Low Muscle Mass Is an Independent Risk Factor for Adverse Events During BRAF/MEK Inhibitor Therapy in Patients with Advanced Melanoma: A Retrospective Cohort Study

Low Muscle Mass Is an Independent Risk Factor for Adverse Events During BRAF/MEK Inhibitor Therapy in Patients with Advanced Melanoma: A Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Low Muscle Mass Is an Independent Risk Factor for Adverse Events During BRAF/MEK Inhibitor Therapy in Patients with Advanced Melanoma: A Retrospective Cohort Study Kohei Yamakawa, Yusuke Kurita, Masahiro Aichi, Hideyuki Ishikawa, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9575167/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background BRAF/MEK inhibitors (BRAF/MEKi) are established therapies for patients with BRAF-mutant melanoma. However, treatment frequently causes adverse events (AEs) that may interrupt therapy and reduce patient quality of life. Low skeletal muscle mass (LSMM) is associated with poor prognosis and altered drug pharmacokinetics in patients with cancer. However, its relationship with toxicity during BRAF/MEKi therapy remains uncertain. This study evaluated the association between skeletal muscle mass and the occurrence of AEs in patients with BRAF-mutant melanoma receiving BRAF/MEKi therapy. Methods We retrospectively analyzed 44 patients with BRAF-mutant melanoma, including those with adjuvant and advanced or unresectable disease, treated with BRAF/MEKi at our institution between 2014 and 2025. LSMM was determined using computed tomography–derived skeletal muscle index (SMI) at the L3 level within one month before treatment initiation (cutoffs: <42 cm²/m² for male and < 38 cm²/m² for female patients). AEs were graded according to the Common Terminology Criteria for Adverse Events v5.0. Clinically significant AEs were defined as grade ≥ 3 events or any-grade events resulting in treatment discontinuation, unplanned hospitalization, or ≥ 2 dose reductions. Results LSMM was identified in 23 of 44 patients (52.3%). AEs occurred significantly more often in patients with LSMM than in those without (77.3% vs. 23.8%, p = 0.002). Multivariate analysis demonstrated that LSMM independently predicted AEs (adjusted odds ratio 6.01; 95% confidence interval 1.31–27.65; p = 0.021). Conclusion LSMM is significantly associated with increased risk of AEs during BRAF/MEKi therapy in patients with melanoma, independent of other clinical factors Muscle mass BRAF/MEK inhibitors melanoma adverse events Figures Figure 1 Introduction The introduction of BRAF/MEK inhibitors (BRAF/MEKi) has transformed the management of patients with advanced BRAF-mutant melanoma. Compared with conventional chemotherapy, these targeted therapies significantly improve progression-free survival (PFS) and overall survival (OS) [ 1 ]. Combination regimens such as dabrafenib plus trametinib (Dab/Tram) and encorafenib plus binimetinib (Enco/Bini) are now standard treatments and produce rapid and durable tumor responses. Despite these benefits, BRAF/MEKi therapy frequently causes treatment-emergent adverse events (AEs) [ 2 ] that can reduce treatment adherence and patient quality of life. Common AEs include pyrexia (> 38.5°C), cutaneous reactions ranging from papulopustular rash to severe photosensitivity, and severe fatigue. These events often require dose reduction, temporary interruption, or permanent discontinuation of therapy, which may compromise treatment efficacy and patient quality of life. In addition, serious AEs, including cytopenias and gastrointestinal bleeding, have been reported during BRAF/MEKi therapy [ 3 , 4 ]. Low skeletal muscle mass (LSMM), characterized by reduced skeletal muscle mass and function, is common among patients with cancer. LSMM has been associated with increased chemotherapy toxicity, altered pharmacokinetics, and poorer survival outcomes. Accumulating evidence indicates that muscle depletion affects both treatment tolerability and prognosis across multiple malignancies. However, the influence of LSMM on toxicity during targeted therapy, particularly BRAF/MEKi treatment, remains unclear and evidence is limited [ 5 – 13 ]. Clarifying this association may improve risk stratification, guide individualized dosing strategies, and support interventions aimed at improving treatment safety and outcomes. Patients and Methods Study Population This retrospective cohort study included 44 consecutive patients with histologically confirmed BRAF V600 mutant cutaneous melanoma who received BRAF/MEKi therapy (Dab/Tram or Enco/Bini) at Yokohama City University Hospital between January 2014 and March 2025. Patients received treatment either as adjuvant therapy after complete resection of stage III disease or as first-line systemic therapy for unresectable or metastatic melanoma. In adjuvant cases, treatment began after curative intent surgical resection. Exclusion criteria included: (1) absence of baseline computed tomography (CT) within 30 days before treatment initiation and (2) participation in interventional clinical trials during the treatment period. Demographic, clinicopathological, and treatment information was extracted from electronic medical records using a standardized case report form. Study Design and Data Collection This retrospective single-center cohort study was conducted at Yokohama City University Hospital, Japan. Clinical data collected from electronic medical records included demographic variables (age, sex, height, and weight), disease characteristics (melanoma subtype and BRAF mutation genotype), and baseline clinical parameters. These parameters included Eastern Cooperative Oncology Group performance status (ECOG PS), pathological stage based on the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma, serum lactate dehydrogenase (LDH), and number of metastatic organ sites. Baseline demographic and laboratory data were obtained on the day of BRAF/MEKi initiation, whereas staging information was collected within 1 month before treatment. Information regarding treatment course and AEs was recorded throughout therapy and during follow up until 6 months after treatment discontinuation or the end of treatment monitoring. Skeletal Muscle Assessment LSMM was defined according to criteria established by the Japan Society of Hepatology using baseline abdominal CT images obtained within 30 days before treatment initiation. Axial CT images at the third lumbar vertebra (L3) level were analyzed using SliceOmatic software (version 5.0, Tomovision). Skeletal muscle area (cm²) was quantified using Hounsfield unit thresholds (− 29 to + 150) [ 14 , 15 ] (Fig. 1 ). The skeletal muscle index (SMI) was calculated by normalizing skeletal muscle area to height squared. Sex-specific diagnostic thresholds based on validated Asian criteria were applied: SMI < 42 cm²/m² for male patients and < 38 cm²/m² for female patients [ 16 ]. Adverse Event Assessment Treatment-emergent AEs were evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Significant AEs were defined as either (1) grade ≥ 3 toxicities, representing severe or medically significant events, or (2) any-grade AEs associated with clinically important outcomes, including treatment discontinuation, unplanned hospitalization, or the requirement for ≥ 2 dose reductions. This definition captured both severe toxicities and lower-grade events with meaningful clinical consequences. Statistical Analysis Continuous variables were compared using the independent