Lung cancer, conceptual image

Topline results from the late-stage LIBRETTO-431 study evaluating the efficacy of Eli Lilly’s oral targeted cancer therapy Retevmo (selpercatinib) in participants with advanced or metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), show increased progression free survival compared to treatment with a PD-1 inhibitor plus chemotherapy.

The randomized phase III clinical trial launched in 2020 with an estimated primary completion date in December 2024, enrolled 261 patients with advanced or metastatic RET fusion-positive NSCLC who hadn’t received prior systemic therapy for metastatic disease. Participants were randomized 2:1 to receive either selpercatinib or platinum-based and permetrexed therapy with or without the PD-1 inhibitor pembrolizumab as initial treatment.

“The LIBRETTO-431 trial aims to answer an important question about the selection of initial treatment for people with advanced RET fusion-positive NSCLC and these results suggest Retevmo should be considered a first-line standard of care,” said David Hyman, MD, chief medical officer at Lilly Oncology in a press statement.

“Additionally, this clinically meaningful achievement of improved outcomes underscores the importance of timely and comprehensive genomic testing to inform initial treatment decisions for all patients with NSCLC. The results of this study provide further confirmation that RET status—like EGFR, ALK, and others in the family of lung cancer oncogenic drivers —should be known prior to initiating therapy.”

The study met its primary endpoint, showing statistically significant and clinically meaningful improvement of progression-free survival in patients with RET-fusion positive NSCLC compared to chemotherapy with or without a PD-1 inhibitor. Safety data for selpercatinib was in line with previous clinical trials of the drug, showing it to be relatively safe and well-tolerated by participants of the study.

Selpercatinib, sold under the brand name Retevmo, was first granted accelerated approval by the FDA in 2020 for the RET fusion-positive non-small-cell lung cancer indication based on positive results from the phase I/II LIBRETTO-001 trial—the largest clinical trial of patients with RET-driven cancers treated with a RET-inhibitor. In September 2022, regular approval for the NSCLC indication was also granted.

The drug—available orally as 40 mg and 80 mg capsules—works by selectively inhibiting the RET kinase protein, whose enhanced expression is a hallmark of many cancers. The RET gene is normally responsible for signalling between cells. However, a cancer cell’s mutated RET gene can move or fuse to another gene leading to enhanced cancer growth and metastasis.

Following the hopeful interim data, Eli Lilly plan to present full results from the LIBRETTO-431 trial at an upcoming medical meeting, submit to a peer-reviewed journal and discuss with health authorities for further proceedings.

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