A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study.

Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients.

To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT).

A multicenter phase 1 trial was conducted at community and academic sites.

Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only).

Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates.

Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients.

D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches.

Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.

European urology. 2023 Jan 28 [Epub ahead of print]

Noah M Hahn, Michael A O'Donnell, Jason A Efstathiou, Marianna Zahurak, Gary L Rosner, Jeff Smith, Max R Kates, Trinity J Bivalacqua, Phuoc T Tran, Daniel Y Song, Alex S Baras, Andres Matoso, Woonyoung Choi, Kellie N Smith, Drew M Pardoll, Luigi Marchionni, Bridget McGuire, Mary Grace Phelan, Burles A Johnson, Tanya O'Neal, David J McConkey, Tracy L Rose, Marc Bjurlin, Emerson A Lim, Charles G Drake, James M McKiernan, Israel Deutsch, Christopher B Anderson, Donald L Lamm, Daniel M Geynisman, Elizabeth R Plimack, Mark A Hallman, Eric M Horwitz, Essel Al-Saleem, David Y T Chen, Richard E Greenberg, Alexander Kutikov, Gordon Guo, Timothy A Masterson, Nabil Adra, Hristos Z Kaimakliotis

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA. Electronic address: ., University of Iowa Carver College of Medicine, Iowa City, IA, USA., Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA., Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA., Hoosier Cancer Research Network, Indianapolis, IN, USA., Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA., Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA; Division of Urology and Urologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA; Department of Radiation Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA., Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA; Department of Radiation Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; Johns Hopkins Bloomberg Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA., Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; Johns Hopkins University School of Medicine, Center for Computational Genomics, Baltimore, MD, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA., Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Division of Medical Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA., Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Urology, University of North Carolina, Chapel Hill, NC, USA., Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Spectrum Health Medical Group, Grand Rapids, MI, USA., Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Janssen Research and Development, Springhouse, PA, USA., Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Urology, Columbia University, New York, NY, USA., Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Radiation Oncology, Columbia University, New York, NY, USA., BCG Oncology, Phoenix, AZ, USA., Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA., Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA., Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA., Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA., Department of Radiation Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA; University Hospitals Cleveland Medical Center, Cleveland, OH, USA., Department of Urology, Indiana University Simon Cancer Center, Indianapolis, IN, USA., Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.