PLX4032 Targets Melanomas with BRAF Mutation
Clinical Trials on Melanoma and Other Cancers Show Great Results
Nov 9, 2009
Melanoma is the most serious type of skin cancer and is mainly caused by exposure to UV radiation from the sun and other sources, such as tanning machines in solariums. More than 160,000 people are diagnosed with melanoma each year, including more than 50,000 people in the US and more than 10,000 people in Australia, which has one of the highest incidences of skin cancer in the world.
Clinical trials being conducted in the US and Australia have shown remarkable results in tumour shrinkage for a product known as PLX4032. Results were presented at the joint 15th Congress of the European CanCer Organisation (ECCO) and 34th Congress of the European Society for Medical Oncology (ESMO) in Berlin, Germany, in late September 2009.
What is PLX4032?
PLX4032 is a Plexxikon drug being co-developed with Roche under a 2006 license and collaboration agreement, and is a targeted therapy. The highly selective drug targets the BRAF V600E cancer-causing mutation that occurs in about 50-60 percent of melanomas and about six to eight percent of all solid tumours including colorectal, thyroid, ovarian and other cancers.
The drug is taken as an oral capsule. In tumour cases where the BRAF gene has mutated to form the cancer (which is in over half the cases), PLX-4032 selectively targets and inhibits tumour cells which contain this cancer-causing mutation. Cancer growth is stopped and existing tumours shrink and sometimes even disappear.
Phase 1 Trial Results for PLX4032
The initial Phase 1 study examined 21 patients whose tumours were shown on genetic sequencing to contain the BRAF mutation. They were given escalating doses of PLX4032 with remarkable results. Tumour shrinkage was seen at several sites including lung, liver and bone. Several patients also reported improvement in pain symptoms. More patients were then recruited for an extended Phase 1 study.
In the extension study, 31 patients were enrolled who mainly had the worst stage of metastatic melanoma and tested positive to the B-RAF V600E mutation. They were treated with PLX4032 at 960mg twice daily. Tumour shrinkage has been observed in the majority of evaluable patients in the extension study, reflecting a 70 percent response rate.
Side Effects of PLX 4032
Unlike chemotherapy, which attacks both good and bad cells, PLX4032 targets only the cancer. Because of the selectivity of the drug, only mild adverse effects have been seen in the trials for PLX4032 and included rash, joint pain, photosensitivity and fatigue. Squamous cell carcinoma of the skin was seen in 23% of trial patients, but was easily treated with excision.
Further Trials of PLX-4032
Phase 2 testing involves evaluating 960mg twice daily in about 100 BRAF positive patients who have progressed after at least one prior melanoma treatment. Enrollment is expected to be complete by the end of 2009. The randomized, Phase 3 trial is expected to start by the end of 2009 in first-line patients. Plexxikon is enrolling a second cohort of patients with colorectal cancer and expects enrollment to be complete by the end of 2009.
A companion diagnostic also is being co-developed in parallel with PLX 4032 to determine the BRAF mutation status of patients. This is so treatment can be targeted at those people most likely to benefit from it, as patients without the BRAF mutation are unlikely to respond. As melanoma has few treatment options available, it is hoped the FDA may fast-track the approval process once trials are complete.
References:
A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma
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