Selpercatinib in RET Fusion–Positive Non–Small Cell Lung Cancer - Final Safety and Efficacy

Sep 23, 2026

LIBRETTO-001 (NCT03157128) is a registrational phase I/II, single-arm, open-label trial of selpercatinib in RET-dependent cancers. With 19 months of additional follow-up, final efficacy and safety were reported in RET fusion–positive NSCLC after prior platinum chemotherapy (N=247) or in treatment-naive patients (N=69). ORR was 62% vs 83%. Median DoR was 31.6 vs 20.3 months, median PFS 26.2 vs 22.0 months, and median OS 47.6 months vs not reached; 3-year landmark survival was 57% vs 66%. CNS activity showed CNS-ORR 85% and CNS-PFS 11.0 months. The safety profile was consistent with earlier reports, supporting durable responses and intracranial activity with manageable toxicity.

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CategoryHealthcare

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Abstract

Introduction

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Clinical Trial Updates Selpercatinib in RET Fusion–Positive Non–Small Cell Lung Cancer: Final Safety and Efﬁcacy, Including Overall Survival, From the LIBRETTO-001 Phase I/II Trial Oliver Gautschi, MD1; Keunchil Park, MD, PhD2,3; Benjamin J. Solomon, MBBS, PhD4 ; Pascale Tomasini, MD5; Herbert H. Loong, MBBS6 ; Filippo De Braud, MD7; Koichi Goto, MD, PhD8 ; Patrick Peterson, PhD9; Scott Barker, PhD9 ; Katherine Liming, BSc9; Geoffrey R. Oxnard, MD9 ; Bente Frimodt-Moller, MSc10; and Alexander Drilon, MD11 DOI [https://doi.org/10.1200/JCO-24-02076](https://doi.org/10.1200/JCO-24-02076) ABSTRACT LIBRETTO-001 ([ClinicalTrials.gov](ClinicalTrials.gov) identiﬁer: NCT03157128) is a registrational phase I/II, single-arm, open-label trial of selpercatinib in RET-dependent cancers. With 19 months of additional follow-up, we report the ﬁnal efﬁcacy and safety results of selpercatinib in patients with RET fusion–positive non–small cell lung cancer (NSCLC) who had previously received platinum-based chemotherapy (N 5 247) or were treatment-nave (N 5 69) . The objective response rate (ORR) was 62% for pretreated patients and 83% for treatment-nave patients. Duration of response (DoR) was 31.6 months for pretreated and 20.3 months for treatmentnave patients (median follow-up approximately 38 months) . Median progression-free survival (PFS) was 26 .2 months for pretreated and 22 . 0 months for treatment-nave patients (median follow-up approximately 40 months) . Median overall survival was 47.6 months in pretreated patients and was not reached in the treatment-nave group (median follow-up approximately 43 months). At the 3-year landmark estimate, 57% of pretreated and 66% of treatment-nave patients were alive. Among 26 patients with measurable CNS metastases at baseline, the CNS-ORR was 85% with a CNS-DoR of 9.4 months and CNS-PFS of 11.0 months. The safety proﬁle of selpercatinib was consistent with previous reports. With substantial additional follow-up, selpercatinib continued to show durable responses and intracranial activity, with a manageable safety proﬁle in patients with RET fusion–positive NSCLC. ACCOMPANYING CONTENT Appendix Data Sharing Statement Protocol Accepted January 15, 2025 Published February 21, 2025 J Clin Oncol 43:1758-1764 © 2025 by American Society of Clinical Oncology View Online Article Creative Commons Attribution Non-Commercial No Derivatives 4.0 License INTRODUCTION RET fusions are targetable alterations in non–small cell lung cancer (NSCLC). Selpercatinib, a highly selective RET kinase inhibitor with CNS penetration,1-3 was approved for the treatment of RET fusion–positive NSCLC on the basis of the results of the single-arm phase I/II trial LIBRETTO-001 ([ClinicalTrials.gov](ClinicalTrials.gov) identiﬁer: NCT03157128).1,4 These results were conﬁrmed in the recent randomized phase III trial LIBRETTO-431 (ClinicalTrials.gov identiﬁer: NCT04194944); atan interim analysis, selpercatinib demonstrated superior progression-free survival (PFS) over platinum-based chemotherapy with or without pembrolizumab in ﬁrst-line treatment.2 On the basis of these data, current treatment guidelines recommend selpercatinib as ﬁrst-line treatment for RET fusion–positive NSCLC.5-7 Here, we report longterm efﬁcacy and safety from the ﬁnal analysis of selpercatinib in patients with RET fusion–positive NSCLC in the LIBRETTO-001 clinical trial, providing 3-year response outcomes, PFS and overall survival (OS), including the ﬁrst reports of median OS in pretreated patients and median PFS in patients with measurable CNS metastasis at baseline. To our knowledge, this is the ﬁrst mature estimation of median OS for selpercatinib and offers insights into how OS may mature in LIBRETTO-431 . METHODS Study Design Patients received selpercatinib in 28-day continuous cycles at doses of 20 mg once daily to 240 mg twice daily during the dose-escalation phase I. The recommended dose for phase II was 160 mg twice

FAQs

What was the LIBRETTO-001 study design and target population?

LIBRETTO-001 is a registrational phase I/II, single-arm, open-label trial of selpercatinib in RET-dependent cancers. It enrolled patients with RET fusion–positive, locally advanced or metastatic NSCLC.

How did efficacy results compare between pretreated and treatment-naive patients?

The objective response rate was 62% in pretreated patients and 83% in treatment-naive patients. Median progression-free survival was 26.2 months versus 22.0 months, and median overall survival was 47.6 months versus not reached.

What CNS outcomes were reported for patients with measurable CNS metastases at baseline?

Among 26 baseline CNS-metastasis patients, CNS-ORR was 85%, CNS-DoR was 9.4 months, and CNS-PFS was 11.0 months.

Sep 23, 2026

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