การใช้ Dabrafenib และ Trametinib ในการรักษาโรคมะเร็งผิวหนังในเด็กและวัยรุ่น: ข้อมูลเชิงประจักษ์จากศูนย์เดียวในโครงการใช้ยาเพื่อมนุษยธรรมในประเทศอิตาลี – Wiley Online Library

เนื้อหาบทความฉบับเต็ม

Cutaneous melanoma is rare among children and adolescents, accounting for ∼6% of all tumors, whereas it represents ∼10% of adolescents and young adults (AYAs) tumors. According to the EUROCARE-6 report, the incidence rate is 0.43/100,000 among patients aged 0–19 years, rising to 6.9/100,000 among AYAs. The prognosis of melanoma in adults has seen unprecedented progress with immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors for patients with BRAF-mutant melanoma. In addition, targeted therapy and ICIs have shown improvement in relapse-free survival (RFS) and distant metastasis-free survival (DMFS) in the adjuvant setting. Since specific clinical data in this age group are missing due to the rarity of the disease and difficulty in enrolling in dedicated clinical trials, the management has been largely extrapolated from adult treatment protocols. Here, we report the efficacy and safety of targeted therapy among children and adolescents treated with dabrafenib and trametinib as compassionate use (CU) at our institution. This study received the approval of our Institutional Review Board. We retrospectively retrieved data from patients affected by melanoma treated with dabrafenib and trametinib at our institution within the CU. All patients provided written informed consent for this program. The CU included pediatric patients with BRAFV600E/K mutant, Stage III or IV melanoma, who had exhausted standard therapies, were unlikely to benefit from standard therapies, and for whom all clinical trials they might qualify for had been ruled out. All patients started treatment at the recommended dose according to age and weight. The duration of treatment was 12 months in the adjuvant setting;

or until disease progression (PD), a report of unacceptable toxic effects or patients' decision in the metastatic setting. Radiological disease assessment was made with whole body contrast-enhanced computed tomography (CT) scan and/or positron emission tomography (PET)/CT scan, performed at baseline and every four courses (i. e. , every 4 months). The radiological response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST;

version 1.1). Demographic and baseline patients' characteristics were collected. BRAF mutation status was determined with PCR amplification and direct sequencing (3500DX Genetic Analyzer; Thermo Fisher Scientific). Disease staging was classified according to the American Joint Committee on Cancer (AJCC) staging system, eighth edition. Data regarding adverse events (AEs) were collected according to the Common Terminology Criteria for Adverse Events (CTCAE;

version 4.0). RFS was defined as the time from treatment start until the date of the first recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause. Overall survival (OS) was defined as the time from treatment start until the date of death from any cause. Data are summarized using basic descriptive statistics. Six patients were included in the dabrafenib–trametinib CU (three female and three male patients). The median age at diagnosis was 15 years (range: 9.5–17.6). At the time of diagnosis, one patient had Stage IIB, five had Stage III disease (two patients had IIIA, two patients had IIIB, and one patient had IIID). The disease stage at the beginning of treatment started was III in four patients and IV in two patients. All patients had BRAFV600E mutation. None of the patients had received prior systemic therapy for melanoma. Table 1 shows patients' baseline characteristics. Three patients received dabrafenib 300 mg/day plus trametinib 2 mg/day, two dabrafenib 250 mg/day plus trametinib 1.5 mg/day, and one dabrafenib 300 mg/day plus trametinib 1.5 mg/day. After a median follow-up of 22 months (range: 5.4–42.4) from the beginning of treatment, all four patients treated with adjuvant therapy are alive with no evidence of disease. One patient with metastatic disease is still under treatment with a prolonged complete response (treatment duration: 19.3 months);

one patient died of disease progression 5.4 months after starting therapy. Regarding safety, five patients reported treatment-related AEs (Table 2). The most frequently reported AEs were mild (i. e. , G1–G2) and included fever and increased creatine-phosphokinase (CPK). Two patients experienced an asymptomatic decrease of more than 10% in left ventricular ejection fraction (LVEF), which was resolved after temporary trametinib interruption;

