MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer

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^1,2.OnehallmarkofUBCis the presence of high rates ofsomatic mutations^3-5. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increasednumber of antigens⁶.However, these cancersmay also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also calledCD274 or B7-H1) in the tumour microenvironment^7,8. Therefore, we examined the anti-PDL1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment ofmetastaticUBC.MPDL3280Ais a high-affinity engineered human anti-PD-L1monoclonal immunoglobulin-G1 antibody that inhibits the interaction ofPD-L1 with PD-1 (PDCD1) and B7.1 (CD80)⁹. BecausePD-L1is expressed onactivatedTcells,MPDL3280A was engineered with amodification 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 (6weeks) and nearly allwere 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 immunecells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC,who areoftenolder and have ahigher incidence of renalimpairment, may be better able to tolerateMPDL3280A versus chemotherapy. These results suggest thatMPDL3280A may have an important role in treating UBC - the drug received breakthrough designation status by theUSFood and DrugAdministration (FDA) in June 2014.