RET Inhibitors in Non-Small-Cell Lung Cancer

Abstract

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.

Keywords: NSCLC; RET; cabozantinib; lenvatinib; pralsetinib; selpercatinib; vandetanib.

Figure 1

RET structure and its activation. The RET protein includes an extracellular, a transmembrane and an intracellular region. The RET extracellular region consists of four highly repeated domains (cadherin-like domains) as well as a cysteine-rich domain. The transmembrane domain links the extracellular region to the intracellular tyrosine kinase domain (TKI), which ends with isoform specific tails (on the left). Glial cell line-derived neurotrophic factor (GDNF) family ligands and GDNF family co-receptors (GFR α1-4) play a central role in RET activation. The binding of the GDNF ligand to the GFR co-receptor determines the construction of a ternary complex which includes RET, the GDNF ligand and the GFR co-receptors. The newly formed ternary complex leads to RET TKI domain phosphorylation. Phosphorylated RET TKI domains then activate the downstream signalling pathways implied in cell proliferation, growth, differentiation and survival such as RAS/MAPK, PI3K/AKT, PKC and JAK-STAT (on the right).