Confirmed and durable responses to multikinase inhibitors with activity against RET can be achieved in a proportion of patients with RET-rearranged or RET-mutant cancers; however, objective response rates are modest. An article published in the Nature Reviews Clinical Oncology emphasize that that novel approaches to targeting RET-dependent tumours are necessary to improve the clinical efficacy of single-agent multikinase inhibition and, thus, hasten approvals of RET-directed targeted therapies.
Activating alterations of the RET kinase are therapeutically actionable oncogenic drivers across a variety of cancers; in-frame RET rearrangements occur in subsets of non-small-cell lung cancer (NSCLC) and papillary thyroid cancers, and germ-line or somatic RET mutations are enriched in medullary thyroid cancers.
Multikinase inhibitors with activity against the receptor-tyrosine kinase RET, such as cabozantinib, vandetanib, and lenvatinib, have demonstrated efficacy in certain tumour types, with confirmed responses and durable disease control achieved in a proportion of patients with thyroid cancers and RET-rearranged NSCLCs in prospective trials. The degree of overall clinical benefit achieved with these drugs is modest compared with the outcomes of targeted therapy in patients with different molecular subtypes of NSCLC or other malignancies.
Several factors might account for the relatively low degree of clinical benefit from RET-directed therapy with multikinase inhibitors. Multikinase inhibitors are characterised by the substantial inhibition of non-RET targets, including VEGFR2, resulting in drug-related adverse events that can limit chronic dosing and full on-target inhibition of RET. On the other hand, the concurrent inhibition of multiple targets might contribute to the observed therapeutic response.
The development of RET-specific inhibitors that have limited off-target effects are likely to elucidate the utility of more-selective inhibition of RET in patients with RET-mutant and RET-rearranged tumours. In parallel with these efforts, combination therapies are being explored in tumours harbouring RET mutations or rearrangements to boost the activity observed with existing agents in the clinic.
The authors concluded that novel approaches to RET-directed targeted therapy are currently being explored; potent and specific RET inhibitors with minimal preclinical off-target activity are being evaluated in early stage clinical trials, as are combination therapies. Salient to the clinical development of potent RET inhibitors for patients of all ages, selective RET inactivation can affect the nervous, genitourinary, gastrointestinal, and haematopoietic systems during early development, but in adulthood, it leads to mild phenotypes.
Drilon A, Hu ZI, Lai GGY, et al. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes.Nature Reviews Clinical Oncology; Published online 14 November 2017. doi:10.1038/nrclinonc.2017.175