Introduction:

Previous studies on melanoma and renal cell carcinoma demonstrated a survival advantage for patients with high body mass index (BMI) receiving immunotherapy for advanced disease. This has been attributed to the fact that the pro-inflammatory state originating from the metabolic syndrome, usually associated with high BMI, determines lymphocytes disfunction. Lymphocytes’ acquaintance to this pro-inflammatory state makes them more susceptible to be de-inhibited by immunotherapy. In this study, we aimed to test whether BMI amongst patients with muscle invasive bladder cancer (MIBC) is associated with a higher response to neoadjuvant immunotherapy.

Methods:

Within the PURE-01 trial, (NCT02736266), 143 patients received three courses of intravenous pembrolizumab before radical cystectomy. The outcome of the study was pathologic complete response (pCR) defined as pT0N0 on the cystectomy specimen. The role of BMI on pCR was investigated as a categorical variable (<25 vs. ≥25 kg/m2), according to prior studies in this context. Analyses were adjusted for tumor mutational burden (TMB), PD-L1 expression and % of CD8+ lymphocytes on the TUR specimen. Comprehensive genomic profiling (Foundation Medicine, Cambridge, MA, USA) was available for 141 patients; whereas whole-transcriptome assay (Decipher Biosciences Laboratory, San Diego, CA, USA) was obtained from the cystectomy specimen of 105 patients. Differences in response at the genomic level were evaluated for patients with high versus low BMI.

Results:

Overall, 57 (40%) patients achieved pCR on final pathology. On multivariable analysis, BMI emerged as a predictor of pCR (OR: 2.45, 95% CI: 1.09,5.51; p=0.03). Longtail plots showing the comparison of genomic alterations in patients with low vs high BMI are presented in Figure 1A and B, demonstrating similar genomic alterations between the two categories. Biological characterization using selected MIBC marker genes associated with subtypes of known biological categories (luminal, basal, EMT, immune, stromal, and neuroendocrine), signatures for fatty acid and cholesterol anabolism and FASN are displayed in Figure 2. No genomic cluster associated with high BMI and response was identified.

Conclusion:

Elevated BMI is a significant predictor of pCR in patients with MIBC treated with neoadjuvant pembrolizumab. Our findings on the lack of differences at the genomic level between patients with high and low BMI are consistent with prior studies that have demonstrated that a greater response to immunotherapy is driven by circulating lymphocytes rather than tumor-related factors. 

Funding: N/A