Cabozantinib Shows Activity in Advanced RET-Rearranged NSCLC


Key Points

  • Cabozantinib produced response in 28% of patients with advanced RET-rearranged NSCLC.
  • Response was observed in patients with KIF5B-RET, RIM33-RET, and CLIP1-RET fusions.

In a phase II trial reported in The Lancet Oncology, Drilon et al found that cabozantinib (Cabometyx) produced responses in some patients with advanced RET-rearranged non–small cell lung cancer (NSCLC). RET rearrangements are found in 1% to 2% of NSCLCs.

In the single-arm study, 25 evaluable patients from a single U.S. center with measurable metastatic or unresectable disease with a RET rearrangement were treated with cabozantinib at 60 mg daily. KIF5B-RET was the predominant fusion type, found in 16 patients.


Confirmed partial response was observed in 7 of 25 patients (overall response rate = 28%, 95% confidence interval [CI] = 12%–49%). Median duration of response was 7.0 months. Response was observed in 3 of 15 patients (20%) with KIF5B-RET fusions and 2 of 6 patients (33%) with unknown genes (fluorescence in situ hybridization–positive). Responses were observed in patients with RIM33-RET or CLIP1-RET fusions but not in those with CCDC6-RET or ERC1-RET fusions. Median progression-free survival was 5.5 months, and median overall survival was 9.9 months.

Adverse Events

Among the total of 25 patients who received cabozantinib, the most common grade 3 treatment-related adverse events were lipase elevation (15%), increased alanine transaminase (8%), increased aspartate transaminase (8%), decreased platelet count (8%), and hypophosphatemia (8%). Adverse events led to dose reduction in 73% of patients. No drug-related deaths were observed. Sixteen patients (62%) died during the course of follow-up.

The investigators concluded: “The reported activity of cabozantinib in patients with RET-rearranged lung cancers defines RET rearrangements as actionable drivers in patients with lung cancers. An improved understanding of tumour biology and novel therapeutic approaches will be needed to improve outcomes with RET-directed targeted treatment.”

The study was supported by Exelixis and a National Cancer Institute Cancer Center support grant.

Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of The Lancet Oncology article.

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