Beth Israel Deaconess Medical Center, Boston, MA, USA.
Genentech, Inc., South San Francisco, CA, USA.
Georgetown Lombardi Comprehensive
Cancer Center, Washington, DC, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Cleveland Clinic Taussig Cancer Institute, Cleveland,
Gustave Roussy, Villejuif, France.
University of California, San Francisco School of Medicine, San Francisco, CA, USA.
Mayo Clinic Hospital –
Florida, Jacksonville, FL, USA.
City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Florida Cancer Specialists, Fort Myers, FL, USA.
Yale School of Medicine, New Haven, CT, USA.
Sarah Cannon Research Institute, Nashville, TN, USA.
Vanderbilt University Medical Center, Nashville,
University of Chicago Medicine, Chicago, IL, USA.
Texas Oncology – Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA.
Royal Marsden Hospital, London, UK.
CHU Hopitaux de Bordeaux – Hôpital Saint-André, Bordeaux, France.
Ospedale San Donato, Azienda USL
Toscana Sudest, Arezzo, Italy.
Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona,
Azienda Ospedaliera Universitaria Senese, Center for Immune-Oncology, Siena, Italy.
Medizinische Hochschule, Zentrum Innere
Medizin, Abt. Hämatologie u. Onkologie, Hannover, Germany.
Dana-Farber Cancer Institute, Boston, MA, USA.
Roche Products Ltd, Welwyn Garden
Barts Cancer Institute and the Royal Free Hospital, Queen Mary University of London, London, UK. *e-mail: firstname.lastname@example.org
berrant angiogenesis and antitumor immune suppression
are hallmarks of many cancers. Clear-cell renal cell carci
noma (RCC) is associated with a hyperangiogenic state due
to overproduction of vascular endothelial growth factor (VEGF) as
a result of inactivation of the von Hippel–Lindau tumor-suppressor
. Over the last decade, treatment for metastatic RCC
(mRCC) has focused on targeting the VEGF signaling pathway with
receptor tyrosine kinase inhibitors, such as sunitinib, or monoclonal
antibodies that block VEGF, such as bevacizumab. Although VEGF
pathway blockade is effective in many patients, it is associated with
development of resistance
Expression of the immune checkpoint molecule programmed
death-ligand 1 (PD-L1) on tumor cells and/or tumor-infiltrating
immune cells (IC) has been reported to suppress antitumor immu
nity and is associated with poor prognosis in mRCC
of PD-L1 to its receptor, programmed death-1 (PD-1), on T cells
results in inhibition of proliferation and effector function of
. Atezolizumab is a humanized engineered immuno-
globulin G1 monoclonal antibody that selectively targets PD-L1 to
block its interaction with PD-1 and the co-stimulatory molecule
B7.1 to reinvigorate tumor-specific T-cell immunity. PD-L1/PD-1
inhibitors, including atezolizumab, have shown durable responses
in patients with previously treated mRCC
In addition to its well-characterized role in angiogenesis, VEGF
is also believed to play a role in cancer immune evasion
from preclinical models and phase 1 studies suggest that anti-
VEGF might enhance the antitumor activity of immune checkpoint
blockade by improving T-cell infiltration, upregulating major his
tocompatibility complex class I expression, and reversing myeloid
. A phase 1 study combining atezoli-
zumab and bevacizumab established the combination to be well-
tolerated in RCC, with evidence of augmentation of antitumor
immunity and encouraging antitumor activity compared with his
torical experience with either single agent alone
Clinical activity and molecular correlates of response
to atezolizumab alone or in combination with
bevacizumab versus sunitinib in renal cell carcinoma
David F. McDermott
*, Mahrukh A. Huseni
, Michael B. Atkins
, Robert J. Motzer
, Brian I. Rini
, Lawrence Fong
, Richard W. Joseph
, Sumanta K. Pal
, James A. Reeves
, John Hainsworth
, W. Kimryn Rathmell
, Walter M. Stadler
, Thomas Hutson
Martin E. Gore
, Alain Ravaud
, Sergio Bracarda
, Cristina Suárez
, Riccardo Danielli
, Toni K. Choueiri
, Dorothee Nickles
, Suchit Jhunjhunwala
, Elisabeth Piault-Louis
, Jiaheng Qiu
, Daniel S. Chen
, Priti S. Hegde
, Christina Schiff
, Gregg D. Fine
and Thomas Powles
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 inter-
val (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.
NATURE MEDICINE | VOL 24 | JUNE 2018 | 749–757 | www.nature.com/naturemedicine
© 2018 Nature America Inc., part of Springer Nature. All rights reserved.