A brighter future

Patients with malignant melanoma, particularly metastatic melanoma, have long suffered from a lack of truly effective therapeutic options, despite the prevalence of the condition. Malignant melanoma is the seventh most common form of cancer in the US and, in countries such as Australia and New Zealand, skin cancer in general (including melanoma) is the most common form of cancer in adults.

Given the sheer number of public awareness campaigns urging preventative action, there are surprisingly few new drugs, and particularly targeted agents, in development for this difficult-to-treat and highly-aggressive form of cancer.

Only three agents have been approved by the US Food and Drug Administration (FDA) specifically for this condition, and just one of these was approved within the last 20 years.

Recently, however, there has been an upsurge in the development of targeted therapeutics for malignant melanoma. Last year, sorafenib (Nexavar), a targeted therapy approved by the FDA and globally for the treatment of kidney and liver cancer, was also undergoing evaluation for melanoma in combination with chemotherapy agents carboplatin and paclitaxel. Unfortunately, the phase III PRISM trial was suspended in April 2009 after interim analysis revealed that the trial had failed to meet the primary endpoint of progression-free survival (PFS).

In spite of the failure of sorafenib, three other targeted therapies are hot on its heels and, promisingly, all have reached phase III testing and now appear to have a reasonable chance of reaching the market.

Oblimersen
Genta's oblimersen (Genasense) is an antisense oligonucleotide targeting bcl-2 expression. This protein (bcl-2) aids the prevention of apoptosis — the intention is that oblimersen sensitises the cells to apoptosis by inhibiting bcl-2 expression. The company filed for approval of the agent in the treatment of melanoma in December 2003, but subsequently withdrew the application after a recommendation against approval.

It was noted, however, that patients with melanoma and normal lactate dehydrogenase (LDH) levels were more likely to exhibit better responses to treatment with the agent, which led to the phase III AGENDA trial being initiated in July 2007. Currently ongoing, this trial is examining the efficacy of the agent with and without dacarbazine in patients with normal LDH levels, constituting approximately two thirds of patients with melanoma. Although this trial is not due to be completed until March 2011, preliminary results have shown some improvements associated with oblimersen treatment.

Ipilimumab
One targeted agent that has perhaps received more attention than others currently in development is Bristol-Myers Squibb's (BMS) ipilimumab. This immunotherapeutic candidate is a monoclonal antibody targeting cytotoxic T cell lymphocyte-associated antigen 4 (CLTA-4), a molecule that plays a critical role in regulating natural immune responses. Thus, ipilimumab specifically blocks the inhibitory signal of CTLA-4, potentially leading to an increase in the immune system's T cell response in fighting disease – in this instance, melanoma. More simply put, the agent acts as a 'brake' on the immune system, theoretically allowing an augmented response against the disease.

Unfortunately, increasing the immune response also has the effect of increasing the number of immune-related adverse events (irAEs) associated with the agent. Although the severity of these effects can be reduced by treatment with steroids, results to date are suggestive of a correlation between response to treatment and the severity of these irAEs, such that treatment with steroids may in fact reduce a patient's response.

In early June, investigators presented results of a phase III trial of ipilimumab at the 46th Annual Meeting of the American Society of Oncology (ASCO 2010), wherein the agent demonstrated evidence of an overall survival (OS) advantage. Although these results must be viewed with a measure of caution — the OS benefit relies on comparison with historical controls rather than a true placebo group per se — they still demonstrate the great promise of this agent, as long as the risk/benefit profile can be maintained in favour of a clear benefit.  

PLX 4032
Last but not least among the targeted agents in phase III is PLX 4032 (Roche/Plexxikon), a small-molecule kinase inhibitor with strong specificity for the V600E mutant form of BRAF. Approximately 60 per cent of all melanomas exhibit this particular mutation, and although the agent is therefore only targeting a subset of the melanoma population, it will still have relatively widespread efficacy, as well as decreased toxicity because of its target specificity.

If phase III results prove as astoundingly successful as those seen in phase I trials, where a 70 per cent response rate was observed, this targeted candidate — which has potent efficacy and minimal toxicity — may well emerge as a 'holy grail' of melanoma treatment.

Making progress
Taken together, the future is getting brighter slowly for those living with malignant melanoma. Three promising targeted agents are currently in phase III trials, the first of their kind in this indication, and they could potentially become the first new treatments to be approved for patients with this pervasive and aggressive cancer since aldesleukin (Proleukin) in 1992.

There are also a number of other potential targeted agents and novel immunotherapies in earlier stages of clinical development for melanoma, including Pfizer's tremelimumab (another CTLA-4 inhibitor) and GSK's GSK2118436. It cannot come a moment too soon, but it appears that progress, and therefore hope, is finally on the way for the hundreds of thousands of patients worldwide who are living with malignant melanoma.

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The Author
Pipeline was written by Claire Pouwels of Adis International - Wolters Kluwer Pharma Solutions - using data derived from Adis R&D Insight, Clinical Trials Insight and inThought
For information on Adis services, contact Kuljeet Sohanpal on 0207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com

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