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

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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

  1. Barts Cancer Institute, Queen Mary University of London, Barts Experimental Cancer Medicine Centre, London EC1M 6BQ, UK,
    Thomas Powles
  2. Yale Cancer Center, 333 Cedar Street, WWW211, New Haven, Connecticut 06520, USA,
    Joseph Paul Eder & Daniel P. Petrylak
  3. Genentech, Inc. 1 DNA Way, South San Francisco, 94080, California, USA
    Gregg D. Fine, Siew-leng Teng, Xiaodong Shen, Zachary Boyd, Priti S. Hegde & Daniel S. Chen
  4. Comprehensive Cancer Centers of Nevada, 3730 S. Eastern Avenue, Las Vegas, 89169, Nevada, USA
    Fadi S. Braiteh
  5. Gustave Roussy, 114 Rue Édouard Vaillant, 94805 Villejuif, France,
    Yohann Loriot
  6. Vall d’Hebron Institute of Oncology (VHIO) and Vall d’Hebron University Hospital. Passeig Vall d’Hebron, 119-129, 08035, Barcelona, Spain,
    Cristina Cruz
  7. Bladder Cancer Center, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA,
    Joaquim Bellmunt
  8. Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, Tennessee 37203, USA,
    Howard A. Burris
  9. University of Nevada School of Medicine and US Oncology/Comprehensive Cancer Centers of Nevada, 3730 S. Eastern Avenue, Las Vegas, 89169, Nevada, USA
    Nicholas J. Vogelzang

Authors

  1. Thomas Powles
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  2. Joseph Paul Eder
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  3. Gregg D. Fine
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  4. Fadi S. Braiteh
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  5. Yohann Loriot
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  6. Cristina Cruz
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  7. Joaquim Bellmunt
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  8. Howard A. Burris
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  9. Daniel P. Petrylak
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  10. Siew-leng Teng
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  11. Xiaodong Shen
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  12. Zachary Boyd
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  13. Priti S. Hegde
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  14. Daniel S. Chen
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  15. Nicholas J. Vogelzang
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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 toThomas 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

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Extended Data Table 2 Table of all-cause adverse events

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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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