Response and Outcomes to Immune Checkpoint Inhibitors in Advanced Urothelial Cancer Based on Prior Intravesical Bacillus Calmette-Guerin

Rafee Talukder¹, Dimitrios Makrakis¹, Leonidas N Diamantopoulos², Lucia Carril-Ajuria³, Daniel Castellano³, Ivan De Kouchkovsky⁴, Vadim S Koshkin⁴, Joseph J Park⁵, Ajjai Alva⁵, Mehmet A Bilen⁶, Tyler F Stewart⁷, Rana R McKay⁷, Victor S Santos⁸, Neeraj Agarwal⁸, Jayanshu Jain⁹, Yousef Zakharia¹⁰, Rafael Morales-Barrera¹¹, Michael E Devitt¹², Michael Grant¹³, Mark P Lythgoe¹³, David J Pinato¹³, Ariel Nelson¹⁴, Christopher J Hoimes¹⁵, Evan Shreck¹⁶, Benjamin A Gartrell¹⁶, Alex Sankin¹⁶, Abhishek Tripathi¹⁷, Roubini Zakopoulou¹⁸, Aristotelis Bamias¹⁹, Jure Murgic²⁰, Ana Fröbe²⁰, Alejo Rodriguez-Vida²¹, Alexandra Drakaki²², Sandy Liu²², Vivek Kumar²³, Giuseppe Di Lorenzo²⁴, Monika Joshi²⁵, Pedro Isaacsson Velho²⁶, Lucia Alonso Buznego²⁷, Ignacio Duran²⁷, Marcus Moses²⁸, Pedro Barata²⁸, Guru Sonpavde²⁹, Evan Y Yu³⁰, Jonathan L Wright³¹, Petros Grivas³², Ali Raza Khaki³³

Affiliations

¹ Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA.
² Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
³ Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
⁴ Division of Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.
⁵ Division of Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI.
⁶ Winship Cancer Institute of Emory University, Atlanta, GA.
⁷ Division of Hematology/Oncology, Department of Medicine, University of California San Diego, La Jolla, CA.
⁸ Division of Oncology, Department of Medicine, University of Utah, Salt Lake City, UT.
⁹ Department of Medicine, University of Iowa, Iowa City, IA.
¹⁰ Division of Oncology, Department of Medicine, University of Iowa, Iowa City, IA.
¹¹ Vall d'Hebron Institute of Oncology, Vall d' Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹² Division of Hematology/Oncology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA.
¹³ Department of Surgery and Cancer, Imperial College London, London, UK.
¹⁴ Division of Medical Oncology, Seidman Cancer Center at Case Comprehensive Cancer Center, Cleveland, OH; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
¹⁵ Division of Medical Oncology, Seidman Cancer Center at Case Comprehensive Cancer Center, Cleveland, OH; Division of Medical Oncology, Duke University, Durham, NC.
¹⁶ Departments of Medical Oncology and Urology, Montefiore Medical Center, Bronx, NY.
¹⁷ Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
¹⁸ Department of Clinical Therapeutics, Alexandra General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
¹⁹ 2nd Propaedeutic Dept of Internal Medicine, ATTIKON University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
²⁰ Department of Oncology and Nuclear Medicine, University Hospital Center Sestre Milosrdnice, Zagreb, School of Dental Medicine, Zagreb, Croatia.
²¹ Medical Oncology Department, Hospital del Mar Research Institute, Barcelona, Spain.
²² Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
²³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
²⁴ Oncology University of Molise and ASL, Salerno, Italy.
²⁵ Division of Hematology/Oncology, Department of Medicine, Penn State Cancer Institute, Hershey, PA.
²⁶ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
²⁷ Hospital Universitario Marques de Valdecilla. IDIVAL. Santander, Spain.
²⁸ Deming Department of Medicine, Section of Hematology/Oncology, Tulane University, New Orleans, LA.
²⁹ Genitourinary Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
³⁰ Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
³¹ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Urology, University of Washington, Seattle, WA.
³² Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. Electronic address: pgrivas@uw.edu.
³³ Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA; Division of Oncology, Department of Medicine, Stanford University, Palo Alto, CA. Electronic address: alikhaki@stanford.edu.

PMID: 35078711
PMCID: PMC8995351
DOI: 10.1016/j.clgc.2021.12.012

Response and Outcomes to Immune Checkpoint Inhibitors in Advanced Urothelial Cancer Based on Prior Intravesical Bacillus Calmette-Guerin

Rafee Talukder et al. Clin Genitourin Cancer. 2022 Apr.

. 2022 Apr;20(2):165-175.

doi: 10.1016/j.clgc.2021.12.012. Epub 2021 Dec 17.

