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

Thomas Powles; Danielle Carroll; Simon Chowdhury; Gwenaelle Gravis; Florence Joly; Joan Carles; Aude Fléchon; Pablo Maroto; Daniel Petrylak; Frédéric Rolland; Natalie Cook; Arjun V. Balar; Srikala S. Sridhar; Matthew D. Galsky; Petros Grivas; Alain Ravaud; Robert Jones; Jan Cosaert; Darren Hodgson; Iwanka Kozarewa; Richard Mather; Robert McEwen; Florence Mercier; Dónal Landers

doi:10.1038/s41591-021-01317-6

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

Thomas Powles, Danielle Carroll, Simon Chowdhury, Gwenaelle Gravis, Florence Joly, Joan Carles, Aude Fléchon, Pablo Maroto, Daniel Petrylak, Frédéric Rolland, Natalie Cook, Arjun V. Balar, Srikala S. Sridhar, Matthew D. Galsky, Petros Grivas, Alain Ravaud, Robert Jones, Jan Cosaert, Darren Hodgson, Iwanka KozarewaRichard Mather, Robert McEwen, Florence Mercier, Dónal Landers

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

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 alterations^2–5. 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 pathway^3–5.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.

Original language	English
Pages (from-to)	793-801
Number of pages	9
Journal	Nature Medicine
Volume	27
Issue number	5
DOIs	https://doi.org/10.1038/s41591-021-01317-6
State	Published - May 2021

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10.1038/s41591-021-01317-6

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Powles, T., Carroll, D., Chowdhury, S., Gravis, G., Joly, F., Carles, J., Fléchon, A., Maroto, P., Petrylak, D., Rolland, F., Cook, N., Balar, A. V., Sridhar, S. S., Galsky, M. D., Grivas, P., Ravaud, A., Jones, R., Cosaert, J., Hodgson, D., ... Landers, D. (2021). An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. Nature Medicine, 27(5), 793-801. https://doi.org/10.1038/s41591-021-01317-6

@article{202f3f81aa0c469681a88e5de5744106,

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

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 alterations2–5. 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 pathway3–5.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.",

author = "Thomas Powles and Danielle Carroll and Simon Chowdhury and Gwenaelle Gravis and Florence Joly and Joan Carles and Aude Fl{\'e}chon and Pablo Maroto and Daniel Petrylak and Fr{\'e}d{\'e}ric Rolland and Natalie Cook and Balar, {Arjun V.} and Sridhar, {Srikala S.} and Galsky, {Matthew D.} and Petros Grivas and Alain Ravaud and Robert Jones and Jan Cosaert and Darren Hodgson and Iwanka Kozarewa and Richard Mather and Robert McEwen and Florence Mercier and D{\'o}nal Landers",

note = "Funding Information: 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{\textquoteright} 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 Espa{\~n}a, 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{\textquoteright} 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. Funding Information: 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. Fl{\'e}chon, Centre L{\'e}on B{\'e}rard, 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{\textquoteright}Ouest, Saint-Herblain. Spain: J. Carles, Vall D{\textquoteright}Hebron Institute of Oncology, Barcelona; J. P. Maroto, Hospital de la Santa Creu i San Pau, Barcelona; J. P. V{\'a}squez, 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{\textquoteright} 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. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = may,

doi = "10.1038/s41591-021-01317-6",

language = "English",

volume = "27",

pages = "793--801",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "5",

}

Powles, T, Carroll, D, Chowdhury, S, Gravis, G, Joly, F, Carles, J, Fléchon, A, Maroto, P, Petrylak, D, Rolland, F, Cook, N, Balar, AV, Sridhar, SS, Galsky, MD, Grivas, P, Ravaud, A, Jones, R, Cosaert, J, Hodgson, D, Kozarewa, I, Mather, R, McEwen, R, Mercier, F & Landers, D 2021, 'An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer', Nature Medicine, vol. 27, no. 5, pp. 793-801. https://doi.org/10.1038/s41591-021-01317-6

TY - JOUR

T1 - An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer

AU - Powles, Thomas

AU - Carroll, Danielle

AU - Chowdhury, Simon

AU - Gravis, Gwenaelle

AU - Joly, Florence

AU - Carles, Joan

AU - Fléchon, Aude

AU - Maroto, Pablo

AU - Petrylak, Daniel

AU - Rolland, Frédéric

AU - Cook, Natalie

AU - Balar, Arjun V.

AU - Sridhar, Srikala S.

AU - Galsky, Matthew D.

AU - Grivas, Petros

AU - Ravaud, Alain

AU - Jones, Robert

AU - Cosaert, Jan

AU - Hodgson, Darren

AU - Kozarewa, Iwanka

AU - Mather, Richard

AU - McEwen, Robert

AU - Mercier, Florence

AU - Landers, Dónal

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2021/5

Y1 - 2021/5

N2 - 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 alterations2–5. 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 pathway3–5.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.

AB - 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 alterations2–5. 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 pathway3–5.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.

UR - http://www.scopus.com/inward/record.url?scp=85105325337&partnerID=8YFLogxK

U2 - 10.1038/s41591-021-01317-6

DO - 10.1038/s41591-021-01317-6

M3 - Article

C2 - 33941921

AN - SCOPUS:85105325337

SN - 1078-8956

VL - 27

SP - 793

EP - 801

JO - Nature Medicine

JF - Nature Medicine

IS - 5

ER -

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

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