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

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'NealDavid 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

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients. Objective: 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). Design, setting, and participants: A multicenter phase 1 trial was conducted at community and academic sites. Intervention: 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). Outcome measurements and statistical analysis: 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. Results and limitations: 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. Conclusions: 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. Patient summary: Durvalumab combination therapy can be safely administered to non–muscle-invasive bladder cancer patients with the goal of increasing durable response rates.

Original languageEnglish
Pages (from-to)486-494
Number of pages9
JournalEuropean Urology
Volume83
Issue number6
DOIs
StatePublished - Jun 2023

Keywords

  • Adjuvants, Immunologic
  • Administration, Intravesical
  • BCG Vaccine/adverse effects
  • Humans
  • Neoplasm Invasiveness/pathology
  • Neoplasm Recurrence, Local/pathology
  • Non-Muscle Invasive Bladder Neoplasms
  • Urinary Bladder Neoplasms/pathology
  • Urinary Bladder/pathology

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