OBESE PATIENTS with metastatic melanoma who are treated with targeted or immune therapies live significantly longer than those with a normal body mass index (BMI), according to a study published in The Lancet Oncology of 1,918 patients in 6 independent clinical cohorts.1
This effect—referred to as the “obesity paradox”—principally manifested itself in men, said Jennifer McQuade, MD, lead author and Instructor of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.
“Even within our metastatic melanoma population, we would not suggest that patients intentionally gain weight. We need to figure out what is driving this paradox….”— Jennifer McQuade, MD
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“Obese men consistently did much better than men with a normal BMI, with nearly a doubling of overall survival,” Dr. McQuade said. The researchers found no significant differences in survival between women with normal, overweight, or obese BMI.
“The question is what underlying mechanism causes this advantage in obese men, and can we take advantage of it to improve outcomes in patients with melanoma?” Dr. McQuade said. “One hint may be the interaction between obesity, sex, and outcomes, which has not been detected before in any cancer.”
Women with metastatic melanoma have long been known to have better outcomes than men, Dr. McQuade noted. In this study, obesity overcame that survival disadvantage for men, leading researchers to look at the possible impact of sex hormones in this effect.
“The public health message is not that obesity is good. Obesity is a proven risk factor for many diseases,” Dr. McQuade said. “Even within our metastatic melanoma population, we would not suggest that patients intentionally gain weight. We need to figure out what is driving this paradox and learn how to use this information to benefit all of our patients.”
Obesity is a known risk factor for developing 13 types of cancer according to the World Health Organization and is set to overtake smoking as the leading preventable cause of cancer. The relationship between obesity and survival in patients who already have cancer is not as consistent. Recent studies have shown a similar survival benefit for obese patients with colorectal or kidney cancer.
The team expected to find obesity to be harmful for patients with melanoma, based in part on research that implicates obesity in the activation of the IGF-1/PI3K/AKT molecular pathway. The researchers analyzed the associations among BMI, progression-free survival, and overall survival in six independent cohorts of patients treated with targeted therapy, immunotherapy, or chemotherapy in pivotal trials that led to U.S. Food and Drug Administration approval of these drugs.
While advantages in progression-free and overall survival emerged in an overall meta-analysis of the entire group, the survival benefit associated with obesity was restricted to men treated with targeted therapy or immunotherapy, where obese men had a 47% decreased risk of death compared to men with a normal BMI.
Doubling of Overall Survival in Men
RESULTS FROM 599 patients receiving the combination targeted therapy of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) were:
A multivariable analysis that included factors such as age, sex, stage, disease burden, certain mutations, and prior treatment showed that obesity still improved survival compared to patients with normal BMI.
The team analyzed results by sex and found significant differences only among men: Men with a normal BMI had a progression-free survival of 7.2 months and overall survival of 16.0 months, whereas obese men had a progression-free survival of 12.8 months and overall survival of 36.5 months.
By contrast, women had an overall median survival of at least 33 months, regardless of BMI. A validation cohort of 240 patients treated with the BRAF inhibitor vemurafenib (Zelboraf) and the MEK inhibitor cobimetinib (Cotellic) yielded similar results.
For immunotherapy, in a 330-patient cohort treated with checkpoint inhibitors blocking either the programmed cell death protein 1 (PD-1) check point on T cells or its PD-L1 ligand, results again showed no differences among women but found the following results in men: Men with a normal BMI had a progression-free survival of 2.7 months and overall survival of 14.3 months, whereas obese men had a progression-free survival of 7.6 months and overall survival of 26.9 months.
A 207-patient cohort of patients treated with the immune checkpoint inhibitor ipilimumab (Yervoy) showed similar results. There was no effect of obesity found among 2 cohorts (541 patients) treated with the chemotherapy dacarbazine alone.
The researchers are following up to understand the biologic factors that might provide an advantage to obese male patients. ■
DISCLOSURE: For full disclosures of the authors, visit thelancet.com.