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A recent report from the National Cancer Registry of Ireland (NCRI) showed that from 2010-2012, approximately 889 melanoma skin cancers were registered per year.1 Excluding NMSC, melanoma skin cancer was the fifth-most commonly diagnosed invasive cancer in Ireland.
An estimated annual average of 153 deaths from melanoma skin cancer occurred, representing 1.7 per cent of all deaths from cancer.1 From 1994-2012, the incidence rate of melanoma skin cancer in females increased at almost 3 per cent per year and in males, by almost 5 per cent over the same period.1 In 2012, the estimated incidence and mortality rates for melanoma skin cancer for both Irish males and females was higher than the EU average.1
Fig 1: Pagetoid spread
The incidence of melanomas in children is rare, accounting for 1 per cent to 4 per cent of all melanomas.15
The prognosis for metastatic melanoma has greatly improved since the approval of targeted kinase inhibitors vemurafenib, dabrafenib and trametinib and the immune checkpoint inhibitor ipilimumab.7
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies
Ipilimumab is a fully-humanised, monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) and was approved by the FDA in 2011 for adult patients with unresectable or metastatic melanoma.3 It was the first immunotherapy to show improvement in overall survival (OS) in patients with advanced or metastatic melanoma.5 It blocks the binding of CTLA-4 to its ligands, thereby enhancing T-cell activity, and improving patients’ ability to mount an anti-tumour immune response.4
The efficacy of ipilimumab has been evaluated in two large, phase III trials of patients with advanced melanoma. In the registration trial reported by Hodi et al, 676 patients with previously-treated stage III or IV melanoma were randomised to receive either 3mg/kg of ipilimumab monotherapy, ipilimumab in combination with gp100 peptide vaccine, or gp100 peptide vaccine monotherapy. The median OS was significantly higher with ipilimumab in combination with gp100 than with gp100 alone (10 months vs 6.4 months; HR 0.68; P<0.001). Median OS was also significantly greater with ipilimumab monotherapy compared with gp100 alone (10.1 months vs 6.4 months; HR: 0.66; P=0.003).5
Fig 2: HMB45 immunohistochemical stain showing deep positivity in the dermal component and highlighting the pagetoid spread
Ipilimumab was the first agent to show a significant survival benefit in metastatic melanoma and in 2011, it was approved by the FDA and the EMEA.6 The majority of patients (84.8 per cent) experience drug-related adverse events but the majority are mild-to-moderate.5
Specific therapy in BRAF-mutated melanoma
BRAF is the most commonly-activated oncogene in melanoma, with mutations found in approximately 40-to-60 per cent of cutaneous melanoma.
Vemurafenib and dabrafenib are BRAF inhibitors specific to melanomas harbouring the BRAF V600E and V600E/K mutations.8 [Fig 5]
Figure 5: The MAPK signalling cascade and potential targets and agents relevant to melanoma 16
Vemurafenib is a selective BRAF inhibitor that targets the V600 mutant forms of the BRAF. In 2011, Vemurafenib (960mg twice daily) received FDA approval based on the results from a phase III trial, which compared vemurafenib to dacarbazine in patients with previously-untreated, unresectable, stage III/IV melanoma. The vemurafenib group demonstrated better overall survival (86 per cent vs 64 per cent at six months) and progression-free survival (median 5.3 months vs 1.6 months) when compared to dacarbazine alone.
Fig 3: Pre-treatment sagittal CT (left) demonstrating lytic metastases in the vertebral bodies of T4 and T8. A follow-up CT (right) shows interval sclerosis of the lesions, in keeping with treatment effect
The overall response rate was 48 per cent for vemurafenib and 5 per cent for dacarbazine. Based on vemurafenib’s superior response, the trial was stopped early at interim analysis and crossover from dacarbazine to vemurafenib was recommended.2
Dabrafenib is another BRAF inhibitor that has demonstrated efficacy in patients with BRAF-mutated melanoma. In an open-label, phase III trial reported by Hauschild et al, patients with BRAF-mutant metastatic melanoma were randomly assigned to receive either dabrafenib (187 patients; 150mg BD) or dacarbazine (63 patients; 1,000mg/m2 IV every three weeks). Response rates were also significantly higher in the dabrafenib group (50 per cent) than in the dacarbazine group (6 per cent). Median progression-free survival was longer in the dabrafenib group (5.1 months) compared to the dabrafenib group (2.7 months; P <0.0001).9
MEK is the immediate downstream target of BRAF action and is an additional target to consider in melanoma therapy.3 In 2013, the FDA approved trametinib (2mg PO OD) for the treatment of adult patients with BRAF V600E/K mutation and unresectable or metastatic melanoma.
Fig 4: Axial CT (left) showing numerous splenic metastases with complete resolution on the follow-up study (right)
Trametinib is not indicated in patients who have previously progressed on a BRAF inhibitor. A recent phase III study, the METRIC trial, compared trametinib vs chemotherapy with either dacarbazine or paclitaxel in 322 patients with BRAF-mutant unresectable melanoma.10 The results showed that trametinib demonstrated a significant improvement in progression-free survival and overall survival compared with either chemotherapy agent.4 An important potential side-effect associated with MEK inhibitors is ocular toxicity.3
Combining BRAF and MEK inhibitors
The rationale for using BRAF and MEK inhibitors together is to lead to a more durable and complete response. Combined therapy with dabrafenib and trametinib was evaluated in a phase II trial for the treatment of melanoma with BRAFV600E mutation. Results confirmed anti-tumour effects and a decreased incidence of skin-related adverse effects.
A subsequent trial combining the same inhibitors recruited 18 patients with metastatic melanoma who had failed a previous BRAF inhibitor. The disease control rate was 67 per cent (three patients (17 per cent) with partial response, nine patients (50 per cent) with stable disease, and six patients (33 per cent) with progressive disease).3
There are three well-defined oncogenes in melanoma: BRAF, NRAS and c-KIT. Mutations of c-KIT are found in approximately 1 per cent of melanomas but almost solely in acral lentiginous and other mucosal melanomas.6 Imatinib is a tyrosine kinase inhibitor (TKI) with the most potent activity against c-KIT. In a phase II, open-label trial reported by Guo et al, 43 patients with metastatic melanoma harbouring c-KIT alterations were treated with imatinib mesylate.
Eighteen patients showed regression of tumour mass. Imatinib demonstrated significant activity in patients with metastatic melanoma harbouring c-KIT aberrations, with an overall response rate of 23.3 per cent.11
Nilotinib is a muti-targeted tyrosine kinase inhibitor (TKI), with activity against BCR-ABL, c-KIT, MAPKII, and others. There is some suggestion that nilotinib may achieve disease control in patients with melanoma harbouring KIT alteration and whose disease progressed after imatinib therapy, supported by the results of a phase II study reported by Carvajal et al.12
Nivolumab is a fully human IgG4 monoclonal antibody directed against the programmed death 1 (PD-1) receptor, which has demonstrated survival benefit in an open-label, phase II trial and was the first PD-1 inhibitor to be approved worldwide.13 A phase III trial is currently ongoing comparing nivolumab, ipilimumab and a combination of nivolumab/ipilimumab (NCT01844505).
Pembrolizumab is an anti PD-1 antibody, which has shown potent anti-tumour activity in patients with metastatic melanoma. It has recently been approved by the FDA based on the results of a multi-centre, open-label, randomised, dose-comparative phase 1 study randomising 173 patients with unresectable or metastatic melanoma, refractory to ipilimumab to receive pembrolizumab 2mg/kg or 10mg/kg intravenously once every three weeks. Overall, response rate was achieved in 26 per cent in both treatment groups and treatment was well tolerated, with similar safety profiles.14
Management of patients with metastatic melanoma has been revolutionised since the introduction in recent years of targeted tyrosine kinase inhibitors and immunomodulatory agents, which have been shown to offer a survival advantage. Before 2011, systemic chemotherapeutic options for metastatic melanoma demonstrated poor improvement in overall survival.
Treatment for metastatic melanoma is determined by the mutational status of the tumour and genotyping should be performed prior to initiation of therapy for BRAF and/or KIT. The future of melanoma therapy will likely be combination therapy, additional studies are needed.
A 16-year-old Caucasian male presented with a 10mm irregular naevus variegated in colour on his posterior neck, with no associated palpable lymphadenopathy. Excisional biopsy showed a superficial, spreading, malignant melanoma, Breslow 2.1mm, and Clarke’s level IV melanoma with five-to-six mitoses per 10/high power fields. No lymphovascular invasion or perineural invasion was observed.
Wide local excision showed clear margins and sentinel lymph node scintigraphy was performed. Staging CT scans were negative. Eighteen months later he had a lymph node recurrence in the right aspect of his neck, confirmed by FNA. He underwent posterior lateral neck dissection and one lymph node was positive for a 9mm metastatic deposit with multifocal microscopic extra-capsular extension. Of note, his metastatic melanoma was BRAF-mutated. He went on to receive post-operative radiotherapy to his neck for a total dose of 66GY in 33frs. A PET CT, which showed some focal increased uptake in the spleen and MRI, confirmed two indeterminate lesions. Follow-up MRI in three months showed an increase in the size of the splenic lesions.
PET CT scan was repeated and demonstrated the presence of multiple avid foci within the spleen, highly suspicious for metastatic disease. Multiple new lytic lesions consistent with metastases were also noted in the left T2 transverse process, anterior T4 vertebral body, T8 and several lesions within the sacrum. Systemic treatments, including immunomodulatory agents and BRAF inhibitors, were discussed based on a diagnosis of stage IV melanoma with multiple bone and-spleen metastases. The patient was enrolled in a phase III, double-blind, randomised clinical trial of ipilimumab and nivolumab alone or in combination. He demonstrated extremely favourable responses to immunotherapy with follow-up CT neck, thorax, abdomen, pelvis and bone scans showing a complete resolution of splenic lesions and healing bone metastases, with no new lesions reported. This is in keeping with a partial response.
He tolerated the treatment very well, apart from a mild-to-moderate, immune-related hypophysitis resulting in a hypothyroidism, for which he was treated with levothyroxine. It is now three years since he was first diagnosed and in view of the extremely favourable response to immunotherapy, he remains on treatment as per protocol, with multidisciplinary input.
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Carvajal RD, Lawrence DP, Weber J et al. Phase II Study of Nilotinib in melanoma harbouring KIT alterations following progression to prior KIT inhibition. Clin Cancer Res 2015 Feb 18. Pii: clincanres. 1630.2014.
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Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose comparison cohort of a phase 1 trial. Lancet 2014; 384: 1109–1117.
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