A decade after the discovery of an activating mutation in the BRAF gene showed the feasibility of targeted therapies, four new drugs, as well as their combinations, offer exciting possibilities
Characterised by malignant transformation of the melanocyte, melanoma is a neoplastic disorder which occurs in areas such as the meninges, mucous membranes, upper oesophagus and – most commonly – the skin, where it arises from melanocytes at the dermal/epidermal junction. The incidence of melanoma is increasing more rapidly than any other malignancy in the US and a tripling in melanoma diagnoses since the 1970s has been observed in the UK in the 15-to-34-year-old age group.
Although treatment for localised melanoma is individualised with respect to surgical decisions and analysing biomarkers of metastatic potential, lack of validated molecular targets has hindered the development of personalised therapies for melanoma once it spreads beyond the regional nodes, historically. However, over the past ten years, much has been accomplished in elucidating the unique biology of this disease and now this research is coming to fruition.
The discovery in 2002 of an activating mutation in the BRAF gene first hinted at the feasibility of targeted therapies. Then the discovery that a blockade of CTLA-4 protein results in the eradication of melanoma tumour cells pointed towards possible immunotherapies. These findings have been clinically validated with the recent US approval of BRAF inhibitor vemurafenib (Zelboraf; Roche, Daiichi Sankyo) and anti-CTLA-4 monoclonal antibody ipilimumab (Yervoy; Bristol-Myers Squibb).
Marking a paradigm shift in the treatment of unresectable or metastatic malignant melanoma, these are the first new drugs since 1992 to be approved in this indication. Other potential targeted therapies include MEK inhibitor trametinib (GlaxoSmithKline [GSK]) as well as another BRAF inhibitor dabrafenib (GSK), both of which are in phase III trials.
Vemurafenib is an orally administered small molecule that selectively inhibits oncogenic BRAFV600E kinase as a treatment for solid tumours, including malignant melanoma, thyroid cancer and colorectal cancer. The BRAFV600E gene, a mutated form of the BRAF kinase gene, is associated with increased tumour aggressiveness, decreased survival, and is found in approximately 70 per cent of malignant melanomas and a large number of colorectal and thyroid tumours.
The pivotal phase III BRIM3 trial of vemurafenib for the treatment of BRAFV600E mutant-positive (mt BRAF) melanoma was initiated in January 2010. The trial enrolled 675 treatment-naive patients and compared vemurafenib (960mg twice daily) with dacarbazine to investigate the co-primary endpoints of overall survival (OS) and progression-free survival (PFS). Interim results announced in January 2011 showed that the trial met both primary endpoints, with the vemurafenib arm experiencing a remarkably extended PFS interval (5.3 vs 1.6 months; hazard ratio [HR] 0.26).
Unusually, patients in the control arm were given the option of crossing over to the treatment arm, even though the trial was not said to have been terminated, due to unequivocal benefit. Updated overall survival results presented at the 2011 European Multidisciplinary Cancer Congress showed an OS HR of 0.44 (95 per cent CI 0.33, 0.59), which favoured vemurafenib. Furthermore, after 6.2 months' follow-up, median OS in the vemurafenib arm has still not been reached.
Even though vemurafenib often leads to dramatic regression of tumour burden and symptom relief, the duration of response is limited by the seemingly inevitable development of resistance. The mechanisms of resistance do not appear to involve additional BRAF mutations, but rather residual RAF-RAF-MEK-ERK pathway activity or signalling via other molecules (PI3K, CRAF, COT). This will necessitate combination or sequential therapy with other agents, such as MEK inhibitors.
Dabrafenib is another highly specific inhibitor of mt BRAF. In fact, it inhibits mt BRAF about four times more strongly than vemurafenib, while maintaining a comparable selectivity for mt BRAF over wild-type BRAF (wt BRAF). Phase I results appear to be at least as impressive as the phase I results for vemurafenib, both in terms of safety and efficacy. In addition, responses have been seen in melanoma patients with brain metastases. Dabrafenib was moved quickly into phase III development by GSK in January 2011.
Unusually, patients in the control arm were given the option of crossing over to the treatment arm ... due to unequivocal benefit
Plexxikon, a subsidiary of Daiichi Sankyo, is also working on second-generation BRAF inhibitors, including those that do not stimulate RAF signalling in the setting of wt BRAF as vemurafenib does. This phenomenon is incompletely understood, but is thought to explain some of the skin toxicities seen with vemurafenib, such as the rapid development of squamous cell carcinomas, and may also facilitate resistance.
Ipilimumab is an anti-CTLA-4 monoclonal antibody that blocks the effects of the negative T-cell regulator CTLA-4, which inhibits T-cell proliferation, and promotes stimulation of adaptive immunity and T-cell activation. This appears to augment T-cell responses to tumour cells.