t-test when normal distribution assumptions were satisfied and the Mann–Whitney U test otherwise. Categorical variables were analyzed using Fisher’s exact test. Multivariate logistic regression analysis was performed to identify independent predictors of AEs. Variables that were significant in univariate analysis, together with age and sex, which are established factors influencing muscle mass, were included in the multivariate model. Statistical analyses were conducted using SPSS Statistics version 29.0.1.0 (IBM, Armonk, NY, USA). A p-value < 0.05 indicated statistical significance. Ethical Considerations This study complied with the Ethical Guidelines for Medical and Biological Research Involving Human Subjects and the principles of the Declaration of Helsinki. The protocol was reviewed and approved by the Yokohama City University Research Ethics Review Committee (F231200026).The requirement for informed consent was waived due to the retrospective nature of the research. Results Patient Characteristics Among 44 patients, 23 were classified as having LSMM and 21 as non-LSMM (Fig. 1 ; Table 1 ). Median age was comparable between groups (Table 2 ). A higher proportion of female patients was observed in the LSMM group, although the difference was not statistically significant. Melanoma subtype, number of metastatic organ sites, LDH level, BRAF mutation status, and first-line therapy were also similar between groups. Table 1 Baseline characteristics of patients with melanoma treated with BRAF/MEK inhibitors. Characteristics n = 44 Age (years) median (range) 69.5 (24–82) Sex, n (%) Female 18 (40.9) Male 26 (59.1) Subtype, n (%) Acral 4 (9.1) Non-acral cutaneous 35 (79.5) Mucosal 1 (2.3) Unknown 4 (9.1) ECOG PS, n (%) 0 27 (61.4) 1 12 (27.3) ≥2 5 (11.4) Stage (AJCC 8th edition), n (%) Ⅲ 26 (59.1) IV (M1a) 3 (6.8) IV (M1b) 4 (9.1) IV (M1c) 7 (15.9) IV (M1d) 4 (9.1) Metastatic organ sites, n (%) 0–1 26 (59.1) ≥2 18 (40.9) LDH, n (%) Normal (< 225 U/l) 30 (68.2) Elevated (≥ 225 U/l) 14 (31.8) BRAF V600, n (%) E 37 (84.1) K or unknown 7 (15.9) First-line, n (%) ICI 12 (27.3) BRAF/MEK 32 (72.7) BRAF/MEKi, n (%) Dab/Tram 38 (86.4) Enco/Bini 6 (13.6) LSMM, n (%) Present 23 (52.3) Absent 21 (47.7) Treatment type, n (%) Non-adjuvant 28 (63.6) Adjuvant 16 (36.4) Abbreviations: AJCC, American Joint Committee on Cancer; BRAF/MEKi, BRAF plus MEK inhibitors; Dab/Tram, dabrafenib plus trametinib; ECOG PS, Eastern Cooperative Oncology Group performance status; Enco/Bini, encorafenib plus binimetinib; ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase; LSMM, low skeletal muscle mass. Table 2 Comparison of baseline characteristics between patients with low muscle mass and normal muscle mass. Characteristics LSMM (n = 23) Non-LSMM (n = 21) p-value Age (years) median (range) 70 (47–82) 69 (24–79) 0.12 Sex, n (%) Female 13 (56.5) 5 (23.8) 0.058 Male 10 (43.5) 16 (76.2) Subtype, n (%) Acral/mucosal 4 (17.4) 2 (9.5) 0.57 NAC/UP 19 (82.6) 19 (90.5) ECOG PS, n (%) 0 12 (52.2) 15 (71.4) 0.23 ≥1 11 (47.8) 6 (28.6) Stage (AJCC 8th edition), IV (M1c/M1d) 4 (17.4) 7 (33.3) 0.44 n (%) Ⅲ/IV (M1a/M1b) 19 (82.6) 14 (66.7) Metastatic organ sites, n (%) 0–1 13 (56.5) 13 (61.9) 0.72 ≥2 10 (43.5) 8 (38.1) LDH, n (%) Normal (< 225 U/l) 14 (60.9) 16 (76.2) 0.28 Elevated (≥ 225 U/l) 9 (39.1) 5 (23.8) BRAF V600, n (%) E 20 (87.0) 18 (85.7) 0.90 K or unknown 3 (13.0) 3 (14.3) First-line, n (%) ICI 8 (34.8) 4 (19.0) 0.24 BRAF/MEK 15 (65.2) 17 (81.0) BRAF/MEKi, n (%) Dab/Tram 17 (73.9) 21 (100.0) 0.012 Enco/Bini 6 (26.1) 0 (0.0) Treatment type, n (%) Non-adjuvant 16 (69.6) 12 (57.1) 0.39 Adjuvant 7 (30.4) 9 (42.9) Abbreviations: AJCC, American Joint Committee on Cancer; BRAF/MEKi, BRAF plus MEK inhibitors; Dab/Tram, dabrafenib plus trametinib; ECOG PS, Eastern Cooperative Oncology Group performance status; Enco/Bini, encorafenib plus binimetinib; ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase; LSMM, low skeletal muscle mass NAC, non-acral cutaneous; UP, unknown primary. Comparison of baseline clinical characteristics demonstrated no significant differences in age, sex, ECOG PS, disease stage, LDH level, or BRAF mutation status between the LSMM and non-LSMM groups (Table 2 ). However, the proportion of patients receiving Enco/Bini was higher in the LSMM group (26.1% vs. 0.0%, p = 0.012). Adverse Events and Muscle Mass Significant AEs occurred in 17 of 23 patients with LSMM (77.3%) compared with 5 of 21 patients without LSMM (23.8%), representing a significant difference (p = 0.002) (Table 3 ). Arthralgia was the most frequently observed AE among patients with LSMM; however, no specific AE type differed significantly between groups. Table 3 Comparison of adverse events between patients with and without sarcopenia. Adverse events LSMM (n = 23) Non-LSMM (n = 21) p-value Rash 0 (0.0) 1 (4.8) 1 Arthralgia 4 (17.4) 1 (4.8) 0.35 Liver dysfunction 2 (4.3) 1 (4.8) 0.61 Pyrexia 2 (8.7) 0 (0.0) 1 Nausea 1 (4.3) 1 (4.8) 1 Headache 1 (4.3) 1 (4.8) 1 Dizziness 1 (4.3) 0 (0.0) 1 Anemia 1 (4.3) 0 (0.0) 1 Leukopenia 1 (4.3) 0 (0.0) 1 Thrombocytopenia 0 (0.0) 1 (4.8) 1 Impaired consciousness 1 (4.3) 0 (0.0) 1 Gastrointestinal bleeding 2 (8.7) 0 (0.0) 1 Amylase elevation 1 (4.3) 0 (0.0) 1 Total 17 (77.3) 5 (23.8) 0.002 Abbreviations: LSMM, low skeletal muscle mass. Univariate and Multivariate Analyses Univariate analysis demonstrated that LSMM was significantly associated with AEs (odds ratio [OR] 9.07; 95% confidence interval [CI]: 2.31–35.65; p = 0.002) (Table 4 ). Table 4 Univariate and multivariate logistic regression analysis of grade ≥ 3 or grade adverse events leading to treatment discontinuation. Characteristics univariate analysis multivariate analysis OR 95% CI p-value OR 95% CI p-value Age ≥65 1.79 (0.52–6.10) 0.36 1.19 (0.24–5.93) 0.84 <65 1 1 Sex Female 4.08 (1.11–15.20) 0.03 2.23 (0.50–9.83) 0.29 Male 1 1 Subtype Acral/mucosal 0.78 (0.12–5.18) 0.8 NAC/UP 1 ECOG PS 0 2.67 (0.76–9.37) 0.13 ≥ 1 1 Adjuvant Adjuvant 1.48 (0.43–5.11) 0.53 Non adjuvant 1 Stage IV (M1c/M1d) 0.51 (0.15–1.77) 0.29 (AJCC 8th edition) Ⅲ/IV (M1a/M1b) 1 BRAF V600 E 2.94 (0.51–17.14) 0.23 K or unknown 1 First-line BRAF/MEKi 0.56 (0.16–1.91) 0.36 ICI 1 BRAF/MEKi Dab/Tram 6.18 (0.66–58.03) 0.11 2.10 (0.16–28.49) 0.58 Enco/Bini 1 1 LSMM present 9.07 (2.31–35.65) 0.002 6.01 (1.31–27.65) 0.021 Absent 1 1 Abbreviations: AJCC, American Joint Committee on Cancer; BRAF/MEKi, BRAF plus MEK inhibitors; CI, confidence interval; Dab/Tram, dabrafenib plus trametinib; ECOG PS, Eastern Cooperative Oncology Group performance status; Enco/Bini, encorafenib plus binimetinib; ICI, immune checkpoint inhibitor; LSMM, low skeletal muscle mass; NAC, non-acral cutaneous; OR, odds ratio; UP, unknown primary. The multivariate model included age and sex as predefined variables, together with BRAF/MEKi regimen, which differed significantly between groups. In multivariate analysis, LSMM remained an independent predictor of AEs (adjusted OR 6.01; 95% CI: 1.31–27.65; p = 0.021). Other clinical factors, including age, sex, melanoma subtype, ECOG performance status, adjuvant therapy, disease stage, BRAF mutation status, and first-line treatment, were not significantly associated with AEs in either univariate or multivariate analyses. Discussion To our knowledge, this study is the first to demonstrate a significant association between LSMM and increased risk of AEs during BRAF/MEKi therapy in patients with BRAF-mutant melanoma. These findings indicate that