RET Fusion-Positive Non-small Cell Lung Cancer - The Evolving Treatment Landscape

Sep 28, 2026

Uploaded by Miles

The objective of this narrative review is to summarize the efficacy and safety of available therapies for RET fusion-positive non-small cell lung cancer (NSCLC), including in patients with central nervous system (CNS) metastases. Background coverage includes RET rearrangements in NSCLC, molecular testing options, and clinical guidelines recommending broad testing, including RET. Reviewed treatments span multikinase inhibitors, RET-selective inhibitors, pemetrexed-based regimens, and immunotherapies from Phase I/II and real-world studies. Resistance mechanisms are also summarized, with selpercatinib and pralsetinib preferred first-line options.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Abstract

Implications for Practice

Introduction

RET Rearrangements and Molecular Testing

RET Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape Silvia Novello*, 1, Raffaele Califano2, Niels Reinmuth3, Antonella Tamma4, Tarun Puri4 1University of Turin, Department of Oncology, AOU San Luigi, Orbassano (Turin), Italy 2The Christie NHS Foundation Trust and Division of Cancer Sciences, The University of Manchester, Manchester, UK 3Thoracic Oncology Department, Asklepios Lung Clinic, Munich-Gauting, Germany 4Medical Oncology, Eli Lilly and Company, Indianapolis, IN, USA * Corresponding author: Silvia Novello, Professor of Medical Oncology, Oncology Department, AOU San Luigi, University of Turin, Italy. Tel: +39 0119026978; Fax +39 0119038616; Email: silvia. novello@unito. it President of WALCE Onlus ([www.womenagainstlungcancer.eu](www.womenagainstlungcancer.eu)) . Abstract The objective of this narrative review is to summarize the efficacy and safety of available therapies for rearranged during transfection ( RET) fusion-positive non-small cell lung cancer (NSCLC), including in patients with central nervous system (CNS) metastases. Background information is provided on RET rearrangements in NSCLC and the molecular testing options available as well as an overview of clinical guidelines for molecular testing, which recommend broad molecular testing, including for RET rearrangements. The efficacy and safety of potential treatments for RET fusion-positive NSCLC, including multikinase inhibitors, RET-selective inhibitors, pemetrexed-based therapy, and immunotherapies are reviewed from Phase I/II and `real-world’ studies, alongside an overview of primary and secondary resistance mechanisms. The RET-selective inhibitors, selpercatinib and pralsetinib, are preferred first-line therapy options for patients with RET fusion-positive metastatic NSCLC and are recommended as subsequent therapy if RET inhibitors have not been used in the first-line setting. Key words: RETfusion-positive NSCLC; treatment; precision medicine; RET rearrangement; oncogene-addiction. Implications for Practice This comprehensive review covers a range of topics in RET fusion-positive NSCLC that have direct relevance to cancer care. Clinically relevant background information on RET rearrangements is provided, along with an overview of molecular testing options available and clinical guidelines for molecular testing, noting that application of guideline-based molecular testing in practice is suboptimal. A key focus of the article is on the efficacy and safety of potential treatments for patients with RET fusion-positive NSCLC, including those with CNS metastases. Introduction Lung cancer remains the leading cause of death from cancer worldwide despite advances in the understanding of risk, biology and immunologic control, and the advent of newer treatment options.1 Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses.2 The identification of oncogenic drivers and the subsequent development of targeted therapies (TTs) has established biomarker-based treatment for metastatic NSCLC as standard of care (SOC) . International guidelines3-5 recommend that patients whose tumor harbors an actionable molecular aberration should receive the appropriate TT. Rearranged during transfection (RET) rearrangements were first identified as oncogenic drivers in NSCLC in 2012.6 The proportion of patients with NSCLC who have RET rearrangements (ie, fusion-positive disease) is approximately 1%-2% .7-10 However, in clinical practice, not all patients with NSCLC are tested for RET rearrangements; therefore, the proportion of patients with RET fusion-positive NSCLC who are eligible for TT will be less than 1%-2%. Improvements can be made in precision medicine with increased biomarker testing and use ofTTs, although equitable access varies among countries.11 In this review, we summarize the efficacy and safety of all available therapies for RET fusion-positi

FAQs

What is the primary goal of this narrative review?

To summarize the efficacy and safety of available therapies for RET fusion-positive NSCLC, including cases with CNS metastases.

Which therapies are reviewed for RET fusion-positive NSCLC?

Multikinase inhibitors, RET-selective inhibitors (selpercatinib and pralsetinib), pemetrexed-based therapy, and immunotherapies from Phase I/II and real-world studies.

How do the guidelines recommend molecular testing for NSCLC?

They recommend broad molecular testing, including for RET rearrangements, so patients with actionable alterations receive the appropriate targeted therapy.

Sep 28, 2026

Uploaded by Miles