The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cutaneous melanoma have been significantly revised over the past few years in response to emerging data on immune checkpoint inhibitor therapies and BRAF-targeted therapy. This article summarizes the data and rationale supporting extensive changes to the recommendations for systemic therapy as adjuvant treatment of resected disease and as treatment of unresectable or distant metastatic disease.

/pdf/cutaneous-melanoma-version-2-2019-1zboabm53q.pdf

Cutaneous melanoma, version 2.2019

https://findresearcher.sdu.dk:8443/ws/files/159859112/PIIS0959804919308342.pdf

European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - Update 2019.

Melanoma is characterised by its ability to metastasise at early stages of tumour development. Current clinico-pathologic staging based on the American Joint Committee on Cancer criteria is used to guide surveillance and management in early-stage disease, but its ability to predict clinical outcome has limitations. Herein we review the genomics of melanoma subtypes including cutaneous, acral, uveal and mucosal, with a focus on the prognostic and predictive significance of key molecular aberrations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.5213

Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities.

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

Melanoma: Cutaneous, Version 2.2021 Featured Updates to the NCCN Guidelines

The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.

https://www.mdpi.com/1422-0067/20/6/1483/pdf

Targeting the ERK Signaling Pathway in Melanoma.

Summary Background Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC–III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF V600 mutation-positive melanoma. Methods BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2) BRAF V600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. Findings The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9–41·6) in cohort 2 and 30·8 months (25·5–40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6–26·5) in the vemurafenib group versus 15·4 months (11·1–35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54–1·18; log-rank p=0·026). In cohort 1 (patients with stage IIC–IIIA–IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4–not estimable) in the placebo group (HR 0·54 [95% CI 0·37–0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3–4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3–4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3–4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. Interpretation The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC–IIIA–IIIB BRAF V600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. Funding F Hoffman–La Roche Ltd.

Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Frederic Kass

Papers

Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial