Retevmo Meets Primary Endpoint in Early-Stage RET+ Lung Cancer Trial

Eli Lilly and Company announced positive topline results from the phase 3 LIBRETTO-432 clinical trial of Retevmo (selpercatinib) as adjuvant therapy versus placebo. The trial met its primary endpoint, demonstrating a highly statistically significant and clinically meaningful improvement in investigator-assessed event-free survival in patients with early-stage (II-IIIA) rearranged during transfection (RET) fusion-positive non-small cell lung cancer.

Treatment with Retevmo reduced the risk of disease recurrence or death compared with placebo in patients with stage 2 to 3A RET fusion-positive non-small cell lung cancer. Event-free survival refers to the length of time after treatment during which a patient remains free from cancer recurrence or death.

Overall survival results trended in favor of Retevmo, though the data were described as immature at the time of analysis, with few events observed. Detailed findings from the study are expected to be presented at an upcoming medical congress, submitted to a peer-reviewed journal and discussed with health authorities globally.

LIBRETTO-432 is the first and only randomized phase 3 study to evaluate the safety and efficacy of a selective RET kinase inhibitor as adjuvant therapy in patients with RET fusion-positive non-small cell lung cancer. The study is a global, multicenter, randomized, double-blind, controlled clinical trial that enrolled 151 patients with RET fusion-positive non-small cell lung cancer following completion of definitive radiotherapy or surgery with curative intent, and other adjuvant therapy if indicated.

Participants were randomized in a 1 to 1 ratio to receive either Retevmo or placebo as adjuvant therapy. The goal was to determine whether Retevmo could reduce the risk of recurrence or death after initial treatment intended to cure the disease.

In LIBRETTO-432, the primary endpoint was event-free survival as assessed by investigators in the primary analysis population, which included patients with stage 2 to 3A RET fusion-positive disease. Secondary endpoints included event-free survival in the overall population, overall survival, event-free survival as assessed by blinded independent central review, time to distant disease recurrence in the central nervous system, progression-free survival on the next line of treatment, positive predictive value of RET tests from investigator-identified laboratories compared with the Lilly-designated RET test, as well as safety and tolerability.

Non-small cell lung cancer accounts for about 85% of all lung cancer diagnoses in the United States, and around 30% of patients with non-small cell lung cancer present with stage 1B to 3A disease. Approximately 50% of people with non-small cell lung cancer have actionable biomarkers. RET fusions have been identified in 1% to 2% of all non-small cell lung cancer cases.

The results from LIBRETTO-432 build on previous studies of Retevmo in advanced non-small cell lung cancer and highlight the importance of genomic testing at diagnosis and across all stages of disease. Identifying RET fusions through appropriate testing can help determine whether a targeted therapy such as Retevmo may be appropriate.

Retevmo is a highly selective and potent RET kinase inhibitor with central nervous system activity. It is an oral prescription medicine approved by the U.S. Food and Drug Administration for adult patients with locally advanced or metastatic non-small cell lung cancer with a RET gene fusion, as detected by an FDA-approved test. The recommended dose is 120 mg or 160 mg depending on weight, taken twice daily until disease progression or unacceptable toxicity.

The drug got an accelerated nod for metastatic RET fusion-positive NSCLC in 2020, and full approval followed in 2022, both based on the phase 1/2 Libretto-001 study. Retevmo came via Lilly's $8 billion purchase of Loxo in 2019.

In LIBRETTO-432, the overall safety profile of Retevmo was generally consistent with previously reported trials in its development program. Serious hepatic side effects occurred in 3% of patients treated with Retevmo. Increased aspartate aminotransferase occurred in 59% of patients, including grade 3 (severe) or 4 (life-threatening) events in 11%, and increased alanine aminotransferase occurred in 55% of patients, including grade 3 or 4 events in 12%.

Severe, life-threatening and fatal interstitial lung disease or pneumonitis can occur with Retevmo. Interstitial lung disease or pneumonitis occurred in 1.8% of patients, including 0.3% with grade 3 or 4 events and 0.3% with fatal reactions. Hypertension occurred in 41% of patients.