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. 2025 Aug;23(4):102385.
doi: 10.1016/j.clgc.2025.102385. Epub 2025 Jun 13.

Comorbidity Burden and Effectiveness of Immunotherapy in Metastatic Renal Cell Carcinoma

Emre Yekedüz  1 , Martin Zarba  2 , Eddy Saad  3 , Razane El Hajj Chehade  3 , Marc Eid  3 , Renee Maria Saliby  4 , Clara Steiner  3 , Marc Machaalani  3 , Rashad Nawfal  3 , Karl Semaan  3 , Yüksel Ürün  5 , Daniel Y C Heng  2 , Toni K Choueiri  6
Affiliations

Comorbidity Burden and Effectiveness of Immunotherapy in Metastatic Renal Cell Carcinoma

Emre Yekedüz et al. Clin Genitourin Cancer. 2025 Aug.

Abstract

Background: Comorbid conditions complicate the care of patients with cancer and frequently cause exclusion of patients from clinical trials.

Methods: Data from patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitor (ICI)-based combinations in the first line setting were collected. The comorbidity burden was assessed at baseline by using the age-adjusted Charlson Comorbidity Index (CCI). Patients were stratified into 2 groups to predict overall survival (OS) through maximally selected rank statistics. The primary outcomes were time to treatment failure (TTF) and OS. The secondary outcome was the rate of adverse events (AEs) leading to dose reduction or treatment discontinuation.

Results: A total of 304 patients were included. Most patients were male (73%), had clear cell RCC (91.4%), and were treated with nivolumab + ipilimumab (53.6%). The most common comorbidities were diabetes (18.4%), followed by previous myocardial infarction (12.8%), chronic kidney disease (6.6%), and chronic pulmonary disease (5.6%). After adjusting for baseline prognostic factors in mRCC including the International mRCC Database Consortium (IMDC) risk, TTF (Hazard Ratio [HR], 1.51, 95% Confidence Interval [CI], 1.09-2.10, P= .013) and OS (HR: 1.98, 95% CI, 1.33-2.94, P= .001) were worse in the CCI-high group vs. the CCI-low group. The rates of AEs leading to dose reduction or treatment discontinuation were comparable between the 2 groups.

Conclusions: Despite similar rates of AEs leading to dose reduction or treatment discontinuation, a high comorbidity burden is associated with worse outcomes in patients with mRCC treated with first-line ICI-based therapies. Our study underscores the necessity for a multidimensional approach to assess the comorbidity burden in patients with mRCC receiving ICI-based combinations.

Keywords: Charlson Comorbidity Index; Chronic disease; Immune checkpoint inhibitors; Kidney cancer; Renal neoplasms.

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Conflict of interest statement

Disclosure Daniel Y. C. Heng: D.H. has received research funding from Pfizer, Novartis, Exelixis, BMS, and Ipsen and consultancy from Pfizer, Novartis, BMS, Janssen, Astellas Pharma, Ipsen, Eisai, and Merck. Toni K. Choueiri: Dr. Choueiri reports institutional and/or personal, paid and/or unpaid, support for research, advisory boards, consultancy, and/or honoraria in the past 5 year, on-going or not, from Alkermes, Arcus Bio, AstraZeneca, Aravive, Aveo, Bayer, Bristol-Myers Squibb, Bicycle Therapeutics, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Institut Servier, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan/PrecedeBio, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH, CCO, and others), outside the submitted work; institutional patents filed on molecular alterations and IO response/toxicity, and ctDNA; equity at Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium, and Bicycle; being a part of committees for NCCN, GU Steering Committee, ASCO (BOD 62024-), ESMO, ACCRU, and KidneyCan; medical writing and editorial assistance support may have been funded by communications companies in part; no speakers’ bureau; mentoring of several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components; probable additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter to the institution (Dana-Farber Cancer Institute). TK. Choueiri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda and Arthur Marcus Fund, and Loker Pinard Funds for Kidney Cancer Research at DFCI. Emre Yekedüz, Martin Zarba, Eddy Saad, Razane El Hajj Chehade, Marc Eid, Renee Maria Saliby, Clara Steiner, Marc Machaalani, Rashad Nawfal, Karl Semaan, Yüksel Ürün: None.

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