Authors

Affiliations

¹ Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA.
² Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
³ Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
⁴ Division of Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.
⁵ Division of Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI.
⁶ Winship Cancer Institute of Emory University, Atlanta, GA.
⁷ Division of Hematology/Oncology, Department of Medicine, University of California San Diego, La Jolla, CA.
⁸ Division of Oncology, Department of Medicine, University of Utah, Salt Lake City, UT.
⁹ Department of Medicine, University of Iowa, Iowa City, IA.
¹⁰ Division of Oncology, Department of Medicine, University of Iowa, Iowa City, IA.
¹¹ Vall d'Hebron Institute of Oncology, Vall d' Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹² Division of Hematology/Oncology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA.
¹³ Department of Surgery and Cancer, Imperial College London, London, UK.
¹⁴ Division of Medical Oncology, Seidman Cancer Center at Case Comprehensive Cancer Center, Cleveland, OH; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
¹⁵ Division of Medical Oncology, Seidman Cancer Center at Case Comprehensive Cancer Center, Cleveland, OH; Division of Medical Oncology, Duke University, Durham, NC.
¹⁶ Departments of Medical Oncology and Urology, Montefiore Medical Center, Bronx, NY.
¹⁷ Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
¹⁸ Department of Clinical Therapeutics, Alexandra General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
¹⁹ 2nd Propaedeutic Dept of Internal Medicine, ATTIKON University Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.
²⁰ Department of Oncology and Nuclear Medicine, University Hospital Center Sestre Milosrdnice, Zagreb, School of Dental Medicine, Zagreb, Croatia.
²¹ Medical Oncology Department, Hospital del Mar Research Institute, Barcelona, Spain.
²² Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA.
²³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
²⁴ Oncology University of Molise and ASL, Salerno, Italy.
²⁵ Division of Hematology/Oncology, Department of Medicine, Penn State Cancer Institute, Hershey, PA.
²⁶ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
²⁷ Hospital Universitario Marques de Valdecilla. IDIVAL. Santander, Spain.
²⁸ Deming Department of Medicine, Section of Hematology/Oncology, Tulane University, New Orleans, LA.
²⁹ Genitourinary Oncology Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
³⁰ Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
³¹ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Urology, University of Washington, Seattle, WA.
³² Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. Electronic address: pgrivas@uw.edu.
³³ Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA; Division of Oncology, Department of Medicine, Stanford University, Palo Alto, CA. Electronic address: alikhaki@stanford.edu.

PMID: 35078711
PMCID: PMC8995351
DOI: 10.1016/j.clgc.2021.12.012

Abstract

Background: Immune checkpoint inhibitors (ICI) improve overall survival (OS) in patients with locally advanced, unresectable, or metastatic urothelial carcinoma (aUC), but response rates can be modest. We compared outcomes between patients with and without prior intravesical Bacillus Calmette-Guerin (BCG), who received ICI for aUC, hypothesizing that prior intravesical BCG would be associated with worse outcomes.

Patients and methods: We performed a retrospective cohort study across 25 institutions in US and Europe. We compared observed response rate (ORR) using logistic regression; progression-free survival (PFS) and OS using Kaplan-Meier and Cox proportional hazards. Analyses were stratified by treatment line (first line/salvage) and included multivariable models adjusting for known prognostic factors.

Results: A total of 1026 patients with aUC were identified; 614, 617, and 638 were included in ORR, OS, PFS analyses, respectively. Overall, 150 pts had history of prior intravesical BCG treatment. ORR to ICI was similar between those with and without prior intravesical BCG exposure in both first line and salvage settings (adjusted odds radios 0.55 [P= .08] and 1.65 [P= .12]). OS (adjusted hazard ratios 1.05 [P= .79] and 1.13 [P= .49]) and PFS (adjusted hazard ratios 1.12 [P= .55] and 0.87 [P= .39]) were similar between those with and without intravesical BCG exposure in first line and salvage settings.

Conclusion: Prior intravesical BCG was not associated with differences in response and survival in patients with aUC treated with ICI. Limitations include retrospective nature, lack of randomization, presence of selection and confounding biases. This study provides important preliminary data that prior intravesical BCG exposure may not impact ICI efficacy in aUC.

Keywords: BCG; Bladder cancer; Immunotherapy; Outcomes; Urinary tract neoplasms.

PubMed Disclaimer

Figures

**Figure 1.**
CONSORT diagram: patient selection & exclusion rationale

**Figure 2.**
Kaplan Meier curves for overall survival with checkpoint inhibitors in first line (A) and salvage (B) setting.

**Figure 3.**
Kaplan Meier curves for progression-free survival with checkpoint inhibitors in first line (A) and salvage (B) setting.

See this image and copyright information in PMC

References

1. Burger M, Catto JWF, Dalbagni G, et al. Epidemiology and Risk Factors of Urothelial Bladder Cancer. Eur Urol. 2013;63(2):234–241. - PubMed
1. Lamm DL, Blumenstein BA, Crawford ED, et al. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Engl J Med 1991;325:1205–9. - PubMed
1. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000;163:1124–9. - PubMed
1. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006; 49:465–466.475–477. - PubMed
1. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383:1218–1230. - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Response and Outcomes to Immune Checkpoint Inhibitors in Advanced Urothelial Cancer Based on Prior Intravesical Bacillus Calmette-Guerin

Affiliations

Response and Outcomes to Immune Checkpoint Inhibitors in Advanced Urothelial Cancer Based on Prior Intravesical Bacillus Calmette-Guerin

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical