Selpercatinib Shows Significant Survival Benefit in Early-Stage RET Fusion-Positive Lung Cancer
Phase 3 LIBRETTO-432 trial met its primary endpoint, showing selpercatinib delivered statistically significant and clinically meaningful improvement in event-free survival versus placebo as adjuvant therapy in early-stage RET fusion-positive NSCLC.
Topline data were announced from a phase 3 trial evaluating selpercatinib as an adjuvant therapy in patients with early-stage (II-IIIA) RET fusion-positive non-small cell lung cancer (NSCLC). The primary endpoint was met, with patients treated with selpercatinib demonstrating a statistically significant and clinically meaningful improvement in event-free survival versus placebo.
Selpercatinib is a highly selective and potent RET kinase inhibitor. It was approved under the brand name Retevmo for the treatment of adult patients with locally advanced or metastatic NSCLC with a RET gene fusion.
The randomized, double-blind, placebo-controlled phase 3 LIBRETTO-432 study (ClinicalTrials.gov Identifier: NCT04819100) evaluated the safety and efficacy of selpercatinib in 151 enrolled patients with RET fusion-positive NSCLC following completion of definitive radiotherapy or surgery with curative intent, and other adjuvant therapy, if indicated. The study is also the first randomized phase 3 trial to assess a selective RET kinase inhibitor in the adjuvant setting in this population.
Study participants were randomly assigned 1:1 to receive either selpercatinib or placebo, as adjuvant therapy. The primary endpoint was event free survival (EFS) as assessed by investigators in the primary analysis population (patients with stage II-IIIA RET fusion-positive NSCLC).
While overall survival data (secondary endpoint) remained immature at the time of analysis, a favorable trend was observed. The limited number of survival events prevented formal assessment. The safety profile of selpercatinib in the trial was largely comparable to the established toxicity profile of the agent.
To be eligible for LIBRETTO-432, patients must be at least 18 years old and have received a diagnosis of histologically confirmed stage IB, II, or IIIA NSCLC with an activating RET gene fusion in the tumor based on polymerase chain reaction, next-generation sequencing, or another approved molecule test. Patients must also have received definitive locoregional therapy with curative intent and undergone or not been suitable for the available anticancer treatments.
In accordance with the study design, no more than 10 weeks was allowed between the completion of definitive therapy and randomization if no chemotherapy was given, and 26 weeks if adjuvant chemotherapy was administered. Adequate hematologic, hepatic, and renal function, and an ECOG performance status of 0 or 1 were also required. If patients had additional oncogenic drivers, they would be excluded from enrollment.
The executive vice president and president of Lilly Oncology stated that the LIBRETTO-432 results demonstrate an effect size in line with the most striking data for targeted adjuvant therapy in lung cancer. The company noted that cancer medicines can deliver their greatest impact when administered early in the course of a patient's treatment journey.
The agent is currently approved for use in 4 indications: adult patients with locally advanced or metastatic NSCLC with a RET gene fusion, as detected by an FDA-approved test; adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer with a RET mutation, as detected by an FDA-approved test, who require systemic therapy; adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory; and adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.
Full results will be presented at an upcoming medical congress and will be submitted to a peer-reviewed journal. Detailed findings from the study will also be discussed with global regulatory agencies.