Cabozantinib Plus Atezolizumab or Cabozantinib Alone in Patients With Advanced Non-Small Cell Lung Cancer Previously Treated With an Immune Checkpoint Inhibitor: Results From the Phase 1b COSMIC-021 Study

Introduction We evaluated efficacy and safety of cabozantinib plus atezolizumab or cabozantinib alone in advanced non-small cell lung cancer (NSCLC) previously treated with an immune checkpoint inhibitor (ICI). Methods COSMIC-021 (NCT03170960) is a phase 1b, multicenter study in advanced solid tumors. This analysis included patients with stage IV non-squamous NSCLC without actionable genomic aberrations in EGFR, ALK, ROS1, or BRAF-V600E who progressed on one prior ICI and ≤2 prior lines of systemic anticancer therapy. Patients received cabozantinib 40 mg orally/day plus atezolizumab 1200 mg intravenously every 3 weeks (combination cohort) or cabozantinib 60 mg orally/day (single-agent cabozantinib cohort). Primary endpoint of the combination cohort was objective response rate (ORR) per RECIST v1.1 by investigator. Outcomes in the single-agent cabozantinib cohort were exploratory. Results Eighty-one patients assigned to combination therapy and 31 assigned to single-agent cabozantinib received ≥1 dose of study treatment. Median (range) follow-up was 26.1 months (12.1–44.2) and 22.4 months (1.5–29.0), respectively. ORR was 20% (95% CI 11.7%–30.1%) in combination cohort and 6% (95% CI 0.8%–21.4%) in single-agent cabozantinib cohort. Treatment-related adverse events (TRAEs) occurred in 86% of patients in the combination cohort, and 90% in the single-agent cabozantinib cohort; grade 3/4 TRAEs were 44% and 48%, respectively. There were two grade 5 TRAEs: pneumonitis (n=1, combination) and gastric ulcer hemorrhage (n=1, single-agent). Neither PD-L1 expression in tumor cells nor tumor mutation burden correlated with outcomes. Conclusions Cabozantinib plus atezolizumab demonstrated modest clinical activity and manageable toxicity in advanced NSCLC after progression on prior ICI.