Cabozantinib achieved an overall response rate of 28% in patients with RET-rearranged NSCLC.

  • Major finding: Cabozantinib achieved an overall response rate of 28% in patients with RET-rearranged NSCLC.

  • Approach: The safety and activity of cabozantinib were tested in an open-label, single-arm, phase II trial.

  • Impact: RET rearrangements may be targeted with cabozantinib in patients with NSCLC.

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RET rearrangements occur in 1% to 2% of non–small cell lung cancers (NSCLC) and drive ligand-independent RET signaling, suggesting that these alterations are potential therapeutic targets. The multikinase inhibitor cabozantinib, which has activity against RET, has antitumor activity in mouse models of RET-rearranged lung cancer and achieved a 10% overall response rate in an unselected population of patients with lung cancer. Drilon and colleagues evaluated the safety and activity of cabozantinib in 26 patients with advanced RET-rearranged NSCLC in an open-label, single-arm, phase II trial. The primary objective was to determine the overall response, and secondary outcomes included progression-free survival, overall survival, and safety. The overall response rate was 28%, with 7 of 25 evaluable patients achieving a partial response, including patients with KIF5B–RET, TRIM33–RET, and CLIP1–RET fusions. The median progression-free survival was 5.5 months, and median overall survival was 9.9 months. Treatment-related adverse events occurred in 96.2% of patients, but were primarily grade 1 or grade 2. Dose reductions were required in 73% of patients due to drug-related toxicities. Next-generation sequencing of 19 cases did not find activating alterations in other kinases targeted by cabozantinib, indicating that the therapeutic effects of cabozantinib are likely due to targeting of RET. In addition to suggesting that cabozantinib has antitumor activity and an acceptable tolerability in patients with RET-rearranged NSCLC, these findings indicate that RET rearrangements are targetable oncogenic drivers. The results of this study support further investigation of cabozantinib or RET-specific kinase inhibitors in patients with RET-rearranged lung cancer.

Drilon A, Rekhtman N, Arcila M, Wang L, Ni A, Albano M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol 2016;17:1653–60.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.