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Prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitor treatment

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Abstract

Purpose

We evaluated the prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitors (ICIs) treatment.

Methods

We conducted a multicenter retrospective study of patients with advanced/metastatic urothelial carcinoma treated with ICIs in four Spanish institutions. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) v.5.0 guidelines. The primary endpoint was overall survival (OS). Other endpoints were overall response rate (ORR) and progression-free survival (PFS). irAEs were evaluated as a time-dependent covariate to avoid immortal time bias.

Results

A total of 114 patients were treated with ICIs between May 2013 and May 2019, 105 (92%) of whom received ICIs as monotherapy. irAEs of any grade were experienced in 56 (49%) patients and 21 (18%) patients had grade ≥ 3 toxicity. The most frequent irAEs were gastrointestinal and dermatological toxicities, reported in 25 (22%) and 20 (17%) patients, respectively. Patients with grade 1–2 irAEs had significantly longer OS compared to those without grade 1–2 irAEs (median 18.2 vs. 8.7 months, HR = 0.61 [95% CI 0.39–0.95], p = 0.03). No association with efficacy was observed for patients with grade ≥ 3 irAEs. No difference in PFS was observed after adjusting for the immortal time bias. ORR was higher in patients who developed irAEs (48% vs 17%, p < 0.001).

Conclusions

Our findings suggest that development of irAEs was associated with higher ORR, and patients who developed grade 1–2 irAEs had longer OS. Prospective studies are necessary to confirm our findings.

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Data availability

The data that support the findings of this study are available from the corresponding author, [RMB], upon reasonable request.

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Acknowledgements

The authors wish to thank the patients who kindly participated in our study and their families. The authors also thank Sarah MacKenzie PhD for providing medical writing assistance.

Funding

This work was supported by the Vall d´Hebron Institute of Oncology. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Medical Oncology, Vall d’Hebron Institute of Oncology, Vall d’ Hebron University Hospital, Universitat Autònoma de Barcelona, Passeig Vall d’Hebron 119-129, 08035, Barcelona, Catalonia, Spain

    Rafael Morales-Barrera, Cristina Suárez, Nely Díaz, Joaquín Mateo, Macarena González & Joan Carles

  2. Oncology Data Science (OdysSey) Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    Guillermo Villacampa

  3. The Institute of Cancer Research, London, UK

    Guillermo Villacampa

  4. Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), CIBERONC, Madrid, Spain

    Natalia Vidal & Javier Puente

  5. Medical Oncology Department, Fundació Althaia Manresa, Manresa, Spain

    Mariona Figols & Montserrat Domenech

  6. Medical Oncology, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Sabadell, Spain

    Julia Giner & Teresa Bonfill

Authors
  1. Rafael Morales-Barrera
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  2. Guillermo Villacampa
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Contributions

Study Concept and design: RM-B and JC. Acquisition of data; ND, MG, NV, MF and JG. Organization of the data: GV. Analysis of the database: RM-B and GV. Interpretation of data: All authors. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: GV. Obtaining funding: None.

Corresponding author

Correspondence to Rafael Morales-Barrera.

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Conflict of interest

The authors declare the following financial interests/personal. RMB: (all unrelated in the last 3 years): Consulting or advisory and/or speakers bureaus for Sanofi Aventis, AstraZeneca, Merck Sharp & Dohme, Astellas, BMS and received travel and accommodations expenses from Roche, Sanofi Aventis, Astellas, Janssen, Merck Sharp & Dohme, Bayer, and Pfizer. GV: has received research honoraria for speaker activities from MSD and advisory role from AstraZeneca. NV: Speaker bureaus for Sanofi, AstraZeneca, Astellas, Janssen, Roche, MSD, Bristol. MF: Advisory and/or speakers bureaus for BMS, Ipsen, Merck and Pfizer. JG: nothing to declare. TB: Advisory and/or speakers bureaus for Merck, Roche, BMS, Pfizer, Astellas and received travel and accommodations expenses from Roche, MSD, Ipsen, Merck and Bayer. CS: Consulting or advisory and/or speakers bureaus for Astellas, Bayer, BMS, Roche, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi Aventis. ND: Travel and accommodations expenses from Sanofi Aventis and Pfizer. JM: has received honoraria and/or acted as consulting or advisory role for AstraZeneca, Roche, MSD, Amgen and Pfizer; JM is also the PI of grants by AstraZeneca and Pfizer to VHIO as institution. MG: Travel and accommodations expenses from Roche, Astellas, Ipsen and Pfizer. MD: Consulting or advisory and/or speakers bureaus for Sanofi Aventis, Bristol-Myers Squibb, Pfizer and received travel and accommodations expenses from Sanofi and Lilly. JP: Honoraria from Pfizer, Bristol-Myers Squibb, Ipsen, AstraZeneca, Roche, MSD Oncology, Janssen-Cilag, Astellas Pharma, EUSA Pharma, Eisai, Pierre Fabre, Sanofi, and Bayer; consulting or advisory role from Pfizer, Astellas Pharma, Janssen-Cilag, Merck Sharpe & Dohme, Bayer, Roche, Bristol-Myers Squibb, Clovis Oncology, Ipsen, Eisai, and Sanofi; research funding from Astellas Pharma and Pfizer; travel/accommodations/expenses from Pfizer, Roche, Janssen-Cilag, Bristol-Myers Squibb, and MSD Oncology. JC: Consulting: Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Johnson & Johnson, MSD Oncology, Novartis (AAA), Pfizer, Roche, Sanofi. Speakers bureaus: Bayer, Asofarma, Astellas, Janssen Fundings / Grants to out institution: AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim España, S.A., Bristol-Myers Squibb International Corporation (BMS), Clovis Oncology, INC, Cougar Biotechnology INC, Deciphera Pharmaceuticals LLC, Exelixis INC, F. Hoffmann-La Roche LTD, Genentech INC, Glaxosmithkline, SA, Incyte Corporation, Janssen-Cilag International NV, Karyopharm Therapeutics INC., Laboratories Leurquin Mediolanum SAS, Lilly, S.A., Medimmune, Millennium Pharmaceuticals, INC., Nanobiotix SA, Novartis Farmacéutica, S.A., Pfizer, S.L.U, Puma Biotechnology, INC, Sanofi-Aventis, S.A., SFJ Pharma LTD. II, Teva Pharma S.L.U.

Ethical approval (Research involving human participants and/or animals), Informed consent

The study was approved by the Ethics Committee at Vall d’Hebron University Hospital (PR[AG]490/2021). All the patients who were alive at the time of the analysis signed the informed consent form.

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Appendix

Appendix

See Table 3.

Table 3 Patient, disease, and treatment characteristics according irAEs occurrence
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Morales-Barrera, R., Villacampa, G., Vidal, N. et al. Prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitor treatment. Clin Transl Oncol 25, 3556–3564 (2023). https://doi.org/10.1007/s12094-023-03213-6

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