‘Obesity Paradox’ in Kidney Cancer Continues in Checkpoint Inhibitor Era

Elevated BMI was tied to improved survival in metastatic renal cell carcinoma (RCC) patients treated with immune checkpoint inhibitors, a retrospective study found.

In the analysis of more than 700 metastatic RCC patients who received PD-1/L1 immunotherapies, those with a BMI of 25 or greater had significantly longer overall survival (OS), with 1-year rates of 79% versus 66% for those with a BMI below that cutoff (HR 0.75, 95% CI 0.57-0.97, P=0.03), Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston, and colleagues reported.

“These findings are consistent with the obesity paradox that was previously seen during the VEGF-targeted therapy era,” the group wrote in JAMA Oncology.

The association between higher BMI and OS was consistent across various tumor- and treatment-related subgroups, including International Metastatic RCC Database Consortium (IMDC) risk category, histology, and line of therapy.

Patients with an elevated BMI had numerically higher response rates compared to those with a lower BMI (30% vs 21%, respectively; adjusted OR 1.51, 95% CI 0.98-2.32, P=0.06) and numerically longer time to treatment failure (7.4 vs 4.9 months; adjusted HR 0.98, 95% CI 0.80-1.20, P=0.83).

“Several hypotheses have attempted to explain this clinical observation in RCC,” Choueiri’s group wrote. “Low fatty acid synthase gene expression, which is inversely correlated with BMI, was associated with longer OS in VEGF-treated patients. 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.”

Tumor mutation burden in patients with next-generation sequencing available (n=319) was no different between groups, at an average 6.8 mutations per megabase for the low and high groups. Analyses of genomic alteration frequencies also revealed no differences.

The multinational analysis included 735 patients in the IMDC who had BMI information available and had been treated with a PD-1/L1 inhibitor either alone or in combination with a VEGF or CTLA-4 inhibitor. Median follow-up time was 13.5 months.

At the start of treatment, 37% of the cohort had a high BMI (≥25), while the remaining 63% had a low BMI (<25).

Patients had a median age of 63, about three-fourths were men, and most had clear cell histology (84%). In all, 69% received a PD-1/L1 immune checkpoint inhibitor as monotherapy, 19% in combination with a VEGF inhibitor, and 12% in combination with a CTLA-4-directed checkpoint inhibitor or other agent. A little less than a third received the PD-1/L1 inhibitor as first-line treatment, 44% in second-line, with the remaining in the third- or fourth-line setting.

Limitations cited by the study authors included the retrospective nature of the study, incomplete gene-expression profiling, and imbalances between groups. For example, patients with a higher BMI were more likely to have better performance status and be in more favorable risk groups, were more likely to have clear cell histology, to have had prior nephrectomy, and to have received a checkpoint inhibitor as first-line therapy, though the investigators adjusted for key prognostic variables in their analyses.

“BMI may have limitations as a surrogate marker of adiposity,” the group added. “More sophisticated, although cumbersome, radiological measurements could better identify sarcopenic obesity.”