpulimab versus sorafenib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC). 2024ESMO, LBA 40.

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