Targeted Therapy and Immunotherapy: Effect of Body Mass Index on Clinical Outcomes in Patients Diagnosed with Metastatic Renal Cell Carcinoma

Abstract

Background: Previous research has identified an association between high body mass index (BMI) and better overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients treated with vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs). Objective: The current study sought to determine whether the effect of BMI on OS extends beyond VEGF-TKIs to mTOR inhibitors or immunotherapy (IO). Design, Setting and Participants: A retrospective study was conducted among patients diagnosed with mRCC treated at a single institution from 2009 to 2017. Demographic and clinical variables were collected. BMI was characterized as high (≥25 kg/m 2) versus low (<25 kg/m 2). Outcomes Measurement and Statistical Analysis: The Kaplan-Meier method was used to estimate the difference in OS, with comparisons based on BMI and by treatment type. Results and Limitations: Among 353 patients (M = 64 years old, 73% male) 66% were overweight or obese (BMI ≥ 25 kg/m 2). Patients were treated with VEGF-TKI (65%), mTOR (23%), or IO (12%). Among patients treated with VEGF-TKI with low BMI, median OS was 24.0 months (95% CI, 20.7-27.2) versus 36.0 months (95% CI, 18.6-53.3) among patients with high BMI (P = 0.02). The median OS for patients with low BMI treated with mTOR was 18.0 months (95% CI, 2.8-33.1), versus 25.0 months (95% CI, 16.6-33.4) among patients with high BMI (P = 0.04). In contrast, patients with low BMI treated with IO had a median OS of 23.6 months (95% CI, 17.5-29.7) versus 19.9 months (95% CI, 10.6-29.2) among patients with high BMI (P = 0.26). The retrospective nature and the small sample size are the main limitations of this study. Conclusions: High-BMI was associated with improved OS in patients with mRCC treated with VEGF-TKI and mTOR, but the inverse trend was observed among patients receiving IO. Our data highlight the need to reassess this phenomenon in the context of IO-based regimens.

Obesity diminishes response to PD-1-based immunotherapies in renal cancer

“…One of these studies, by Bergerot et al, found that elevated BMI was beneficial when RCC patients received targeted therapies such as VEGF or mTOR inhibitors, but found a detrimental trend when immune checkpoint inhibitors were used at the same institution. 18 A 2019 report by Sanchez et al examined retrospective outcomes from an observational cohort of RCC patients (n=203) treated at Memorial Sloan Kettering between 2011 and 2018 with immune checkpoint inhibitors (monotherapy or any combination of anti-PD-1/PD-L1/CTLA-4). 16 In this cohort, obesity was not associated with increased mortality after adjusting for IMDC risk score.…”

“…We began by examining survival outcomes of RCC patients with and without obesity following anti-PD-1 treatment. Recent retrospective studies investigating Open access the effects of obesity on immunotherapy outcomes in RCC have provided intriguing but conflicting results: that increased adiposity (defined as BMI >25 kg/m 2 ) trended toward being detrimental, 18 that obesity (BMI >30 kg/m 2 ) had no impact on outcomes in multivariate analysis, 16 or that obesity improved PFS but not OS in patients who showed primary clinical benefit. 19 We examined this issue by evaluating outcome data for all RCC patients treated with standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation at the UAB Hospital (n=54) and the UI Hospitals and Clinics (n=18).…”

“… 14 17 One such study found that a BMI >25 kg/m 2 was associated with a trending reduction in overall survival (OS) in RCC patients (n=42) treated with anti-PD-1 or programmed cell death ligand (PD-L)1, but improved OS in RCC patients receiving targeted therapies at the same institution. 18 However, another 2019 study of 90 RCC patients reported no difference in BMI status between patients who derived clinical benefit from anti-PD-1/PD-L1 versus those who were resistant to therapy. 19 A third study found that in RCC patients (n=203) treated with immunotherapy (any monotherapy or combination of anti-PD-1/PD-L1/CTLA-4 during clinical trials or standard of care), obesity did not alter immune infiltration or improve survival after adjusting for risk score, but instead decreased PD-L1 expression and increased angiogenesis in renal tumors.…”

Biological Support to Obesity Paradox in Renal Cell Carcinoma: A Review

“…However, the difference failed to reach statistical significance after adjusting for IMDC risk score. As a contradiction, an inverse trend was reported by Bergerot et al [71], where a small group of immunotherapy-treated metastatic RCC patients with low BMI had a median OS of 23.6 months compared to 19.9 months in overweight/obese patients. A study by Labadie et al [72] reported that BMI was not correlated with OS in ccRCC patients with primary resistance to immunotherapy, while the correlation was positive in immunotherapy-sensitive patients.…”

Antineoplastic dosing in overweight and obese cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper

“…116 Bergerot et al have recently described a similar trend on a smaller case series. 117 In metastatic EGFR-mutated non-small cell lung cancer (NSCLC), however, no correlation has been found between patient nutritional status (defined by BMI, body weight and BSA) and response to gefitinib, 118 whereas a potential higher risk of grade 2 hepatic dysfunction has been observed in overweight subjects. 119 As for other targeted agents, BMI did not impact on molecular RR of nilotinib and dasatinib, while a delayed and low rate of molecular responses were observed for imatinib as frontline treatment in obese patients, probably due to the effect of the drug on signaling regulation of macrophages via platelet-derived growth factor (PDGF) receptors adipogenesis stimulation.…”