skeletal muscle mass at treatment initiation may be an important factor when evaluating AE risk during BRAF/MEKi therapy. In this cohort, Enco/Bini was more frequently administered to patients with LSMM. This distribution likely reflects clinical selection bias rather than biological differences. Clinicians may preferentially select Enco/Bini to reduce the risk of pyrexia or creatine kinase elevation, which are well-recognized toxicities of Dab/Tram and may be particularly burdensome in frail patients. However, previous studies have reported no significant differences in PFS, OS, or incidence of severe AEs between these regimens [ 17 ]. Notably, multivariate analysis identified LSMM, rather than treatment regimen, as the independent predictor of AEs. These results suggest that the increased toxicity observed in patients with LSMM cannot be explained solely by treatment selection. Future studies using uniform BRAF/MEKi regimens are necessary to clarify the independent effect of muscle mass on treatment-related toxicity. Previous studies have demonstrated an association between LSMM and increased toxicity during molecular targeted therapy, particularly with multikinase inhibitors such as sorafenib. In renal cell carcinoma, LSMM increased toxicity risk 4.1-fold, with dose-limiting toxicities occurring in 37% of patients with LSMM compared with 5% in patients without LSMM [ 18 ]. Similarly, in hepatocellular carcinoma, early dose-limiting toxicities occurred in 81.8% of patients with LSMM versus 31.0% in those without LSMM (p = 0.005). In addition, grade 3 diarrhea occurred in 45.5% of patients with LSMM compared with 6.9% of patients without LSMM (p = 0.01) [ 19 ]. However, evidence regarding the relationship between LSMM and AEs in patients with melanoma receiving BRAF/MEKi remains limited. Therefore, the present findings provide new evidence relevant to the clinical management of this population. Recent research involving patients with metastatic melanoma harboring BRAF mutations reported that BRAF/MEKi therapy significantly reduced skeletal muscle area and fat-free mass after 4–6 months of therapy [ 20 ]. Dose-limiting toxicities occurred in 35.9% of patients with baseline LSMM. Given the substantial muscle loss reported during BRAF/MEKi therapy, assessment of muscle mass should be considered not only at baseline but also during treatment. Additional studies are needed to determine whether treatment-related muscle loss further increases the risk of adverse events. Several mechanisms may explain the association between LSMM and increased toxicity. Patients with LSMM frequently exhibit hypoalbuminemia and reduced antioxidant capacity, which may impair drug metabolism and increase susceptibility to treatment-related complications [ 21 , 22 ]. Altered body composition may also influence pharmacokinetics of BRAF/MEKi, potentially resulting in higher effective drug concentrations and greater toxicity. In addition, systemic inflammation is common in patients with LSMM and is characterized by elevated cytokines such as interleukin-6 and tumor necrosis factor-alpha[ 23 , 24 ]. Chronic inflammation promotes muscle catabolism and may impair tissue repair, further increasing vulnerability to treatment-related toxicity. Additionally, BRAF/MEKi inhibit the MAPK/ERK signaling pathway, which plays an important role in skeletal muscle regeneration and maintenance [ 25 ]. Inhibition of this pathway may impair muscle repair processes, thereby exacerbating pre-existing LSMM and increasing susceptibility to AEs. Considering these findings, assessment of skeletal muscle mass may be a valuable component of routine evaluation before initiation of BRAF/MEKi therapy. Although further research is necessary to establish clinical guidelines, early identification of LSMM may allow clinicians to implement supportive care strategies. Preventive interventions, including individualized nutritional support and resistance exercise programs, may help reduce treatment-related toxicity and improve outcomes, although their effectiveness in this setting requires further investigation [ 26 , 27 ]. Prospective studies are required to validate these approaches and clarify the biological mechanisms linking LSMM to drug toxicity during BRAF/MEKi therapy. Limitations This study has several limitations, including its retrospective single-center design and relatively small sample size. Larger prospective studies are required to confirm these findings and to evaluate potential intervention strategies. Conclusions LSMM is an independent risk factor for AEs in patients with melanoma receiving BRAF/MEKi therapy.Routine assessment of skeletal muscle mass may improve risk stratification and support more individualized treatment approaches in clinical practice. Abbreviations AE, Adverse event; AJCC, American Joint Committee on Cancer; BRAF, BRAF, B-Raf proto-oncogene, serine/threonine kinase (formerly known as v-Raf murine sarcoma viral oncogene homolog B1); BRAF/MEKi, BRAF plus MEK inhibitors; CI, Confidence interval; CT, Computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; Dab/Tram, dabrafenib plus trametinib; ECOG PS, Eastern Cooperative Oncology Group performance status; Enco/Bini, encorafenib plus binimetinib; HR, Hazard ratio; LDH, Lactate dehydrogenase; LSMM, Low skeletal muscle mass; MEK, Mitogen-activated extracellular signal–regulated kinase; OR, Odds ratio; OS, Overall survival; PFS, Progression-free survival; SMI, Skeletal muscle index. Declarations Funding No funding was received. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate The present study was approved by the Institutional Review Board of Yokohama City University (Yokohama, Japan; approval no. F231200026). The requirement for written informed consent was waived due to the retrospective nature of the study, and an opt-out method was used instead. Patient consent for publication Not applicable. Conflict of Interest The authors declare that they have no competing interests. Authors' contributions KY and YY conceptualized and designed the study. KY, YK, MA, HI, TW and YW acquired the clinical data. KY and YK analyzed and interpreted the patient data. KY wrote the first draft of the manuscript. KY, YK, MA, HI, TW, YW, and YY revised the manuscript critically for important intellectual content. 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Eur J Med Res 22:25. https://doi.org/10.1186/s40001-017-0266-9 Shi H, Scheffler JM, Zeng C, Pleitner JM, Hannon KM, Grant AL, Gerrard DE (2009) Mitogen-activated protein kinase signaling is necessary for the maintenance of skeletal muscle mass. Am J Physiol Cell Physiol 296:C1040–C1048. https://doi.org/10.1152/ajpcell.00475.2008 Deutz NEP, Ashurst I, Ballesteros MD, Bear DE, Cruz-Jentoft AJ, Genton L, Landi F, Laviano A, Norman K, Prado CM (2019) The Underappreciated Role of Low Muscle Mass in the Management of Malnutrition. J Am Med Dir Assoc 20:22–27. https://doi.org/10.1016/j.jamda.2018.11.021 Cereda E, Turri A, Klersy C, Cappello S, Ferrari A, Filippi AR, Brugnatelli S, Caraccia M, Chiellino S, Borioli V, Monaco T, Stella GM, Arcaini L, Benazzo M, Grugnetti G, Pedrazzoli P, Caccialanza R (2019) Whey protein isolate supplementation improves body composition, muscle strength, and treatment tolerance in malnourished advanced cancer patients undergoing chemotherapy. Cancer Med 8:6923–6932. https://doi.org/10.1002/cam4.2517 Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 08 May, 2026 Reviewers invited by journal 05 May, 2026 Editor assigned by journal 03 May, 2026 First submitted to journal 30 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9575167","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":634518355,"identity":"32b605de-fdb2-452f-9b35-16133067cb14","order_by":0,"name":"Kohei Yamakawa","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0003-7724-883X","institution":"Yokohama City University School of Medicine Graduate School of Medicine: Yokohama Shiritsu Daigaku Igakubu Daigakuin Igaku Kenkyuka","correspondingAuthor":true,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Yamakawa","suffix":""},{"id":634518356,"identity":"edff0f11-507c-4aca-8361-ac33bfdebedb","order_by":1,"name":"Yusuke Kurita","email":"","orcid":"","institution":"Yokohama City University School of Medicine Graduate School of Medicine: Yokohama Shiritsu Daigaku Igakubu Daigakuin Igaku Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Kurita","suffix":""},{"id":634518357,"identity":"e30e024e-ee74-4922-b933-00e6071de251","order_by":2,"name":"Masahiro Aichi","email":"","orcid":"","institution":"Yokohama City University School of Medicine Graduate School of Medicine: Yokohama Shiritsu Daigaku Igakubu Daigakuin Igaku Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Aichi","suffix":""},{"id":634518358,"identity":"c796c812-76fb-4593-8197-61a893df9db4","order_by":3,"name":"Hideyuki Ishikawa","email":"","orcid":"","institution":"Yokohama City University School of Medicine Graduate School of Medicine: Yokohama Shiritsu Daigaku Igakubu Daigakuin Igaku Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Hideyuki","middleName":"","lastName":"Ishikawa","suffix":""},{"id":634518359,"identity":"722c7e03-59e4-41ff-87db-754595e21813","order_by":4,"name":"Tomoya Watanabe","email":"","orcid":"","institution":"Yokohama City University School of Medicine Graduate School of Medicine: Yokohama Shiritsu Daigaku Igakubu Daigakuin Igaku Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Tomoya","middleName":"","lastName":"Watanabe","suffix":""},{"id":634518360,"identity":"b51c3e4c-9d6d-49dd-bf12-81726eb20346","order_by":5,"name":"Yuko Watanabe","email":"","orcid":"","institution":"Yokohama City University School of Medicine Graduate School of Medicine: Yokohama Shiritsu Daigaku Igakubu Daigakuin Igaku Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Watanabe","suffix":""},{"id":634518361,"identity":"3520a95a-0e29-464c-ad92-9ce6ca1927ce","order_by":6,"name":"Yukie Yamaguchi","email":"","orcid":"https://orcid.org/0000-0002-0297-6627","institution":"Yokohama City University School of Medicine Graduate School of Medicine: Yokohama Shiritsu Daigaku Igakubu Daigakuin Igaku Kenkyuka","correspondingAuthor":false,"prefix":"","firstName":"Yukie","middleName":"","lastName":"Yamaguchi","suffix":""}],"badges":[],"createdAt":"2026-04-30 09:42:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9575167/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9575167/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109214946,"identity":"397fe93e-c94c-492a-a705-8bc3ac088710","added_by":"auto","created_at":"2026-05-13 17:49:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1725257,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentativeCT images for diagnosing muscle mass at the L3 level. The psoas major muscle (green), paraspinal and gluteal muscles (yellow), and abdominal wall muscles (orange) represent skeletal muscle compartments. Visceral adipose tissue (red) and subcutaneous adipose tissue (dark blue) are also delineated. The cross-sectional skeletal muscle area at this level was used to calculate the skeletal muscle index (SMI). Based on the definitions of the Japan Society of Hepatology, low skeletal muscle mass (LSMM) was defined as an SMI of \u0026lt;42 cm²/m² in men and \u0026lt;38 cm²/m² in women.\u003c/p\u003e\n\u003cp\u003eCT, computed tomography; SMI, skeletal muscle index; Low skeletal muscle mass, LSMM.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9575167/v1/69e7418f010a8a9c66f726e0.png"},{"id":109405075,"identity":"00a2cc73-0963-4442-b21f-405f426c1a51","added_by":"auto","created_at":"2026-05-17 12:54:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1984318,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9575167/v1/3ea3c373-e7bc-4ac7-a80c-f567a8a909bb.pdf"}],"financialInterests":"","formattedTitle":"Low Muscle Mass Is an Independent Risk Factor for Adverse Events During BRAF/MEK Inhibitor Therapy in Patients with Advanced Melanoma: A Retrospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe introduction of BRAF/MEK inhibitors (BRAF/MEKi) has transformed the management of patients with advanced BRAF-mutant melanoma. Compared with conventional chemotherapy, these targeted therapies significantly improve progression-free survival (PFS) and overall survival (OS) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Combination regimens such as dabrafenib plus trametinib (Dab/Tram) and encorafenib plus binimetinib (Enco/Bini) are now standard treatments and produce rapid and durable tumor responses.\u003c/p\u003e \u003cp\u003eDespite these benefits, BRAF/MEKi therapy frequently causes treatment-emergent adverse events (AEs) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] that can reduce treatment adherence and patient quality of life. Common AEs include pyrexia (\u0026gt;\u0026thinsp;38.5\u0026deg;C), cutaneous reactions ranging from papulopustular rash to severe photosensitivity, and severe fatigue. These events often require dose reduction, temporary interruption, or permanent discontinuation of therapy, which may compromise treatment efficacy and patient quality of life. In addition, serious AEs, including cytopenias and gastrointestinal bleeding, have been reported during BRAF/MEKi therapy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLow skeletal muscle mass (LSMM), characterized by reduced skeletal muscle mass and function, is common among patients with cancer. LSMM has been associated with increased chemotherapy toxicity, altered pharmacokinetics, and poorer survival outcomes. Accumulating evidence indicates that muscle depletion affects both treatment tolerability and prognosis across multiple malignancies. However, the influence of LSMM on toxicity during targeted therapy, particularly BRAF/MEKi treatment, remains unclear and evidence is limited [\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10 CR11 CR12\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Clarifying this association may improve risk stratification, guide individualized dosing strategies, and support interventions aimed at improving treatment safety and outcomes.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study included 44 consecutive patients with histologically confirmed BRAF V600 mutant cutaneous melanoma who received BRAF/MEKi therapy (Dab/Tram or Enco/Bini) at Yokohama City University Hospital between January 2014 and March 2025.\u003c/p\u003e \u003cp\u003ePatients received treatment either as adjuvant therapy after complete resection of stage III disease or as first-line systemic therapy for unresectable or metastatic melanoma. In adjuvant cases, treatment began after curative intent surgical resection.\u003c/p\u003e \u003cp\u003eExclusion criteria included: (1) absence of baseline computed tomography (CT) within 30 days before treatment initiation and (2) participation in interventional clinical trials during the treatment period. Demographic, clinicopathological, and treatment information was extracted from electronic medical records using a standardized case report form.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Design and Data Collection\u003c/h3\u003e\n\u003cp\u003eThis retrospective single-center cohort study was conducted at Yokohama City University Hospital, Japan. Clinical data collected from electronic medical records included demographic variables (age, sex, height, and weight), disease characteristics (melanoma subtype and BRAF mutation genotype), and baseline clinical parameters. These parameters included Eastern Cooperative Oncology Group performance status (ECOG PS), pathological stage based on the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma, serum lactate dehydrogenase (LDH), and number of metastatic organ sites.\u003c/p\u003e \u003cp\u003eBaseline demographic and laboratory data were obtained on the day of BRAF/MEKi initiation, whereas staging information was collected within 1 month before treatment. Information regarding treatment course and AEs was recorded throughout therapy and during follow up until 6 months after treatment discontinuation or the end of treatment monitoring.\u003c/p\u003e\n\u003ch3\u003eSkeletal Muscle Assessment\u003c/h3\u003e\n\u003cp\u003e LSMM was defined according to criteria established by the Japan Society of Hepatology using baseline abdominal CT images obtained within 30 days before treatment initiation. Axial CT images at the third lumbar vertebra (L3) level were analyzed using SliceOmatic software (version 5.0, Tomovision). Skeletal muscle area (cm\u0026sup2;) was quantified using Hounsfield unit thresholds (\u0026minus;\u0026thinsp;29 to +\u0026thinsp;150) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe skeletal muscle index (SMI) was calculated by normalizing skeletal muscle area to height squared. Sex-specific diagnostic thresholds based on validated Asian criteria were applied: SMI\u0026thinsp;\u0026lt;\u0026thinsp;42 cm\u0026sup2;/m\u0026sup2; for male patients and \u0026lt;\u0026thinsp;38 cm\u0026sup2;/m\u0026sup2; for female patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eAdverse Event Assessment\u003c/h3\u003e\n\u003cp\u003eTreatment-emergent AEs were evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Significant AEs were defined as either (1) grade\u0026thinsp;\u0026ge;\u0026thinsp;3 toxicities, representing severe or medically significant events, or (2) any-grade AEs associated with clinically important outcomes, including treatment discontinuation, unplanned hospitalization, or the requirement for \u0026ge;\u0026thinsp;2 dose reductions. This definition captured both severe toxicities and lower-grade events with meaningful clinical consequences.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were compared using the independent t-test when normal distribution assumptions were satisfied and the Mann\u0026ndash;Whitney U test otherwise. Categorical variables were analyzed using Fisher\u0026rsquo;s exact test.\u003c/p\u003e \u003cp\u003eMultivariate logistic regression analysis was performed to identify independent predictors of AEs. Variables that were significant in univariate analysis, together with age and sex, which are established factors influencing muscle mass, were included in the multivariate model. Statistical analyses were conducted using SPSS Statistics version 29.0.1.0 (IBM, Armonk, NY, USA). A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated statistical significance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEthical Considerations\u003c/h2\u003e \u003cp\u003e This study complied with the Ethical Guidelines for Medical and Biological Research Involving Human Subjects and the principles of the Declaration of Helsinki. The protocol was reviewed and approved by the Yokohama City University Research Ethics Review Committee (F231200026).The requirement for informed consent was waived due to the retrospective nature of the research.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatient Characteristics\u003c/h2\u003e \u003cp\u003eAmong 44 patients, 23 were classified as having LSMM and 21 as non-LSMM (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Median age was comparable between groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A higher proportion of female patients was observed in the LSMM group, although the difference was not statistically significant. Melanoma subtype, number of metastatic organ sites, LDH level, BRAF mutation status, and first-line therapy were also similar between groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of patients with melanoma treated with BRAF/MEK inhibitors.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;44\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge (years) median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.5 (24\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18 (40.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26 (59.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubtype, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-acral cutaneous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35 (79.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMucosal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27 (61.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (27.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (11.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage (AJCC 8th edition), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eⅢ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26 (59.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIV (M1a)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (6.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIV (M1b)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIV (M1c)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (15.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIV (M1d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMetastatic organ sites, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26 (59.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18 (40.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNormal (\u0026lt;\u0026thinsp;225 U/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30 (68.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eElevated (\u0026ge;\u0026thinsp;225 U/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14 (31.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF V600, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37 (84.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eK or unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (15.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFirst-line, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (27.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBRAF/MEK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32 (72.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF/MEKi, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDab/Tram\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38 (86.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEnco/Bini\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (13.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLSMM, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePresent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23 (52.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21 (47.