Obesity Paradox With Immunotherapy in NSCLC

Pam Harrison

January 02, 2020

Being overweight or obese is a clear risk factor for many cancers, but new findings suggest that overweight and obese patients with cancer live longer following treatment with an immune checkpoint inhibitor compared with their normal weight counterparts. The finding comes from a pooled analysis of four trials involving more than 2000 patients.

"Previous studies have explored a concept called the 'obesity paradox,' where obesity is associated with increased risk for developing certain cancers and, counter-intuitively, may protect and give greater survival benefits in certain individuals," lead author Ganessan Kichenadasse, MD, Flinders Centre for Innovation in Cancer in Bedford Park, Australia, said in a statement.

"Our study provides new evidence to support the hypothesis that high body mass index (BMI) and obesity may be associated with [a better] response to immunotherapy," he added. 

The study was published online December 26 in JAMA Oncology.

The pooled analysis of the four trials included 2261 patients with advanced non-small cell lung cancer (NSCLC) who received immunotherapy with the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab (Tecentriq, Genentech) or chemotherapy with docetaxel (Taxotere, sanofi-aventis). Data were available for 2110 of the 2261 patients.

Approximately half of the cohort were normal weight, 34% were overweight, and 7% were obese.

"Overall survival (OS) differed significantly between the patients with normal weight, overweight, and obesity treated with atezolizumab," researchers report.

Compared with patients with a normal body mass index (BMI of 18.5 to 24.9 kg/m2), OS was 19% longer among overweight patients (BMI of 25.0 to 29.9 kg/m2) and it was 36% longer among individuals who were obese (BMI 30 kg/m2 and higher).

"The association between BMI groups and OS was consistent for men and women...but was significantly different between PD-L1-positive and PD-L1-negative tumors," the authors observe.

Among patients with PD-L1-positive tumors, for example, OS was 27% longer among patients who were overweight and 52% longer for patients who were obese compared with normal weight patients, investigators note.

And for patients whose tumors had the highest levels of PD-L1 expression, (50% or greater of tumor cells or 10% or greater of tumor-infiltrating immune cells), OS was 31% longer for overweight patients and 64% longer for obese patients compared with patients who were normal weight.

In contrast, overweight or obese patients with PD-L1-negative tumors did not derive any survival benefit from treatment with atezolizumab compared with normal weight patients.

Similarly, no significant association was observed between OS and BMI among patients who were treated with docetaxel.

Progression-Free Survival Differences

Analyzed as separate groups, progression-free survival (PFS) was not significantly in favor of patients who were either overweight or obese vs those who were not.

However, the PFS advantage was apparent for patients whose tumors expressed PD-L1, where PFS was 14% longer for those who were overweight and 22% longer for those who were obese (P =.03).

Again, patients whose tumors expressed the highest levels of PD-L1 also enjoyed an PFS advantage, where it was 28% longer for overweight patients and 32% longer for obese patients compared with normal weight controls.

The incidence of treatment-related adverse events (AEs) was, in contrast, not significantly different between the three BMI categories, the investigators point out.

Nor were there any significant differences in the frequency of immune-related AEs across the same BMI categories with the exception of skin-related immune AEs, where the incidence was higher among patients who were overweight.

"To our knowledge, the present analyses, which pooled data from multiple prospectively conducted clinical trials of atezolizumab, is the largest study to evaluate the association between obesity and immune checkpoint inhibitor therapy outcomes," Kichenadasse and colleagues write.

"While our study only looked at [BMI] at baseline and during treatment, we believe it warrants more studies into the potentially protective role of high BMI in other cancer treatments," he concluded in a statement.

The World Health Organization estimates that approximately 2.8 million people die each year as a result of being overweight or obese.

The study was funded by the Cancer Council South Australia and the National Breast Cancer Foundation. Kichenadasse has disclosed no relevant financial relationships. Several coauthors have declared financial relationships with industry. The full list can be found with the original article.

JAMA Oncol. Published online December 26, 2019. Abstract

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