title: MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.
abstract: There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor. One hallmark of UBC is the presence of high rates of somatic mutations. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens. However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also called CD274 or B7-H1) in the tumour microenvironment. Therefore, we examined the anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80). Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC-the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Experimental Cancer Medicine Centre, London EC1M 6BQ, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.affiliation: Yale Cancer Center, 333 Cedar Street, WWW211, New Haven, Connecticut 06520, USA.
authors.forename: Joseph Paul
authors.initials: JP
authors.lastname: Eder
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Fine
authors.affiliation: Comprehensive Cancer Centers of Nevada, 3730 S. Eastern Avenue, Las Vegas, Nevada 89169, USA.
authors.forename: Fadi S
authors.initials: FS
authors.lastname: Braiteh
authors.affiliation: Gustave Roussy, 114 Rue Édouard Vaillant, 94805 Villejuif, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Loriot
authors.affiliation: Vall d'Hebron Institute of Oncology (VHIO) and Vall d'Hebron University Hospital. Passeig Vall d'Hebron, 119-129, 08035, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cruz
authors.affiliation: Bladder Cancer Center, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, Tennessee 37203, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.affiliation: Yale Cancer Center, 333 Cedar Street, WWW211, New Haven, Connecticut 06520, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Petrylak
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Siew-leng
authors.initials: SL
authors.lastname: Teng
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Shen
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Boyd
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Priti S
authors.initials: PS
authors.lastname: Hegde
authors.affiliation: Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Chen
authors.affiliation: University of Nevada School of Medicine and US Oncology/Comprehensive Cancer Centers of Nevada, 3730 S. Eastern Avenue, Las Vegas, Nevada 89169, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen / Q000378:metabolism; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C000594389:atezolizumab