Melanoma, though relatively rare, is the most aggressive form of skin cancer due to its high metastatic potential and mortality rate. Immunotherapy, such as pembrolizumab, has improved outcomes for patients. However, access to these therapies remains limited in low- and middle-income countries, including Brazil, where real-world evidence is scarce and population genetics may influence treatment response and adverse drug reactions (ADRs).
Objective
This study aimed to analyze the effectiveness and safety of first-line treatment for advanced melanoma with pembrolizumab, with a focus on the kinetics of ADRs.
Methods
This retrospective study included patients from the Brazilian Public Health System, with a follow-up period of 1 year (CAAE: 95157018.9.0000.5274).
Results
The study analyzed 40 patients (57.5% male, median age 65.5 years). The most frequent primary site of melanoma was the lower limbs (47.5%), and the main histological types were acral (30%) and nodular melanoma (30%). ADRs were identified in 87.5% of the patients, with pruritus (40%) and vitiligo (37.5%) being the most common. Cutaneous reactions were observed in the early cycles and persisted until the end of treatment. The cohort exhibited a different ADR profile and fewer severe events (10.5%) compared to clinical trials. The median progression-free survival was 7.7 months, and the overall survival rate was 60%.
Conclusion
Pembrolizumab was effective and safe as a first-line treatment for advanced melanoma patients in a real-world Brazilian public health setting. Additionally, we characterized the kinetics of ADRs, offering practical insights for healthcare teams in managing these events throughout the treatment course.
SaginalaKBarsoukAAluruJS, et al.Epidemiology of melanoma. Med Sci (Basel)2021; 9: 63.
2.
CarrSSmithCWernbergJ. Epidemiology and risk factors of melanoma. Surg Clin North Am2020; 100: 1–12.
3.
ArnoldMSinghDLaversanneM, et al.Global burden of cutaneous melanoma in 2020 and projections to 2040. JAMA Dermatol2022; 158: 495–503.
4.
SantosMOLimaFCSMartinsLFL, et al.Estimativa de incidência de câncer no brasil, 2023–2025. Rev Bras Cancerol2023; 69: e-213700.
5.
SchadendorfDUgurelSSchuler-ThurnerB, et al.Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol2006; 17: 563–570.
6.
CorreaFMGuerraRLFernandesRRA, et al.Terapia-alvo versus dacarbazina no tratamento de primeira linha do melanoma avançado não cirúrgico e metastático: análise de impacto orçamentário na perspectiva do Sistema Único de Saúde, 2018–2020. Epidemiol Serv Saude2019; 28: 1–12.
7.
BitegheFANPadayacheeEDavidsLM, et al.Desensitization of metastatic melanoma cells to therapeutic treatment through repeated exposure to dacarbazine. J Photochem Photobiol B2020; 211: 111982.
8.
CarlinoMSLarkinJLongGV. Immune checkpoint inhibitors in melanoma. Lancet2021; 398: 1002–1014.
9.
LazaroffJBolotinD. Targeted therapy and immunotherapy in melanoma. Dermatol Clin2023; 41: 65–77.
10.
RobertCLongGVBradyB, et al.Nivolumab in previously untreated melanoma without BRAF mutation. New Engl J Med2015; 372: 320–330.
11.
AsciertoPALongGVRobertC, et al.Survival outcomes in patients with previously untreated BRAF wild-type advanced melanoma treated with nivolumab therapy: three-year follow-up of a randomized phase 3 trial. JAMA Oncol2019; 5: 187–194.
12.
RobertCRibasASchachterJ, et al.Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol2019; 20: 1239–1251.
13.
HamidORobertCDaudA, et al.Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol2019; 30: 582–588.
14.
RibasAPuzanovIDummerR, et al.Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol2015; 16: 908–918.
15.
DoniaMKimper-KarlMLHøyerKL, et al.The majority of patients with metastatic melanoma are not represented in pivotal phase III immunotherapy trials. Eur J Cancer2017; 74: 89–95.
16.
QianMFBetancourtNJPinedaA, et al.Health care utilization and costs in systemic therapies for metastatic melanoma from 2016 to 2020. Oncologist2023; 28: 268–275.
