Safety and Efficacy Analysis of Targeted and Immune Combination Therapy in Advanced Melanoma-A Systematic Review and Network Meta-Analysis

Anna Sára Lengyel; Fanni Adél Meznerics; Noémi Ágnes Galajda; Noémi Gede; Tamás Kói; Alzahra Ahmed Mohammed; Petra Nikolett Péter; Alexandra It Lakatos; Máté Krebs; Dezső Csupor; András Bánvölgyi; Péter Hegyi; Péter Holló; Lajos V Kemény

doi:10.3390/ijms252312821

Safety and Efficacy Analysis of Targeted and Immune Combination Therapy in Advanced Melanoma-A Systematic Review and Network Meta-Analysis

Int J Mol Sci. 2024 Nov 28;25(23):12821. doi: 10.3390/ijms252312821.

Authors

Anna Sára Lengyel^{1

2

3

4}, Fanni Adél Meznerics^{1

2}, Noémi Ágnes Galajda^{1

2}, Noémi Gede^{2

5}, Tamás Kói^{2

6}, Alzahra Ahmed Mohammed^{1

2

3}, Petra Nikolett Péter^{1

2

3

4}, Alexandra It Lakatos^{2

3

4}, Máté Krebs^{1

2

3

4}, Dezső Csupor^{2

5

7}, András Bánvölgyi^{1

2}, Péter Hegyi^{2

5

8}, Péter Holló¹, Lajos V Kemény^{1

2

3

4

9}

Affiliations

¹ Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, 1085 Budapest, Hungary.
² Centre for Translational Medicine, Semmelweis University, 1085 Budapest, Hungary.
³ HCEMM-SU Translational Dermatology Research Group, Semmelweis University, 1094 Budapest, Hungary.
⁴ Department of Physiology, Semmelweis University, Tűzoltó Str. 37-47, 1094 Budapest, Hungary.
⁵ Institute for Translational Medicine, Medical School, University of Pécs, 7623 Pécs, Hungary.
⁶ Department of Stochastics, Institute of Mathematics, Budapest University of Technology and Economics, 1111 Budapest, Hungary.
⁷ Institute of Clinical Pharmacy, Faculty of Pharmacy, University of Szeged, 6725 Szeged, Hungary.
⁸ Institute of Pancreatic Diseases, Semmelweis University, 1083 Budapest, Hungary.
⁹ MTA-SE Lendület "Momentum" Dermatooncology Research Group, 1094 Budapest, Hungary.

Abstract

The combinations of BRAF inhibitor-based targeted therapies with immune checkpoint inhibitors currently represent less common therapeutic approaches in advanced melanoma. The aim of this study was to assess the safety and efficacy of currently available melanoma treatments by conducting a systematic review and network meta-analysis. Four databases were systematically searched for randomized clinical studies that included patients with advanced/metastatic melanoma receiving chemotherapy, immune checkpoint inhibitors, BRAF/MEK inhibitor therapy, or combinations thereof. The primary endpoints were treatment-related adverse events (TRAE), serious adverse events (SAE) of grade ≥ 3 adverse events, therapy discontinuation, progression-free survival (PFS), as well as objective response rate (ORR) and complete response rate (CRR). A total of 63 articles were eligible for our systematic review; 59 of them were included in the statistical analysis. A separate subgroup analysis was conducted to evaluate the efficacy outcomes, specifically in BRAF-positive patients. Triple combination therapy or triple therapy (inhibiting BRAF, MEK and PD1/PDL1 axis) showed significantly longer progression-free survival compared to BRAF + MEK combination therapies (HR = 0.76; 95% CI 0.64-0.9), but similar objective and complete response rates in BRAF-mutated melanoma. This safety analysis suggests that triple therapy is not inferior to combined immune checkpoint inhibitors (ICI) and BRAF/MEK therapies in terms of serious adverse events and therapy discontinuation rates. However, monotherapies and BRAF/MEK combinations showed notable advantage over triple therapy in terms of treatment-related adverse events. Combination strategies including BRAF/MEK-targeted therapies with ICI therapies are effective first-line options for advanced, BRAF-mutant melanoma; however, they are associated with more frequent side effects. Therefore, future RCTs are required to evaluate and identify high-risk subpopulations where triple therapy therapies should be considered.

Keywords: advanced melanoma; immune checkpoint inhibitor; network meta-analysis; targeted therapy; triple therapy.

Publication types

Systematic Review
Meta-Analysis
Review

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / adverse effects
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Humans
Immune Checkpoint Inhibitors* / adverse effects
Immune Checkpoint Inhibitors* / therapeutic use
Immunotherapy / methods
Melanoma* / drug therapy
Melanoma* / pathology
Molecular Targeted Therapy / adverse effects
Network Meta-Analysis*
Progression-Free Survival
Protein Kinase Inhibitors / adverse effects
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins B-raf* / antagonists & inhibitors
Proto-Oncogene Proteins B-raf* / genetics
Treatment Outcome

Substances

Immune Checkpoint Inhibitors
Proto-Oncogene Proteins B-raf
BRAF protein, human
Protein Kinase Inhibitors

Grants and funding

L.V.K. is a recipient of the János Bolyai Research Scholarship from the Hungarian Academy of Sciences and is supported by the Hungarian National Research, Development and Innovation Office (OTKA FK138696) grant. L.V.K. and the MTA-SE Lendület "Momentum” Dermatooncology Research Group are the recipients of the Lendület “Momentum” grant from the Hungarian Academy of Sciences (LP2024-12/2024). This project was funded by grant agreement No. 739593 of the EU Horizon 2020 research and innovation program.