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An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer

Nature Medicine volume 27, pages 793–801 (2021)Cite this article

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Abstract

Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC)1. AUC is characterized by several recurrent targetable genomic alterations2,3,4,5. This study (NCT02546661, BISCAY) combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory AUC populations including: (1) fibroblast growth factor receptor (FGFR) inhibitors in tumors with FGFR DNA alterations (FGFRm); (2) pharmacological inhibitor of the enzyme poly-ADP ribose polymerase (PARP) in tumors with and without DNA homologous recombination repair deficiency (HRRm); and (3) TORC1/2 inhibitors in tumors with DNA alteration to the mTOR/PI3K pathway3,4,5.This trial adopted a new, biomarker-driven, multiarm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms. Response rates (RRs) ranged 9–36% across the study arms, which did not meet efficacy criteria for further development. Overall survival (OS) and progression-free survival (PFS) were similar in the combination arms and durvalumab monotherapy arm. Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFRm. Sequential circulating tumor DNA analysis showed that changes to FGFRm correlated with clinical outcome. Our data support the clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations. These findings question the targeted/immune therapy approach in AUC.

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Fig. 1: Biomarker landscape of enrolled patients in tumor and plasma.
Fig. 2: Efficacy data for different arms of the BISCAY study.
Fig. 3: Longitudinal mutation tracking on treatment.
Fig. 4: Correlation of FGFR mutant allele fraction ctDNA and response to therapy.

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Data availability

The authors declare that access to the clinical and biomarker data analyzed here may be obtained in accordance with AstraZeneca’s data-sharing policy as part of an external collaborative request (https://astrazenecagroup-dt.pharmacm.com//DT/Home/Index/) or an external data access request (https://vivli.org/ourmember/astrazeneca/)

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Acknowledgements

We thank the patients and their families who gave their time and commitment to participate in this study; the CRUK Experimental Cancer Medicine Centre; and staff and investigators at participating sites, including the following. Canada: M. Sawyer, University of Alberta—Cross Cancer Institute; S. S. Sridhar, Princess Margaret Cancer Centre, Toronto; C. Ferrario, Jewish General Hospital, Montreal. France: A. Fléchon, Centre Léon Bérard, Lyon; G. Gravis, Institute Paoli-Calmettes, Marseille; F. Joly, Centre Francois Baclesse, Caen; L. Mourey, Institut Claudius Regaud, Toulouse; A. Ravaud, Bordeaux University Hospital; F. Rolland, Institut de Cancerologie de l’Ouest, Saint-Herblain. Spain: J. Carles, Vall D’Hebron Institute of Oncology, Barcelona; J. P. Maroto, Hospital de la Santa Creu i San Pau, Barcelona; J. P. Vásquez, Hospital Clinico San Carlos, Madrid; A. Rodriquez-Vida, IMIM Hospital del Mar Medical Research Instutute, Barcelona. UK: H.-T. Arkenau, Sarah Cannon Research Institute, London; S. Chowdhury, Guys and St Thomas’ Medical School, London; N. Cook, The Christie NHS Foundation Trust, Manchester (Research at the Christie NHS Foundation Trust was supported by the NIHR Manchester Clinical Research Facility and Manchester Experimental Cancer Medicine Centre award); S. Crabb, University of Southampton; R. Jones, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow; T. Powles, Barts Cancer Institute, London. USA: A. V. Balar, Perlmutter Cancer Center, NYU Langone Health, New York; J. Bendell, Tennessee Oncology, Nashville; A. Drakaki, Ronald Reagan UCLA Medical Center, Hematology Oncology, Santa Monica; P. Grivas, University of Washington, Seattle; M. Galsky, Icahn School of Medicine at Mount Sinai, New York; N. Hahn, Johns Hopkins University School of Medicine, Baltimore; E. Lim, New York Presbyterian, Columbia University Irving Medical Centre, New York; D. Petrylak, Yale School of Medicine, New Haven; J. Reeves Jr., Florida Cancer Specialists and Research Institute; B. Rini and P. Grivas, Cleveland Clinic, Cleveland; P. Van Veldhuizen, HCA Midwest, Kansas City. We thank the staff at Sarah Cannon Development Innovations and AstraZeneca who supported this clinical study. Medical writing support was provided by S. Hurrell (Bioscript Medical) and was funded by AstraZeneca. We thank A. Reddy (AstraZeneca) for support with data analysis.

