Assessment of Immune Checkpoint Inhibitors and Genomic Alterations by Body Mass Index in Advanced Renal Cell Carcinoma

An elevated body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) has been associated with an increased risk of renal cell carcinoma (RCC).¹ Previously, higher BMI was shown to be a positive prognostic factor for patients with metastatic clear cell RCC (mRCC) who were treated during the vascular endothelial growth factor (VEGF)–targeted therapy era.² However, the treatment landscape has shifted to include immune checkpoint inhibitors (ICIs) for most patients. We investigated this obesity paradox in patients with mRCC who were treated with programmed cell death 1 protein/programmed cell death 1 ligand 1 (PD-1/PD-L1)–based ICIs and explored potential genomic alterations according to BMI status.

Using the International Metastatic RCC Database Consortium (IMDC) database, we included patients treated with PD-1/PD-L1–based ICI alone or in combinations. Institutional review board approval was obtained from the Dana-Farber Cancer Institute and each participating site within the IMDC consortium, and participants provided written informed consent. Comparisons between patients who were defined as having a high BMI (≥25) vs low (<25) were conducted using χ² and Fisher tests. We investigated the association of BMI with overall survival (OS; time from ICI initiation to death or censoring at last follow-up), time to treatment failure (TTF; time from ICI initiation to treatment cessation, progression, death, or censoring), and objective response (complete/partial response, by Response Evaluation Criteria in Solid Tumor, version 1.1]). Associations of BMI were assessed in multivariable logistic (objective response rate [ORR]) and Cox (TTF; OS) regression, which were adjusted for IMDC risk classifications (favorable, intermediate, or poor), age, sex, race/ethnicity, histology, sarcomatoid features, line, and type of ICI. In patients with available next-generation sequencing data (OncoPanel, 275-447 genes³), genomic alteration frequencies (nonsense, insertions/deletions, and missense by a Polyphen-2/Mutation Assessor⁴), and tumor mutational burden were compared by BMI status using Fisher exact and Mann-Whitney U tests. Statistical tests were 2-sided and performed using SAS, version 9.4 (SAS Institute), and R, version 3.6.1 (R Foundation). Results were considered statistically significant if P < .05 or q < 0.05.

Within the IMDC database, 735 patients with mRCC with a recorded BMI were treated with PD-1/PD-L1–based ICI. Overall, 229 (31%) received first-line ICI, and 230 (31%) received combination ICI (142 [19%] with VEGF; 88 [12%] with CTLA-4 (cytotoxic T-lymphocyte–associated protein 4)/other therapies). At ICI initiation, 274 patients (37%) had what was considered low BMI and 461 (63%) a high BMI (Table). Median follow-up was 13.5 months (range, <1 to 78.6 months). Patients with a high BMI displayed significantly improved OS compared with those with a low BMI (1-year OS: 79% vs 66%; adjusted hazard ratio, 0.75; 95% CI, 0.57-0.97; P = .03) (Figure). This association was consistent in subgroup analysis by sex, IMDC group, histology, and type/line of therapy. Patients with higher BMIs also had a numerically higher ORR (30% vs 21%) and TTF (median [95% CI], 7.4 [6.7-9.0] vs 4.9 [3.8-6.9] months), although these were not statistically significant in multivariable models (ORR: adjusted odds ratio, 1.51; 95% CI, 0.98-2.32; P = .06; TTF: adjusted hazard ratio, 0.98; 95% CI, 0.80-1.20; P = .83). In 319 patients with available next-generation sequencing data, genomic alteration frequencies (all q > 0.50), and tumor mutational burden (6.8 vs 6.8 mutations per megabase; P = .90) were found to be similar between BMI groups.

In this multinational analysis from the IMDC, an elevated BMI was independently associated with improved OS in patients with mRCC who were treated with PD-1/PD-L1–based ICIs. These findings are consistent with the obesity paradox that was previously seen during the VEGF-targeted therapy era.² Several hypotheses have attempted to explain this clinical observation in RCC. Low fatty acid synthase gene expression, which is inversely correlated with BMI, was associated with longer OS in VEGF-treated patients.² Transcriptomic analysis suggests that patients with obesity have tumors with increased angiogenesis gene signatures and peritumoral adipose tissues with increased hypoxia, inflammation, and immune cell infiltration signatures.⁵ The limitations of this study include biases that were associated with the retrospective analysis and lack of robust gene-expression profiling. While baseline characteristics differed between groups, we adjusted for key prognostic variables in multivariable models. Further, BMI may have limitations as a surrogate marker of adiposity; more sophisticated, although cumbersome, radiological measurements could better identify sarcopenic obesity.⁶ Ultimately, further correlative work is required to explore the biological underpinnings for similar findings across other solid tumors that are treated with ICIs.

Accepted for Publication: December 17, 2020.

Published Online: March 4, 2021. doi:10.1001/jamaoncol.2021.0019

Corresponding Author: Toni K. Choueiri, MD, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Dana 1230, Boston MA 02215 (toni_choueiri@dfci.harvard.edu).

Author Contributions: Drs Heng and Choueiri had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lalani, Choueiri.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Lalani, Farah, Heng.

Critical revision of the manuscript for important intellectual content: Lalani, Bakouny, Donskov, Dudani, Heng, Choueiri.

Statistical analysis: Lalani, Bakouny, Farah.

Administrative, technical, or material support: Lalani, Heng, Choueiri.

Supervision: Choueiri.

Conflict of Interest Disclosures: Dr Lalani reported personal fees from AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche, and TerSera and grants from BioCanRx, Bristol Myers Squibb, Novartis, Roche, Ipsen, and EMD Serrono outside the submitted work. Dr Bakouny reported grants from Genentech/imCORE and nonfinancial support from Bristol Myers Squibb outside the submitted work. Dr Donskov reported grants from Pfizer, Ipsen, and MSD outside the submitted work. Dr Heng reported grants from Pfizer, Bristol Myers Squibb, Merck, and Roche outside the submitted work. Dr Choueiri reported personal fees from Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Journal, Lancet Oncology, Lilly, Lpath, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, and UpToDate; research support from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, US Department of Defense, Corvus Pharmaceuticals, Eisai, Exelixis, Foundation Medicine, GATEWAY for Cancer Research, GlaxoSmithKline, Ipsen, Merck, National Cancer Institute, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche, Genentech, Seattle Genetics/Astellas, Takeda, and TRACON Pharma; patent applications PCT/US2018/058430 and PCT/US2018/12209; and medical writing and editorial assistance support funded by communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, and Parexel. No other disclosures were reported.

Funding/Support: This research was supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE, and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute (Dr Choueiri).

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Ronan Flippot, MD (Gustave Roussy), John A. Steinharter, MS (Dana-Farber Cancer Institute), Pier V. Nuzzo, MD (Dana-Farber Cancer Institute), Justin H. Fleischer, BS (Dana-Farber Cancer Institute), Sumanta K. Pal, MD (City of Hope), Nityam Rathi, BSc (Cleveland Clinic Lerner College of Medicine), Aaron R. Hansen, MBBS (Princess Margaret Cancer Center), Takeshi Yuasa, MD (Japanese Foundation for Cancer Research), Ulka Vaishampayan, MD (Rogel Cancer Center), Mathushan Subasri, BSc (University of Western Ontario), J. Connor Wells, MD (Tom Baker Cancer Centre), and Naveen S. Basappa, MD (Cross Cancer Institute) for assistance with data collection and helpful discussion on interpretation. We also thank Wanling Xie, MS (Dana-Farber Cancer Institute) for assistance with data analysis. They were not compensated.