medwireNews: A pooled analysis of clinical trial data points to a link between obesity and an increased risk for any-grade immune-related adverse events (irAEs) among people receiving nivolumab monotherapy for advanced cancer.
Although the overall risk for grade 3–4 irAEs did not appear to be elevated with obesity, there was an increase among women, report Jennifer McQuade (University of Texas MD Anderson Cancer Center, Houston, USA) and colleagues in JAMA Oncology.
They continue: “The results of this analysis highlight the importance of BMI as a clinical covariate for patients receiving ICIs and support further evaluation in prospective studies of associations between body composition and patient outcomes during ICI [immune checkpoint inhibitor] treatment.”
The researchers pooled data from 3772 participants of 12 CheckMate trials who received nivolumab monotherapy at a dose of 3 mg/kg (NIVO3; n=2746), NIVO3 plus ipilimumab 1 mg/kg (NIVO3 plus IPI1; n=713), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1 plus IPI3; n=313) for advanced cancer.
The most common tumor type in the NIVO3 monotherapy group was non-small-cell lung cancer (24.9%), followed by melanoma (18.9%) and renal cell carcinoma (14.8%). The NIVO3 plus IPI1 group comprised patients with renal cell carcinoma (72.0%) or microsatellite instability-high or mismatch repair deficient colorectal cancer (28.0%), while the NIVO1 plus IPI3 group consisted of melanoma patients from a single trial.
In the single-agent NIVO3 cohort, the incidence of any-grade irAEs was higher among the 543 people with an obese BMI and the 881 with an overweight BMI than the 1266 with normal or underweight BMI, at 70.0% and 63.6%, respectively, versus 57.7%.
The risk for irAEs was a significant 1.71-fold greater for patients with obesity relative to those with normal or underweight BMI, and the association “was consistent across subgroups of age, sex, smoking status, and ECOG performance status,” say the investigators.
By contrast, the risk for grade 3 or 4 irAEs did not differ significantly by BMI, either in the overall NIVO3 group or subgroups, with the only exception being women with an obese BMI, who had a significant 1.73-fold increased risk relative to women with a normal or underweight BMI.
The team writes: “Although a formal comparison of irAE likelihood was not conducted for the groups with overweight vs normal weight or underweight BMI, we observed a trend for increasing incidence of any-grade irAEs with increasing BMI category, supporting a biological association between BMI and irAEs.”
Exploratory analyses of the NIVO3 plus IPI1 cohort showed an increase in the rate of any-grade, but not grade 3 or 4, irAEs with increasing BMI, from 82.3% for participants with normal or underweight BMIs to 85.2% for those with overweight BMI and 88.0% for those with an obese BMI. But there was no such increase in the NIVO1 plus IPI3 cohort.
“Further evaluation of BMI and safety associations among patients receiving combination therapy is needed to draw more definitive conclusions,” say McQuade et al.
Discussing the findings, the researchers say that “[o]besity, a risk factor for developing many tumor types, has paradoxically been associated with improved outcomes for patients receiving ICIs,” with possible underlying mechanisms including “increased chronic inflammation, increased programmed cell death 1 expression on CD8+ T cells, decreased T-cell function, and increased frequency of exhausted T cells.”
They add that “[i]t is unclear whether some or all of the suggested mechanisms involved in the increased effectiveness of ICIs in patients with obesity may contribute to increased incidence of irAEs,” and highlight the need for additional research to “elucidate the associated mechanisms.”
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