CapuchoHCBritoAMaiolinoA, et al.Incorporation of medicines in the unified health system (SUS): comparison between oncology and the specialized component of pharmaceutical care. Ciência e Saúde Coletiva2022; 27: 2471–2479.
20.
EisenhauerEATherassePBogaertsJ, et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer2009; 45: 228–247.
21.
Common Terminology Criteria for Adverse Events. U.S. Department of Health and Human Services. version 5.0, 2017.
22.
OkenMMCreechRHTormeyDC, et al.Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol1982; 5: 649–656.
HamidORobertCDaudA, et al.Long-term outcomes in patients with advanced melanoma who had initial stable disease with pembrolizumab in KEYNOTE-001 and KEYNOTE-006. Eur J Cancer2021; 157: 391–402.
25.
RozemanEAVersluisJMMoritzR, et al.Diagnostic performance of early increase in S100B or LDH as outcome predictor for non-responsiveness to anti-PD-1 monotherapy in advanced melanoma. Clin Chim Acta2022; 533: 71–78.
26.
CarvalhoLADAguiarFCSmalleyKSM, et al.Acral melanoma: new insights into the immune and genomic landscape. Neoplasia2023; 46: 100947.
27.
CoitDGThompsonJAAlbertiniMR, et al.Cutaneous melanoma, version 2.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw2019; 17: 367–402.
28.
Sociedade Brasileira de Oncologia Clínica (SBOC). Guia Sociedade Brasileira de Oncologia Clínica (SBOC)- Melanoma cutâneo. 2023.
29.
CarlinoMSLarkinJLongGV. Immune checkpoint inhibitors in melanoma. Lancet2021; 398: 1002–1014.
30.
SimonsenABKaaeJEllebaekE, et al.Cutaneous adverse reactions to anti-PD-1 treatment: a systematic review. J Am Acad Dermatol2020; 83: 1415–1424.
31.
MartinsFSofiyaLSykiotisGP, et al.Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol2019; 16: 563–580.
32.
RobertCHwuWJHamidO, et al.Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: a landmark analysis in patients with advanced melanoma. Eur J Cancer2021; 144: 182–191.
33.
KuzmanovszkiDKissNTóthB, et al.Anti-PD-1 monotherapy in advanced melanoma-real-world data from a 77-month-long retrospective observational study. Biomedicines2022; 10: 1737.
34.
CacabelosRNaidooVCorzoL, et al.Genophenotypic factors and pharmacogenomics in adverse drug reactions. Int J Mol Sci2021; 22: 13302.
35.
Suarez-KurtzG. Farmacogenômica e a diversidade genética da população brasileira. Cadernos de Saúde Pública2009; 25: 1650–1651.
36.
Lev-AriSSerzanMWuT, et al.The impact of immunosuppressive agents on immune checkpoint inhibitor efficacy in patients with advanced melanoma: a real-world, multicenter, retrospective study. Cancer2023; 129: 1885–1894.
37.
CasarottoEChandwaniSMortierL, et al.Real-world effectiveness of pembrolizumab in advanced melanoma: analysis of a French national clinical biological database. Immunotherapy2021; 13: 905–916.
38.
Ab RahmanASStrotherRMPaddisonJ. New Zealand National retrospective cohort study of survival outcomes of patients with metastatic melanoma receiving immune-checkpoint inhibitors. Asia Pac. J. Clin. Oncol2023; 19: 179–186.
39.
MoserJCWeiGColonnaSV, et al.Comparative-effectiveness of pembrolizumab vs. Nivolumab for patients with metastatic melanoma. Acta Oncol2020; 59: 434–437.
40.
MaioMGrobJJAamdalS, et al.Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol2015; 33: 1191–1196.
41.
FernandesRRAZimmermanIRAndradeKRC. Acesso a oncológicos no Brasil: um estudo de monitoramento pós recomendação de incorporação pela CONITEC no caso do Melanoma Metastático. J Assist Farmacêutica Farmacoeconomia2023; 1: 90.