both patients resumed trametinib at a reduced dose without further cardiac toxicity. One patient permanently discontinued trametinib due to intestinal bleeding, which was not considered treatment-related. This brief report on targeted therapy for the treatment of BRAF-mutant pediatric melanoma patients aims to highlight the efficacy and safety of targeted therapy in this population in both the adjuvant and metastatic settings. BRAF mutations are found in ∼50% of cutaneous melanomas and are known pathogenic drivers of disease progression and metastasis. Although the efficacy of targeted therapy is well-established for adult melanoma treatment, data regarding its use in children and adolescents are limited. The main reasons for this are the rarity of the disease and the difficulty of enrolling these patients in dedicated clinical trials. The BRIM-P Phase I clinical trial aimed to identify the optimal dose of vemurafenib for BRAF-mutant melanoma patients aged 12–17, but was terminated prematurely due to low enrollment, preventing the determination of a maximum tolerated dose (MTD). By contrast, solid data on the pharmacokinetics and safety of targeted therapy are available in the setting of BRAF-mutant pediatric glioma, leading to the approval of dabrafenib and trametinib for the treatment of both low-grade and high-grade glioma. Recently, data from a large retrospective series of pediatric and adolescent melanoma patients treated with anti-PD1 therapy were published as part of the MELCAYA study. The findings suggest that the efficacy of these drugs in the adjuvant setting is similar to that observed in adults, while outcomes in the metastatic setting appear to be inferior, possibly due to a distinct melanoma biology in this age group. In contrast, the safety profile is comparable to that in adults. Based on these data, the authors recommend the use of anti-PD1 therapies in patients under 18 years of age, including those younger than 12 years. Although limited by the sample size, our series suggests that treatment with dabrafenib and trametinib is effective in this patient subgroup, with a safety profile comparable to that in adults and in the previous published pediatric studies. In our series, two patients experienced an asymptomatic, reversible decrease in LVEF, underscoring the need for regular cardiac monitoring to allow prompt treatment interruption and restarting at a reduced dose. In conclusion, our report indicates that targeted therapy in pediatric BRAF-mutant melanoma is safe and provides survival rates comparable to those observed among adults. This evidence, coupled with the recent approval of combination therapy for pediatric gliomas, may pave the way for extending its indication to pediatric patients with BRAF-mutated melanoma. In addition, enrolling pediatric and adolescent melanoma patients in adult clinical trials and EAP should be encouraged to facilitate the testing of new drugs and expand treatment opportunities in this patient subgroup. Dabrafenib and trametinib were provided by Novartis as compassionate use according to Italian law D. M. 2 November 2017. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data on BRAF/MEK inhibitors in pediatric and adolescent melanoma patients are limited. We report data of patients treated with dabrafenib/trametinib for compassionate use at our institution. From January 2020, four patients with Stage III and two patients with Stage IV disease were treated. Our report demonstrates that targeted therapy in children and adolescents is safe and achieves survival rates comparable to those observed in adults. These findings support granting young patients with adult-onset tumors access to compassionate use, as well as increasing their inclusion in clinical trials. Such measures would ensure equitable access to treatments available for adult patients and contribute to improved treatment outcomes. Abbreviation: AJCC, American Joint Committee on Cancer. Abbreviations: AEs, adverse events;

ALP, alkaline phosphatase; CPK, creatine-phosphokinase; CR, complete response; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction;

NED, no evidence of disease; NR, not reported; OS, overall survival; PD, progressive disease; RFS, relapse-free survival;

