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Melanoma drugs slow disease, boost hopes for combination therapy

Two melanoma drugs have been shown to slow the disease in large studies of patients with advanced cancer, according to results presented on 5 June at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago and published in the New England Journal of Medicine.

One of the drugs is the famed vemurafenib (formerly known as PLX4032), which targets cancers bearing a mutation in the BRAF protein. Last year, researchers reported that the drug shrank tumours by at least 30% in 24 of 32 patients with metastatic melanoma. (See ‘Rare victory in fight against melanoma’ for more.)

Now, researchers report that vemurafenib reduced the relative risk of death by 63% compared to an older chemotherapy called dacarbazine in a phase 3 trial of 675 patients with the BRAF mutation. After six months, 84% of the patients on vemurafenib were still alive, compared to 64% of those on dacarbazine.

The drug worked so well that an interim review of the data led study monitors to recommend that patients in the control arm of the study receive vemurafenib as well.

Roche, which makes vemurafenib, also announced on Sunday that vemurafenib would receive a priority review by the US Food and Drug Administration (FDA). A decision on the drug’s approval is expected by late October.

It is not yet known how vemurafenib impacted the median length of time patients lived (also known as ‘overall survival’). What is clear, however, is that the effects of vemurafenib are short-lived: tumours activate pathways that circumvent the drug, and typically resurge within a year. As a result, drug developers are eager to develop combination therapies that might slow the emergence of resistance by blocking off a tumour’s escape routes.

At the ASCO meeting on 6 June, researchers at the London-based pharmaceutical firm GlaxoSmithKline are slated to present early results from one such trial – a combination of its own BRAF inhibitor and a drug that inhibits another protein called MEK. The study in 45 patients found that the combination was no more toxic than either drug alone.

The BRAF mutation is found in about 60% of all melanomas, and also about 8% of other solid tumours. Roche is also studying the drug in thyroid cancer, but early results presented at last year’s ASCO meeting suggested that the drug had little impact on colon cancer, despite the dramatic results in melanoma.

Meanwhile, on 5 June researchers also presented new data on the recently approved melanoma drug, ipilimumab (affectionately known as ‘ipi’). That drug, which fires up the immune system to attack cancer cells, was approved by the FDA in March. In the new study of 502 patients, survival was improved by just over 2 months overall – a disappointing decline from the 4 added months of overall survival suggested by previous work. Some patients respond dramatically to the treatment and live for years, but such responses are relatively rare and at present there is no clear test to determine which patients are likely to respond.

Those rare but long-lasting responses have led researchers to wonder if it might be possible to develop a combination therapy that would harness both the broader efficacy of vemurafenib, which works in 48% of patients with the BRAF mutation, and the more durable effects of ipi. The answer to that question may be on its way: on 2 June, Roche and Bristol-Myers Squibb, the New York-based pharma firm that makes ipi, announced that they would unite to test the two drugs in combination.


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