Research in context
Evidence before this study
We searched PubMed for articles published in any language between Jan 1, 2000, and July 1, 2016, using the search terms “RET rearrangement” and “non-small cell lung cancer”. RET is a proto-oncogene. Activation by mutation and rearrangement drive oncogenesis in thyroid and lung cancers. The first reports of RET rearrangements in non-small-cell lung cancers (NSCLCs) were published in late 2011 and early 2012. The most common gene rearrangement in RET-rearranged NSCLC is KIF5B-RET. RET rearrangements were found predominantly in lung adenocarcinomas from patients with minimum to no previous tobacco exposure. Multikinase inhibitors were tested in RET-rearranged models in vitro and in vivo and resulted in decreased cell viability and inhibition of tumour growth. Prior to this publication, case reports of clinical responses to the multikinase inhibitors cabozantinib and vandetanib described benefit with the use of these drugs.
Added value of this study
This study prospectively showed that cabozantinib is active in patients with advanced RET-rearranged lung cancers, producing an overall response of 28%, a median progression-free survival of 6 months, and a median overall survival of 10 months. Responses were brisk and durable. Dose reductions were frequent due to drug-related adverse events.
Implications of all the available evidence
Launched in 2012, shortly after the first reports of RET fusions in lung cancer, this protocol represented the first prospective clinical trial initiated to establish the activity of a RET inhibitor for patients with RET-rearranged NSCLCs. The activity reported was similar to the activity of single-drug tyrosine kinase inhibition in other molecular cohorts of patients with NSCLCs (dabrafenib in BRAFV600E-mutant lung cancers). The overall response achieved with cabozantinib in RET-rearranged NSCLCs also exceeded the overall response of cabozantinib in unselected patients with NSCLCs, and of single-drug chemotherapies used in the second-line setting for the treatment of NSCLCs.