Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

References

  1. Choueiri, T. K. et al. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J. Clin. Oncol. 30, 507–512 (2012)

    Article  CAS  Google Scholar 

  2. Bellmunt, J. et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J. Clin. Oncol. 27, 4454–4461 (2009)

    Article  CAS  Google Scholar 

  3. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014)

  4. Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013)

    Article  ADS  CAS  Google Scholar 

  5. Kandoth, C. et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013)

    Article  ADS  CAS  Google Scholar 

  6. Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013)

    Article  Google Scholar 

  7. Chen, D. S., Irving, B. A. & Hodi, F. S. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin. Cancer Res. 18, 6580–6587 (2012)

    Article  CAS  Google Scholar 

  8. van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, e439–e442 (2013)

    Article  Google Scholar 

  9. Herbst, R. S. et al. Predictive correlates of response to anti-PD-L1 in cancer patients. Nature http://dx.doi.org/10.1038/nature14011 (this issue)

  10. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012)

    Article  CAS  Google Scholar 

  11. Bellmunt, J. et al. Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J. Clin. Oncol. 28, 1850–1855 (2010)

    Article  Google Scholar 

  12. Sonpavde, G. et al. Time from prior chemotherapy enhances prognostic risk grouping in the second-line setting of advanced urothelial carcinoma: a retrospective analysis of pooled, prospective phase 2 trials. Eur. Urol. 63, 717–723 (2013)

    Article  Google Scholar 

  13. Wrammert, J. et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453, 667–671 (2008)

    Article  ADS  CAS  Google Scholar 

  14. De Santis, M. et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J. Clin. Oncol. 30, 191–199 (2012)

    Article  CAS  Google Scholar 

  15. Dreicer, R., Gustin, D. M., See, W. A. & Williams, R. D. Paclitaxel in advanced urothelial carcinoma: its role in patients with renal insufficiency and as salvage therapy. J. Urol. 156, 1606–1608 (1996)

    Article  CAS  Google Scholar 

  16. Gallagher, D. J. et al. Phase II study of sunitinib in patients with metastatic urothelial cancer. J. Clin. Oncol. 28, 1373–1379 (2010)

    Article  CAS  Google Scholar 

  17. Necchi, A. et al. Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial. Lancet Oncol. 13, 810–816 (2012)

    Article  CAS  Google Scholar 

  18. Seront, E. et al. Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers. Ann. Oncol. 23, 2663–2670 (2012)

    Article  CAS  Google Scholar 

  19. Vaughn, D. J. et al. Vinflunine in platinum-pretreated patients with locally advanced or metastatic urothelial carcinoma: results of a large phase 2 study. Cancer 115, 4110–4117 (2009)

    Article  CAS  Google Scholar 

  20. Sweeney, C. J. et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J. Clin. Oncol. 24, 3451–3457 (2006)

    Article  CAS  Google Scholar 

  21. Ko, Y. J. et al. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 14, 769–776 (2013)

    Article  CAS  Google Scholar 

  22. Culine, S. et al. A phase II study of vinflunine in bladder cancer patients progressing after first-line platinum-containing regimen. Br. J. Cancer 94, 1395–1401 (2006)

    Article  CAS  Google Scholar 

  23. Chen, G. J., Galsky, M. D., Latini, D. M., Sonpavde, G. & DeBakey, M. E. Patterns of chemotherapy and survival in elderly patients with advanced bladder cancer: a large Medicare database study. J. Clin. Oncol. (suppl.) abstr. 4551. (2013)

  24. Okamura, H. et al. Cloning of a new cytokine that induces IFN-γ production by T cells. Nature 378, 88–91 (1995)

    Article  ADS  CAS  Google Scholar 

  25. Iwai, Y. et al. An IFN-γ-IL-18 signaling loop accelerates memory CD8+ T cell proliferation. PLoS ONE 3, e2404 (2008)

    Article  ADS  Google Scholar 

  26. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012)

    Article  CAS  Google Scholar 

  27. Dahlberg, S. E., Shapiro, G. I., Clark, J. W. & Johnson, B. E. Evaluation of statistical designs in phase I expansion cohorts: the Dana-Farber/Harvard Cancer Center experience. J. Natl Cancer Inst. 106, dju163 (2014)

    Article  Google Scholar 

  28. Wolchok, J. D. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15, 7412–7420 (2009)

    Article  CAS  Google Scholar 

  29. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009)

    Article  CAS  Google Scholar 

Download references

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.

Author information

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.

Ethics declarations

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

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature13904

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing