A phase 1 clinical trial using a new formulation of an experimental drug that targets the BRAF cancer gene, has shown early promise in treating melanoma in patients with a mutated form of the gene and whose skin cancer has progressed to the metastatic stage.

A paper on the trial appears in the 26 August issue of the New England Journal of Medicine, NEJM.

Lead and corresponding author, Dr Keith Flaherty, director of Developmental Therapeutics at the Massachusetts General Hospital (MGH) Cancer Center in Boston, told the press that:

“Metastatic melanoma has a devastating prognosis and is one of the top causes of cancer death in young patients.”

In the US, the current prognosis for surviving metastatic melanoma, where the skin cancer has spread to other parts of the body, is about 9 months. About 9,000 Americans die of the disease every year.

Many melanomas have a mutation of BRAF that activates a protein called serine-threonine kinase (B-RAF or BRAF) that drives the growth of cancer cells. The mutation is called V600E. These mutations of BRAF also occur in other cancers.

In this phase 1 trial, Flaherty and colleagues from other research centers in the US and Australia, found that a new formulation of PLX4032 (an earlier formulation had not succeeded in a previous trial), inhibited the V600E mutation of BRAF and 26 of the 32 patients they treated with it (81 per cent) showed a partial or complete response that lasted at least 19 months.

The BRAF mutation that the new drug targets is active in more than half of all melanomas, and until this discovery patients and doctors had very few, reliable therapies. Flaherty said “these findings can really change the outlook for patients whose tumors are fueled by this mutation”.

If caught in the early stage, melanoma can often be removed surgically, but once the cancer has spread to other parts of the body, the chances of survival are vastly diminished.

There are FDA-approved drugs available, interleukin-2 and dacarbazine, however only 10 to 20 per cent of melanoma patients respond to them.

Researchers at the Sanger Institute in Britain discovered that the BRAF mutation drives cancer cell growth in 2002. Shortly after this Flaherty, who was at the University of Pennsylvania Abramson Cancer Center, began to investigate potential drugs that target the mutation as a way to interfere with tumor growth.

After experimenting with one drug that didn’t work, he teamed up with co-author Dr Paul Chapman from the Memorial Sloan-Kettering Cancer Center in New York, and they started working on PLX4032, an experimental drug developed by Plexxikon and licensed to Roche Pharmaceuticals, the two companies that funded this latest NEJM study.

The first trial with PLX4032 (also known as RG7204) did not succeed, but this latest study uses a new formulation that increases the bioavailability of PLX4032.

The first stage of the study was to establish the effective dose. This took place in six sites in the US and Australia and involved 55 cancer patients with metastatic melanoma.

The researchers gave the patients escalating doses of the drug until they developed unacceptable side effects. The results of this stage showed that 16 of the patients had melanomas containing BRAF mutations, and in 11 of these, their tumors shrank very quickly and in one case, even disappeared altogether.

Tumors also shrank in three other patients with thyroid cancers containing BRAF mutations, after they received the PLX4032 treatment.

For the second stage of the study, Flaherty, Chapman and colleagues enrolled 32 patients with BRAF-mutated melanoma and treated them with PLX4032 at 960 mg orally, twice a day, the dosage established in the first stage.

The participants continued receiving the treatment until disease progression. They all underwent pharmacokinetic analysis and tumor-response assessments, and some also had biopsy tests before and during treatment.

The tumors in 26 of the participants shrank by more than 30 per cent, which is the threshold for clinical response. In two of the participants the tumors disappeared completely, and another two also showed some reduction in tumor size.

The researchers estimated that the median progression-free survival among all patients was more than 7 months.

Flaherty, Chapman and colleagues concluded that:

“Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the BRAF mutation resulted in complete or partial tumor regression in the majority of patients.”

Flaherty said the figures suggest PLX4032 can shrink tumors in about 90 per cent of patients with BRAF-mutated melanomas.

He said it was “truly remarkable” that the results also showed the drug is reliable. Patients in pain and feeling fatigued began to feel better within a week of taking the drug, giving them a better quality of life, he added.

Unfortunately, as often seen in trials of targeted cancer treatments, resistance to the drug developed in many of the participants, and their tumors eventually started growing again.

An MGH statement reported that the latest information shows tumor suppression has lasted from three months to more than two years, with an average progression-free survival of eight months.

Further studies are now looking at how resistance develops and how it might be possible to prevent or delay it. Two clinical trials have already started at MGH: one phase 2 trial with patients who didn’t respond to the FDA-approved drugs, and another phase 3 trial that compares PLX4032 with dacarbazine in newly diagnosed patients.

Flaherty said this was the first time that a “credible first treatment option for metastatic melanoma” has been available.

It has “completely transformed how we approach treatment for patients with the BRAF mutation,” he added, explaining that while “we don’t know how long response may last, the ability to beat this disease down in the short term will buy us time to strategize second-line therapies and design the next generation of trials”.

“Inhibition of Mutated, Activated BRAF in Metastatic Melanoma.”
Keith T. Flaherty, Igor Puzanov, Kevin B. Kim, Antoni Ribas, Grant A. McArthur, Jeffrey A. Sosman, Peter J. O’Dwyer, Richard J. Lee, Joseph F. Grippo, Keith Nolop, and Paul B. Chapman.
N Engl J Med, 2010; 363:809-819.
DOI: 10.1056/NEJMoa1002011
Published online on 26 August 2010

Additional source: Massachusetts General Hospital .

Written by: Catharine Paddock, PhD