Treatment of High Risk Resected Melanoma in Australia: Current Landscape and Practises

Abstract

Stage III melanoma involves regional lymph nodes and/or in-transit or satellite disease, without spread to distant metastatic sites. Stage IIIA melanoma includes a T1a-T2a primary lesion with N1a or N2a nodal involvement, whilst stage IIID melanoma includes a T4b primary lesion with N3a-N3c nodal involvement. With surgery alone, patients with stage IIIA melanoma have 10-year survival rates of~88%; however, patients with stage IIID melanoma have 10-year survival rates of only~24%. Targeted therapy and immunotherapy are being explored in stage III disease as adjuvant therapy after surgical resection, to eliminate micro-metastatic disease and thereby prevent relapse of melanoma and increase patient survival. A number of pivotal trials published in the last two years have shown improved relapsefree survival (RFS) and overall survival in patients with stage III melanoma treated with adjuvant therapy. COMBI-AD showed adjuvant dabrafenib and trametinib improving RFS compared with placebo (HR 0.49; 95% CI 0.40-0.59). Checkmate-238 demonstrated an improvement in RFS of adjuvant nivolumab over ipilimumab (HR 0.68, P < 0.001) whilst Keynote-054 demonstrated an improvement in RFS with adjuvant pembrolizumab over placebo (HR 0.57, P < 0.001). Many nuances need to be considered when interpreting this data, including implications of an updated staging system, which patients are suitable for adjuvant therapy and the choice between adjuvant targeted therapy and immunotherapy in BRAF mutant patients. This review article summaries the currently available literature on adjuvant targeted therapy and provides a guide on applying this data in everyday practise.

Contemporary management of locoregionally advanced melanoma in Australia and New Zealand and the role of adjuvant systemic therapy

“…Vemurafenib, an alternative first‐generation BRAF inhibitor, was compared to placebo in the BRIM8 Phase III study in patients who had resected stage IIC and stage III melanoma and a BRAF V600E mutation. The results did not show a significant difference in disease‐free survival, 60 which may have been due to the statistical design as well as the likely requirement for dual agent therapy for the successful blockade of the MAP kinase pathway 61 …”

“…The results did not show a significant difference in disease-free survival, 60 which may have been due to the statistical design as well as the likely requirement for dual agent therapy for the successful blockade of the MAP kinase pathway. 61 Stage IIIA disease and adjuvant therapy The clinical trials discussed above classified all tumours using the seventh edition of the AJCC staging system. Post-hoc analysis of the COMBI-AD and Keynote 054 studies was undertaken where patients were reclassified according to the AJCC eighth edition to assess whether the improvement of RFS remained consistent across all subgroups, when compared to placebo.…”

Proteomic profiling of cutaneous melanoma explains the aggressiveness of distant organ metastasis

“…Despite recent developments in targeted therapy and immunotherapy for the management of metastatic melanomas, the rate of patient's response to these therapies and their overall survival remains low 4,8,9,29,30 . Consequently, there is a need to understand better the molecular mechanisms behind melanoma metastasis that will assist with the identification of novel and more effective therapeutic targets.…”

“…BRAF and MEK inhibitors) and checkpoint inhibitors (i.e. PD‐1 inhibitor) have shown to improve response rates and survival in metastatic melanoma patients 4–7 . These improvements have been due to our better understanding of the molecular and biological changes during melanoma progression and their microenvironment.…”

Management of cutaneous melanoma in Australia: a narrative review

“…Adjuvant therapy aims to treat residual micrometastatic disease after histologically complete resection, thus decreasing the chance of recurrence and in turn improving survival. 52 The first trial to explore the use of adjuvant ICIs compared four doses of ipilimumab with placebo in patients with completely resected stage III melanoma. Although a significant improvement in recurrence-free survival and overall survival was demonstrated, 45% of patients developed severe adverse events.…”