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment type, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-adjuvant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28 (63.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjuvant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16 (36.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: AJCC, American Joint Committee on Cancer; BRAF/MEKi, BRAF plus MEK inhibitors; Dab/Tram, dabrafenib plus trametinib; ECOG PS, Eastern Cooperative Oncology Group performance status; Enco/Bini, encorafenib plus binimetinib; ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase; LSMM, low skeletal muscle mass.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of baseline characteristics between patients with low muscle mass and normal muscle mass.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLSMM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-LSMM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge (years) median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70 (47\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69 (24\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (56.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5 (23.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (43.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16 (76.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubtype, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcral/mucosal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNAC/UP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (82.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19 (90.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (52.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15 (71.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (47.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6 (28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage (AJCC 8th edition),\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIV (M1c/M1d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eⅢ/IV (M1a/M1b)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (82.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic organ sites, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (56.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13 (61.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (43.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8 (38.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNormal (\u0026lt;\u0026thinsp;225 U/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (60.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16 (76.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eElevated (\u0026ge;\u0026thinsp;225 U/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (39.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5 (23.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF V600, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (87.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18 (85.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eK or unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3 (14.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-line, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (34.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4 (19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBRAF/MEK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (65.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17 (81.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBRAF/MEKi, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDab/Tram\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e17 (73.9)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e21 (100.0)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEnco/Bini\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e6 (26.1)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0 (0.0)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment type, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-adjuvant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (69.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjuvant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (30.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: AJCC, American Joint Committee on Cancer; BRAF/MEKi, BRAF plus MEK inhibitors; Dab/Tram, dabrafenib plus trametinib; ECOG PS, Eastern Cooperative Oncology Group performance status; Enco/Bini, encorafenib plus binimetinib; ICI, immune checkpoint inhibitor; LDH, lactate dehydrogenase; LSMM, low skeletal muscle mass NAC, non-acral cutaneous; UP, unknown primary.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eComparison of baseline clinical characteristics demonstrated no significant differences in age, sex, ECOG PS, disease stage, LDH level, or BRAF mutation status between the LSMM and non-LSMM groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). However, the proportion of patients receiving Enco/Bini was higher in the LSMM group (26.1% vs. 0.0%, p\u0026thinsp;=\u0026thinsp;0.012).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAdverse Events and Muscle Mass\u003c/h2\u003e \u003cp\u003eSignificant AEs occurred in 17 of 23 patients with LSMM (77.3%) compared with 5 of 21 patients without LSMM (23.8%), representing a significant difference (p\u0026thinsp;=\u0026thinsp;0.002) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Arthralgia was the most frequently observed AE among patients with LSMM; however, no specific AE type differed significantly between groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of adverse events between patients with and without sarcopenia.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLSMM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-LSMM\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArthralgia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePyrexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDizziness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImpaired consciousness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal bleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmylase elevation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17 (77.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (23.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: LSMM, low skeletal muscle mass.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eUnivariate and Multivariate Analyses\u003c/h2\u003e \u003cp\u003eUnivariate analysis demonstrated that LSMM was significantly associated with AEs (odds ratio [OR] 9.07; 95% confidence interval [CI]: 2.31\u0026ndash;35.65; p\u0026thinsp;=\u0026thinsp;0.002) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate logistic regression analysis of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 or grade adverse events leading to treatment discontinuation.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eunivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c9\" namest=\"c7\"\u003e \u003cp\u003emultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ge;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.52\u0026ndash;6.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.24\u0026ndash;5.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(1.11\u0026ndash;15.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.50\u0026ndash;9.