Lilly Submits NDA in China for Selpercatinib, a Tumor-Agnostic RET Inhibitor Therapy

Source: Medicinal Observer

Today (November 9), the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) announced that Eli Lilly and Company has submitted an application for the market approval of Selpercatinib capsules in China, which has been accepted. Selpercatinib (LOXO-292) is a RET inhibitor acquired by Eli Lilly through an approximately $8 billion acquisition of Loxo Oncology. The drug was approved for marketing in the United States in 2020 and is the first precision therapy specifically designed to treat cancer patients with RET gene alterations.

Screenshot source: CDE official website

RET gene alterations include gene fusions and activating point mutations, which can lead to overactivation of the RET signaling pathway and uncontrolled cell growth. Since the RET oncogene is present in various cancers such as lung cancer, medullary thyroid carcinoma, thyroid cancer, colorectal cancer, breast cancer, and pancreatic cancer, it has become one of the important signaling pathways for "tumor-agnostic" therapies. Cancers carrying RET gene alterations primarily rely on the abnormal activation of this protein kinase to promote their proliferation and growth, making them highly sensitive to RET inhibitors.

Selpercatinib is a highly specific and potent oral RET inhibitor that can not only inhibit the native RET signaling pathway but also suppress potential acquired resistance. In May 2020, the FDA approved selpercatinib for the treatment of patients with non-small cell lung cancer (NSCLC), medullary thyroid cancer, and thyroid cancer carrying RET gene fusions or mutations.

In China, selpercatinib has been approved for several clinical trials. According to the Drug Clinical Trial Registration and Information Disclosure Platform, selpercatinib is being studied in multiple trials involving Chinese patients, including two randomized, open-label international multicenter Phase 3 clinical trials: ① One trial is in patients with advanced or metastatic RET fusion-positive NSCLC, aiming to compare the efficacy and safety of selpercatinib versus pemetrexed plus platinum-based chemotherapy, with or without pembrolizumab, in treating these patients; ② The other trial is in patients with RET-mutant medullary thyroid cancer, aiming to compare the safety and efficacy of selpercatinib versus cabozantinib or vandetanib in treating these patients.

In August 2020, *The New England Journal of Medicine* (NEJM) published the results of the Phase 1/2 registrational clinical trial supporting the approval of selpercatinib in the United States. The study on selpercatinib for the treatment of RET fusion-positive NSCLC showed: In previously untreated patients, 85% achieved partial response, and 10% had stable disease; at 6 months of treatment, 90% of patients still demonstrated sustained response to the therapy. In previously treated patients: 2% achieved complete response, 62% had partial response, and 29% had stable disease; the median duration of response was 17.5 months, and at a median follow-up time of 12 months, 63% of patients were still in remission; the median progression-free survival (PFS) was 16.5 months.

Data from the Phase 1/2 clinical study of Selpercatinib in thyroid cancer showed: In 55 previously treated patients with RET-mutant medullary thyroid cancer, the objective response rate was 69%, and the one-year progression-free survival rate was 82%; in 88 previously untreated patients with RET-mutant medullary thyroid cancer, the objective response rate was 73%, and the one-year progression-free survival rate was 92%; in 19 previously treated patients with RET fusion-positive thyroid cancer, the objective response rate was 79%, and the one-year progression-free survival rate was 64%.

Public data shows that RET gene fusions occur in approximately 2% of non-small cell lung cancer patients, about 10-20% of thyroid cancer patients, and a small number of other cancer types. Activating RET point mutations are found in approximately 60% of medullary thyroid cancer patients.

Note: The original text has been abridged.

References:

[1] Center for Drug Evaluation, National Medical Products Administration of China. Retrieved Nov. 9, 2021, from https://www.cde.org.cn/main/xxgk/listpage/9f9c74c73e0f8f56a8bfbc646055026d

[2] The New England Journal of Medicine Publishes Phase I/II Clinical Trial Data of Retevmo™ (selpercatinib) in RET-Driven Advanced Lung and Thyroid Cancers. Retrieved Aug 27, 2020, from https://mp.weixin.qq.com/s/fIc9eVDPZWe4xDekDh-PFQ

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