Cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy. Seventy-six patients were enrolled; of these, 33 achieved a cCR (43%, 95% confidence interval (CI): 32%, 55%), and 32 of 33 who achieved a cCR opted to forgo immediate cystectomy. The positive predictive value of cCR was 0.97 (95% CI: 0.91, 1), meeting the co-primary objective. The most common adverse events were fatigue, anemia, neutropenia and nausea. Somatic alterations in pre-specified genes (ATM, RB1, FANCC and ERCC2) or increased tumor mutational burden did not improve the positive predictive value of cCR. Exploratory analyses of peripheral blood mass cytometry and soluble protein analytes demonstrated an association between the baseline and on-treatment immune contexture with clinical outcomes. Stringently defined cCR after gemcitabine, cisplatin, plus nivolumab facilitated bladder sparing and warrants further study. ClinicalTrials.gov identifier: NCT03451331 .
Nature medicine. 2023 Oct 02 [Epub ahead of print]
Matthew D Galsky, Siamak Daneshmand, Sudeh Izadmehr, Edgar Gonzalez-Kozlova, Kevin G Chan, Sara Lewis, Bassam El Achkar, Tanya B Dorff, Jeremy Paul Cetnar, Brock O Neil, Anishka D'Souza, Ronac Mamtani, Christos Kyriakopoulos, Tomi Jun, Mahalya Gogerly-Moragoda, Rachel Brody, Hui Xie, Kai Nie, Geoffrey Kelly, Amir Horwitz, Yayoi Kinoshita, Ethan Ellis, Yohei Nose, Giorgio Ioannou, Rafael Cabal, G Kenneth Haines, Li Wang, Kent W Mouw, Robert M Samstein, Reza Mehrazin, Nina Bhardwaj, Menggang Yu, Qianqian Zhao, Seunghee Kim-Schulze, Robert Sebra, Jun Zhu, Sacha Gnjatic, John Sfakianos, Sumanta K Pal
Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ., Department of Urology, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, Los Angeles, CA, USA., Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Urology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Department of Radiology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Medical Oncology & Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA., Department of Urology, University of Utah, Salt Lake City, UT, USA., Division of Hematology and Medical Oncology, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, Los Angeles, CA, USA., Division of Hematology and Medical Oncology, University of Pennsylvania Abramson Cancer Center, Philadelphia, PA, USA., Division of Hematology and Medical Oncology, University of Wisconsin Carbone Cancer Center, Madison, WI, USA., Genentech, South San Francisco, CA, USA., Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Pathology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA., Department of Radiation Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Urology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Biostatistics and Medical Informatics, University of Wisconsin Carbone Cancer Center, Madison, WI, USA.