Lilly Launches Phase 3 Trial of Selpercatinib as First-Line Therapy for RET-Mutant Medullary Thyroid Cancer

December 31, 2019 /Bio ValleyBIOON/ -- U.S. pharmaceutical giant Eli Lilly recently announced the launch of the Phase III LIBRETTO-531Clinical Trials(NCT04211337), evaluating the oral RET kinase inhibitor selpercatinib (also known as LOXO-292) as first-line treatment for patients with RET-mutant medullary thyroid carcinoma (MTC). This is the second Phase III study assessing selpercatinib; previously,Eli LillyThe first Phase III LIBRETTO-431 trial has been initiated to evaluate selpercatinib as first-line treatment for patients with RET fusion-positive non-small cell lung cancer (NSCLC).

This study will enroll 400 patients with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who have not previously received systemic therapy for metastatic disease. In the study, patients will be randomized in a 2:1 ratio to receive one of two regimens as initial treatment: (a) selpercatinib; or (b) investigator’s choice of therapy (cabozantinib or vandetanib). RET mutations will be identified using local testing. The efficacy endpoints of the study include progression-free survival (PFS), time to failure of survival (TFFS), overall survival (OS), overall response rate (ORR), and duration of response (DoR). Patients randomized to the control arm are permitted to cross over upon disease progression.

By the end of September this year,Eli LillyData from the Phase I/II clinical study LIBRETTO-001 were presented at the 2019 ESMO Annual Meeting. This study represents the largest clinical trial to date evaluating a RET inhibitor in patients with RET-altered cancers. The results showed that selpercatinib achieved objective response rates (ORR) of 59% and 56% in treatment-naïve and previously treated patients with RET-mutant medullary thyroid cancer (MTC), respectively. Previously reported data from the NSCLC cohort demonstrated that selpercatinib yielded ORRs of 85% and 68% in treatment-naïve and previously treated patients with RET fusion-positive non-small cell lung cancer (NSCLC), respectively. Furthermore, selpercatinib is the first RET inhibitor to demonstrate robust central nervous system (CNS) activity, with a CNS ORR as high as 91%.

Lori Wirth, Medical Director of the Cancer Center and the Head and Neck Cancer Center at Massachusetts General Hospital, stated, “Approximately 60% of patients with medullary thyroid carcinoma (MTC) harbor activating RET point mutations, but current treatment regimens are suboptimal for many patients. This Phase III trial, conducted in patients with advanced or metastatic RET-mutant MTC, aims to establish a new standard of care. We hope this will provide more effective therapeutic options for this patient population.”

Gary Bloom, Executive Director of the Thyroid Cancer Survivors’ Association (ThyCa), stated, “Although medullary thyroid cancer (MTC) is rare, the incidence of RET mutations in MTC is high. Therefore, we are very excited about the initiation of this Phase III trial, as it will bring hope to patients with advanced and metastatic RET-mutant MTC. Due to new treatment options, MTC patients must discuss with their physicians whether and when they should undergoTumorGenomic testing should be performed. This will ensure that patients with RET mutations have the opportunity to receive potential treatments and participate inClinical Trials, such as this trial targeting selpercatinib.”

Selpercatinib Molecular Structure (Image Source: medchemexpress.cn)

Selpercatinib (LOXO-292) is a potent, oral, highly selective inhibitor of the rearranged during transfection (RET) kinase, indicated for the treatment of patients with RET-altered cancers. The RET gene, a proto-oncogene that undergoes rearrangement during transfection and derives its name from this process, encodes a transmembrane receptor tyrosine kinase. Aberrations in this gene serve as rare driver alterations in various tumor types. RET fusions are estimated to occur in approximately 2% of non-small cell lung cancer (NSCLC) cases, 10–20% of papillary thyroid cancer (PTC) and other thyroid cancer subtypes, as well as in subsets of other malignancies such as colorectal cancer. RET point mutations are present in approximately 60% of medullary thyroid cancer (MTC) cases. Cancers harboring RET fusions or RET point mutations predominantly rely on RET kinase activation to sustain proliferation and survival, a dependency commonly referred to as “oncogene addiction,” making suchTumorHighly sensitive to small-molecule RET inhibitors.

Selpercatinib is designed to inhibit native RET signaling and anticipated acquired resistance mechanisms. The drug is currently in clinical development for patients with tumors harboring aberrant RET kinase. Regarding US regulatory aspects,FDABreakthrough Therapy Designation (BTD) has been granted to selpercatinib for the treatment of three patient populations, specifically: (1) those who have received platinum-based chemotherapy and a PD-1 or PD-L1Tumor(1) Patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) who have experienced disease progression following immunotherapy and require systemic therapy; (2) Patients with RET-mutant medullary thyroid cancer (MTC) who have experienced disease progression after prior treatment, have no acceptable alternative treatment options, and require systemic therapy; (3) Patients with advanced RET fusion-positive thyroid cancer who have experienced disease progression after other regimens, have no acceptable alternative treatment options, and require systemic therapy.

Selpercatinib by the United StatesTumorPrecision drug developer Loxo Oncology found that,Eli Lillyacquired it for $8 billion in early January this year. In addition to selpercatinib, it also obtained multiple targeted drugs from Loxo, including: (1) the “broad-spectrum” anticancer drug Vitrakvi (larotrectinib), withBayerco-developed, is a tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of NTRK gene fusion-positive solid tumors; (2) LOXO-195, co-developed with Bayer, is a next-generation TRK inhibitor designed to overcome potential acquired resistance; (3) LOXO-305, a reversible BTK inhibitor in preclinical development for the treatment of B-cell malignancies; (4) FGFR program, in preclinical development, for the treatment of cancers with abnormal alterations in fibroblast growth factor receptors (FGFR). (Bioon.com)

Original Source:Lilly Opens Phase 3 Clinical Trial in RET-Mutant Medullary Thyroid Cancer