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Authors and Affiliations

  1. Barts Cancer Institute, QMUL, Barts Cancer Centre, London, UK

    Thomas Powles

  2. AstraZeneca IMED Biotech Unit, Cambridge, UK

    Danielle Carroll, Darren Hodgson, Iwanka Kozarewa & Robert McEwen

  3. Guys and St Thomas’ Hospital, London, UK

    Simon Chowdhury

  4. Institute Paoli-Calmettes, Marseille, France

    Gwenaelle Gravis

  5. UNICANCER, Centre Léon Bérard, Lyons, France

    Florence Joly

  6. Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

    Joan Carles

  7. Centre Léon Bérard, Lyon, France

    Aude Fléchon

  8. Hospital de la Santa Creu i San Pau, Barcelona, Spain

    Pablo Maroto

  9. Yale School of Medicine, New Haven, CT, USA

    Daniel Petrylak

  10. Institut de Cancerologie de l’Ouest, Saint-Herblain, France

    Frédéric Rolland

  11. The Christie NHS Foundation Trust and The University of Manchester, Manchester, UK

    Natalie Cook

  12. Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA

    Arjun V. Balar

  13. Princess Margaret Hospital, Toronto, Ontario, Canada

    Srikala S. Sridhar

  14. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Matthew D. Galsky

  15. University of Washington, Seattle, WA, USA

    Petros Grivas

  16. Bordeaux University Hospital, Bordeaux, France

    Alain Ravaud

  17. University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK

    Robert Jones

  18. AstraZeneca Oncology R&D, Research and Early Development, Cambridge, UK

    Jan Cosaert, Richard Mather & Florence Mercier

  19. CRUK Manchester Institute Cancer Biomarker Centre, Manchester, UK

    Dónal Landers

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  1. Thomas Powles
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Contributions

T.P., S.C., D.P., A.J.B., P.G., D.H., R. Mather, R. McEwen and D.L. contributed to the conception and design of the study. T.P., A.F., D.P., S.S.S., M.D.G., R.J., I.K. and R. Mather acquired the data. T.P., S.C., D.P., A.J.B. S.S.S., M.G., P.G., R.J., D.H., I.K., R. Mather, R. McEwen, F.M. and D.L. contributed to data analysis and interpretation. T.P., S.C., J. Carles, A.F., P.M., D.P., G.G., F.R., N.C., A.J.B., S.S.S., M.G., P.G., A.R., R.J., J. Cosaert and R. Mather contributed to clinical management, patient recruitment and data collection. T.P., A.F., D.P., D.H. and R. Mather contributed administrative, technical or material support. T.P., S.C., D.P., R. Mather, R. McEwen and F.M. contributed to the drafting of the manuscript. T.P., S.C., J. Carles, A.F, P.M., D.P., N.C., A.J.B., S.S.S., M.G., P.G., A.R., R.J., J. Cosaert, D.H., I.K. and D.L. critically revised the manuscript for intellectual content. All authors reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Thomas Powles.

