Adjuvant Treatment of Melanoma: Recent Developments and Future Perspectives

Testori, Alessandro; Ribero, Simone; Indini, Alice; Mandalà, Mario

doi:10.1007/s40257-019-00456-4

Cited by 32 publications

(25 citation statements)

References 87 publications

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“…Here, all but one patients had an indication of BRAF/MEKi for unresectable or metastatic melanoma; nonetheless, similar cutaneous adverse events have been described in patients under another indication 30,47 . Moreover, it has to be mentioned that the use of dabrafenib–trametinib is also approved in the adjuvant setting, and therefore in a disease‐free context, when the occurrence of a SCAR could have a serious impact on survival 48,49 …”

Section: Discussionmentioning

confidence: 67%

Systematic review of BRAF/MEK inhibitors‐induced Severe Cutaneous Adverse Reactions (SCARs)

Torres‐Navarro

Unamuno‐Bustos

Botella‐Estrada

2020

Acad Dermatol Venereol

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Severe cutaneous adverse reactions (SCARs) [Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic syndrome (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed eruption (GBFE)] are severe drug reactions that often require hospitalization and could be fatal. BRAF and MEK inhibitors (BRAF/MEKi) are a standard of care in patients with BRAF‐mutated metastatic melanomas. These agents are administered until disease progression or unacceptable toxicity occurs. This review has focus on BRAF/MEKi‐induced SCARs. A systematic search of the following terms: ‘vemurafenib’, ‘cobimetinib’, ‘dabrafenib’, ‘trametinib’, ‘encorafenib’, ‘binimetinib’, ‘Acute Generalized Exanthematous Pustulosis’, ‘Stevens Johnson syndrome’, ‘Toxic Epidermal Necrolysis’, ‘Generalized Bullous Fixed Eruption’ ‘Drug Hypersensitivity Syndrome’, and ‘DRESS’ in simple combination (every drug with each disease) and all in combination, was performed on MEDLINE, EMBASE, Web of Knowledge and The Cochrane Library repositories, with no restriction on language, for original studies. One hundred sixty‐eight original articles were found, 26 (retrospective series, case reports and conference abstracts) were selected, and 21 were included in the qualitative synthesis. A total of 31 SCAR cases (23 DRESS and 8 SJS/TEN – 1 SJS and 7 TEN –) were identified. Vemurafenib was the culprit drug in all but one case, which was dabrafenib‐induced. Mean time to SCAR onset from drug intake was 15.5 and 11.4 days, for SJS/TEN and DRESS, respectively. For the DRESS cases, hepatic involvement occurred in 96% and renal alterations in 87% of patients. Overall, BRAF/MEKi‐induced SCARs are rare. Among them, vemurafenib is the drug that requires more close monitoring for SCARs. Prior immunotherapy can favour SCARs. Vemurafenib DRESS is likely to occur within the first fifteen days of treatment accompanied by hepatic and renal involvement. Following vemurafenib‐induced SCAR resolution, switching to dabrafenib seems to be a safe alternative for these patients’ treatment.

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Section: Discussionmentioning

confidence: 67%

Systematic review of BRAF/MEK inhibitors‐induced Severe Cutaneous Adverse Reactions (SCARs)

Torres‐Navarro

Unamuno‐Bustos

Botella‐Estrada

2020

Acad Dermatol Venereol

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“…Adjuvant systemic therapy for melanoma has radically changed over the recent past [61]. Adjuvant IFN should be reserved only for patients with ulcerated melanomas and no metastases or small metastases in the SN in those countries where there is no reimbursement for the newer adjuvant therapies.…”

Section: Discussionmentioning

confidence: 99%

Adjuvant Therapy for Melanoma: Past, Current, and Future Developments

Testori

Chiellino

Akkooi

2020

Cancers

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This review describes the progress that the concept of adjuvant therapies has undergone in the last 50 years and focuses on the most recent development where an adjuvant approach has been scientifically evaluated in melanoma clinical trials. Over the past decade the development of immunotherapies and targeted therapies has drastically changed the treatment of stage IV melanoma patients. These successes led to trials studying the same therapies in the adjuvant setting, in high risk resected stage III and IV melanoma patients. Adjuvant immune checkpoint blockade with anti-CTLA-4 antibody ipilimumab was the first drug to show an improvement in recurrence-free and overall survival but this was accompanied by high severe toxicity rates. Therefore, these results were bypassed by adjuvant treatment with anti-PD-1 agents nivolumab and pembrolizumab and BRAF-directed target therapy, which showed even better recurrence-free survival rates with more favorable toxicity rates. The whole concept of adjuvant therapy may be integrated with the new neoadjuvant approaches that are under investigation through several clinical trials. However, there is still no data available on whether the effective adjuvant therapy that patients finally have at their disposal could be offered to them while waiting for recurrence, sparing at least 50% of them a potentially long-term toxic side effect but with the same rate of overall survival (OS). Adjuvant therapy for melanoma has radically changed over the past few years—anti-PD-1 or BRAF-directed therapy is the new standard of care.

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“…the combination of BRAF and MEK inhibitors), which is constitutively activated in approximately 50% of cutaneous melanoma patients, namely those harboring a BRAFV600 mutation [7][8][9]. Given the survival benefit provided by these drugs in the metastatic setting, in recent years efforts have been made to evaluate their role as adjuvant treatment for high-risk resected disease [10]. The first immunotherapy to demonstrate a significant improvement in relapsefree survival (RFS) and overall survival (OS) compared with placebo was the anti-CTLA4 antibody ipilimumab in the European Organisation for Research and Treatment of Cancer (EORTC) 18071/CA184-029 trial [11,12].…”

Section: Adjuvant Therapy In Melanomamentioning

confidence: 99%

Impact of Circulating and Tissue Biomarkers in Adjuvant and Neoadjuvant Therapy for High-Risk Melanoma: Ready for Prime Time?

et al. 2021

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The prognosis of patients with metastatic melanoma has substantially improved over the last years with the advent of novel treatment strategies, mainly immune checkpoint inhibitors and BRAF and MEK inhibitors. Given the survival benefit provided in the metastatic setting and the evidence from prospective clinical trials in the early stages, these drugs have been introduced as adjuvant therapies for high-risk resected stage III disease. Several studies have also investigated immune checkpoint inhibitors, as well as BRAF and MEK inhibitors, for neoadjuvant treatment of high-risk stage III melanoma, with preliminary evidence suggesting this could be a very promising approach in this setting. However, even with new strategies, the risk of disease recurrence varies widely among stage III patients, and no available biomarkers for predicting disease recurrence have been established to date. Improved risk stratification is particularly relevant in this setting to avoid unnecessary treatment for patients who have minimum risk of disease recurrence and to reduce toxicities and costs. Research for predictive and prognostic biomarkers in this setting is ongoing to potentially shed light on the complex interplay between the tumor and the host immune system, and to further personalize treatment. This review provides an insight into available data on circulating and tissue biomarkers, including the tumor microenvironment and associated gene signatures, and their predictive and prognostic role during neoadjuvant and adjuvant treatment for cutaneous high-risk melanoma patients. Key PointsStage III melanoma patients are a heterogeneous population and biomarkers for disease recurrence have not been established to date.Biomarkers for a strong adaptive immune response seem to identify patients who derive clinical benefit from adjuvant therapy.Results in a neoadjuvant setting need to be implemented and prospectively confirmed to be employed in everyday clinical practice.

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Adjuvant Treatment of Melanoma: Recent Developments and Future Perspectives

Cited by 32 publications

References 87 publications

Systematic review of BRAF/MEK inhibitors‐induced Severe Cutaneous Adverse Reactions (SCARs)

Systematic review of BRAF/MEK inhibitors‐induced Severe Cutaneous Adverse Reactions (SCARs)

Adjuvant Therapy for Melanoma: Past, Current, and Future Developments

Impact of Circulating and Tissue Biomarkers in Adjuvant and Neoadjuvant Therapy for High-Risk Melanoma: Ready for Prime Time?

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