The addition of PD-1/PD-L1 axis blockade to BRAF and MEK inhibition for advanced melanoma patients harboring BRAF mutations: a systematic review and meta-analysis

ABSTRACT

Objectives: Immune-checkpoint inhibitors (ICI) and targeted-therapies (TT) have become standard options for BRAF-V600 metastatic melanomas (MM). Recently, randomized trials (RCT) addressed the efficacy of combined approaches, with conflicting results. We sought to evaluate efficacy and safety of first-line combination ICI and BRAF/MEK inhibitors (triplets) versus BRAF/MEKi (doublets).

Methods: We performed a systematic review and metaanalysis of RCT comparing triplet versus doublet published in MEDLINE and EMBASE from 2016-September/2020. We obtained pooled effect estimates through random-effects model assuming p<0.05 as statistically significant.

Results: Among 1,784 studies, 3 RCT were selected. Triplets demonstrated progression-free survival (PFS) (HR 0.79 - CI 0.68-0.91, p=0.001) and overall survival (OS) improvement (HR 0.81 - CI 0.67-0.98, p=0.03), with increased rates of grades 3/4 adverse events (AEs), any grade pyrexia, arthralgia, and aminotransferases elevation. AEdiscontinuation rates of all drugs remained similar.

Conclusions: Triplets improved PFS and OS with manageable toxicities. These are preliminary results and mature data are expected.

RESUMO

Objetivos: Inibidores de checkpoints imunológicos (ICI) e terapias-alvo (TT) tornaram-se opções padrão para melanomas metastáticos (MM) BRAF-V600 mutados. Recentemente, ensaios clínicos randomizados (ECR) abordaram a eficácia das abordagens combinadas, com resultados conflitantes. Procuramos avaliar a eficácia/segurança da combinação de ICI e inibidores BRAF/ MEK de primeira linha (terapia triple) versus BRAF/MEKi (terapia dupla).

Métodos: Realizamos uma revisão sistemática e metanálise de ECR comparando terapia tripla versus dupla publicados no MEDLINE e EMBASE de 2016 a setembro/2020. Obtivemos estimativas de efeito agrupado por meio do modelo de efeitos aleatórios assumindo p<0,05 como estatisticamente significativo.

Resultados: Entre 1.784 estudos, 3 ECR foram selecionados. Os triplets demonstraram melhora na sobrevida livre de progressão (SLP) (HR 0,79-CI 0,68- 0,91, p=0,001) e na sobrevida global (SG) (HR 0,81-CI 0,67-0,98, p=0,03), com maiores taxas de eventos adversos (EAs) graus 3/4, pirexia, artralgia e elevação de aminotransferases de qualquer grau. As taxas de descontinuação de EA de todos os medicamentos permaneceram semelhantes.

Conclusão: A terapia tripla melhorou a SLP e a SG com toxicidades manejaveis. Estes são resultados preliminares e dados maduros sao esperados. RESUMO Descritores: Melanoma; Imunoterapia; Receptor de morte celular programada 1; Proteínas proto-oncogênicas B-raf; Sistema de sinalização MAP kinase.

Keywords:

Melanoma - Programmed Cell Death 1 receptor - Proto-oncogene proteins b-raf - MAP kinase signaling system - Immunotherapy

Descritores:

Melanoma - Imunoterapia - Receptor de morte celular programada 1 - Proteínas proto-oncogênicas B-raf - Sistema de sinalização MAP kinase

Publikationsverlauf

Eingereicht: 29. August 2021

Angenommen: 15. Oktober 2021

Artikel online veröffentlicht:
24. Februar 2022

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