Early results of a trial found that a new drug that targets a genetic mutation found in over half of melanoma cases and some other cancers caused tumors to shrink and patients to live around 6 months longer without their disease getting worse, including those whose cancer had spread to the liver, lung and bone.

The results of the phase I trial on the experimental drug PLX4032 were released earlier this week at the American Society of Clinical Oncology conference in Orlando, Florida. The drug is being developed by Roche and Plexxikon.

Principal investigator Dr Keith T Flaherty, assistant professor at the Abramson Cancer Center of the University of Pennsylvania, said that:

“PLX4032 has shown both tumour shrinkage and delay in tumour progression in patients whose tumours harbour a BRAF mutation, as well as improved quality of life for symptomatic patients.”

“Seven years after BRAF mutations were first identified we have validation that this mutation is a cancer driver and therapeutic target,” he said, adding that he and his co-investigators were very excited about this new development, especially for their melanoma patients for whom there are few treatment options.

The gene mutation also occurs in about 10 to 15 per cent of colorectal tumors and 8 per cent of other solid tumors, said the researchers.

The trial showed that patients treated with PLX4032 had a median progression free survival of at least six months, including those with advanced metastatic cancer that had spread to other organs such as liver, lungs and bone. Current treatments usually give patients with advanced stage melanoma about two months extra life before their disease progresses.

The researchers also found that:

  • PLX4032 was well tolerated at therapeutic doses.

  • Nine mutation-positive melanoma patients showed partial responses and four mutation-positive melanoma patients showed minor responses.

  • Disease control lasted up to 14 months with continuous therapy, with many responding patients still receiving treatment.

  • A small group of patients without the BRAF mutation did not respond to treatment, and progression-free survival was less than two months, consistent with historical data.

  • Drug-related adverse events included rash and photosensitivity and were classified as mild in grade.

Roche also reported that:

“Serious adverse events, including diagnosis of cutaneous squamous cell carcinoma, were observed in some patients after chronic treatment; however the safety profile has been warranted favourable for this population and the trial authorised to proceed to the next stage of investigation.”

PLX4032 targets and destroys cancer cells that carry the BRAF mutation.

BRAF is a gene that plays an important role in cell growth and division. The mutation, however, leads to uncontrolled cell growth and division which then causes 60 per cent of melanomas, the most deadly form of skin cancer, and about 8 per cent of all solid tumors.

Roche told the press they expect the new drug’s “potency and selectivity” will lead to a treatment that is “both effective and well tolerated”.

Roche and its partner Plexxikon are also working on a companion diagnostic that will help identify which patients have the BRAF mutation.

The companies are now planning the next stage: bigger trials and a registration programme starting later this year.

If this goes well, they will launch a tissue-based companion diagnostic test, which the companies describe as “another step forward in personalising cancer treatment”.

The two companies want to extent the use of PLX4032 for other cancers that harbour the BRAF mutation, and they are also developing the companion diagnostic test to select patients for clinical trials and then later for treatment with the drug.

Malingnant melanoma is the most serious form of skin cancer and about 160,000 people worldwide every year are diagnosed with it.

It is treatable if caught early, but once it has spread to other organs, the patient’s prospects are not good. Fewer than 2 per cent of patients with systemic metastases live more than two years.

Roche said the results on the new drug represent not only a step forward in understanding how to treat malignant melanoma but they also represent:

“A significant advance in the use of biomarkers and diagnostic tools and the potential benefits of tailoring cancer treatment to individual patients.”

“Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer.”
ASCO Abstract #9000, presented Monday 1 June 2009.
J Clin Oncol 27:15s, 2009 (suppl; abstr 9000)

Sources: Roche, ASCO abstracts, Vanderbilt University.

Written by: Catharine Paddock, PhD