ULN, upper limit of normal. a Patient experienced G3 intestinal bleeding not related to treatment. 1A. Indini, F. Didonè, D. Massi, et al. , “Incidence and Prognosis of Cutaneous Melanoma in European Adolescents and Young Adults (AYAs): EUROCARE-6 Retrospective Cohort Results, ” European Journal of Cancer 213 (2024): 115079.10.1016/j. ejca. 2024.115079PubMed Web of Science® Google Scholar 2J. D. Wolchok, V. Chiarion-Sileni, P. Rutkowski, et al. , “Final, 10-Year Outcomes With Nivolumab Plus Ipilimumab in Advanced Melanoma, ” New England Journal of Medicine 392 (2025): 11–22, https: //doi. org/10.1056/NEJMoa2407417.10.1056/NEJMoa2407417CAS PubMed Web of Science® Google Scholar 3G. V. Long, M. S. Carlino, C. McNeil, et al. , “Pembrolizumab Versus Ipilimumab for Advanced Melanoma: 10-Year Follow-Up of the Phase III KEYNOTE-006 Study, ” Annals of Oncology 35, no. 12 (2024): 1191–1199, https: //doi. org/10.1016/j. annonc. 2024.08.2330.10.1016/j. annonc. 2024.08.2330CAS PubMed Google Scholar 4C. Robert, J. J. Grob, D. Stroyakovskiy, et al. , “Five-Year Outcomes With Dabrafenib Plus Trametinib in Metastatic Melanoma, ” New England Journal of Medicine 381 (2019): 626–636, https: //doi. org/10.1056/NEJMoa1904059.10.1056/NEJMoa1904059CAS PubMed Web of Science® Google Scholar 5D. Schadendorf, R. Dummer, K. T. Flaherty, et al. , “COLUMBUS 7-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600E/K-Mutant Melanoma, ” European Journal of Cancer 204 (2024): 114073, https: //doi. org/10.1016/j. ejca. 2024.114073.10.1016/j. ejca. 2024.114073CAS PubMed Web of Science® Google Scholar 6G. V. Long, A. Hauschild, M. Santinami, et al. , “Final Results for Adjuvant Dabrafenib Plus Trametinib in Stage III Melanoma, ” New England Journal of Medicine 391, no. 18 (2024): 1709–1720, https: //doi. org/10.1056/NEJMoa2404139.10.1056/NEJMoa2404139CAS PubMed Web of Science® Google Scholar 7A. M. Eggermont, M. Kicinski, C. U. Blank, et al. , “Seven-Year Analysis of Adjuvant Pembrolizumab Versus Placebo in Stage III Melanoma in the EORTC1325 /KEYNOTE-054 Trial, ” European Journal of Cancer 211 (2024): 114327, https: //doi. org/10.1016/j. ejca. 2024.114327.10.1016/j. ejca. 2024.114327CAS PubMed Web of Science® Google Scholar 8J. Larkin, M. Del Vecchio, M. Mandalá, et al. , “Adjuvant Nivolumab Versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results From CheckMate 238, ” Clinical Cancer Research 29 (2023): 3352–3361, https: //doi. org/10.1158/1078-0432. CCR-22-3145.10.1158/1078-0432. CCR-22-3145CAS PubMed Web of Science® Google Scholar 9J. C. Chisholm, J. Suvada, I. J. Dunkel, et al. , “BRIM-P: A Phase I, Open-Label, Multicenter, Dose-Escalation Study of Vemurafenib in Pediatric Patients With Surgically Incurable, BRAF Mutation-Positive Melanoma, ” Pediatric Blood & Cancer 65 (2018): e26947, https: //doi. org/10.1002/pbc. 26947.10.1002/pbc. 26947PubMed Web of Science® Google Scholar 10H. Davies, G. R. Bignell, C. Cox, et al. , “Mutations of the BRAF Gene in Human Cancer, ” Nature 417 (2002): 949–954, https: //doi. org/10.1038/nature00766.10.1038/nature00766CAS PubMed Web of Science® Google Scholar 11M. W. Kieran, B. Geoerger, I. J. Dunkel, et al. , “A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients With Recurrent or Refractory BRAF V600 Mutation-Positive Solid Tumors, ” Clinical Cancer Research 25 (2019): 7294–7302.10.1158/1078-0432. CCR-17-3572CAS PubMed Web of Science® Google Scholar 12E. Bouffet, B. Geoerger, C. Moertel, et al. , “Efficacy and Safety of Trametinib Monotherapy or in Combination with Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma, ” Journal of Clinical Oncology 41 (2023): 664–674.10.1200/JCO. 22.01000CAS PubMed Web of Science® Google Scholar