Lorne 2012: Melanoma treatment blasts off

Only a decade ago, being diagnosed with metastatic melanoma was dire news indeed. While around eight out of 10 individuals can be rid of melanoma through surgery, once the cancer spread throughout the body, it is notoriously difficult to treat.

With Australia having the highest incidence of melanoma in the world, this has been of pressing concern particularly to researchers like Richard Kefford, Professor of Medicine at the University of Sydney, Westmead Hospital and Director of the Westmead Institute for Cancer Research, and Co-Director of Research at Melanoma Institute Australia.

Yet in just the last few years there has been something of a revolution in the treatment of metastatic melanoma, says Kefford. He is currently involved in evaluating a suite of new drugs that are making real inroads into treating this recalcitrant disease.

“Until these drugs came alone, less than five per cent of patients survived more than two years,” he says. “We had no effective drug treatment whatsoever. I myself have conducted over 40 clinical trials of agents in metastatic melanoma, and none of them prolonged survival. That’s the dismal landscape we were moving from.”

Breaking BRAF

The breakthrough was the discovery in 2002 of a mutation in a gene called BRAF, which was found in around 50 per cent of metastatic melanomas. It turned out this gene coded for a protein kinase that is involved in a crucial signalling pathway within the cancer cells.

The mutation effectively made BRAF ignore other molecules that would turn down its activity, causing it to overstimulate other kinases further down the pathway, encouraging cell proliferation and survival. This made BRAF a textbook oncogene, and an attractive target for a new range of drugs that inhibit the kinase.

Frustratingly, initial attempts fell flat. One of the first employed sorafenib, marketed by Bayer and Onyx Pharmaceuticals as Nexavar, and approved for sale by the U.S. Food and Drug Administrations in 2005 for treatment of non-melanoma cancers.

Sorafenib inhibits a number of kinases, but is appears to be a relatively poor BRAF inhibitor. It was more potent against others, including BRAF’s cousin CRAF. While hopes were high, trials yielded disappointing results, with the drug having a minimal effect on metastatic melanomas.

Another contender was Roche’s PLX4032, also known as vemurafenib, which showed far more promising results, particularly when given to patients who were screened for the BRAF mutation.

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A trial reported in late 2010 found 81 per cent of patients given vemurafenib experienced partial or complete shrinkage of their tumours and stayed in remission for an average of seven months, which is dramatically higher than the usual 10 to 15 per cent who respond to conventional treatments.

GlaxoSmithKline also released a mutant BRAF inhibitor, GSK2118436, that demonstrated very similar levels of tumour shrinkage as Roche’s vemurafenib.

Kefford has worked with both, including doing the first-in-human trial with the GSK drug at Westmead, and was amazed at the results. “When you inhibit BRAF, you get a dramatic and immediate cell cycle arrest and, under certain circumstances at least, you get cell death,” he says.

“What you see in the clinic is that, within days, as the metabolism of tumour shuts down, the patients get a massive improvement in quality of life and in wellbeing, and that parallels a complete shutdown of the tumour on FDG-PET. Over a period of weeks a majority of patients get shrinkage of their tumours.”

The two drugs both have only mild side effects, with vemurafenib notably causing some photosensitivity and GSK2118436 causing fever, but both are minor and are manageable, says Kefford.

GSK’s GSK2118436 also has the added and surprising advantage of targeting brain metastases, which was unexpected as it was designed not to enter the brain, so somehow it’s bypassing the blood-brain barrier, but to positive effect.

However, despite these enticing results, there was a catch, says Kefford. “Very few patients get complete remission. So there’s a significant problem of drug resistance.” Progression occurs in around half the patients after seven months, and very few patients eliminated the cancer completely. After relapse, the tumours returned and remained resistant to treatment.

“Obviously this has led to some intensive studies of the mechanisms of resistance. There’s now well described set of abnormalities that occur under drug inhibition, and the melanomas select out ways to get around the block.”

It seems that while the tumours are addicted to that kinase pathway – which goes from BRAF to MEK to ERK – they find ways to bypass BRAF and kick the remainder of the pathway into gear further down the track at MEK. There also appears to be multiple mechanisms by which the tumours bypass BRAF, but most of these mechanisms are still reliant on MEK further down the signalling pathway.

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Double action

Thus all is not lost: MEK is also a suitable target for inhibition, and one current thrust of Kefford’s research is investigating using BRAF and MEK inhibitors in combination. “We, and others, are currently involved in a phase I study putting these two inhibitors together, and that turns out to be very exciting,” he says.

“It also happens that some of the side effects of the BRAF inhibitor is paradoxical induction of squamous cell carcinomas. And it turns out that when you put the MEK inhibitor in combination with it then you block that side effect.

“So you’re getting a very interesting and unique development in oncology, where you put two anti-cancer drugs together and you get less side effects. So it’s turned out to be a very safe combination, and we hope, superior in both activity and toxicity to using BRAF inhibitors alone.”

Kefford is currently pursuing the combination therapies, and is hopeful that they might lead to a significant step forward in the treatment of metastatic melanoma. He’s also excited about the prospects of combining these kinase inhibitors with immunotherapy, which has also been making some inroads against melanoma.

Thus a multipronged approach might enable a patient to eliminate the tumours before they have an opportunity to mutate and adapt to the therapies.

A great deal has happened over the past few years in treating metastatic melanoma, which was once considered to be one of the more intractable cancers. The discovery of the mutant BRAF and the melanoma’s addiction to that kinase pathway, and the development of kinase inhibitors, has been a significant milestone in the treatment of the cancer.

Kefford expects 2012 to be another momentous year, with several key studies underway and some important results to be released at the American Society of Clinical Oncology meeting, which will be held in Chicago in June.

Kefford compares the end goal of all these studies to the space race of the 1960s. “I liken where we’re at as the Sputnik launch phase in the race to the moon,” he says. “It’s a big step forward, but there’s still a hell of a long way to go. But compared to where we were, we didn’t even have jumping jacks four years ago.”