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Melanoma: new treatments and hopes

Published on 19/09/11 at 07:30am
Lorena Tonarelli
metastatic melanoma
A patient with metastatic melanoma

It usually starts with a subtle change of colour or shape in an existing mole. But if left undiagnosed and untreated, this seemingly harmless change could be the beginning of one of the most difficult-to-treat solid tumours: melanoma.

As its name suggests, melanoma most commonly develops from skin cells that produce melanin (the substance that gives the skin its natural colour), but it can also form in the eye and in the intestine. The cause of melanoma is still unclear, but the evidence so far points to sun exposure and genetic makeup playing a major role. Indoor tanning seems to be just as dangerous, increasing the risk of developing the disease three-fold.

Melanoma is mostly curable when treated in its early stages, but if not caught in time, the disease can progress. In its late stages, the average survival rate is just six months with a one year mortality rate of 75%, making it one of the most aggressive forms of cancer. These rates are based on a meta-analysis of 42 phase II trials of more than 2,100 previously-treated and treatment-naïve patients with Stage IV metastatic melanoma conducted by multiple co-operative groups from 1975-2005.

Moreover, the American Cancer Society estimates that melanoma has one of the fastest growing incident rates of all cancers. Despite major research efforts, the mortality rates associated with metastatic melanoma remain high. There are an estimated 48,000 deaths every year globally and this number is growing steadily. Melanoma typically affects people over 50, but is becoming more common among younger individuals as well.

Patients with advanced melanoma have very few treatment options. They are advised to undergo surgery, and chemotherapy afterwards. The latter is risky, since it also destroys healthy cells, and has limited benefits.

“This often comes as a shock to patients,” says Dr Russ Hargreaves, from cancer charity Macmillan’s information and support centre.  “They hear a great deal about a wide range of options for other types of cancers, like breast or prostate cancer, so they are disappointingly surprised by the lack of treatments for melanoma.

Beyond surgery and chemotherapy

The outlook for these patients has been bleak for many years, but this now looks set to change. Over the last ten years, important discoveries in cell signalling pathways that control cell growth have led to an increase of research activities into new ways to prevent or stop melanoma.

As a result, the majority of today’s big players in the pharma industry have at least one candidate for the disease in the pipeline. Ranging from genetically-engineered molecules to vaccines and antibodies, the new agents could eventually lead to a significant step forward in the fight against melanoma.

Unsurprisingly, the competition is fierce. Leading the pack is Bristol-Myers Squibb with Yervoy (ipilimumab), a recombinant, human monoclonal antibody. Administered intravenously, Yervoy works by blocking a molecule found on T-cells called cytotoxic T-lymphocite antigen 4 (CTLA-4), which is thought to reduce the immune system’s ability to fight cancer.

In March, the drug was given the go-ahead by the FDA as a first- and second-line treatment of late-stage or metastatic melanoma, the form that cannot be surgically removed. European Medicines Agency approval  followed in July, and the drug is expected to be launched in Europe shortly. The approvals were based on the results from a phase III study showing for the drug a median overall survival of 10.1 months, compared to 6.4 months for gp 100, a phase II experimental cancer vaccine. The decision made Yervoy the first and only approved agent with demonstrated benefits for melanoma. It is estimated that the drug will achieve $820 million to $1.7 billion in annual sales, by 2015.

BRAF inhibitors

But there are a number of rival treatments not far behind. Zelboraf (vemurafenib) (also known as RG7024 and PLX4032) has been developed by Roche in collaboration with Plexxikon, a member of the Daiichi Sankyo Group. This drug takes a different approach against melanoma,  targeting and blocking a mutated form of a protein kinase called BRAF. This is found in approximately 40-60% of patients with advanced melanoma, and thus requires a companion diagnostic to detect which patients will benefit and which will not.

The BRAF protein is part of the cell signalling pathway that controls cell growth in several body tissues. It was recently discovered that a mutation in the BRAF gene, known as V600 BRAF mutation, causes the protein to become abnormally active, leading to the rapid and uncontrolled cell growth characteristic of cancer. Zelboraf works by inhibiting the activity of BRAF with the V600 mutation, suppressing the growth of cancer cells, which, in turn, leads to tumour shrinkage.

In a recent phase III trial (BRIM3), Roche’s candidate reduced the mortality risk of patients with previously untreated BRAF V600 mutation-positive metastatic melanoma by a staggering 63%, compared to chemotherapy. What’s more, the drug reduced the risk of the disease getting worse by 74 per cent.

