Journal Article

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

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

2021

Overview

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. The adaptive, biomarker-driven BISCAY trial evaluating durvalumab with targeted agents in patients with metastatic urothelial carcinoma based on tumor genomic alterations finds no added clinical benefit over durvalumab monotherapy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 692/699/67/1059 / 692/699/67/589 / Adenosine diphosphate / Antibodies, Monoclonal - therapeutic use / Antineoplastic Agents, Immunological - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / B7-H1 Antigen - antagonists & inhibitors / Benzamides - therapeutic use / Biological markers / Biomarkers / Biomarkers, Tumor - blood / Biomarkers, Tumor - genetics / Biomedical and Life Sciences / Biomedicine / Bladder cancer / Cancer / Cancer Research / Chemotherapy / Deoxyribonucleic acid / DNA / DNA repair / Drug therapy / Fibroblast growth factor receptors / Gene mutations / Genetic aspects / Genomics / Growth factors / Homologous recombination / Homologous recombination repair / Homology / Humans / Immunotherapy / Infectious Diseases / Inhibitors / Letter / Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors / Mechanistic Target of Rapamycin Complex 1 - genetics / Mechanistic Target of Rapamycin Complex 2 - antagonists & inhibitors / Mechanistic Target of Rapamycin Complex 2 - genetics / Metabolic Diseases / Metastases / Metastasis / Molecular Medicine / Molecular targeted therapy / Molecular Targeted Therapy - methods / Monoclonal antibodies / Morpholines - therapeutic use / Neurosciences / Oncology, Experimental / PD-L1 protein / Phosphatidylinositol 3-Kinases - genetics / Phthalazines - therapeutic use / Piperazines - therapeutic use / Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors / Poly (ADP-Ribose) Polymerase-1 - genetics / Poly(ADP-ribose) polymerase / Progression-Free Survival / Pyrimidines - therapeutic use / Receptors, Fibroblast Growth Factor - antagonists & inhibitors / Receptors, Fibroblast Growth Factor - genetics / Ribose / Safety engineering / Survival / Targeted cancer therapy / TOR protein / TOR Serine-Threonine Kinases - genetics / Tumors / Urinary tract cancer / Urologic Neoplasms - drug therapy / Urologic Neoplasms - genetics / Urologic Neoplasms - pathology / Urothelial cancer / Urothelial carcinoma / Urothelium - pathology