Final results of a phase II study of cabozantinib in patients with <i>MET</i> -altered lung cancers.

Abstract

8645 Background: MET alterations define a subgroup of non-small cell lung cancers (NSCLC) sensitive to MET tyrosine kinase inhibitors (TKIs). Currently, only type I MET TKIs are approved for treating these patients. We evaluated the activity of cabozantinib, a type II multikinase inhibitor, in MET-altered lung cancers. Methods: This is a single-arm, phase 2 trial in which patients with metastatic MET-altered lung cancers received cabozantinib (60 mg daily) until disease progression or intolerable toxicity. A Simon two-stage minimax design was used, with a null hypothesis (H0) of a 10% response rate and an alternative hypothesis (H1) of 30%. With a type I error of 10% and a power of 90%, 16 patients were enrolled in the first stage, with at least two responses required to advance to the second stage, enrolling an additional nine patients. The primary endpoint was objective response rate (ORR) and would be considered met if five or more patients provided an objective response among the 25 evaluable patients treated. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: Twenty-eight patients were treated. The median age was 68 (range 38–85) years. Most patients (82%; 23/28) had MET exon 14 alterations; 7% (2/28) had MET amplification only, and 12% (3/28) had concurrent MET exon 14 alteration and amplification. The median number of prior systemic therapies was two (range 1–6), and 86% had previously received a MET TKI. Among the 25 evaluable patients, the ORR was 20% (95% CI, 8.9–39.1). Four out of five patients who achieved a partial response had received prior MET TKI: two with crizotinib, one with tepotinib, and one with capmatinib. The median PFS and OS were 4.5 (95% CI, 3.3-5.7) months and 7.2 (95% CI, 2.9-11.5) months, respectively. Treatment-related adverse events were primarily grade 1 or 2, with the most common being fatigue (39%), diarrhea (39%), palmar-plantar erythrodysesthesia (36%), and anorexia (36%). Grade 3 or higher events included hypophosphatemia (14%), hypertension (11%), and elevated lipase (11%). No treatment-related deaths occurred. Conclusions: This trial met its primary endpoint. Cabozantinib demonstrated activity in MET-altered NSCLC, and prospective clinical proof-of-concept that type II MET TKI switching can rescue type I MET TKI progression was established. Clinical trial information: NCT01639508 .