Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non–small-cell Lung Carcinoma

Introduction: Cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against MET, vascular endothelial growth factor receptor 2, AXL, ROS1, and RET was assessed in patients with non–small-cell lung carcinoma (NSCLC) as part of a phase II randomized discontinuation trial with cohorts from 9 tumor types. Patients and Methods: Patients received cabozantinib 100 mg/day during a 12-week open-label lead-in stage. Those with stable disease per Response Evaluation Criteria in Solid Tumors version 1.0 at week 12 were randomized to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and progression-free survival (PFS) after randomization. Results: Sixty patients with NSCLC who had received a median of 2 prior lines of therapy were enrolled. ORR at week 12 was 10%; 6 patients had a confirmed partial response, and no patients had a complete response. Overall disease-control rate (ORR + stable disease) at week 12 was 38%. Tumor regression was observed in 30 (64%) of 47 patients with post-baseline radiographic tumor assessments, including 3 or 4 patients with KRAS or epidermal growth factor receptor mutations, respectively. Median PFS after randomization was 2.4 months for both the cabozantinib and placebo arms. Median PFS from first dose for the entire cohort was 4.2 months. The most common grade 3/4 adverse events were fatigue (13%), palmar-plantar erythrodysesthesia (10%), diarrhea (7%), hypertension (7%), and asthenia (5%); 1 treatment-related grade 5 adverse event (hemorrhage) was reported during the lead-in stage. Conclusion: Cabozantinib exhibited clinical activity based on ORR and regression of tumor lesions in pretreated patients with NSCLC, including in patients with KRAS mutations. Cabozantinib is an inhibitor of receptor tyrosine kinases, including MET, vascular endothelial growth factor receptors, AXL, RET, and ROS1. We assessed cabozantinib in 60 patients with non–small-cell lung carcinoma enrolled in a phase II randomized discontinuation trial. Tumor regression was observed in most patients, including patients with KRAS and epidermal growth factor receptor mutations. The safety profile was consistent with that reported for cabozantinib in other solid tumors.