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89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer

Nature Medicine volume 24, pages 1852–1858 (2018)Cite this article

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Abstract

Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade is effective in a subset of patients with several tumor types, but predicting patient benefit using approved diagnostics is inexact, as some patients with PD-L1-negative tumors also show clinical benefit1,2. Moreover, all biopsy-based tests are subject to the errors and limitations of invasive tissue collection3,4,5,6,7,8,9,10,11. Preclinical studies of positron-emission tomography (PET) imaging with antibodies to PD-L1 suggested that this imaging method might be an approach to selecting patients12,13. Such a technique, however, requires substantial clinical development and validation. Here we present the initial results from a first-in-human study to assess the feasibility of imaging with zirconium-89-labeled atezolizumab (anti-PD-L1), including biodistribution, and secondly test its potential to predict response to PD-L1 blockade (ClinicalTrials.gov identifiers NCT02453984 and NCT02478099). We imaged 22 patients across three tumor types before the start of atezolizumab therapy. The PET signal, a function of tracer exposure and target expression, was high in lymphoid tissues and at sites of inflammation. In tumors, uptake was generally high but heterogeneous, varying within and among lesions, patients, and tumor types. Intriguingly, clinical responses in our patients were better correlated with pretreatment PET signal than with immunohistochemistry- or RNA-sequencing-based predictive biomarkers, encouraging further development of molecular PET imaging for assessment of PD-L1 status and clinical response prediction.

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Fig. 1: 89Zr-atezolizumab biodistribution and PD-L1 IHC in healthy tissue.
Fig. 2: 89Zr-atezolizumab tumor uptake.
Fig. 3: Autoradiography and IHC of postimaging tumor biopsy.
Fig. 4: 89Zr-atezolizumab tumor uptake as predictor for response.

Data availability

The RNA-sequencing dataset presented in this manuscript is available through GEO (series accession GSE115594). The data are annotated with a short summary and a description of the study design and can be freely downloaded via the GEO website (https://www.ncbi.nlm.nih.gov/geo/). Clinical details of the cases and laboratory data, restricted to non-identifying data owing to privacy concerns, can be requested by e-mail from the corresponding author, who will handle all requests.

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Acknowledgements

We thank patients and their families for participating in this study. This work was supported by the Dutch Cancer Society grant RUG 2016-10034 (POINTING) and the ERC Advanced grant OnQview ERC 293445, both awarded to E.G.E.d.V., a personal Dutch Cancer Society fellowship RUG 2014-6625 awarded to F.B., and a research grant from Hoffmann–La Roche/Genentech, which was made available to the UMCG.

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Authors and Affiliations

  1. Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

    Frederike Bensch, Elly L. van der Veen, Iris C. Kok, Sjoukje F. Oosting, Carolina P. Schröder, Jourik A. Gietema & Elisabeth G. E. de Vries

  2. Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

    Marjolijn N. Lub-de Hooge & Annelies Jorritsma-Smit

  3. Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

    Marjolijn N. Lub-de Hooge, Ronald Boellaard, Thomas C. Kwee & Adrienne H. Brouwers

  4. Pulmonary Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

    T. Jeroen N. Hiltermann, Anthonie J. van der Wekken & Harry J. M. Groen

  5. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

    Sjoerd G. Elias

  6. Genentech, San Francisco, CA, USA

    Sandra Sanabria Bohorquez, Alex de Crespigny, Simon-Peter Williams & Bernard M. Fine

  7. Genentech, Basel, Switzerland

    Christoph Mancao

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Contributions

F.B., E.G.E.d.V., B.M.F., and A.d.C. designed the study. F.B., E.L.v.d.V., M.N.L.-d.H., A.J.-S., R.B., S.G.E., B.M.F., C.M., and A.d.C. developed the methodology. Acquisition of data was performed by F.B., C.M., T.C.K., E.L.v.d.V., I.C.K., S.F.O., C.P.S., T.J.N.H., A.J.v.d.W., H.J.M.G., J.A.G., A.H.B., and S.S.B. S.G.E., F.B., C.M., E.L.v.d.V., and S.-P.W. conducted statistical analyses and preclinical experiments. A.H.B. and E.G.E.d.V. provided supervision. F.B., E.G.E.d.V., B.M.F., S.-P.W., S.S.B., C.M., and S.G.E. wrote the manuscript. Results were discussed by all authors, who also commented on the manuscript.

Corresponding author

Correspondence to Elisabeth G. E. de Vries.

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Competing interests

The authors declare the following as competing interests: H.J.M.G. received research support from Hoffmann–La Roche (payment to the institution) and has an advisory role for Roche Netherlands; B.M.F., C.M., S.S.B., A.d.C., and S.-P.W. are employed by Hoffman–La Roche/Genentech and own stock in Hoffman–La Roche/Genentech; E.G.E.d.V. received research support from Hoffman–La Roche/Genentech (payment to the institution) and is a member of the ESMO Magnitude of Clinical Benefit Scale.

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Bensch, F., van der Veen, E.L., Lub-de Hooge, M.N. et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med 24, 1852–1858 (2018). https://doi.org/10.1038/s41591-018-0255-8

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