A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable

Abstract

Background Recent evidence suggested a potential correlation between overweight and the efficacy of immune checkpoint inhibitors (ICIs) in cancer patients. Patients and methods We conducted a retrospective study of advanced cancer patients consecutively treated with anti-PD-1/PD-L1 inhibitors, in order to compare clinical outcomes according to baseline BMI levels as primary analysis. Based on their BMI, patients were categorized into overweight/obese (≥ 25) and non-overweight (< 25). A gender analysis was also performed, using the same binomial cut-off. Further subgroup analyses were performed categorizing patients into underweight, normal weight, overweight and obese. Results Between September 2013 and May 2018, 976 patients were evaluated. The median age was 68 years, male/female ratio was 663/313. Primary tumors were: NSCLC (65.1%), melanoma (18.7%), renal cell carcinoma (13.8%) and others (2.4%). ECOG-PS was ≥2 in 145 patients (14.9%). PD-1/PD-L1 inhibitors were administered as first-line treatment in 26.6% of cases. Median BMI was 24.9: 492 patients (50.6%) were non-overweight, 480 patients (50.4%) were overweight/obese. 25.2% of non-overweight patients experienced irAEs of any grade, while 55.6% of overweight/obese patients ( p < 0.0001). ORR was significantly higher in overweight/obese patients compared to non-overweight (p < 0.0001). Median follow-up was 17.2 months. Median TTF, PFS and OS were significantly longer for overweight/obese patients in univariate (p < 0.0001, for all the survival intervals) and multivariate models ( p = 0.0009, p < 0.0001 and p < 0.0001 respectively). The significance was confirmed in both sex, except for PFS in male patients ( p = 0.0668). Conclusions Overweight could be considered a tumorigenic immune-dysfunction that could be effectively reversed by ICIs. BMI could be a useful predictive tool in clinical practice and a stratification factor in prospective clinical trials with ICIs. Electronic supplementary material The online version of this article (10.1186/s40425-019-0527-y) contains supplementary material, which is available to authorized users.

The impact of body composition parameters on severe toxicity of nivolumab

“…Daly et al [10] also reported an association between BMI >25 kg/m 2 and toxicity, but patients with BMI >25 kg/m 2 had lower MA than patients with a normal BMI, and the increased risk of toxicity could most likely be attributed to the low MA. A higher incidence of irAEs of any grade and a better clinical outcome were reported in overweight patients or patients with obesity treated with ICIs [23]. A non-linear relationship between BMI and ICI efficacy was found and might rather suggest a relationship between muscle loss and survival [24].…”

Weighing the role of skeletal muscle mass and muscle density in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: a multicenter real-life study

“…Given to the emerging association between BMI, patients sex and clinical outcomes of cancer patients receiving immunotherapy 13,14 , we did not used the already available sex-specific, BMI-incorporated, cut offs values for SMI and muscle attenuation 15 , which were established before the advent of immune checkpoint inhibitors. On the other hand, several correlations between sex 16 , BMI 3,17 and skeletal muscle are already known.…”

“…It is known that body composition and sex affect the immune system 16,17 , and several studies have already investigated the complex inter-relationships between BMI, sex and clinical outcomes with ICIs 13,14,29 . The aim of our study was to assess whether (and how) the skeletal muscle (sarcopenia and muscle degradation) affected immunotherapy clinical outcomes, not the role of BMI.…”

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…238,[241][242][243][244][245] Specifically, patients treated with ICB had reduced risk of death by 3.6% with every point increase in BMI. 237,246 While those studies find an obesity-ICB efficacy link regardless of sex for most survival measures, one study found the obesity-associated boost in ICB efficacy for males only. 236 Of special consideration is cytokine release syndrome or "cytokine storm" and immunotherapy-induced immune-related adverse events (irAEs) that may be potentially exacerbated in obesity, reported in one mouse obesity study in tumor-free mice.…”

“…234 Indeed, clinical reports show that obese or overweight patients have improved immunotherapy efficacy in metastatic melanoma, non-small cell lung cancer (NSCLC), and other cancers leading to increased overall survival and/ or progression-free survival with higher PD-L1 associated with better hazard ratios. [235][236][237][238][239][240] Proposed mechanisms of action include inflammatory cytokines and mediators such as C-reactive protein or leptin signaling to modulate the T cell repertoire. 238,[241][242][243][244][245] Specifically, patients treated with ICB had reduced risk of death by 3.6% with every point increase in BMI.…”