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

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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 poor1,2. One hallmark of UBC is the presence of high rates of somatic mutations3,4,5. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens6. 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 microenvironment7,8. 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)9. 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.

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Figure 1: PD-L1 prevalence and response rates in patients with UBC.
Figure 2: MPDL3280A anti-tumour activity in patients with UBC.

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Acknowledgements

We thank the patients and their families. Additionally, we thank the investigators and their staff, including the Barts Health NHS Trust and the Royal Free Foundation Trust, A. Balmanoukian and O. Hamid (The Angeles Clinic and Research Institute), J. Powderly (Carolina BioOncology Institute), P. Cassier (Centre Léon-Bérard), F. Steven Hodi (Dana-Farber Cancer Institute), J.-C. Soria (Gustave Roussy), J. P. DeLord (Institute Claudius Regaud), C. Drake and L. Emens (Johns Hopkins), D. Lawrence and R. Lee (Massachusetts General Hospital), S. Antonia and J. Zhang (Moffitt Cancer Center), M. Gordon (Pinnacle Oncology Hematology), H. Kohrt and S. Srinivas (Stanford University Cancer Institute), and J. Tabernero (Vall d'Hebron University Hospital). Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd.

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Authors and Affiliations

Authors

Contributions

T.P., G.D.F., D.P.P., D.S.C. and N.J.V. contributed to the overall study design; Z.B. and P.S.H. provided the biomarker studies; S.-l.T. performed the statistical analysis. All authors analysed the data. All authors contributed to writing the paper.

Corresponding author

Correspondence to Thomas Powles.

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Competing interests

T.P., consultant/advisory for GlaxoSmithKline, Genentech; F.S.B., speaker and advisory for Inctye; consultant/advisory for BMS; Research funding from Roche; Y.L., Research grants from Astellas, Sanofi; consultant for Astellas, Sanofi, Cellgen, Pierre Fabre; J.B., uncompensated consultant/advisory for Genentech; N.J.V., consultant to Roche/Genentech; G.D.F., S.-l.T., X.S., Z.B., P.S.H. and D.S.C. are employees of Genentech. C.C., D.P.P., H.A.B. and J.P.E. have no disclosures.

Extended data figures and tables

Extended Data Figure 1 Time between tissue collection and starting MPDL3280A.

A histogram depicting the length of time between the collection of tissue samples used in biomarker analyses and cycle 1, day 1 of a patient’s course of treatment with MPDL3280A.

Extended Data Figure 2 A patient with a complete response to MPDL3280A.

a, Example of PD-L1 staining within the patient’s tumour at baseline (×20 magnification). Several clusters of PD-L1-negative tumour cells are seen within a stroma densely infiltrated by immune cells. Staining for PD-L1 is observed in tumour-infiltrating immune cells in the form of variably sized clusters or single scattered cells. The morphology of PD-L1-positive tumour-infiltrating immune cells ranges from small lymphoid cells to larger cells with more abundant cytoplasm. b, The patient’s circulating tumour cells had dropped from 104 to 0 by cycle 3 corresponding with the change in the SLD. This patient had ≤100% reduction of the target lesions due to lymph node target lesions and his lymph nodes returned to normal size as per Response Evaluation Criteria in Solid Tumours v1.1. CTC, circulating tumour cells; SLD, sum of the longest diameters; WB, whole blood.

Extended Data Figure 3 Pharmacodynamic markers of MPDL3280A activity.

Graphs depicting IFN-γ (n = 53), IL-18 (n = 61) and CD3+CD8+HLA-DR+Ki-67+ T-cell levels (n = 59) over cycles (C) and days (D) of treatment with MPDL3280A. Data range (95% confidence interval) is indicated in light blue. FC, fold change.

Extended Data Table 1 Table of treatment-related adverse events (grade 1–2) occurring in one patient
Extended Data Table 2 Table of all-cause adverse events
Extended Data Table 3 Table of PD-L1 tumour cell IHC and response

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Powles, T., Eder, J., Fine, G. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014). https://doi.org/10.1038/nature13904

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