Melanoma Q & A

Melanoma is very uncommon isn’t it? Do we really have to worry about it?
Melanoma is not common but the incidence is increasing rapidly. In Ireland every year there are approximately 630 new cases of melanoma and 110 people die of the disease  Melanoma accounts for only a small percentage of  total cancer deaths (1-2%) but, as it tends to affect younger people, it accounts for a significantly greater proportion of potential life-years-lost.

Melanoma mortality is increasing very rapidly with the number of deaths per year expected to reach 150 by 2020.

I heard that the prognosis for melanoma patients is good; is it not?
It is true that the majority of patients are diagnosed with very superficial melanoma (<1mm) and most of these patients are cured with surgery alone. But for the 10% of patients diagnosed with Metastatic disease, or the patients who develop distant recurrence, the prognosis is appalling: median survival for these patients is 8-18months depending on sub-stage.
Single agent chemotherapy (DTIC) and high dose Interleukin-2 both are both licensed for first line treatment although their impact on overall survival is not certain. Some patients (perhaps 5-10%) treated with the high dose IL-2 Immunotherapy have significant responses which are durable but it is not possible to predict who these patients are and the treatment is toxic.
Until very recently there have been no approved second-line options for previously-treated patients.

I heard that there are new ‘wonder-drugs’ for melanoma…is this true?
No. Yes there are some new treatment options but they fall a long way short of the description ‘wonder-drugs’. That said, there is much relief and excitement in the melanoma research community that, after many years of painstaking (and ultimately futile) research into all types of drug therapy, finally something has been shown to  improve the prognosis for these most unfortunate patients: Ipilimumab and Vemurafenib.

Ipilimumab is a monoclonal antibody directed against the down-regulating cytotoxic T-lymphocyte-associated antigen (CTLA-4). Treatment is administered intravenously every 3 weeks x 4 cycles.

The first randomised controlled trial of this agent was in second-line treatment of patients with metastatic melanoma .(Hodi et al, 2010  )
In this pivotal 676-patient 3-arm study, subjects were randomised to receive Ipilimumab 3mg/kg either alone or in combination with a peptide vaccine (gp100), versus the vaccine without Ipilimumab. The Study met its primary endpoint of improved overall survival for patients treated with Ipilimumab either alone (Hazard Ratio = 0.6, p=0.0026) or in combination with gp100 peptide vaccine (hazard ratio 0.68, p=0.0004). Patients who received Ipilimumab were almost twice as likely to be alive at 1 year and 2 year time points (46% versus 24% and 25% and 14%, respectively). The 2 year time-point is most interesting as it seem that the extra 10% or so of patients alive at this time as a result of Ipilimumab may have very durable remissions.

A second randomised controlled trial investigated the use of  Ipilimumab as first-line treatment (Robert et al. 2011 ). This study randomised 502 previously-untreated patients to DTIC + Ipilimumab at dose 10mg/kg q 3/52×4 or DTIC alone. Results were published in NEJM June 2011. Patients who received Ipilimumab were more likely to be alive at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%). Median overall survival was significantly improved with the DTIC+ipilimumab combination versus DTIC alone (11.2 months vs. 9.1months (hazard ratio 0.72; P<0.001)).

Ipilimumab has been licensed in United States since March 2011 for first-line and second-line (following prior treatment with chemotherapy or IL-2) at dose 3mg/kg iv q 3/52 x 4cycles. The same dose and schedule has been licensed by European Union (EMA) July 2011, for second line treatment. The National Cancer Control Programme has approved the drug for use in Ireland May 2012.

ECOG has started an adjuvant trial of Ipilimumab versus Interferon in resected melanoma patients with T4 or node positive disease. We in the melanoma sub-group of the Irish Clinical Oncology Research Group expect to open this study to patients in Ireland soon.

Vemurafenib
Approximately 40 to 60% of cutaneous melanomas carry mutations in BRAF that lead to constitutive activation of downstream signalling through the MAP kinase pathway. Vemurafenib (PLX4032) is a potent inhibitor of mutated BRAF which is administered orally at dose of 960mg bd.

A phase 2 trial (BRIM-2 ) showed a response rate of 53% and a median response duration of 6.7 months.

The subsequent BRIM-3 trial 675 patients with BRAF-mutated advanced melanoma were randomised to receive either chemotherapy (DTIC) or vemurarenib and was published in June 2011 (Chapman et al NEJM ). After just 6 months of follow-up, vemurafenib was seen to result in major improvement in  response rate ( 48% vs 5%) and overall survival (84% vs 64%). Vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with DTIC (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended.

While Roche seeks regulatory approval of vemurafenib, a global Expanded Access Programme will make this drug available to patients with BRAF V600 mutation-positive metastatic melanoma. This EAP will open in Ireland by April 2012.

A randomised clinical trial of a similar BRAF inhibitor manufactured by GSK has recently been conducted through ICORG and has reached its accrual goals. Results are awaited but are expected to be similarly positive and result in licensing approval.

Adjuvant trials are planned to see if administering these drugs to high risk patients without evidence of metastatic disease will improve cure rates over surgery alone.

Cancer Trends No.7, NCRI Report Jan 2011
Burnet et al. BJC (2005) 92, 241-245
Hodi et al. NEJM (Aug 2010) 363(8), 711-723
Robert al al. NEJM (Jun 2011)
BRIM-2; J Clin Oncol 2011; 29:S8509
Chapman et al NEJM (Jun 2011) 364;26, 2011