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BRAF selective inhibitors in advanced melanoma. The revolution has begun

07 Jun 2011
Melanoma and other skin tumours
Raffaele Califano

These are exciting times for clinicians treating patient with Malignant Melanoma. Metastatic melanoma carries a poor prognosis and despite the tremendous efforts in cancer research the results have been disappointing.
Things are now changing very quickly. This year has seen Ipilimumab, an anti-CTLA-4 monoclonal antibody, approved by the Food and Drug Administration (FDA) for advanced melanoma. The registration study was, up to few days ago, the only clinical trial demonstrating an overall survival advantage in the history of melanoma and set a new standard of care.

Practice-changing data have been presented the 5th June at the 2011 American Society of Clinical Oncology Annual Meeting, currently being held in Chicago, USA.
The BRIM-3 trial, presented during the Plenary Session by Dr P. Chapman was in tandem published on the New England Journal of Medicine as electronic publication.

BRIM-3 is a large multicentre, randomised, phase 3 trial evaluating vemurafenib with dacarbazine in 675 patients with untreated metastatic melanoma harbouring the BRAF V600E mutation. Approximately 50-60% of cutaneous melanomas harbour a BRAF mutation that constitutively activates the signalling through the MAPK kinase pathway. Most of these mutations result in the substitution of glutamic acid for valine at codon 600 (BRAF V600E).
Vemurafenib (RG7204, PLX4032), is an orally available inhibitor of mutated BRAF. Preliminary data from the phase I trial of PLX4032 was reported in 2010 in the New England Journal of Medicine (Flaherty, et al. NEJM 2010). The trial enrolled 55 patients (of which 49 diagnosed with melanoma) in a dose escalation phase and further 32 patients harbouring the BRAF V600E mutation enrolled in an extension phase receiving the recommended dose of 960mg twice daily. Notably this trial demonstrated 81% response rate (RR) in the extended phase. The phase II trial (BRIM-2) was a single arm, multicentre, open label trial in which 132 patients received vemurafenib until progression. The RR was 52% and 30% of patients achieved stable disease.  The median progression-free (PFS) was 6.2 months and, as with the phase I trial, median overall survival has not yet been reached.

In the BRIM-3 trial patients were randomised (1:1) to receive vemurafenib at the dose of 960 mg BD orally or dacarbazine 1000 mg/m2 iv every 3 weeks. Patients were stratified according to stage, performance status (PS), geographic region and LDH level. The rates of overall survival and PFS were coprimary endpoints. Tumour response was evaluated by investigators according to RECIST 1.1.
The final analysis was planned after 196 deaths and the interim analysis was planned after 50% of projected deaths. The data presented on this paper are based on data as of December 2010. At the time of the interim analysis, 118 patients had died and the data and safety monitoring board stated the coprimary endpoints had met the prespecified criteria for advantage from vemurafenib. This led to an amendment of the trial protocol that allowed patients originally randomised to dacarbazine, to crossover to vemurafenib. Median follow up for the interim analysis is short (3.8 vs 2.3 months for vemurafenib and dacarbazine group, respectively).
Patients treated with vemurafenib experienced a 63% relative reduction in the risk of death (HR 0.37; 95 CI 0.26-055, p<0.001) and a 74% relative reduction in the risk of progression (HR 0.26; 95% CI 0.20-0.33, p<0.001). Improvement in Overall survival and progression-free survival was observed in all subgroups. Unfortunately the follow-up was too short to provide reliable Kaplan-Meier estimates of the survival curves.
Only 65% of the patients were evaluable for response (randomised at least 14 weeks before clinical cut-off date). Patients in the vemurafenib arm experienced higher RR than the standard arm (48% vs 5%, p<0.001) for vemurafenib vs dacarbazine. The response rate for dacarbazine is lower than historical control. This could be related to the more aggressive behaviour of malignant melanomas harbouring the BRAF V600E mutation.
Most common adverse events in the experimental arm were cutaneous, arthralgia and fatigue and dose interruption/modification were required in 38% of the patients.
Eighteen percent of patients in the vemurafenib group developed squamous cell carcinoma of the skin or keratoacanthoma which was only excised and did not require discontinuation of treatment. The mechanism underlying development of new cutaneous cancer is still not defined, but could be related to the fact that BRAF V600 inhibition could paradoxically stimulate the MAP-Kinase cascade on BRAF wild-type cells.
Understanding the mechanism of resistance to vemurafenib is crucial and further translational research is needed. This trial is a landmark in the history of melanoma. Vemurafenib has set a new standard in the treatment for this subgroup of patients and opens new research avenues to evaluate combination treatment.
Dark times for melanoma are getting brighter. The revolution has only just begun.

Last update: 07 Jun 2011

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