In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432 ), avelumab/best supportive care (BSC) significantly prolonged overall survival relative to BSC alone as maintenance therapy after first-line chemotherapy. Exploratory biomarker analyses were performed to identify biological pathways that might affect survival benefit. Tumor molecular profiling by immunohistochemistry, whole-exome sequencing and whole-transcriptome sequencing revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity and the number of alleles encoding high-affinity variants of activating Fcγ receptors. Pathways connected to tissue growth and angiogenesis might have been associated with reduced survival benefit. Individual biomarkers did not comprehensively identify patients who could benefit from therapy; however, multi-parameter models incorporating genomic alteration, immune responses and tumor growth showed promising predictive utility. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial cancer and suggest that multiple biomarkers might be needed to identify patients who would benefit from treatment.
Nature medicine. 2021 Dec 10 [Epub ahead of print]
Thomas Powles, Srikala S Sridhar, Yohann Loriot, Joaquim Bellmunt, Xinmeng Jasmine Mu, Keith A Ching, Jie Pu, Cora N Sternberg, Daniel P Petrylak, Rosa Tambaro, Louis M Dourthe, Carlos Alvarez-Fernandez, Maureen Aarts, Alessandra di Pietro, Petros Grivas, Craig B Davis
Barts Cancer Institute, Experimental Cancer Medicine Centre, Queen Mary University of London, St. Bartholomew's Hospital, London, UK. ., Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Gustave Roussy, INSERMU981, Université Paris-Saclay, Villejuif, France., Department of Medical Oncology, Beth Israel Deaconess Medical Center and IMIM-PSMAR Lab, Harvard Medical School, Boston, MA, USA., Computational Biology, Oncology Research and Development, Pfizer, La Jolla, CA, USA., Statistics, Global Biometrics and Data Management, Pfizer, La Jolla, CA, USA., Englander Institute for Precision Medicine, Weill Cornell Medicine, Hematology/Oncology, Meyer Cancer Center, New York, NY, USA., Yale Cancer Center, New Haven, CT, USA., Istituto Nazionale per lo Studio e la Cura dei Tumori, IRCCS Fondazione Giovanni Pascale, Naples, Italy., Service d'Oncologie Médicale, Clinique St Anne, Strasbourg, France., Department of Medical Oncology, Hospital Universitario Central de Asturias. Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain., Department of Medical Oncology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands., Pfizer Italia srl, Milano, Italy., Department of Medicine, Division of Medical Oncology, University of Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA, USA., Translational Oncology, Pfizer, La Jolla, CA, USA. .