The anti–PD-L1 antibody atezolizumab is safe and active in patients with metastatic RCC.
Major finding: The anti–PD-L1 antibody atezolizumab is safe and active in patients with metastatic RCC.
Concept: Activity is associated with immune cell PD-L1 expression and increased ratios of Teff–Treg genes.
Impact: Combined treatment with anti-VEGF therapies may increase the efficacy of atezolizumab.
Expression of the immune checkpoint protein programmed death ligand 1 (PD-L1) on tumor-infiltrating immune cells enables tumor immune evasion and is correlated with poor prognosis in renal cell carcinoma (RCC). Antibodies directed against PD-L1 have shown clinical activity in various solid tumors, including RCC, prompting McDermott and colleagues to assess the safety and activity of atezolizumab (MPDL3280A), a humanized monoclonal IgG1 anti–PD-L1 antibody, in patients with metastatic RCC in a phase Ia clinical trial. Seventy patients with locally advanced or metastatic RCC were treated with atezolizumab, and PD-L1 expression in both tumor cells and tumor-infiltrating immune cells at diagnosis was determined. Atezolizumab exhibited a manageable safety profile, with no dose-limiting toxicities and the majority of treatment-related adverse events or immune-mediated adverse events being grade 1 or 2. Among 63 evaluable patients with clear-cell RCC (ccRCC), the objective response rate (ORR) was 15%, the median progression-free survival was 5.6 months, and the median overall survival (OS) was 28.9 months. In particular, the ORR among patients with poor prognostic features, such as high tumor grade and/or sarcomatoid features, was 22%. Furthermore, tumor shrinkage was observed in 46% of patients with ccRCC. Increased expression of PD-L1 in tumor-infiltrating immune cells, but not tumor cells, was associated with higher ORR (18% vs. 9%) and improved 2-year OS. In addition, decreased plasma levels of VEGFA, a marker of RCC tumor burden, on-treatment decreases in acute-phase inflammatory proteins, and a higher baseline ratio of T effector cell (Teff) to regulatory T cell (Treg) gene signatures correlated with longer OS, identifying potential biomarkers of atezolizumab response. These findings provide further evidence of the antitumor activity of immunotherapy in RCC and support ongoing clinical studies to test the combination of atezolizumab with other agents such as anti-VEGF therapies in RCC.
McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atezolizumab, an anti–programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol 2015 Jan 11 [Epub ahead of print].
- ©2016 American Association for Cancer Research.