Reliable, conclusive data regarding median overall survival are not available, yet, due to the small number of patients in long-term follow-up. However, findings from a previous study suggest that patients on vemurafenib could live up to 10.5 months, compared to 7.8 months if they received chemotherapy.

The most common Grade 3 or higher adverse events were keratoacanthomas, rash, joint pain, sensitivity to the sun and fatigue. Squamous cell carcinoma (cSCC, a common type of skin cancer) was reported in 12 percent of patients. In cases of cSCC, the lesions were removed and the patients continued with treatment.

The drug was approved by the FDA in August under the  name Zelboraf - Roche awaits a decision by the EMA at the end of this year. Analysts forecast that Roche’s oral agent could earn the company and co-developer Plexxikon $452 million (£264 million) to $1 billion (£622 million) annually, by 2015.

Other agents in late-stage development include GlaxoSmithKline’s BRAF V600 inhibitors, GSK2118436 and GSK1120212, and Amgen’s first-in-class cancer vaccine, OncoVEXGM-CFS.

GM-CSF stands for ‘granulocyte and macrophage colony stimulating factor’. It is a growth factor that can encourage the immune system to recognise and attack cancer cells. Small amounts of GM-CSF are produced naturally in the body. But you can have larger amounts by injection.

Pfizer’s tremelimumab (CP675,206) is currently in phase II, and is a fully human igG2 monoclonal antibody. The drug’s development was shelved in April 2008, only to be revived in early 2010. Pfizer announced that it had discontinued a phase III trial for patients with advanced melanoma after the Data Safety Monitoring Board (DSMB) review of interim data showed that the trial would not demonstrate superiority to standard chemotherapy. But analysis of the data from this trial identified the biomarker which will be used in patient selection for the upcoming trial.

Meanwhile, Novartis’ Tasigna (nilotinib), a BCR-ABL kinase inhibitoris also being studied for particularly hard to treat sub-types of melanoma. Tasigna works by blocking the c-kit protein, which plays a role in numerous cancers.

Dr. Howard Kaufman, director of the Rush University Cancer Center in Chicago and lead investigator of the study at Rush, said that this kind of ‘targeted’ therapy holds out hope of transforming cancer from a lethal disease into a chronic, but manageable disease.

Targeting mutations

The genomic revolution is supporting greater understanding of the disease, and uncovering many more sub-types. Richard Marais is a professor of molecular oncology at the London Institute of Cancer Research (ICR), and leads the division of cancer biology. “The novel drugs have already changed the way we approach the disease,” he says. “Until now, patients could only receive drugs that alleviate the symptoms of melanoma. The new agents target the mechanisms that underlie the disease, to stop or slow it down.”

Marais is one of the researchers who originally discovered BRAF mutations in melanoma, and is currently working at the development of several BRAF inhibitors and an anti-cancer gene therapy technique known as Gene Directed Enzyme Prodrug Therapy (GDEPT). He says that Zelboraf, in particular, “probably represents the first breakthrough in melanoma research for 30 years.”

The drug is not a solution for all, however. As we have seen, it acts by selectively blocking the cancer-causing V600 BRAF mutation. This particular type of mutation is found in about 8% of all tumours, and in about 40 to 60% of malignant melanomas. It is only in these cases that vemurafenib can be effective. One implication is that, before receiving treatment, patients need to be tested for the presence of V600, to ensure that this particular approach for melanoma will benefit them. In this regard, Roche has developed a testing tool - the cobas Mutation Test, which was also approved by the FDA in August.

People were enrolled in the BRIM3 study based on the results of this investigational diagnostic, which Roche says, allows for the rapid and accurate identification of patients with the mutation. Even if a patient is thought to be a suitable candidate for a BRAF inhibitor like Zelboraf, and starts receiving the drug, resistance can develop quite rapidly. Studies on zebra fish embryos conducted by a team of researchers at Children’s Hospital Boston, led by Dr Leonard Zon, suggest that resistance could be overcome by administering Zelboraf in combination with Sanofi’s Arava (leflunomide).

Leflunomide is already approved and marketed for the treatment of certain forms of arthritis.

The researchers are now planning a study to test the efficacy of the drug in combination with Zelboraf for the treatment of malignant melanoma.

Side effects are another concern. In patients taking the drug, these are generally mild, and mostly include joint pain. However, about 12% of participants in the trials developed skin lesions due to a curable type of cancer known as squamous-cell carcinoma.

“Patients do have some problems, so we need to learn how to make the drug work better and give longer remission to the patient,” Marais says. “However, to date, none of those problems have precluded people from taking the drug, and most feel better on it than without it. To my mind, the benefits massively outweigh the disadvantages.”

