Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma

• Published in: Nature medicine Vol. 24; no. 6; pp. 749 - 757
• Main Authors: McDermott, David F., Huseni, Mahrukh A., Atkins, Michael B., Motzer, Robert J., Rini, Brian I., Escudier, Bernard, Fong, Lawrence, Joseph, Richard W., Pal, Sumanta K., Reeves, James A., Sznol, Mario, Hainsworth, John, Rathmell, W. Kimryn, Stadler, Walter M., Hutson, Thomas, Gore, Martin E., Ravaud, Alain, Bracarda, Sergio, Suárez, Cristina, Danielli, Riccardo, Gruenwald, Viktor, Choueiri, Toni K., Nickles, Dorothee, Jhunjhunwala, Suchit, Piault-Louis, Elisabeth, Thobhani, Alpa, Qiu, Jiaheng, Chen, Daniel S., Hegde, Priti S., Schiff, Christina, Fine, Gregg D., Powles, Thomas
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2018; Nature Publishing Group
• Subjects: 631/67/1059/2325; 631/67/1857; 631/67/589/1588/1351; 692/308/2779/777; Adult; Aged; Aged, 80 and over; Angiogenesis; Angiogenesis inhibitors; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Bevacizumab - adverse effects; Bevacizumab - pharmacology; Bevacizumab - therapeutic use; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer metastasis; Cancer Research; Carcinoma; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Clinical trials; Comparative analysis; Confidence intervals; Development and progression; Dosage and administration; Drug therapy; Endothelial growth factors; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; Humans; Immune checkpoint; Immunotherapy; Infectious Diseases; Inflammation; Kaplan-Meier Estimate; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Male; Medical schools; Metabolic Diseases; Metastases; Middle Aged; Molecular chains; Molecular Medicine; Monoclonal antibodies; Mutation - genetics; Neoantigens; Neurosciences; PD-L1 protein; Renal cell carcinoma; Sunitinib; Sunitinib - adverse effects; Sunitinib - pharmacology; Sunitinib - therapeutic use; Targeted cancer therapy; Treatment Outcome; Tumor antigens; Tumors; Vascular endothelial growth factor; γ-Interferon
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-018-0053-3

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69–1.45) and 1.19 (95% CI, 0.82–1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38–1.08) and 1.03 (95% CI, 0.63–1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade. An exploratory randomized controlled clinical trial of renal cell carcinoma identifies molecular patterns distinguishing responders to immune checkpoint blockade alone or combined with angiogenesis inhibitor versus angiogenesis inhibitor alone.