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSubtype\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAcral/mucosal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.12\u0026ndash;5.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNAC/UP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eECOG PS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.76\u0026ndash;9.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAdjuvant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdjuvant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.43\u0026ndash;5.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon adjuvant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eStage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIV (M1c/M1d)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.15\u0026ndash;1.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e(AJCC 8th edition)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eⅢ/IV (M1a/M1b)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eBRAF V600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.51\u0026ndash;17.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eK or unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003eFirst-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBRAF/MEKi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.16\u0026ndash;1.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eICI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eBRAF/MEKi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDab/Tram\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(0.66\u0026ndash;58.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(0.16\u0026ndash;28.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEnco/Bini\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eLSMM\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003epresent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e9.07\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e(2.31\u0026ndash;35.65)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e6.01\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e(1.31\u0026ndash;27.65)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e0.021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eAbsent\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eAbbreviations: AJCC, American Joint Committee on Cancer; BRAF/MEKi, BRAF plus MEK inhibitors; CI, confidence interval; Dab/Tram, dabrafenib plus trametinib; ECOG PS, Eastern Cooperative Oncology Group performance status; Enco/Bini, encorafenib plus binimetinib; ICI, immune checkpoint inhibitor; LSMM, low skeletal muscle mass; NAC, non-acral cutaneous; OR, odds ratio; UP, unknown primary.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe multivariate model included age and sex as predefined variables, together with BRAF/MEKi regimen, which differed significantly between groups. In multivariate analysis, LSMM remained an independent predictor of AEs (adjusted OR 6.01; 95% CI: 1.31\u0026ndash;27.65; p\u0026thinsp;=\u0026thinsp;0.021). Other clinical factors, including age, sex, melanoma subtype, ECOG performance status, adjuvant therapy, disease stage, BRAF mutation status, and first-line treatment, were not significantly associated with AEs in either univariate or multivariate analyses.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this study is the first to demonstrate a significant association between LSMM and increased risk of AEs during BRAF/MEKi therapy in patients with BRAF-mutant melanoma. These findings indicate that skeletal muscle mass at treatment initiation may be an important factor when evaluating AE risk during BRAF/MEKi therapy.\u003c/p\u003e \u003cp\u003eIn this cohort, Enco/Bini was more frequently administered to patients with LSMM. This distribution likely reflects clinical selection bias rather than biological differences. Clinicians may preferentially select Enco/Bini to reduce the risk of pyrexia or creatine kinase elevation, which are well-recognized toxicities of Dab/Tram and may be particularly burdensome in frail patients. However, previous studies have reported no significant differences in PFS, OS, or incidence of severe AEs between these regimens [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Notably, multivariate analysis identified LSMM, rather than treatment regimen, as the independent predictor of AEs. These results suggest that the increased toxicity observed in patients with LSMM cannot be explained solely by treatment selection. Future studies using uniform BRAF/MEKi regimens are necessary to clarify the independent effect of muscle mass on treatment-related toxicity.\u003c/p\u003e \u003cp\u003ePrevious studies have demonstrated an association between LSMM and increased toxicity during molecular targeted therapy, particularly with multikinase inhibitors such as sorafenib. In renal cell carcinoma, LSMM increased toxicity risk 4.1-fold, with dose-limiting toxicities occurring in 37% of patients with LSMM compared with 5% in patients without LSMM [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Similarly, in hepatocellular carcinoma, early dose-limiting toxicities occurred in 81.8% of patients with LSMM versus 31.0% in those without LSMM (p\u0026thinsp;=\u0026thinsp;0.005). In addition, grade 3 diarrhea occurred in 45.5% of patients with LSMM compared with 6.9% of patients without LSMM (p\u0026thinsp;=\u0026thinsp;0.01) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, evidence regarding the relationship between LSMM and AEs in patients with melanoma receiving BRAF/MEKi remains limited. Therefore, the present findings provide new evidence relevant to the clinical management of this population.\u003c/p\u003e \u003cp\u003eRecent research involving patients with metastatic melanoma harboring BRAF mutations reported that BRAF/MEKi therapy significantly reduced skeletal muscle area and fat-free mass after 4\u0026ndash;6 months of therapy [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Dose-limiting toxicities occurred in 35.9% of patients with baseline LSMM. Given the substantial muscle loss reported during BRAF/MEKi therapy, assessment of muscle mass should be considered not only at baseline but also during treatment. Additional studies are needed to determine whether treatment-related muscle loss further increases the risk of adverse events.\u003c/p\u003e \u003cp\u003eSeveral mechanisms may explain the association between LSMM and increased toxicity. Patients with LSMM frequently exhibit hypoalbuminemia and reduced antioxidant capacity, which may impair drug metabolism and increase susceptibility to treatment-related complications [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Altered body composition may also influence pharmacokinetics of BRAF/MEKi, potentially resulting in higher effective drug concentrations and greater toxicity. In addition, systemic inflammation is common in patients with LSMM and is characterized by elevated cytokines such as interleukin-6 and tumor necrosis factor-alpha[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Chronic inflammation promotes muscle catabolism and may impair tissue repair, further increasing vulnerability to treatment-related toxicity. Additionally, BRAF/MEKi inhibit the MAPK/ERK signaling pathway, which plays an important role in skeletal muscle regeneration and maintenance [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Inhibition of this pathway may impair muscle repair processes, thereby exacerbating pre-existing LSMM and increasing susceptibility to AEs.