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Competing interests

T.P. has received research funding from AstraZeneca, Astellas, Bristol-Myers Squibb, Roche and Merck; and received honoraria for lectures or advisory boards from AstraZeneca, Astellas, Bristol-Myers Squibb, Roche, Merck, Johnson & Johnson, Ipsen, Exelixis, Pfizer, Novartis and Seattle Genetics. D.C. is a full-time employee at AstraZeneca and owns stocks/shares in AstraZeneca. S.C. has held advisory roles for Astellas Pharma, Bayer, Beigene, Clovis Oncology, Janssen-Cilag, and Pfizer; participated in speakers’ bureaux for Pfizer; received honoraria from Clovis Oncology and Novartis; received research funding from Clovis Oncology and Sanofi/Aventis; and received travel expenses from Beigene and Clovis Oncology. G.G. has received travel expenses for symposia from Bristol-Myers Squibb, Sanofi, Astellas, Ipsen, Janssen and Pfizer. F.J. has provided consultancy for Roche, Ipsen, AstraZeneca, Janssen, Tesaro, Bristol-Myers Squibb, Pfizer, Novartis and Sanofi, Astellas. F.J. has received travel/accommodation expenses from Roche, Ipsen, AstraZeneca, Janssen, Tesaro and Bristol-Myers Squibb and has received funding (institution) from Astellas. J. Carles has received research funding from AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, Inc., Astellas Pharma, AstraZeneca AB, Aveo Pharmaceuticals, Bayer AG, Blueprint Medicines, BN Immunotherapeutics, Boehringer Ingelheim España, Bristol-Myers Squibb, Clovis Oncology, Cougar Biotechnology, Deciphera Pharmaceuticlas, Exelixis, Hoffmann-La Roche, Genentech, GlaxoSmithKline, Incyte Corporations, Janssen-Cilag, Karyopharm Therapeutics, Laboratoires Leurquin Mediolanum, Lilly, MedImmune, Millennium Pharmaceuticals, Nanobiotix, Novartis Farmaceutica, Pfizer, Puma Biotechnology, Sanofi-Aventis, SFJ Pharma and Teva; has participated in advisory boards for Bayer, Johnson & Johnson, Bristol-Myers Squibb, Astellas, Pfizer, Sanofi, MSD Oncology, Roche and AstraZeneca; has participated in speakers’ bureaux for Bayer, Johnson & Johnson, Asofarma and Astellas; and received travel expenses from Bristol-Myers Squibb, Ipsen, Roche and AstraZeneca. A.F. has received honoraria and travel expenses from AstraZeneca, MSD, Roche, Janssen and Astellas. P.M. declares no competing interests. D.P. consults for Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Exelixis, Incyte, Janssen, Mirati, Monopteros, Pfizer, Pharmacyclics, Roche, Seattle Genetics and Urogen; has received research funding from Ada Cap, Agensys, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol-Myers Squibb, Clovis Oncology, Eisai, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics and Replimune; and is a stockholder in Bellicum. F.R. has received honoraria from Merck KGaA and MSD. N.C. has received research funding from RedX Pharmaceuticals, Tarveda, AstraZeneca, Roche, Novartis, Eisai, Boehringer Ingelheim and Taiho; has participated in advisory boards for RedX Pharmaceuticals; and has been an advisor (unpaid) to Roche Pharmaceuticals. Research at the Christie NHS Foundation Trust was supported by the NIHR Manchester Clinical Research Facility and Manchester Experimental Cancer Medicine Centre award. A.B. has received research funding from Genentech, Merck, AstraZeneca, MedImmune, Nektar, Seattle Genetics and Immunomedics; has held a consultancy or advisory role for Genentech, Incyte, Merck, Pfizer, AstraZeneca, MedImmune, Nektar and Seattle Genetics; has had speaker engagements for Genentech, Merck, AstraZeneca and MedImmune; and has participated in steering groups and advisory boards for Merck. S.S.S. has consulted for or served on advisory boards for AstraZeneca, Pfizer, Roche, Merck, Bristol-Myers Squibb, Astellas, Janssen and Bayer. M.G. has held a consultancy or advisory role for Aileron Therapeutics and is a stockholder in Rappta Therapeutics. P.G. has consulted for AstraZeneca, Bayer, Biocept, Bristol-Myers Squibb, Clovis Oncology, Driver, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, Heron Therapeutics, Janssen, Merck, Mirati Therapeutics, Pfizer, Seattle Genetics, QED Therapeutics and GlaxoSmithKline; has delivered educational programs to GlaxoSmithKline; and has received research funding from AstraZeneca, Bayer, Genentech/Roche, Merck, Mirati Therapeutics, Oncogenex, Pfizer, Clovis Oncology, Bavarian Nordic, Immunomedics, Debiopharm and Bristol-Myers Squibb. A.R. has received research funding from Pfizer and Merck GA; and has received honoraria and participated in advisory boards for Pfizer, Merck GA, Bristol-Myers Squibb, AstraZeneca, Roche, Novartis, MSD and Ipsen. R.J. has received research funding from AstraZeneca, MSD, Merck Serono, Pfizer, Bristol-Myers Squibb, Roche, Janssen and Astellas; has received honoraria for speaking and advisory boards from AstraZeneca, MSD, Merck Serono, Pfizer, Bristol-Myers Squibb, Janssen and Astellas; and has written for the educational company Mirrors of Medicine (noncompensated). J. Cosaert is an AstraZeneca employee. D.H., I.K., R. Mather and R. McEwen are AstraZeneca employees and stockholders. F.M. is a contract employee of AstraZeneca and shareholder in StatProcess and Health Data Process. D.L. is a former employee of AstraZeneca (as Senior Director Physician on this study), consults for AstraZeneca and has received research funding from Decision Science.

