Association of Cabozantinib Dose Reductions for Toxicity With Clinical Effectiveness in Metastatic Renal Cell Carcinoma (mRCC): Results From the Canadian Kidney Cancer Information System (CKCis)

Jeffrey Graham; Sunita Ghosh; Rodney H Breau; Lori Wood; Simon Tanguay; Dominick Bosse; Aly-Khan Lalani; Bimal Bhindi; Daniel Heng; Antonio Finelli; Nazanin Fallah-Rad; Vincent Castonguay; Naveen S Basappa; Denis Soulières; Frédéric Pouliot; Christian Kollmannsberger; Georg A Bjarnason

doi:10.1016/j.clgc.2024.02.011

Association of Cabozantinib Dose Reductions for Toxicity With Clinical Effectiveness in Metastatic Renal Cell Carcinoma (mRCC): Results From the Canadian Kidney Cancer Information System (CKCis)

Clin Genitourin Cancer. 2024 Feb 23:102060. doi: 10.1016/j.clgc.2024.02.011. Online ahead of print.

Authors

Jeffrey Graham¹, Sunita Ghosh², Rodney H Breau³, Lori Wood⁴, Simon Tanguay⁵, Dominick Bosse⁶, Aly-Khan Lalani⁷, Bimal Bhindi⁸, Daniel Heng⁹, Antonio Finelli¹⁰, Nazanin Fallah-Rad¹¹, Vincent Castonguay¹², Naveen S Basappa¹³, Denis Soulières¹⁴, Frédéric Pouliot¹⁵, Christian Kollmannsberger¹⁶, Georg A Bjarnason¹⁷

Affiliations

¹ CancerCare Manitoba, Division of Medical Oncology and Hematology, University of Manitoba, Winnipeg, MB, Canada. Electronic address: jgraham9@cancercare.mb.ca.
² Department of Medical Oncology, Faculty of Medicine and Dentistry University of Alberta, Edmonton, AB, Canada.
³ Division of Urology, University of Ottawa, Ottawa, ON, Canada.
⁴ Division of Medical Oncology, QEII Health Sciences Center, Halifax, NS, Canada.
⁵ Department of Surgery, McGill University, Montreal, QC, Canada.
⁶ Division of Medical Oncology, University of Ottawa, Ottawa, ON, Canada.
⁷ Division of Medical Oncology, McMaster University, Hamilton, ON, Canada.
⁸ Division of Urology, University of Calgary, Calgary, AB, Canada.
⁹ Division of Medical Oncology, University of Calgary, Calgary, AB, Canada.
¹⁰ Division of Urology, Departments of Surgery and Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and University of Toronto, Toronto, ON, Canada.
¹¹ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
¹² Centre de recherche du Centre Hospitalier Universitaire de Québec - Université Laval (CRCHUQc-UL), Centre de recherche sur le cancer (CRC) de l'Université Laval, Québec, QC, Canada.
¹³ Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, AB, Canada.
¹⁴ Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
¹⁵ Cancer Research Center, Centre Hospitalier Universitaire de Québec - Université Laval, Québec, QC, Canada.
¹⁶ BC Cancer - Vancouver Centre, Vancouver, BC, Canada.
¹⁷ Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

PMID: 38521648
DOI: 10.1016/j.clgc.2024.02.011

Abstract

Background: Cabozantinib, an oral multi-targeted tyrosine kinase inhibitor (TKI), has demonstrated efficacy in metastatic renal cell carcinoma (mRCC). The association between toxicity and therapeutic effectiveness has been established with other TKIs. We investigated whether cabozantinib dose reductions, a surrogate for toxicity and adequate drug exposure, were associated with improved clinical outcomes in mRCC.

Methods: Employing the CKCis database, we analyzed patients treated with cabozantinib in the second line or later between 2011 to 2021. The cohort was stratified into those needing dose reductions (DR) during treatment and those not (no-DR). Outcomes, including objective response rate (ORR), time to treatment failure (TTF), and overall survival (OS), were compared based on dose reduction status. The influence of the initial dose on outcomes was also explored.

Results: Among 319 cabozantinib-treated patients, 48.3% underwent dose reductions. Response rates exhibited no significant difference between the DR and no-DR groups (15.1% vs. 18.2%, P = .55). Patients with DR had superior median OS (26.15 vs. 15.47 months, P = .019) and TTF (12.74 vs. 6.44 months, P = .022) compared to no-DR patients. These differences retained significance following adjustment for IMDC risk group (OS HR = 0.67, P = .032; TTF HR = 0.65, P = .008). There was no association between the initial dose and ORR, OS, or TTF.

Conclusion: This study highlights the link between cabozantinib dose reductions due to toxicity and improved survival and time to treatment failure in mRCC patients. These findings underscore the potential of using on-treatment toxicity as an indicator of adequate drug exposure to individualize dosing and optimize treatment effectiveness. Larger studies are warranted to validate these results and develop individualized strategies for cabozantinib when given alone or in combination with immunotherapy.

Keywords: Real world data.