Selpercatinib Meets Primary Endpoint in Global Phase III LIBRETTO-431 Trial for First-Line Treatment of RET Fusion-Positive NSCLC

Recently, Eli Lilly announced the primary results of the global Phase III clinical trial LIBRETTO-431 for its highly selective RET inhibitor, selpercatinib. This study evaluated the efficacy of selpercatinib monotherapy versus pemetrexed plus platinum-based chemotherapy (with or without pembrolizumab) as a first-line treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC) positive for rearranged during transfection (RET) gene fusions. Based on a pre-specified interim efficacy analysis conducted by the Independent Data Monitoring Committee (IDMC), the study met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with selpercatinib. In terms of safety, the adverse events observed in the LIBRETTO-431 study were generally consistent with those previously reported for selpercatinib in other studies (LIBRETTO-001, LIBRETTO-121, LIBRETTO-321).

Selpercatinib was developed by Eli Lilly and Company. In March 2022, Innovent Biologics and Eli Lilly and Company further deepened their strategic cooperation in the field of oncology. This included Innovent Biologics obtaining exclusive commercial rights to selpercatinib in China from Eli Lilly and Company, taking full responsibility for the pricing, importation, marketing, distribution, and sales promotion of selpercatinib.

LIBRETTO-431 is an open-label, randomized, controlled Phase III study aimed at comparing the efficacy and safety of selpercatinib monotherapy versus pemetrexed plus cisplatin/carboplatin chemotherapy (with or without the PD-1 inhibitor pembrolizumab) as first-line treatment for RET fusion-positive and EGFR/ALK-negative advanced or metastatic NSCLC.

Dr. David Hyman, Chief Medical Officer of Loxo@Lilly, stated, "The LIBRETTO-431 trial aims to address a significant issue in the initial treatment of patients with advanced RET fusion-positive NSCLC. The findings indicate that patients experience clinically meaningful improvements after receiving selpercatinib, thus selpercatinib should be considered as the first-line standard treatment. Additionally, timely and comprehensive genetic testing is particularly crucial, as it can guide decision-making for the initial treatment of all non-small cell lung cancer patients. The results further confirm that the RET target status (such as EGFR, ALK, and other lung cancer oncogenic driver genes) should be fully understood before initiating first-line treatment. We look forward to sharing these data more extensively with the oncology community in the future."

These data are based on the LIBRETTO-001 study, which is the largest global clinical trial evaluating selpercatinib for the treatment of patients with RET-driven cancers. The study covers 16 countries and 85 centers, including a dose-escalation phase (Phase 1) and a dose-expansion phase (Phase 2). In this clinical trial, selpercatinib demonstrated clinically meaningful and durable responses across various types of RET-driven cancers.

The full results of the LIBRETTO-431 study will be presented at an upcoming medical conference, submitted to a journal for peer review, and discussed with health authorities.

About the LIBRETTO-431 Study

LIBRETTO-431 is a randomized Phase III clinical trial for untreated RET fusion-positive NSCLC patients. The trial enrolled 261 patients with advanced or metastatic RET fusion-positive NSCLC who had not previously received systemic treatment for metastatic disease. Patients included in the trial were randomized in a 2:1 ratio to receive either selpercatinib or a platinum-based drug (carboplatin or cisplatin) + pemetrexed (with or without pembrolizumab) as the initial treatment for advanced or metastatic RET fusion-positive NSCLC. The RET fusion target can be identified through local testing. The primary endpoint of the trial is progression-free survival (PFS), with secondary endpoints including overall survival (OS), overall response rate (ORR), duration of response (DoR), and intracranial ORR. For patients randomized to the control group, crossover is allowed upon progression.

About Selpercatinib

Selpercatinib is a first-in-class, highly selective and inhibitory small-molecule RET inhibitor with central nervous system (CNS) activity that can inhibit various RET alterations. Selpercatinib is the world's first approved high-selectivity RET inhibitor, acting by inhibiting the activity of abnormal RET kinase. Selpercatinib has successively received three Breakthrough Therapy Designations and Priority Review from the U.S. FDA, and was approved for marketing by the U.S. FDA in May 2020 (U.S. brand name Retevmo®) for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) positive for rearranged during transfection (RET) gene fusions, adult and pediatric patients aged 12 years and older with advanced or metastatic medullary thyroid cancer carrying RET mutations who require systemic therapy, and adult and pediatric patients aged 12 years and older with advanced or metastatic thyroid cancer positive for RET fusions who require systemic therapy and are refractory to radioactive iodine therapy (if applicable). In September 2022, the FDA approved selpercatinib as the first and only tumor-agnostic RET inhibitor for adult patients with advanced or metastatic solid tumors with RET gene fusions, while also granting regular approval for the drug to treat adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) positive for RET fusions.

Editor: Mu Mian

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