Additional information

Peer review information Nature Medicine thanks David McConkey, Sumanta Pal and the other, anonymous reviewers for their contribution to the peer review of this work. Javier Carmona was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Consort diagram for screened and enrolled participants.

Consort diagram for screened and enrolled participants. Enrolment periods: AZD4547 monotherapy and AZD4547 + durvalumab, Oct 2016 to Jun 2018; olaparib + durvalumab (selected), Feb 2017 to April 2018; olaparib + durvalumab (unselected), Aug 2018 to Mar 2019; vistusertib + durvalumab, Apr 2017 to Jan 2018; durvalumab monotherapy, Oct 2016 to May 2017. R, randomized.

Extended Data Fig. 2 Most frequent DNA alterations from archived tissue.

Common alterations: Mutations: 65% TERT promoter, 59% TP53, 36% KMT2D, 27% KDM6A and 23% KMT2C. Copy number alterations: 31% CDKN2A loss, 31% CDKN2B loss, 12% MDM2 amplification, 12% FRS2 amplification, 11% CCND1 amplification.

Extended Data Fig. 3

Molecular classification of tumours derived from RNA sequencing data.

Extended Data Fig. 4 TGE signature (IFNG, CXCL9, CD274) comparison (n = 22 and n = 18 subjects in AZD4547 and durvalumab arms, respectively).

Each boxplot displays the median, first and third quartiles (lower and upper hinges), the largest value smaller and the smallest value larger than 1.5 interquartile (upper and lower whiskers).

Extended Data Fig. 5 OS according to tumor TMB.

TMB < 10 mutations/Mb was associated with numerically shorter OS when combining the arms irrespective of treatment (HR 1.924 [0.953; 3.884] from Cox model) Logrank test, P = 0.063. HR, hazard ratio; OS, overall survival; TMB, tumor mutational burden.

Extended Data Fig. 6 PFS according to tumor TMB.

TMB < 10 mutations/Mb was associated with shorter PFS when combining the arms irrespective of treatment (HR 1.904 [1.178; 3.078]) Logrank test, P = 0.007. Analysis performed: Kaplan Meier analysis according to the TMB at baseline and Cox model for HR. HR, hazard ratio; PFS, progression-free survival; TMB, tumor mutational burden.

Extended Data Fig. 7 OS according to blood TMB.

TMB ≤ 16 mutations/Mb was associated with similar OS when combining the arms irrespective of treatment (HR 1.21 [0.69–2.13] from Cox model) Logrank test: p = 0.50. HR, hazard ratio; OS, overall survival; TMB, tumor mutational burden.

Extended Data Fig. 8 PFS according to blood TMB.

TMB ≤ 16 mutations/Mb was associated with shorter PFS when combining the arms irrespective of treatment (HR 1.60 [1.05; 2.42]) Logrank test, p = 0.0025. Analysis performed: Kaplan Meier analysis according to the TMB at baseline and Cox model for HR. HR, hazard ratio; PFS, progression-free survival; TMB, tumor mutational burden.

Extended Data Fig. 9 Oncoprint for ctDNA (Guardant Health) n = 111 from baseline samples (patients receiving treatment).

bTMB, blood-derived tumor mutational burden; ctDNA, circulating tumor deoxyribonucleic acid; DDRm, DNA damage repair mutation.

Extended Data Fig. 10 Correlation between expression of mutations and radiological response.

ctDNA, circulating tumor deoxyribonucleic acid; PD, progressive disease; PR, partial response; SD, stable disease.

Supplementary information

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Supplementary Figs. 1 and 2 and Supplementary Tables 1–4.

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Powles, T., Carroll, D., Chowdhury, S. et al. An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. Nat Med 27, 793–801 (2021). https://doi.org/10.1038/s41591-021-01317-6

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