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 3rd; 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

doi:10.1016/j.eururo.2023.01.017

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

Eur Urol. 2023 Jun;83(6):486-494. doi: 10.1016/j.eururo.2023.01.017. Epub 2023 Jan 28.

Authors

Noah M Hahn¹, Michael A O'Donnell², Jason A Efstathiou³, Marianna Zahurak⁴, Gary L Rosner⁴, Jeff Smith⁵, Max R Kates⁶, Trinity J Bivalacqua⁷, Phuoc T Tran⁸, Daniel Y Song⁹, Alex S Baras¹⁰, Andres Matoso¹⁰, Woonyoung Choi⁶, Kellie N Smith¹¹, Drew M Pardoll¹¹, Luigi Marchionni¹², Bridget McGuire⁶, Mary Grace Phelan⁶, Burles A Johnson 3rd⁶, Tanya O'Neal⁴, David J McConkey⁶, Tracy L Rose¹³, Marc Bjurlin¹⁴, Emerson A Lim¹⁵, Charles G Drake¹⁶, James M McKiernan¹⁷, Israel Deutsch¹⁸, Christopher B Anderson¹⁷, Donald L Lamm¹⁹, Daniel M Geynisman²⁰, Elizabeth R Plimack²⁰, Mark A Hallman²¹, Eric M Horwitz²¹, Essel Al-Saleem²², David Y T Chen²³, Richard E Greenberg²³, Alexander Kutikov²³, Gordon Guo²⁴, Timothy A Masterson²⁵, Nabil Adra²⁶, Hristos Z Kaimakliotis²⁵

Affiliations

¹ 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: nhahn4@jhmi.edu.
² University of Iowa Carver College of Medicine, Iowa City, IA, USA.
³ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
⁴ Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
⁵ Hoosier Cancer Research Network, Indianapolis, IN, USA.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Urology, University of North Carolina, Chapel Hill, NC, USA.
¹⁵ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Spectrum Health Medical Group, Grand Rapids, MI, USA.
¹⁶ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Janssen Research and Development, Springhouse, PA, USA.
¹⁷ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Urology, Columbia University, New York, NY, USA.
¹⁸ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Radiation Oncology, Columbia University, New York, NY, USA.
¹⁹ BCG Oncology, Phoenix, AZ, USA.
²⁰ Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²¹ Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²² Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²³ Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²⁴ Department of Radiation Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA; University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
²⁵ Department of Urology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.
²⁶ Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.

PMID: 36717286
PMCID: PMC10192088 (available on 2024-06-01)
DOI: 10.1016/j.eururo.2023.01.017

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.

Keywords: Bacillus Calmette-Guerin; Bacillus Calmette-Guerin unresponsive; Bladder cancer; Clinical trial; Durvalumab; Non–muscle invasive; PD-L1; Radiation; Urothelial carcinoma.

Publication types

Clinical Trial, Phase I
Multicenter Study
Research Support, N.I.H., Extramural

MeSH terms

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

Substances

BCG Vaccine
durvalumab
Adjuvants, Immunologic

Abstract

Publication types

MeSH terms

Substances

Grants and funding