Eli Lilly's Tumor-Agnostic RET Inhibitor Selpercatinib Shows Robust Efficacy in Pivotal Phase 1/2 Trial Published in NEJM

Source | Medical Panorama

On August 27, The New England Journal of Medicine (NEJM) officially published the results of the phase 1/2 registration clinical trial of Eli Lilly and Company’s RET kinase inhibitor selpercatinib (Retevmo) for the treatment of non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). Selpercatinib is the first precision therapy approved for patients with cancers harboring RET gene alterations.

Selpercatinib is a highly selective and potent oral RET inhibitor acquired by Eli Lilly and Company through its acquisition of Loxo Oncology. It not only inhibits the native RET signaling pathway but also addresses potential acquired resistance. The drug was previously granted Breakthrough Therapy Designation, Orphan Drug Designation, and Priority Review by the U.S. FDA. In May this year, selpercatinib received U.S. FDA approval for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), as well as patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) or advanced or metastatic RET fusion-positive thyroid cancer. This marks the first precision therapy approved for cancer patients harboring RET genetic alterations.

Published in the NEJM are the results of the phase 1/2 registration clinical trial supporting the approval of selpercatinib. Data from the phase 1/2 clinical study on thyroid cancer showed that among 55 patients with previously treated RET-mutant medullary thyroid cancer, the objective response rate was 69%, and the one-year progression-free survival rate reached 82%; among 88 patients with previously untreated RET-mutant medullary thyroid cancer, the objective response rate was 73%, and the one-year progression-free survival rate was 92%; among 19 patients with previously treated RET-fusion thyroid cancer, the objective response rate was 79%, and the one-year progression-free survival rate was 64%. Currently, the research team has initiated an international phase 3 trial to further evaluate the efficacy of selpercatinib as a first-line treatment for RET-mutant medullary thyroid cancer.

A Phase 1/2 trial in non-small cell lung cancer (NSCLC) enrolled a total of 144 patients with advanced RET fusion-positive disease. The study showed that among treatment-naïve patients, 85% achieved a partial response and 10% had stable disease; at 6 months of treatment, 90% of patients maintained a durable response to the therapy. Among previously treated patients: 2% achieved a complete response, 62% achieved a partial response, and 29% had stable disease; the median duration of response was 17.5 months, and at a median follow-up of 12 months, 63% of patients remained in response; the median progression-free survival (PFS) was 16.5 months.

RET gene alterations include gene fusions and activating point mutations, which can lead to hyperactivation of the RET signaling pathway and uncontrolled cell growth. RET gene fusions occur in 2% of non-small cell lung cancers, 10–20% of thyroid cancers, and a small subset of other cancer types. Activating RET point mutations are found in 60% of patients with medullary thyroid cancer. Cancers harboring RET gene alterations rely primarily on the abnormal activation of this protein kinase to drive their proliferation and growth; therefore, these cancers are highly sensitive to RET inhibitors. The advent of selpercatinib is expected to enhance and improve the quality of life for patients with RET-altered cancers.

References:

[1] Lori J. Wirth, et al., (2020). Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med, DOI: 10.1056/NEJMoa2005651

[2] Alexander Drilon, et al., (2020). Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer. N Engl J Med, DOI: 10.1056/NEJMoa2005653

[3] The New England Journal of Medicine published Phase I/II clinical study data on Retevmo™ (selpercatinib) in RET-driven advanced lung cancer and thyroid cancer. Retrieved Aug 27, 2020, from https://mp.weixin.qq.com/s/fIc9eVDPZWe4xDekDh-PFQ

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