More serious are the safety concerns associated with Yervoy. Its benefits, in terms of increased survival, come with a high risk for potentially fatal autoimmune reactions.

About 13% of melanoma patients treated with the drug developed such things as hepatitis, enterocolitis, epidermal necrolysis, endocrinopathy and neuropathy, in trials.

This did not stop the FDA from granting approval, which shows that Yervoy’s benefits outweigh the risks. However, the regulatory agency has issued a Risk Evaluation and Mitigation Strategy (REMS), to warn healthcare professionals about the serious side effects associated with the drug.

And then there are the costs to consider. All the novel melanoma drugs are likely to be very expensive. Take Yervoy, for example. Patients on this agent need a 90-minute infusion every 20 days for a total of four doses. The full course of treatment costs an astonishing $120,000 (£74,400).

Combination treatment

As in other types of cancer, combining treatments is seen as the way forward. BMS and Roche recently agreed to collaborate on trials combining their two drugs to treat patients with BRAF-mutated metastatic melanoma.

The two companies will conduct a phase I/II study to determine the safety and efficacy of the combination, and may conduct further development of the combination. “We have made significant progress in treating metastatic melanoma and hope to further improve outcomes by combining two agents that target this deadly disease in different ways,” said Hal Barron, Roche’s head of global product development.

The companies may conduct further work into the safety and efficacy of the combination. Roche is also conducting a trial  combining its drug with another of its pipeline compounds, GDC-0973, a MEK inhibitor, in patients who previously received Zelboraf alone. MEK is a protein involved in cell growth and survival.

A PATIENT’S PERSPECTIVE

Stephen Brothwell, from Stoke-on-Trent, is a melanoma survivor of three years. “When I was first diagnosed with the disease, in December 2008, surgery was the only option. So, I think that having new treatments is a good thing, especially because it looks as though they are going to make a real difference in the future.”

He says patients would like to know more about new ways to treat melanom, but the information available to them is often lacking or misleading. “Rarely do I pick up a paper without seeing some news about a drug that has been found in trial to be ‘the answer to cancer,’” Brothwell says. “You see a patient’s face light up, because it seems as though there is hope, suddenly. Then you read carefully, and discover that the results refer to a phase I study.” It can take years from this stage before a drug is approved by regulatory bodies, assuming that its benefits are confirmed in late-stage studies. “And even if it is approved for clinical use, we still have to persuade the PCT to pay for it.” On the other hand, the life expectancy for malignant melanoma can be as short as a few months after surgery. “So, if you are a vulnerable cancer patient, reading that sort of news can be quite hurtful.”

Not only that. There appears to be a general lack of information about how to take part in trials.

This kind of information is not widely available and, yet, many patients would like to be given the chance to participate in one. Brothwell says: “Personally, I am aware of trials and new drugs under development because I am on the National Cancer Research Institute’s melanoma clinical studies group. But the majority of patients have to rely on their clinical nurse specialist or their consultant for this type of information, as well as accurate information about new melanoma treatments and their efficacy and safety performance in studies.”

Cancer support groups also play a major role in this regard. Hargreaves, the manager of Macmillan’s information and support centre, says: “One of our priorities is to spend time with patients and their families to make them aware of new classes of drugs and how these might impact on a patient’s life, since it’s absolutely crucial that they make informed choices about treatment.” Macmillan has recently campaigned for the introduction of the £200 million Cancer Drugs Fund to improve access to drugs, and continues to campaign to ensure greater access to new treatments, as they become available.

For Brothwell, the organisation’s help has been invaluable. “I cannot praise them highly enough, especially for the help they gave me to set up our melanoma support group.”

He refers to the Stoke-on-Trent melanoma support group (also called ‘The Moles’), of the University Hospital of North Staffordshire. “The group meet every month, and is making a positive difference in the life of so many patients, especially newly diagnosed ones,” Brothwell says. “It’s good to talk to people who had the same disease that you have got, and to learn from them that you can make a full recovery.” Melanoma is, nevertheless, an incredibly difficult cancer to live with. Many patients will have an operation to remove the tumour, and will have to live with the scarring afterwards. “These are the lucky ones,” says Hargreaves. “What’s more, their cancer may return, which can be terribly difficult to adjust to.”

In view of this, the fact that people with melanoma who until now had very few treatment options, could benefit from at least two breakthrough novel drugs in the non-distant future is encouraging, and cautiously reassuring.

Hopefully, together with increased awareness, truthful information, and a great deal of support from healthcare professionals and support organisations, a wider choice of treatments will lead to the point - as Hargreaves notes - where: “the threat abates and patients will begin to live their lives again.”

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