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

Abstract

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.

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Fig. 1: Positive independent review facility (IRF)-assessed efficacy associated with atezolizumab + bevacizumab in mRCC patients with PD-L1+ IC.
Fig. 2: Baseline tumor gene signature analyses.
Fig. 3: Association between tumor mutations and clinical outcome.

Change history

  • 05 October 2018

    In the version of this article originally published, there was an error in Fig. 2n. The top line of the HR comparison chart originally was Atezo + bev vs sun. It should have been Atezo + bev vs atezo. The error has been corrected in the HTML and PDF versions of this article.

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Acknowledgements

The authors thank A. Bailey for her contributions to development of the protocol and Z. Boyd for his contributions to the development of the PD-L1 IHC assay and its implementation in this study. Support for third-party writing assistance for this manuscript—by P.S. Davies of Health Interactions, Inc.—was provided by F. Hoffmann-La Roche, AG. This study was sponsored by F. Hoffmann-La Roche, AG. Authors were funded by NCI grants P50 CA101942-13 to D.F.M, M.B.A., and T.K.C.; P30 CA008748 to R.J.M.; and P30 CA14599 to W.M.S.

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D.F.M., M.B.A., R.J.M., B.I.R., B.E., and T.P. contributed to the conception, trial design, and data acquisition, analysis, and interpretation; T.P. was the principal investigator of the study; M.A.H., S.J., and D.N. performed biomarker analyses and interpretation; J.Q. supervised the analysis of the clinical data; M.A.H. and P.S.H. supervised the analysis of biomarker data; L.F., R.W.J., S.K.P., J.A.R., M.S., J.H., W.K.R., W.M.S., T.H., M.E.G., A.R., S.B., C. Suárez, V.G., T.K.C., D.N., A.T., C. Schiff, E.P.-L., R.D., and G.D.F. made substantial contributions to the acquisition of data and data analysis and interpretation; P.S.H., M.A.H., and D.S.C. had overall biomarker oversight; C. Schiff, G.D.F., and D.S.C. had overall medical oversight.

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Correspondence to David F. McDermott.

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Competing interests

D.F.M. reports a consulting/advisory role for Bristol-Myers Squibb, Merck, Roche/Genentech, Pfizer, Exelixis, Novartis, Eisai, X4 Pharmaceuticals, and Array BioPharma; and reports that his home institution receives research funding from Prometheus Laboratories. M.B.A. has been a paid consultant to Roche/Genentech, Bristol-Myers Squibb, Merck, Pfizer, Novartis, Exelixis, and Eisai. R.J.M. reports consulting fees from Roche/Genentech, Novartis, Pfizer, Eisai, and Exelixis, and research funds from Roche/Genentech, Bristol Myers Squibb, Pfizer, Novartis, Eisai, and Exelixis to the hospital for which he is employed. B.I.R. reports research funding to his institution from Roche/Genentech during the conduct of the study and grants/fees from Pfizer and Merck outside the submitted work. B.E. reports honoraria and research funding from Bristol-Myers Squibb, Novartis, Pfizer, and Ipsen; honoraria from Eusa Pharma, Roche, and Eisai; and research funding from Aveo. L.F. reports research funding to his institution from Roche/Genentech outside the submitted work. R.W.J. reports a consulting/advisory role with Bristol-Myers Squibb, Nektar, Genoptix, Eisai, Novartis, and Exilixis and research funding from Merck and Bristol-Myers Squibb; his home institution is in a consulting/advisory role with Merck and receives research funding from Roche/Genentech, X4 Pharmaceuticals, and Amgen. S.K.P. reports honoraria and a consulting/advisory role with Novartis, Astellas Pharma, Pfizer, Aveo, Myriad Pharmaceuticals, Roche/Genentech, Exelixis, Bristol-Myers Squibb, Ipsen, and Eisai and honoraria and research funding from Medivation. M.S. reports stock option interest in Amphivena Therapeutics, Intensity Therapeutics, and Adaptive Biotechnologies; a consulting role with Bristol-Myers Squibb, Roche/Genentech, AstraZeneca/MedImmune, Pfizer, Nektar, Lilly, Merck, Alexion Pharmaceuticals, Theravance, Baxalta/Shire, Seattle Genetics, Ignyta, Pierre Fabre, Incyte, Newlink Genetics, Celldex, Gritstone, and Innate Pharma; and an advisory role with Symphogen, Adaptimmune, Omniox, Lycera, and Molecular Partners. W.K.R. reports research funding to her home institution from Pfizer, Novartis, Tracon Pharmaceuticals, Bristol-Myers Squibb, Calithera Biosciences, and Peloton Therapeutics and research funding to an immediate family member from Incyte and Merck. W.M.S. reports honoraria and a consulting/advisory role with CVS Caremark, AstraZeneca, Bristol-Myers Squibb, Roche/Genentech, and Pfizer; research funding to his home institution from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Exelixis, Novartis, Roche/Genentech, Pfizer, Merck, Janssen, and X4 Pharmaceuticals; and other relationships with UpToDate and American Cancer Society. M.E.G. acknowledges NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research, London UK. A.R. reports honoraria, accommodations, and a consulting/advisory role with Pfizer, Novartis, and Bristol-Myers Squibb; a consulting/advisory role with Ipsen and Roche; and research funding to his home institution from Pfizer and Novartis. S.B. reports personal fees and nonfinancial support for advisory boards from Pfizer, Astellas, Bristol-Myers Squibb, and Novartis; nonfinancial support for advisory boards from Bayer and Roche/Genentech; and nonfinancial support from Exelixis. V.G. reports grants from Bristol-Myers Squibb, Merck, Pfizer, and AstraZeneca, personal fees and nonfinancial support from Bristol-Myers Squibb, Merck, Roche, Novartis, Ipsen, Pfizer, AstraZeneca, Eisai, Eusa Pharma, and Cerulean outside the submitted work. T.K.C. reports consulting/advisory fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Cerulean, Eisai, Foundation Medicine, Exelixis, Roche/Genentech, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Laboratories, and Corvus; and research funding to his home institution from AstraZeneca, Bristol-Myers Squibb, Exelixis, Genentech, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Roche, Tracon, and Eisai. C. Schiff and P.S.H. report employment, including stock, with Genentech, Inc. G.D.F. reports employment, including stock, with Genentech, Inc. and stock with Foundation Medicine. T.P. reports honoraria and a consulting/advisory role with Roche/Genentech, Bristol-Myers Squibb, and Merck; a consulting/advisory role with AstraZeneca and Novartis; research funding from AstraZeneca/MedImmune and Roche/Genentech; and other relationships with Ipsen and Bristol-Myers Squibb (ASCO). M.A.H, D.N., S.J., E.P-L., J.Q., and D.S.C. are employees of Genentech, Inc. A.T. is an employee of Roche Products Ltd. J.A.R., J.H., T.H., C. Suárez, and R.D. have nothing to disclose.

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McDermott, D.F., Huseni, M.A., Atkins, M.B. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 24, 749–757 (2018). https://doi.org/10.1038/s41591-018-0053-3

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