RET Inhibitors in Non-Small-Cell Lung Cancer.

Giovanna Esposito,Paolo Muto,Guido Carillio,Claudia Sandomenico,Alessandro Morabito,Carmine Picone,Nicola Normanno,Roberto Bianco,Priscilla Cascetta,Maria Carmela Piccirillo,Giuseppe Totaro,Agnese Montanino,Vincenzo Sforza,Raffaele Costanzo,Rossella De Cecio,Carmine La Manna,Giuliano Palumbo,Anna Manzo

doi:10.3390/cancers13174415

Abstract

Simple SummaryNon-small cell lung cancer (NSCLC) remains a significant cause of death worldwide, despite the significant progresses to date. Multiple molecular alterations have been identified in NSCLC, leading to the development of target-based agents that have shown significant clinical benefits. Rearranged during Transfection (RET) fusions have recently emerged as a new potential target and a number of non-selective and selective RET inhibitors have been tested in RET positive NSCLC. In this review we analyse and summarise the characteristics of RET functions and its alterations in NSCLC. We then present the state of the art RET inhibitors in the treatment of NSCLC, discussing the ongoing trials and the future perspectives for RET positive (RET+) NSCLC patients.RET rearrangements are observed in 1–2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.

Highlights

The RET (Rearranged during Transfection) gene encodes a single-pass transmembrane receptor tyrosine kinase (RTK) physiologically involved in renal morphogenesis, neural and neuroendocrine tissue development as well as spermatogonial stem cell maintenance.The RET protein consists of an extracellular, a transmembrane and an intracellular region.The N-terminal extracellular region contains four highly repeated domains as well as a cysteine-rich domain and each domain is implied in both normal protein conformation and the construction of active ternary complexes [1]
The efficacy of vandetanib was tested in four phase III trials as single agents or in combination with chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC) unselected for RET
Based on the aforementioned results, the FDA have granted an accelerated approval of selpercatinib and pralsetinib for the treatment of adult patients with metastatic RET+ NSCLC

Summary

Introduction

The RET (Rearranged during Transfection) gene encodes a single-pass transmembrane receptor tyrosine kinase (RTK) physiologically involved in renal morphogenesis, neural and neuroendocrine tissue development as well as spermatogonial stem cell maintenance. Newly formed ternary complexes lead to the auto-phosphorylation of the RET TKI domains, resulting in the activation of downstream signalling pathways normally implied in cell proliferation, growth, differentiation and survival, such as RAS/MAPK, PI3K/AKT, PKC and JAKSTAT [2]. By sequencing more than 10,000 different metastatic tumours, RET alterations have been found in 2.4% of all cases, primarily in thyroid cancers and NSCLC. By analysing 4871 different tumour samples, the co-occurrence of genetic abnormalities has been found in the majority of RET- altered patients (81.8%, 72/88 patients), the most common being TP-53 associated genes (59.1%, 52/88 patients), cell cycle-associated genes (39.8%, 35/88 patients), the PI3K signalling pathway (30.7%, 27/88 patients), MAPK effectors (22.7%, 20/88 patients) or other tyrosine kinase families (21.6%, 19/88 patients) such as FGFR families, EGFR, ALK, HER2, PDGFRα and PDGFRβ [6]. In an additional and larger retrospective study, no difference in the incidence of lymphangitic carcinomatosis was seen among RET+ , ALK+ or ROS1+ advanced NSCLC patients. RET fusions have been related to a low response to immune checkpoint inhibitors due to a low TMB (tumour mutational burden) as well as a low level of PD-L1 expression [20]

Cabozantinib

Vandetanib

Lenvatinib

Selective RET Inhibitors

Selpercatinib

Pralsetinib

Findings

Discussion

Conclusions