Low Response Rate With Multikinase Inhibitors in RET-rearranged NSCLC

Currently-available multikinase inhibitors that target RET kinase had limited activity in patients with non-small cell lung cancer (NSCLC) with RET rearrangements, according to the Global, Multicenter RET Registry (GLORY) results published in the Journal of Clinical Oncology.¹

Targeted therapy is commonly used to treat NSCLC that harbors mutations in EGFR, BRAF, or ROS1. Prospective trials are difficult to conduct for diseases with more rare mutations, including RET rearrangements. This registry was established to evaluate the use of multikinase inhibitors in patients with RET-rearranged NSCLC.

The GLORY registry included 165 patients with any stage NSCLC with RET rearrangements. Multikinase targeted therapies included cabozantinib, vandetanib, sunitinib, sorafenib, alectinib, lenvatinib, nintedanib, ponatinib, and regorafenib.

Patients included in the study were a median age of 51 years; 63% were never smokers, 98% had adenocarcinoma, and 72% had stage IV disease at diagnosis. Rearrangements included KIF5B-RET (72%), CCDC6-RET (23%), NCOA4-RET (2%), EPHA5-RET (1%), and PICALM-RET (1%). Targeted therapy was initiated in 53 patients.

The majority of patients were treated with cabozantinib (21 patients), which resulted in a complete response (CR) among 5% of patients, partial response (PR) in 32%, and stable disease (SD) in 26%. Among those treated with vandetanib (11 patients), 0% experienced CR, 18% had a PR, and 27% had SD. Treatment with sunitinib (10 patients) resulted in CR in 0%, PR in 22%, and SD in 33%.

Among the treated cohort, median progression-free survival was 2.2 months (95% CI, 0.7-0.5 months); median overall survival (OS) was 6.8 months (95% CI, 1.1 months-not reached [NR]). When stratified by targeted agent, median OS was 4.9 months with cabozantinib, 10.2 months with vandetanib, and 6.8 months with sunitinib.

The authors speculated that suboptimal inhibition of RET kinase and the molecular heterogeneity of NSCLC may explain the low observed response rate.

Reference

1. Gautschi O, Milia J, Filleron T, et al. Targeting RET in patients with RET-rearranged lung cancers: results from the Global, Multicenter RET Registry. J Clin Oncol. 2017 March 13. doi: 10.1200/JCO.2016.70.9352 [Epub ahead of print]