Sarcopenia associated with a body mass index (BMI) > 25 kg/m² predicts severe acute toxicity of nivolumab and pembrolizumab in melanoma patients

Background

Anti PD-1 antibodies nivolumab and pembrolizumab are checkpoint inhibitors widely used in metastatic melanoma. Although less frequent than with anti-CTLA4 therapy, severe immune-related adverse events can occur. Since the dose is calculated in mg/kg, we hypothesized that patients with abnormal body composition resulting in reduced distribution volume may be overexposed. We studied whether body composition could predict early severe toxicity in patients with advanced melanoma receiving either nivolumab or pembrolizumab.

Methods

All melanoma patients treated with anti PD-1 between August 2014 and February 2016 in our center were retrospectively reviewed. Early severe toxicity was defined as any toxicity occurring in the first 3 months of treatment leading to definitive or temporary treatment discontinuation. Muscle mass was measured on CT scan performed closest to treatment initiation. Patients having a skeletal muscle index inferior to the median of the studied population were defined as sarcopenic.

Results

71 patients were included (33 females; median age 65 years, range 22 to 91 years). 68% received pembrolizumab and 32% nivolumab. 30% of tumors harbored BRAF V600 mutations, 23% NRAS mutations and 39% were wild type. Anti PD-1 antibody was the first line therapy for 36% of the patients. 42 (59%) patients had a BMI > 25 kg/m² and 10 (14%) had both sarcopenia and a BMI > 25 kg/m². A total of 11 (15%) patients experienced severe acute toxicity: pneumonitis (n = 1), nephritis (n = 1), polymyositis (n = 1), hepatitis (n = 2), uveitis (n = 1), cytopenia (n = 3) or polyarthritis (n = 2). No toxic death occurred. These events occurred early, 72% following either the first or second infusion. Treatment discontinuation was definitive (n = 9) or temporary (n = 2). Sarcopenic patients with a BMI > 25 kg/m² experienced more early severe toxicities: 40% of early severe toxicity (n = 4) among sarcopenic-overweight patients compared to 11% (n = 7) among the other patients (p = 0, 04).

Conclusions

Patients with sarcopenia and a BMI > 25 kg/m² experienced significantly more early severe toxicities, suggesting an abnormally high exposure. Precautions should be taken when prescribing anti PD-1 antibodies in this subset of patients.

Clinical trial identification

Legal entity responsible for the study

Hôpital Cochin APHP

Funding

Hôpital Cochin APHP

Disclosure

All authors have declared no conflicts of interest.