Loss of skeletal muscle area and fat-free mass during dabrafenib/trametinib and vemurafenib/cobimetinib treatments in patients with BRAF-mutant metastatic malignant melanoma

Abstract

This study aimed to assess whether dabrafenib/trametinib and vemurafenib/cobimetinib treatments are associated with a change in skeletal muscle area (SMA) and total fat-free mass (FFM) assessed by computed tomography (CT), and to compare the efficacy and safety profile of these treatments in patients with metastatic melanoma. Thirty-one patients treated with B-Raf proto-oncogene, serine/threonine kinase/MAPK extracellular receptor kinase inhibitors were included between 2016 and 2019. Eighteen patients received dabrafenib/trametinib and remaining patients received vemurafenib/cobimetinib. CT scans were performed at baseline and at 4–6 months of follow-up to measure cross-sectional areas of SMA. FFM and skeletal muscle index (SMI) values were calculated. Of the patients, including 18 treated with dabrafenib/trametinib (58.1%) and 13 with vemurafenib/cobimetinib (41.9%); 58.1% were male, 41.9% were female and median age was 52 years. A significant decrease in SMA was observed after dabrafenib/trametinib and vemurafenib/cobimetinib treatments (P = 0.003 and P = 0.002, respectively). A significant decrease in FFM values was observed after dabrafenib/trametinib and vemurafenib/cobimetinib treatments (P = 0.003 and P = 0.002, respectively). Dose-limiting toxicity (DLT) was observed in 35.9% of the patients with sarcopenia. No significant difference was seen between the dabrafenib/trametinib and vemurafenib/cobimetinib groups in median progression-free survival (PFS) (11.9 vs. 7.3 months, respectively, P = 0.28) and in median overall survival (OS) (25.46 vs. 13.7 months, respectively, P = 0.41). Baseline sarcopenia was not significantly associated with PFS or OS (P = 0.172 and P = 0.326, respectively). We found a significant decrease in SMI values determined at 4–6 months compared to the values before treatment both in dabrafenib/trametinib and vemurafenib/cobimetinib groups. DLT was similar with both treatments. Baseline sarcopenia was not significantly associated with PFS or OS.

Cellular and Molecular Mechanisms of MEK1 Inhibitor–Induced Cardiotoxicity

“…Upon euthanasia, 88% of mice (16 of 18) exhibited reductions in body weight, consistent with clinical findings ( Figure 1B ). 10 Terminal complete blood counts were assessed for signs of immunotoxicity. Trametinib-treated animals exhibited leukocytosis, with marked neutrophilia and monocytosis, with no detectable changes in lymphocyte count ( Figure 1C ).…”

Comprehensive assessment of pretreatment sarcopenia impacts on patients with EGFR‐mutated NSCLC treated with afatinib

“…Sarcopenia only played a prognostic role among patients treated with multikinase inhibitors (MKIs) with low response rates 4,5 . By contrast, sarcopenia was not associated with any prognostic value among patients treated with specific TKIs for driver mutation, including EGFR‐TKIs to treat EGFR ‐mutant NSCLC 6,20,21 . which might be due to the ability to reverse sarcopenia with active treatment 7 .…”

“… 4 , 5 By contrast, sarcopenia was not associated with any prognostic value among patients treated with specific TKIs for driver mutation, including EGFR‐TKIs to treat EGFR ‐mutant NSCLC. 6 , 20 , 21 which might be due to the ability to reverse sarcopenia with active treatment. 7 Sarcopenia had a limited impact on toxicity among patients with cancer treated with MKIs.…”

“…Previous studies have demonstrated that sarcopenia is negatively associated with progression‐free survival (PFS) among patients treated with sunitinib for gastrointestinal stromal tumor (GIST) 4 and patients treated with regorafenib for colorectal cancer. 5 However, in another study, baseline sarcopenia was not significantly associated with PFS among patients treated with BRAF‐targeted therapy for melanoma, 6 and sarcopenia was found to be reversible in some GIST patients treated with imatinib. 7 Pretreatment sarcopenia is a predictive factor for the occurrence of nonsevere toxicities among patients with GIST treated with imatinib.…”

Role of Sarcopenia in Advanced Malignant Cutaneous Melanoma Treated with Immunotherapy: A Meta-Analysis

“…Furthermore, the full texts of the remaining 15 articles were checked for possible data inclusion. Overall, 6 articles met the inclusion criteria [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. The following data were acquired for the analysis: authors, year of publication, number of patients, prevalence of sarcopenia, and statistical data about influence of sarcopenia on relevant outcomes (hazard/odds ratios and 95% CI).…”