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.

Addressing challenges with real-world synthetic control arms to demonstrate the comparative effectiveness of Pralsetinib in non-small cell lung cancer

“…Thus, this study involved comparisons between RET fusion-positive patients from the ARROW trial to two types of RWD patient groups: 1) the subset of RET fusion-positive patients from the CGDB, and 2) RET fusion status unknown patients from the EDM, which has many more patients than the CGDB. The assumption based on currently available evidence that RET fusion status is not distinctly prognostic allowed for flexibility in using the EDM for cohort development 11 – 14 .…”

“…With the first goal to investigate the comparative effectiveness of pralsetinib relative to other therapies, we had to consider that since the prevalence of RET fusions is low in NSCLC (1–2%) 10 , using RWD for studies involving patients with RET fusion-positive status would be challenging. Thus, since we expected to have a limited number of RET fusion-positive patients available in RWD sources, and the prognostic value of RET fusion status appears to be limited based on the evidence currently available 11 – 14 , additional comparisons with aNSCLC patients of RET fusion unknown status were assessed. This allowed us to maximise the sample sizes of the RWD cohorts, translating into much higher statistical power and ability to adjust for imbalances in patient characteristics between cohorts.…”

FDA-Approved Small Molecule Compounds as Drugs for Solid Cancers from Early 2011 to the End of 2021

“…STAT : signal transducer and activator of transcription. Created with BioRender.com based on information in [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ].…”

Designing Novel Compounds for the Treatment and Management of RET-Positive Non-Small Cell Lung Cancer—Fragment Based Drug Design Strategy

“…A PRODRG server was used to generate the ligand topology files. The prepared protein-ligand complexes were solvated in a dodecahedron box with a volume of 7.66 nm 3 . The box was configured with simple point charge waters and eight chlorine counter ions to neutralize the total system charge.…”

“…The RET receptor consists of an intercellular domain, a transmembrane, and an extracellular region. The activation of RET protein involves the formation of ternary complexes with glial cell line-derived neurotrophic factors and its co-receptors, autophosphorylation of tyrosine kinase domain of RET, and finally resulting in the activation of downstream pathways that are implied in cell growth, differentiation, and proliferation [ 3 ]. Recently, genetic alterations of RET have been identified in diverse cancer types [ 4 ].…”