Dose-Ranging Phase 2 Results of Nivolumab Therapy in Metastatic Renal-Cell Carcinoma
Nivolumab is a fully human monoclonal antibody that inhibits the programmed death-1 (PD-1) immune checkpoint receptor to restore T-cell antitumor immune responses, and has shown clinical activity in metastatic renal-cell carcinoma (mRCC). Motzer and colleagues presented updated data on overall survival (OS) and duration of response from a blinded, dose-ranging, phase 2 clinical trial that evaluated 3 doses of nivolumab in patients with mRCC whose disease progressed while receiving inhibitors of the vascular endothelial growth factor (VEGF) pathway (Motzer R, et al. ESMO 2014: Abstract 810O).
In this trial, eligible patients with clear-cell mRCC (?1 agent targeting the VEGF pathway; ?3 previous systemic therapies) were randomized to receive intravenous nivolumab 0.3 mg/kg, 2 mg/kg, or 10 mg/kg every 3 weeks until disease progression or toxicity. The majority of the 168 patients enrolled in this trial had received ?2 previous systemic therapies, including VEGF receptor tyrosine kinase inhibitors (98%), mTOR inhibitors (38%), and immunotherapy (24%).
Across the doses tested, the overall response rates (ORRs) were similar, at approximately 20%, the median duration of response was not reached for the 0.3-mg/kg and 2-mg/kg doses, and the median duration of response for the 10-mg/kg dose was 22.3 months. The median progression-free survival (PFS) was 2.7 months, 4 months, and 4.2 months for the 0.3-mg/kg, 2-mg/kg, and 10-mg/kg cohorts, respectively. The median OS was 18.2 months for the 0.3-mg/kg dose and approximately 25 months for the 2-mg/kg and 10-mg/kg doses.
By PD-1 ligand 1 (PD-L1) expression, there was preliminary evidence of survival improvement in PFS, OS, and ORR in patients with PD-L1–positive disease, but this needs further validation.
The incidence of grade 3 or 4 treatment-related adverse events (including skin, gastrointestinal, endocrine, and hepatic toxicities) was ?17% across the doses, and was consistent with previously described events. There was no grade 3 or 4 pneumonitis.
These results suggest that nivolumab monotherapy is well tolerated in the treatment of patients with mRCC and is associated with encouraging efficacy, with no evidence of a clear dose–response relationship.