Eli Lilly announces results from both LIBRETTO-431, LIBRETTO-531 Phase 3 studies

Eli Lilly announced results from both the LIBRETTO-431 Phase 3 study, which evaluated Retevmo versus platinum-based chemotherapy – with or without pembrolizumab – as an initial treatment for patients with advanced or metastatic rearranged during transfection fusion-positive non-small cell lung cancer, and the LIBRETTO-531 Phase 3 study, which evaluated Retevmo versus multikinase inhibitors in patients with advanced or metastatic RET-mutant medullary thyroid cancer. In both clinical studies, results were based on pre-specified interim efficacy analyses conducted by independent data monitoring committees. Results from the LIBRETTO-431 and LIBRETTO-531 Phase 3 trials were presented in a Presidential Symposium at the European Society for Medical Oncology Congress 2023 and simultaneously published in the New England Journal of Medicine. The labeling for Retevmo contains warnings and precautions for hepatotoxicity, interstitial lung disease/pneumonitis, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, tumor lysis syndrome, risk of impaired wound healing, hypothyroidism, and embryo-fetal toxicity. LIBRETTO-431 is a Phase 3, randomized, open-label trial that evaluated Retevmo in patients with advanced or metastatic, treatment-naive RET fusion-positive NSCLC. In the study, patients were randomly assigned to receive Retevmo, or pemetrexed and the investigator’s choice of platinum-based chemotherapy with or without pembrolizumab – which is a current first-line standard of care treatment option. LIBRETTO-431 is the first randomized trial that compared the safety and effectiveness of a targeted therapy to a PD-1 inhibitor plus chemotherapy in a biomarker-selected NSCLC patient population. The primary endpoint was tested first in patients stratified by intent-to-treat with pembrolizumab if assigned to the control arm, then tested in the ITT population if deemed positive. A total of 256 patients received at least one dose of study treatment. Of the 261 patients in the ITT population, 159 were randomly assigned to Retevmo and 102 to the control arm. Of the 212 patients in the ITT-pembrolizumab population, 129 were randomly assigned to Retevmo and 83 to pembrolizumab with chemotherapy. Patients randomized to the control arm who had disease progression confirmed by blinded independent central review were eligible for optional crossover to Retevmo. In the ITT-pembrolizumab population, the median PFS by BICR was 24.8 months with Retevmo versus 11.2 months in the control arm, corresponding to a hazard ratio of 0.465. PFS was longer with Retevmo than in the control arm across all pre-specified subgroups. The overall response rate by BICR with Retevmo was 83.7% compared to 65.1% in the control arm. Similar results were observed in the ITT population in both BICR and investigator-assessed endpoints and across all pre-specified subgroups. Retevmo demonstrated superior PFS with an HR of 0.482 and an increase of more than 13 months in median PFS by BICR, showing 24.8 months with Retevmo versus 11.2 months with control. Overall survival results remain immature with a censoring rate of approximately 80% in the ITT-pembrolizumab arm. Intracranial baseline assessments were available for evaluation by neuroradiologic BICR for 192 patients in the central nervous system-pembrolizumab population. Time to CNS progression was longer with Retevmo than in the control arm, with eight patients on Retevmo having a first event of CNS progression compared to 13 patients in the control arm. Forty-two of the 192 patients were confirmed to have brain metastases at baseline, of which 29 were measurable. In the patients with measurable baseline brain metastases, the intracranial response rate for those who received Retevmo was 82.4% versus 58.3% in the control arm. Complete responses were observed in 35.3% of patients with Retevmo versus 16.7% in the control arm. Median intracranial response duration was not yet mature, but at 12 months, 76.0% of patients remained in response with Retevmo versus 62.5% in the control arm. LIBRETTO-531 is a Phase 3, randomized, open-label trial that evaluated Retevmo versus physician’s choice of MKIs cabozantinib or vandetanib, which are currently approved first-line options for patients with advanced or metastatic, kinase inhibitor-naive RET-mutant MTC. It is the first randomized trial that compared the safety and effectiveness of a highly selective RET-kinase inhibitor versus MKIs in this population. A total of 291 patients with progressive RET-mutant MTC and no prior history of MKI therapy for advanced or metastatic disease were randomized in the study. One hundred and ninety-three patients were randomized to the Retevmo arm and 98 to the control arm to receive investigator’s choice of cabozantinib or vandetanib. Patients randomized to the control arm who experienced disease progression confirmed by BICR were eligible to cross over to Retevmo. At the interim analysis, the study had met the criteria for positive PFS. At a median follow-up of approximately 12 months, the BICR-assessed median PFS in the Retevmo arm was not reached and remained inestimable, whereas the BICR-assessed median PFS in the control arm was 16.8 months. This corresponded to a HR of 0.280. Investigator-assessed PFS yielded similar results with an HR of 0.187. Both BICR and investigator-assessed PFS were longer with Retevmo across all pre-planned subgroups. Treatment with Retevmo resulted in a significant improvement in treatment failure-free survival with an HR of 0.254. The ORR with Retevmo was 69.4% compared to 38.8% in the control arm. OS results remain immature with a censoring rate of more than 90%, although a favorable trend was observed. The safety profile observed for Retevmo in both studies was generally consistent with those identified across the previously reported Retevmo development program.