Lilly recently announced that its RET inhibitor, selpercatinib (loxo-292), has been granted priority review status by the U.S. FDA and is expected to accelerate its approval for the treatment of patients with advanced RET fusion positive non-small cell lung cancer (NSCLC), RET mutated medullated thyroid cancer (MTC) and RET fusion positive thyroid cancer. The FDA is expected to respond to the new drug application (NDA) in the third quarter of this year.
RET (rearranged during transfection) is a proto-oncogene, located on chromosome 10. It is a member of the cadherin superfamily and encodes a receptor tyrosine kinase (RTK). As a cell surface molecule, it can convert signals used for cell growth and differentiation. This gene plays an important role in the development of neural spine. RET mutation activation will activate downstream signaling pathways (including RAS, MAPK, ERK, PI3K, AKT, etc.), leading to cell proliferation, migration and differentiation. The main mutations are fusions and point mutations with other genes.
RET gene mutations include gene fusion and activating point mutations, which can lead to excessive activation of the RET signaling pathway and uncontrolled cell growth. RET gene fusion refers to the fusion of a gene that expresses the RET receptor with other genes, which causes the tyrosine kinase activity of the RET receptor to be continuously activated. The most common fusion partners are KIF5B, CCDC6, and NCOA4. It is similar to RET point mutations, leading to the continued activeness of the RET signaling pathway, and is an important factor driving cancer development.
RET gene fusions occur in 2% of non-small cell lung cancers, 10-20% of thyroid cancers, and a few other cancer types. In contrast, activated RET point mutations occur in 60% of patients with myeloid thyroid cancer. Cancers carrying mutations in the RET gene rely on abnormal activation of this protein kinase to promote their proliferation and growth, so these cancers are very sensitive to RET inhibitors.
Selpercatinib is a highly specific, potent oral RET inhibitor obtained when Eli Lilly acquired Loxo Oncology. It not only inhibits the natural RET signaling pathway, but also inhibits acquired resistance that may arise. It has been granted FDA-approved breakthrough therapy designation and orphan drug qualification to treat patients with NSCLC carrying RET gene fusions, patients with MTC carrying RET-activated mutations, and patients with advanced thyroid cancer carrying RET gene fusions.
The submission of the new drug application is based on positive data obtained by selpercatinib in a phase 1/2 trial of LIBRETTO-001 for patients with lung cancer and thyroid cancer carrying RET mutations. According to previously published data, as of June 17, 2019, selpercatinib achieved an objective response rate (ORR) of 68% among these NSCLC patients who had received multiple previous treatments, with a complete response rate (CR) of 2%. As many as 50% of patients with NSCLC carrying the RET gene fusion may have brain metastases. Among the subgroup of patients with brain metastases, selpercatinib showed as high as 91% of the central nervous system ORR, with a complete response rate of 18%. In terms of duration of efficacy, the duration of response (DOR) for this patient population was 20.3 months, and the median progression-free survival (PFS) was 18.4 months. Based on the fact that most patients are still in the non-progressive or remission phase, these median values are expected to be further extended as the follow-up time increases.
“We are pleased that the FDA has granted selpercatinib priority review of new drug applications, which represents an important step in providing new precision therapies to RET-driven cancer patients,” said Ms. Anne White, President of Lilly Oncology, “The positive momentum is very satisfied and we hope to provide patients with RET-driven cancer with new methods that break through conventional therapies as soon as possible. ”
Targeted therapy of RET gene fusion has been progressing slowly because of the low selectivity of existing drugs. And LOXO-292 is a highly selective oral RET inhibitor and can enter the brain effectively. Clinical data show that it is highly effective and non-toxic for treating non-small cell lung cancer with RET gene fusion, and also has good effect on brain metastasis. It is hoped that the clinical trial of LOXO-292 will progress smoothly and be launched as soon as possible, bringing good news to patients with RET gene fusion!
References:
- Drilon et. al. LIBRETTO-001: A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. 6/2/18. ASCO 2018 Annual Meeting.