As first-line therapy, US approval for ipilimumab was supported by study 024 which compared ipilimumab + dacarbazine versus dacarbazine alone. Results were presented at the American Society of Clinical Oncology (ASCO) annual meeting in June 2011, which demonstrated an overall survival benefit for ipilimumab. However, the magnitude of the benefit (2.1 months; HR 0.72) was somewhat underwhelming. Nevertheless, fast-track status was granted in this indication.
As second-line therapy, ipilimumab 3mg/kg was launched in the US following approval by the Food and Drug Administration (FDA) in March 2011. It was approved in the EU in July 2011 and has since been launched in the UK.
In a phase III trial (study 020) used to support the regulatory filing, patients received second-line ipilimumab alone or in combination with the gp100 peptide vaccine MDX 1379 versus controls (patients who received MDX 1379 alone). The overall survival duration was significantly extended in ipilimumab recipients, compared with controls (10.0-10.1 vs 6.4 months; p<0.01).
However, there are still problems surrounding ipilimumab. It is a potentially toxic agent, with the prescribing information for the product including a boxed warning relating to immune-mediated reactions that include any organ system. The most common severe immune-related adverse events are enterocolitis, hepatitis, dermatitis, neuropathy and endocrinopathy. Ipilimumab is also expensive, costing an estimated $120,000 at the approved 3mg/kg dose. Study 020 used a higher 10mg/kg dose and could therefore be significantly more expensive. Furthermore, unlike vemurafenib, there is no viable biomarker (clinical or immunobiological) that permits identification of patients most likely to respond to ipilimumab. Plans are being made to combine ipilimumab with a variety of other melanoma agents and the ipilimumab development programme is poised to expand into other tumour types. However, the net benefit to patients and healthcare systems remains to be seen.
Trametinib is a highly specific inhibitor of MEK, the serine-threonine kinase that is activated by RAF in the RAF-MEK-ERK pathway. Phase I data shows a good safety profile, with the most common serious adverse events being rash (five per cent of patients) and diarrhoea (three per cent). For melanoma patients with mt BRAF, 27 per cent had a partial response (PR) and 45 per cent had stable disease (SD). Interestingly, 22 per cent of melanoma patients with wt BRAF also had PR. As with dabrafenib, trametinib was quickly moved into phase III development. A phase III trial of trametinib (METRIC) in patients with advanced or metastatic mt BRAF melanoma has completed enrolment of 297 patients in the US, Canada, Australia, EU, Norway, Switzerland and New Zealand and is now active. Patients have been randomised to treatment with trametinib or chemotherapy (investigator choice of paclitaxel or dacarbazine). The primary endpoint is progression-free survival and the expected completion date is September 2012.
This is an exciting time for research into treating unresectable or metastatic malignant melanoma. ...investigations into the use of combinations have barely begun
Although trametinib is the most advanced MEK inhibitor programme, Array BioPharma has two MEK inhibitors in phase II development for melanoma: selumetinib, which is partnered with AstraZeneca, and ARRY 162, which is partnered with Novartis. If trametinib is approved, one or both of these compounds may not be far behind.
As they do with the BRAF inhibitors, melanoma cells appear to develop resistance to trametinib relatively quickly. Preclinical studies suggest that inhibiting the RAF-MEK-ERK pathway at two points simultaneously may significantly delay development of resistance while offering an improved safety profile. To test this hypothesis, GSK has initiated a phase I/II study in which both the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib are administered. Preliminary results were presented at ASCO in June, showing that the combination is active (PR = 81 per cent, SD = 19 per cent) and possibly better tolerated than either agent alone. The incidences of squamous cell carcinomas and other hyperproliferative skin lesions, which are hallmarks of vemurafenib and dabrafenib monotherapy, were markedly reduced (<1 per cent) in the phase I portion of the combination trial. In addition, the incidence of rash, seen in 75-80 per cent of patients on MEK inhibitors, was only 25 per cent, with just a 2 per cent incidence of grade 3 rash or higher.
This is an exciting time for research into treating unresectable or metastatic malignant melanoma. In addition to targeted and immunological therapies recently approved or in advanced development, investigations into the use of combinations have barely begun. Not only might the combination of dabrafenib and trametinib provide an effective one-two hit against melanoma, but it and other combinations may also improve tolerability as well as efficacy. Although there is a long way to go, the future has never looked brighter for the treatment of this challenging disease.
R&D Pipeline was written by Melody Watson of Adis International (Wolters Kluwer Pharma Solutions) using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For further information on Adis services, contact Daniela Ranzani on +39 02 423 4562 or email: Daniela.Ranzani@wolterskluwer.com