BMI May Stratify Clinical Trials to Measure Survival With Immunotherapy in NSCLC

High body mass index (BMI) in patients with non–small cell lung cancer (NSCLC) is independently associated with an improvement in survival outcomes following treatment with atezolizumab (Tecentriq), according to results of a pooled post hoc analysis published in JAMA Oncology.

“The association between BMI and OS remained significant after adjustment for trial-specific stratification factors and several clinically relevant confounders. The strength of the association was further increased by the presence of PD-L1 in the tumor and immune cells,” wrote investigators led by Ganessan Kichenadasse, MBBS, FRACP

Patient data in this study was obtained from the phase III OAK trial (NCT02008227), phase II POPLAR trial (NCT01903993), phase II BIRCH trial (NCT02031458), and the phase II FIR trial (NCT01846416). A pooled analysis of these trials was used to show correlation within a large cohort of patients who were treated with atezolizumab. The overall goal of this study was to investigate whether BMI was linked to survival outcomes and adverse events (AEs) in patients with NSCLC treated with atezolizumab and docetaxel.

Together, the 4 trials consisted of 2,261 patients, 1,548 of whom received atezolizumab. After 114 participants were excluded from the analysis due to unavailable BMI information, 1,434 were examined, and 705 of these patients were of normal weight (49%), 490 were overweight (34%), and 239 were obese (7%). The majority of patients who were classified as obese were Caucasian males and were previous smokers with a neutrophil to lymphocyte ratio less than 3, and lower C-reactive protein concentrations.

A significant difference in survival was observed between patients of normal weight, overweight patients, and obese patients (P <.001). Notably, those who were obese showed the highest overall survival (OS; HR, 0.64; 95% CI, 0.51-0.81), followed by overweight patients (HR, 0.81; 95% CI, 0.68-0.95), compared with individuals who had a normal BMI. The association between BMI and survival was consistent in men and women.

In terms of PD-L1 expression, however, a survival advantage was observed in patients with PD-L1 positive tumors who were obese (HR, 0.73; 95% CI, 0.58-0.91) or overweight (HR, 0.48; 95% CI, 0.34-0.66) compared with patients who had PD-L1-negative tumors. The 436 subjects with the highest PD-L1 expression of ≥50% or ≥10% tumor-infiltrating immune cells demonstrated an HR of 0.36 (95% CI, 0.21-0.62) and 0.69 (95% CI, 0.48-0.98) for the obese and overweight populations, respectively.

In terms of progression-free survival (PFS), there was no statistical significance among the 2 high BMI populations. For overweight patients, the HR was 0.89 (95% CI, 0.78-1.01) versus the obese group who had an HR of 0.86 (95% CI, 0.73-1.01; P =.09).

Kichenadasse et al noticed the most obvious association between BMI and PFS in patients with PD-L1-positive tumors. For patients classified as overweight, the HR was 0.86 (95% CI, 0.72-1.01) compared with the obese group (HR, 0.78; 95% CI, 0.62-0.96; P =.03). Not much of a correlation was observed with PD-L1-negative tumors. Among patients with the highest PD-L1 expression, the investigators observed HRs of 0.68 for the group with obesity (95% CI, 0.49-0.94) and 0.72 for the overweight group (95% CI, 0.56-0.92).

The 3 BMI categories had no significant difference in the incidence of treatment-related AEs (TRAEs). Any-grade TRAEs occurred in 64% of patients with obesity and 65% of patients who were classified as overweight (P =.92). Grade 3 to 5 TRAEs occurred in 12% of patients in the obese group and 14% of patients in the overweight group (P =.66). There was also no significant difference in immune-related AEs (irAEs), with the exception of skin-related irAEs, which was frequent in patients who were overweight (HR, 1.47; 95% CI, 1.2-

2.0).

In the subgroup of patients treated with docetaxel from the OAK and POPLAR clinical trials, no association between BMI and OS was observed, including in patients with PD-L1 expression.

This pooled analysis is the largest study to date to investigate the association between obesity and survival outcomes with an immune checkpoint inhibitor. Kichenadasse et al hypothesized that BMI may be a predictive biomarker for response to immune checkpoint inhibitors like atezolizumab as well as durvalumab (Imfinzi), nivolumab (Opdivo), and pembrolizumab (Keytruda) based on prior data, which aimed to find a solution for the percentage of patients who do not derive benefit from these agents.

“The findings suggest that high BMI was associated with improved OS in patients with advanced NSCLC. We believe we have identified for the first time that there may be a nearly linear relationship between BMI and OS with atezolizumab therapy when normal, overweight, and obese categories were compared,” wrote Kichenadasse et al.

_Reference:

_{Kichenadasse, G. Miners JO, Mangoni AA, et al. Association Between Body Mass Index and Overall Survival With Immune Checkpoint Inhibitor Therapy for Advanced Non–Small Cell Lung Cancer. JAMA Oncol. 2020;6(4):512-518. doi:10.1001/jamaoncol.2019.5241}