\u003c/p\u003e \u003cp\u003eConsidering these findings, assessment of skeletal muscle mass may be a valuable component of routine evaluation before initiation of BRAF/MEKi therapy. Although further research is necessary to establish clinical guidelines, early identification of LSMM may allow clinicians to implement supportive care strategies. Preventive interventions, including individualized nutritional support and resistance exercise programs, may help reduce treatment-related toxicity and improve outcomes, although their effectiveness in this setting requires further investigation [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Prospective studies are required to validate these approaches and clarify the biological mechanisms linking LSMM to drug toxicity during BRAF/MEKi therapy.\u003c/p\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003cp\u003eThis study has several limitations, including its retrospective single-center design and relatively small sample size. Larger prospective studies are required to confirm these findings and to evaluate potential intervention strategies.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eLSMM is an independent risk factor for AEs in patients with melanoma receiving BRAF/MEKi therapy.Routine assessment of skeletal muscle mass may improve risk stratification and support more individualized treatment approaches in clinical practice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAE, Adverse event; AJCC, American Joint Committee on Cancer; BRAF, BRAF, B-Raf proto-oncogene, serine/threonine kinase (formerly known as v-Raf murine sarcoma viral oncogene homolog B1); BRAF/MEKi, BRAF plus MEK inhibitors; CI, Confidence interval; CT, Computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; Dab/Tram, dabrafenib plus trametinib; ECOG PS, Eastern Cooperative Oncology Group performance status; Enco/Bini, encorafenib plus binimetinib; HR, Hazard ratio; LDH, Lactate dehydrogenase; LSMM, Low skeletal muscle mass; MEK, Mitogen-activated extracellular signal\u0026ndash;regulated kinase; OR, Odds ratio; OS, Overall survival; PFS, Progression-free survival; SMI, Skeletal muscle index.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNo funding was received.\u003c/p\u003e \u003cp\u003eAvailability of data and materials\u003c/p\u003e \u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e \u003cp\u003eEthics approval and consent to participate\u003c/p\u003e \u003cp\u003e The present study was approved by the Institutional Review Board of Yokohama City University (Yokohama, Japan; approval no. F231200026). The requirement for written informed consent was waived due to the retrospective nature of the study, and an opt-out method was used instead.\u003c/p\u003e \u003cp\u003e Patient consent for publication\u003c/p\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003cp\u003eConflict of Interest\u003c/p\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003ch2\u003eAuthors' contributions\u003c/h2\u003e \u003cp\u003eKY and YY conceptualized and designed the study. KY, YK, MA, HI, TW and YW acquired the clinical data. KY and YK analyzed and interpreted the patient data. KY wrote the first draft of the manuscript. KY, YK, MA, HI, TW, YW, and YY revised the manuscript critically for important intellectual content. KY and HI confirm the authenticity of all the raw data. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe authors would like to thank Editage for English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRobert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D (2015) Improved overall survival in melanoma with combined dabrafenib and trametinib. 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Cancer Med 8:6923\u0026ndash;6932. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/cam4.2517\u003c/span\u003e\u003cspan address=\"10.1002/cam4.2517\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Muscle mass, BRAF/MEK inhibitors, melanoma, adverse events","lastPublishedDoi":"10.21203/rs.3.rs-9575167/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9575167/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBRAF/MEK inhibitors (BRAF/MEKi) are established therapies for patients with BRAF-mutant melanoma. However, treatment frequently causes adverse events (AEs) that may interrupt therapy and reduce patient quality of life. Low skeletal muscle mass (LSMM) is associated with poor prognosis and altered drug pharmacokinetics in patients with cancer. However, its relationship with toxicity during BRAF/MEKi therapy remains uncertain. This study evaluated the association between skeletal muscle mass and the occurrence of AEs in patients with BRAF-mutant melanoma receiving BRAF/MEKi therapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed 44 patients with BRAF-mutant melanoma, including those with adjuvant and advanced or unresectable disease, treated with BRAF/MEKi at our institution between 2014 and 2025. LSMM was determined using computed tomography\u0026ndash;derived skeletal muscle index (SMI) at the L3 level within one month before treatment initiation (cutoffs: \u0026lt;42 cm\u0026sup2;/m\u0026sup2; for male and \u0026lt;\u0026thinsp;38 cm\u0026sup2;/m\u0026sup2; for female patients). AEs were graded according to the Common Terminology Criteria for Adverse Events v5.0. Clinically significant AEs were defined as grade\u0026thinsp;\u0026ge;\u0026thinsp;3 events or any-grade events resulting in treatment discontinuation, unplanned hospitalization, or \u0026ge;\u0026thinsp;2 dose reductions.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eLSMM was identified in 23 of 44 patients (52.3%). AEs occurred significantly more often in patients with LSMM than in those without (77.3% vs. 23.8%, p\u0026thinsp;=\u0026thinsp;0.002). Multivariate analysis demonstrated that LSMM independently predicted AEs (adjusted odds ratio 6.01; 95% confidence interval 1.31\u0026ndash;27.65; p\u0026thinsp;=\u0026thinsp;0.021).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eLSMM is significantly associated with increased risk of AEs during BRAF/MEKi therapy in patients with melanoma, independent of other clinical factors\u003c/p\u003e","manuscriptTitle":"Low Muscle Mass Is an Independent Risk Factor for Adverse Events During BRAF/MEK Inhibitor Therapy in Patients with Advanced Melanoma: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-13 17:49:49","doi":"10.21203/rs.3.rs-9575167/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-05-08T14:27:14+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-05T05:19:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-03T09:51:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2026-04-30T05:08:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"704f9dcc-2bae-4bab-b044-b4fb964906be","owner":[],"postedDate":"May 13th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"","date":"2026-05-08T14:27:14+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-05T05:19:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-03T09:51:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2026-04-30T05:08:43+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T17:49:49+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-13 17:49:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9575167","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9575167","identity":"rs-9575167","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}