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Combination targeted and immune therapy in the treatment of advanced melanoma: a valid treatment option for patients?

ABSTRACT: Melanomas harboring an activating BRAFV600 mutation account for 50% of all advanced melanomas. The approval of BRAF-targeted therapy revolutionized treatment of these patients with achievement of impressive responses. However, development of resistance to these drugs is a significant problem, and as such, duration of response remains low, with median progression free survival of around 11-15 months. Immune checkpoint blockers exploit the immune system to eradicate cancer and can produce durable disease control that results in long-term, treatment-free survival in some patients. These drugs have shown very impressive survival in patients with BRAF-mutated melanoma. Thus, there is a need to continue to utilize emerging data to achieve long-term disease control for patients with advanced melanoma. Combining targeted therapy with immune therapy may be one possible way to achieve this goal. In this review, the mechanisms of action of these two pathways, including the mechanistic basis of this combination, are summarized, along with results of completed and ongoing trials in triple therapy.

SUBMITTER: Bari S

PROVIDER: S-EPMC9036333 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Combination targeted and immune therapy in the treatment of advanced melanoma: a valid treatment option for patients?

Bari Shahla S Muzaffar Jameel J Eroglu Zeynep Z

Therapeutic advances in medical oncology 20220422

Melanomas harboring an activating BRAFV600 mutation account for 50% of all advanced melanomas. The approval of BRAF-targeted therapy revolutionized treatment of these patients with achievement of impressive responses. However, development of resistance to these drugs is a significant problem, and as such, duration of response remains low, with median progression free survival of around 11-15 months. Immune checkpoint blockers exploit the immune system to eradicate cancer and can produce durable ...[more]

PMID: 35478991

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Project description:BackgroundImmune checkpoint inhibitors (ICIs) and targeted treatments have improved the health outcomes of patients with advanced melanoma. However, due to the high cost of novel therapies, it is crucial to evaluate their value by considering both effectiveness and cost. To compare the cost-effectiveness of these novel agents (atezolizumab-vemurafenib-cobimetinib, vemurafenib-plus-cobimetinib, dabrafenib-plus-trametinib, and encorafenib-plus-binimetinib) for first-line treatment of metastatic melanoma with the BRAFV600 mutation.MethodsA patient-level model was developed to project the health outcomes of 4 strategies for patients with advanced melanoma. We estimated transition probabilities from the IMspire150 (ClinicalTrials.gov, NCT02908672), COMBI-AD (NCT01682083), and COLUMBUS (NCT01909453) trials using a parametric survival model. All health outcomes, including direct cost, quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER), were estimated from the US payer perspective. Lifetime cost, QALYs, life-years (LYs), and ICERs were calculated. Univariable and probabilistic sensitivity analyses were performed to test model robustness, along with multiple scenario analyses.ResultsOf the 4 competing strategies, atezolizumab-vemurafenib-cobimetinib produced the best health outcomes, and the vemurafenib-cobimetinib strategy was the least expensive option. Atezolizumab-vemurafenib-cobimetinib, dabrafenib-plus-trametinib, and vemurafenib-cobimetinib formed the cost-effective frontier, indicating that the ordered ICERs were $325,113/QALYs for dabrafenib-plus-trametinib vs. vemurafenib-cobimetinib strategies and $2,247,500/QALYs for atezolizumab-vemurafenib-cobimetinib vs. dabrafenib-plus-trametinib strategies. Encorafenib-plus-binimetinib was dominated by the other 3 competing strategies. The drug price and first-line utility significantly influenced the model utcomes.ConclusionsFor BRAF-mutant advanced melanoma, the vemurafenib-cobimetinib strategy could be considered the most cost-effective treatment at the willingness-to-pay threshold of $150,000.

Project description: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.

Dataset Information

Combination targeted and immune therapy in the treatment of advanced melanoma: a valid treatment option for patients?

Publications

Combination targeted and immune therapy in the treatment of advanced melanoma: a valid treatment option for patients?

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