Lilly Launches Pivotal Phase 3 LIBRETTO-431 Trial of Selpercatinib as First-Line Therapy for RET Fusion-Positive Non-Small Cell Lung Cancer

December 14, 2019 /Bio ValleyBIOON/ -- U.S. pharmaceutical giantEli Lilly(Eli Lilly) recently announced the initiation of the Phase III LIBRETTO-431 trialClinical Trials(NCT04194944), evaluating the efficacy and safety of oral RET kinase inhibitor selpercatinib (also known as LOXO-292) 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 fusion-positive non-small cell lung cancer (NSCLC) who have not previously received systemic therapy for metastatic disease. In the study, patients will be randomized in a 1:1 ratio to receive one of two regimens: (a) selpercatinib; or (b) platinum-based chemotherapy (carboplatin or cisplatin) plus pemetrexed, with or without a PD-1 inhibitor.TumorImmunotherapy with Keytruda (pembrolizumab) as initial treatment. RET fusions will be identified using local testing. The primary endpoint of the study is progression-free survival (PFS), and secondary endpoints include overall survival (OS), overall response rate (ORR), duration of response (DoR), and intracranial ORR. 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 trial 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 of up to 91%.

Professor Ben Solomon of the Peter MacCallum Cancer Centre in Australia, Principal Investigator of the LIBRETTO-431 study, stated, “Given the remarkable results of the LIBRETTO-001 trial, I am pleased to initiate this pivotal Phase III LIBRETTO-431 study.”Clinical TrialSelpercatinib is a highly selective and potent molecule that has previously demonstrated a well-tolerated safety profile and durable treatment responses. The LIBRETTO-431 trial aims to generate outcome data establishing RET fusions alongside EGFR mutations and ALK fusions as driver gene-positive populations, for whom targeted therapy should be applied in the first-line setting rather than chemoimmunotherapy.

Eli LillyTumorAnne White, President of Eli Lilly and Company, stated, “This is an important milestone that will further demonstrate the therapeutic benefits of selpercatinib and its potential compared to the current standard of care in the first-line treatment of patients with advanced or metastatic RET fusion-positive non-small cell lung cancer. The initiation of a trial of this scale underscores the importance of including RET fusions in genomic testing for lung cancer.”

Molecular Structure of Selpercatinib (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 is a proto-oncogene that undergoes rearrangement during transfection, from which it derives its name. This gene encodes a receptor tyrosine kinase located on the cell membrane, and its abnormalities serve as rare driver alterations in various types of tumors. It is estimated that RET fusions are present in approximately 2% of non-small cell lung cancer (NSCLC) cases, 10–20% of papillary thyroid carcinoma (PTC) and other thyroid cancer subtypes, as well as in subsets of other cancers such as colorectal cancer; RET point mutations are found in approximately 60% of medullary thyroid carcinoma (MTC) cases. Cancers harboring RET fusions or RET point mutations are primarily dependent on RET kinase activation to maintain their proliferation and survival, a dependency commonly referred to as “oncogene addiction,” making this class ofTumorHighly 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 U.S. regulatory matters,FDASelpercatinib has been granted Breakthrough Therapy Designation (BTD) 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 NSCLC who have experienced disease progression after immunotherapy and require systemic treatment; (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 treatment; (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 treatment.

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 acquired multiple targeted drugs from Loxo, including: (1) the “broad-spectrum” anticancer drug Vitrakvi (larotrectinib), andBayerco-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 First Ever Randomized Phase 3 Clinical Trial in Treatment-Naïve RET Fusion-Positive Non-Small Cell Lung Cancer