Non-Small-Cell Lung Cancers (NSCLCs) Harboring RET Gene Fusion, from Their Discovery to the Advent of New Selective Potent RET Inhibitors: "Shadows and Fogs"

被引:1
|
作者
Spitaleri, Gianluca [1 ]
Aliaga, Pamela Trillo [1 ]
Attili, Ilaria [1 ]
Del Signore, Ester [1 ]
Corvaja, Carla [1 ]
Pellizzari, Gloria [2 ,3 ]
Katrini, Jalissa [2 ,3 ]
Passaro, Antonio [1 ]
de Marinis, Filippo [1 ]
机构
[1] IRCCS, European Inst Oncol IEO, Div Thorac Oncol, Via Ripamonti 435, I-20141 Milan, Italy
[2] IRCCS, European Inst Oncol, Div New Drugs & Early Drug Dev Innovat Therapies, I-20141 Milan, Italy
[3] Univ Milan, Dept Oncol & Haematol DIPO, I-20122 Milan, Italy
关键词
NSCLC; RET; RET gene fusion; RET multi-targeted inhibitors; new selective RET inhibitors; pralsetinib; selpercatinib; toxicity; resistance mechanism; new drugs; TYROSINE KINASE INHIBITOR; DEMONSTRATES ROBUST ACTIVITY; PHASE I/II ARROW; OPEN-LABEL; ACQUIRED-RESISTANCE; PATIENTS PTS; SINGLE-ARM; NEUROTROPHIC FACTOR; HIGHLY POTENT; TARGETING RET;
D O I
10.3390/cancers16162877
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Simple Summary RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1-2% of all NSCLCs. Chemotherapy and immunotherapy have a low impact on the prognosis of patients with RET fusions positive NSCLC. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy in minimizing the known toxicities of the old drugs. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.Abstract RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1-2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the 'old' multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.
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页数:29
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