Contrary to investigators' expectations, an observational study found that obesity is associated with increased progression-free survival (PFS) and overall survival (OS) in patients with metastatic melanoma who were treated with a combination of dabrafenib (Tafinlar) and trametinib (Mekinist). These results were presented at the 2016 ASCO Annual Meeting.
“Obesity has been associated with worse outcomes in a variety of malignancies but had not yet been systematically studied in melanoma patients being treated with targeted therapies,” said lead investigator Jennifer Leigh McQuade, MD, hematology/oncology fellow at the University of Texas MD Anderson Cancer Center. “Because metabolic signaling pathways like IGF-1R promote resistance to MAPK pathway inhibitors in preclinical models, we had hypothesized that obese patients would fare worse than normal weight patients.”
The investigators examined the association of patient body mass index (BMI) at treatment initiation with outcomes in 2 cohorts ofBRAF-mutant metastatic melanoma patients treated with dabrafenib and tramatenib. The first cohort consisted of patients enrolled in 3 multi-institution, prospective randomized clinical trials (n = 599). The second cohort consisted of patients treated off-protocol at MD Anderson Cancer Center (n = 78).
Patients were categorized as underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25-30), or obese (BMI >30). “We ended up excluding underweight patients due to their low prevalence of about 2%,” McQuade said. “We also had concerns that they might be experiencing cachexia.”
The investigators used a Kaplan-Meier analysis to estimate PFS and OS. In on-trial patients treated with dabrafenib and trametinib, obese patients showed significantly improved median PFS of 15.7 months versus 9.6 months in normal weight patients (HR 0.73; 95% CI, 0.58-0.95;P= 0.02). The median OS of obese patients was 33 months compared to 19.8 for normal weight patients (HR 0.63; 95% CI, 0.46-0.86;P= 0.004).
Exploratory analysis of this on-trial cohort suggests that the effect of BMI on outcomes may be sex-dependent, with a greater effect of BMI observed in men. The median PFS for obese men was 12.8 months compared to 7.4 months for those with normal BMI (HR 0.69; 95% CI, 0.49-0.99). The PFS difference was less pronounced at 17.1 months for obese women versus 14.5 months in normal weight women (HR 0.74; 95% CI, 0.48-1.12).
The median OS for obese men was 36.5 months versus 16 months for normal weight men (HR 0.46; 95% CI, 0.3-0.7). OS for obese women was 33 months but has not yet been reached for normal weight women (HR 0.89; 95% CI, 0.55-1.45).
Differences in median PFS and median OS remained significant when analyzed using multivariate analysis correcting for other prognostic factors that included age, performance status, disease stage, lactate dehydrogenase (LDH) levels, tumor burden and prior immunotherapy.
The trends were similar for the obese patients treated off-protocol. They had a median OS of 24.3 months compared to 13.6 months for normal weight patients (HR 0.8; 95% CI, 0.4-1.5). There were no significant differences in disease stage, LDH levels, or prior immunotherapy between obese and normal weight patients in this group.
Possible study limitations include the fact that the analysis was based on patients’ weights at the time the study began. “It’s possible that patients reached normal weight during the study and that was the protective factor,” said McQuade.
She added that the association of BMI with outcomes is currently being explored in other cohorts of melanoma patients, including those with clinically localized and regional disease and those who have been previously treated with immunotherapy. The investigators are also examining the molecular, immune, and/or clinical factors (like concurrent medications) underlying the associations they observed.
“Although more work needs to be done, the findings support the so-called obesity paradox, in which obesity may, counterintuitively, be protective and associated with greater survival in certain groups of people,” McQuade said. “Significantly, our results were consistent across multiple institutions, not just those from the Texas cohort, where the obesity rate is quite high.”
McQuade JL, Haydu LE, Frankian S, et al. The impact of obesity on outcomes in metastatic melanoma (MM) patients (pts) treated with dabrafenib and trametinib.J Clin Oncol34, 2016 (suppl; abstr 9566).