Lilly Announces Pivotal Phase III Results for Selpercatinib in RET Fusion-Positive NSCLC and RET-Mutant Medullary Thyroid Cancer

Eli Lilly and Company presented the results of the global Phase III studies LIBRETTO-431 and LIBRETTO-531 for Selpercatinib at the 2023 European Society for Medical Oncology (ESMO) Congress. The LIBRETTO-431 global Phase III study evaluated the efficacy of Selpercatinib monotherapy versus pemetrexed plus platinum-based chemotherapy (with or without pembrolizumab) as an initial treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC) positive for rearranged during transfection (RET) gene fusions. The LIBRETTO-531 global Phase III study assessed the efficacy of Selpercatinib compared to multi-kinase inhibitors (MKIs) in treating patients with advanced or metastatic rearranged during transfection (RET)-mutant medullary thyroid carcinoma (MTC). The outcomes of both clinical trials were based on a pre-specified interim efficacy analysis conducted by the Independent Data Monitoring Committee (IDMC). The results of the LIBRETTO-431 and LIBRETTO-531 global Phase III trials were announced at the Presidential Symposium of the 2023 European Society for Medical Oncology (ESMO) Congress and simultaneously published in The New England Journal of Medicine.

RET Fusion-Positive Non-Small Cell Lung Cancer (NSCLC):
LIBRETTO-431 Study Data

LIBRETTO-431 is an open-label, randomized, controlled Phase III study designed to evaluate the efficacy of selpercatinib in patients with advanced or metastatic, previously untreated RET fusion-positive NSCLC. In this study, patients were randomly assigned to receive either selpercatinib monotherapy or pemetrexed plus cisplatin/carboplatin chemotherapy (with or without pembrolizumab), the latter being the current first-line standard of care. LIBRETTO-431 is the first randomized trial to compare the safety and efficacy of targeted therapy versus PD-1 inhibitor combined with chemotherapy in a biomarker-selected NSCLC patient population. The trial initially assessed the primary endpoint in the ITT-pembrolizumab population (patients within the intent-to-treat (ITT) group who received pembrolizumab combination therapy), and if the result was positive, it would proceed to evaluation in the overall ITT population.

A total of 256 patients received at least one dose of the study treatment (158 in the Selpercatinib group; 98 in the control group). Among the 261 patients in the ITT population, 159 were randomly assigned to the Selpercatinib group and 102 to the control group. Among the 212 patients in the ITT-Pembrolizumab population, 129 were randomly assigned to the Selpercatinib group and 83 to the chemotherapy plus Pembrolizumab group. Patients randomly assigned to the control group who had confirmed disease progression by blinded independent central review (BICR) were eligible to cross over to the Selpercatinib group.

In the ITT population receiving pembrolizumab, the median PFS assessed by BICR was 24.8 months (95% CI: 16.9, not estimable [NE]) in the selpercatinib group and 11.2 months (95% CI: 8.8, 16.8) in the control group. The HR was 0.465 (95% CI: 0.309, 0.699; p < 0.001). Consistent PFS benefits were also observed in the ITT population. Among 29 patients with measurable brain metastases at baseline, the intracranial ORR was 82.4% (95% CI: 56.6, 96.2) in the selpercatinib group and 58.3% (95% CI: 27.7, 84.8) in the control group. The median duration of response was not reached.

RET-Mutated Medullary Thyroid Carcinoma (MTC):
LIBRETTO-531 Study Data

LIBRETTO-531 Study is a Phase III, randomized, open-label trial designed to evaluate the efficacy of selpercatinib compared to multi-kinase inhibitors (MKIs) cabozantinib or vandetanib, which are currently approved as first-line treatments for advanced or metastatic RET-mutated medullary thyroid carcinoma (MTC) patients who have not received prior kinase inhibitors. This is the first randomized trial to compare the safety and efficacy of a highly selective RET kinase inhibitor with multi-kinase inhibitors (MKIs) in this patient population.

A total of 291 patients with progressive RET-mutant MTC who had not previously received MKI treatment for advanced or metastatic medullary thyroid carcinoma were randomly enrolled in the study. Among them, 193 patients were randomly assigned to the selpercatinib group, and 98 patients were randomly assigned to the control group, receiving either cabozantinib (73 patients) or vandetanib (25 patients). Patients in the control group who were confirmed to have disease progression by blinded independent central review (BICR) were eligible to crossover to the selpercatinib group.

In terms of safety, the adverse events observed in the two studies were generally consistent with those previously observed with selpercatinib in various studies (LIBRETTO-001, LIBRETTO-121, LIBRETTO-321).

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 randomly assigned 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 could be identified through local testing. The primary endpoint of the trial was progression-free survival (PFS), and secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DoR), and intracranial ORR. For patients randomized to the control group, crossover was allowed upon progression.

About the LIBRETTO-531 Study

LIBRETTO-531 Study is a randomized, Phase III clinical trial involving patients with advanced RET-mutant medullary thyroid cancer (MTC) who have not received prior kinase inhibitor therapy. The trial enrolled 291 patients, randomly assigned in a 2:1 ratio to receive either selpercatinib or the investigator's choice of cabozantinib or vandetanib as the initial treatment for advanced RET-mutant MTC. The RET mutation can be identified through local testing. The primary endpoint of the study is progression-free survival (PFS), with secondary endpoints including treatment-free failure survival (TFFS), objective response rate (ORR), duration of response (DoR), and overall survival (OS). Patients randomized to the control arm are allowed to cross over 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 highly selective 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. trade 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 who require systemic therapy and carry RET mutations, 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 harboring RET gene fusions, while also granting regular approval for the drug in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) positive for RET fusions.

Editor: Mu Mian

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