Obesity Linked to Improved Outcomes in Men With Metastatic Melanoma

Jennifer McQuade, MD

Obese men treated with targeted or immune therapies for metastatic melanoma had a 47% reduced risk of death compared with men who had a normal BMI, according to results from a retrospective multicohort analysis published in The Lancet Oncology.¹

In obese male patients treated with either targeted therapy or immunotherapy, median overall survival (OS) was almost double that of patients with normal a BMI (HR, 0.53; 95% CI, 0.40-0.70; P = .04). BMI from 18.5 to 24.9 kg/m² was considered normal. BMI ≥30 kg/m² was considered obese.

Investigators found no significant differences in survival between women with normal, overweight, or obese BMI (HR, 0.85; 95% CI, 0.61-1.18, P_interaction = .03). Median OS was at least 33 months for all women in the study.

Jennifer McQuade, MD, lead author and instructor of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center, said the effect is an example of the “Obesity Paradox” at work. Investigators had hypothesized that obesity would be associated with poorer outcomes.

“Obese men consistently did much better than men with a normal BMI, with nearly a doubling of overall survival,” she said in a press release. “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? One hint may be the interaction between obesity, sex, and outcomes, which has not been detected before in any cancer.”

McQuade and her colleagues reviewed data collect on 2046 patients treated with targeted therapy, immunotherapy, or chemotherapy from August 2006 to January 2016. A total of 1918 patients grouped into 6 cohorts were included in this analysis.

Two cohorts included patients from randomized controlled trials treated with targeted therapy: dabrafenib (Tafinlar) plus trametinib (Mekinist; n = 599) and vemurafenib (Zelboraf) plus cobimetinib (Cotellic; n = 240). Two cohorts included patients treated with immunotherapy, a randomized controlled trial of ipilimumab (Yervoy) plus dacarbazine (n = 207) and a retrospective cohort treated with pembrolizumab (Keytruda), nivolumab (Opdivo), or atezolizumab (Tecentriq; n = 331). Two cohorts included patients treated with chemotherapy in 2 randomized controlled trials of dacarbazine. The patients were classified as normal BMI (36%), overweight (37%), or obese (27%).

For all patients assigned to dabrafenib and trametinib (n = 599), the median progression-free survival (PFS) for patients with a normal BMI was 9.6 months and the median OS was 19.8 months. In comparison, the median PFS was 15.7 months for obese patients and the median OS was 33.0 months.

In a multivariable analysis that included factors such as age, sex, stage, disease burden, certain mutations, and prior treatment, obesity still improved PFS and OS compared with normal BMI patients. However, when analyzing the results by sex alone, the investigators only identified significant variance among men.

In the 347 patients in the dabrafenib/trametinib cohort who were male, the median PFS was 12.8 versus 7.4 months among obese patients and those with a normal BMI, respectively. The median OS was 36.5 versus 16.0 months, respectively.

In a cohort of patients treated with PD-1/PD-L1 inhibitors, investigators again found that obesity was associated with superior PFS (7.6 vs 2.7 months in normal BMI patients) and OS (26.9 vs 14.3 months) for male patients, but similar differences were again not found among women.

A cohort of patients treated with ipilimumab (n = 207) showed similar results. There was no effect of obesity found among 2 cohorts (n = 541) treated only with dacarbazine.

According to the World Health Organization, obesity is a known risk factor for 13 types of cancer and is set to overtake smoking as the leading preventable cause of cancer. The relationship between obesity and survival in patients with cancer is not consistent, and recent studies have shown a similar survival benefit for obese patients with colorectal or kidney cancer.

“The public health message is not that obesity is good. Obesity is a proven risk factor for many diseases,” 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.”

In an accompanying editorial, Andrew J. Hayes, MBBS, PhD, and James Larkin, PhD, of The Royal Marsden NHS Foundation Trust, London, wrote that finding a beneficial effect associated with obesity should not be too surprising.² Previous data, including a meta-analysis of 22 trials of patients with various malignancies, showed a similar effect for obese men treated with either cytotoxic chemotherapy or targeted therapy.

“How should these new data be used to counsel patients, given the overwhelming evidence on a population level that obesity is a major risk factor for developing and dying of cancer?” wrote Hayes and Larkin. “These results apply only to male patients in one tumor type undergoing targeted or immune therapy and, because of the complexity of the relation between obesity and cancer, as yet they should not be extrapolated further.

“However, some overweight patients with melanoma who are under active treatment might be reassured that the oft-cited negative association of obesity with cancer outcome does not apply to them at that point in time.”

References

1. McQuade JL, Daniel CR, Hess KR, et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis [published online February 12, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30078-0.
2. Hayes AJ, Larkin J. BMI and outcomes in melanoma: more evidence for the obesity paradox [published online February 12, 2018]. Lancet Oncol. doi: 10.1016/ S1470-2045(18)30077-9.