Melanoma is one of the cancers that has made great strides in treatment over the past 20 years. Metastatic melanoma was once with a very poor prognosis and no survival benefit from systemic treatment, now shows over 50% of patients may gain durable survival benefit. There are now at least four regimens of immunotherapy and three regimens of targeted therapy that increase survival. Survival curves from clinical studies plateau at the three-year mark, and it is therefore likely that a patient who is alive at three years will gain prolonged cancer remission. Immune therapy has an effect after treatment has been ceased, and clinicians may cease treatment due to the risk of delayed immune-related adverse events and the high cost burden on the healthcare system of perpetual therapy. The challenge with this approach is currently there is no consensus on the length of checkpoint treatment. The initial trials defined a two-year treatment duration, but even shorter treatment durations are appropriate in some patients.
The standard staging method for melanoma is the AJCC-8-TNM system. This traditional TNM staging system also features primary site and depth, extent of ulceration and mitotic rate that can be used to assess the risk of nodal metastasis. Sentinel node status added to the AJCC-8 melanoma staging system greatly improved prognostic ability between node-negative and node-positive disease.
Melanoma is among the solid tumours with the highest mutational burden, and some of these mutations are important targets for treatment. Approximately 50% of melanomas have the BRAF mutation that results in activation of MEK and ERK signalling. This provides the rationale for combined BRAF and MEK inhibition and BRAF testing should be done in stage 3 or 4 melanoma. The AJCC-8 TNM system does not currently include these and other important molecular characterisations. Work is currently underway to develop better staging systems to include prognostic mutations to help guide treatment and outcome of disease.
This article focuses on pharmacological treatment, however surgical intervention should not go unmentioned due to over 90 percent of patients having localised disease. Traditionally wide margins of 5cm were used, and this has recently been revised and shown smaller margins of 2cm or even 1cm being as effective. With sentinel node biopsy, the traditional practice of complete lymph node dissection has changed. Now only nodes receiving direct lymphatic drainage are removed, lessening complications associated with full lymph node dissection. Patients with nodal metastasis can elect nodal observation as well in many circumstances, which has been shown to not increase risk for recurrence.
Advanced melanoma is treated with systemic drugs, both BRAF/MEK inhibition and/or immunotherapy. In BRAF mutation melanoma patients that employ both treatments, the best sequence of treatment is still unknown and depends largely on individual clinical factors and patient choice. Combination therapy with anti-PD-1 and ipilimumab has shown to have higher response rates, progression-free survival (PFS) and overall survival (OS) than anti-PD-1 alone, as well as a reduced need for subsequent therapy. The downside of treating with combination PD-1/ipilimumab is the increased risk and increased severity of immune-related adverse effects.
No comparative studies have been done with BRAF and MEK inhibitor combinations. Therefore, no difference can be ascertained in overall survival or response rates between the different regimens. Combining the PD-1 inhibitor atezolizumab with vemurafenib and cobimetinib has been shown to improve PFS compared to combination BRAF/MEK therapy alone. Symptomatic patients with a large tumour burden may benefit from up-front BRAF and MEK inhibition due to the rapid response associated with targeted therapy compared to immunotherapy.
Interferon was for many years the only option available for adjuvant treatment of melanoma. This, unfortunately, was associated with numerous toxicities and an inconclusive survival benefit. Immunotherapy has been shown to improve survival, and PD-1 inhibition has shown to have benefits in survival and toxicity over ipilimumab. PD-1 inhibition is the current standard adjuvant therapy for patients with stage III resectable BRAF wild-type melanoma. For melanoma stage III BRAF mutation patients, combination targeted therapy with trametinib and dabrafenib is recommended. Twelve months treatment is recommended for adjuvant patients. The threshold for risk of recurrence remains unresolved in adjuvant treatment and no head-to-head comparisons have been performed for BRAF vs immune blockade. There are also ongoing trials for high-risk stage II melanoma and immune checkpoint blockade.
Neoadjuvant treatment is also being explored and a trial investigating BRAF and MEK inhibition was stopped early due to observed benefit of treatment group. Preclinical data and small trials suggest that checkpoint blockade may be more effective before surgery than after surgery, and combination therapy is being explored. The higher response rates associated with combination therapy is also unfortunately associated with adverse effects.
Vaccination development in melanoma has spanned over a hundred years. Tamilogene laherparepvec (TVEC) is a genetically modified herpes simplex virus with decreased virulence and selective intratumoral replication. A phase 3 trial showed durable rates of clinical response and may be an option for patients whom the toxic effects of checkpoint blockade are not acceptable.
The sequence of targeted and immune checkpoint therapy is an area of current research, and the results will guide treatment in the future. There are a number of trials comparing BRAF/MEK inhibition followed by immunotherapy vs immunotherapy followed by BRAF/MEK inhibition. There is also the SECOMBIT trial underway comparing the sequencing of BRAF/MEK inhibition then ipilimumab/nivolumab after eight weeks with two other groups changing after disease progression changing from ipilimumab/nivolumab to BRAF/MEK inhibition and BRAF/MEK to ipilimumab/nivolumab.
Adoptive cellular therapies with the use of tumour infiltrating lymphocytes holds some promise in the future. The infrastructure for scaling up of cell processing now exists, and clinical trials are now underway in combination with interleukin-2 and sequential immunotherapy.
Uveal melanoma is also an area of current research due to immunotherapy being less effective than in the more common subcutaneous subtype of melanoma. New molecules targeting protein kinase C and gp100 are being investigated in clinical trials.
Melanoma is a disease with great improvements in treatment in the past ten years. With current research, the optimisation of treatment involving both surgical and systemic therapy to give even better outcomes will be a factor in the future. Pharmacists can play a pivotal role in ensuring these optimal treatments can be managed by the patient.
- Cancer Institute NSW. eviQ. Alexandria, Australia.
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- Michielin O, Atkins MB, Koon HB, Dummer R, Ascierto PA. Evolving impact of long-term survival results on metastatic melanoma treatment. Journal for ImmunoTherapy of Cancer 2020; 8: e000948.
- National Comprehensive Cancer Network. NCCN Guidelines – Metastatic Melanoma; 2021.
- Warburton L, Celapre L, Pereira MR, Reid A, Robinson C, Amanuel B, et al. Circulating tumor DNA in advanced melanoma patients ceasing PD-1 inhibition in the absence of disease progression. Cancers (Basel). 2020; 12(11): 348.