Summary
PLX-4032, a Plexxikon drug being co-developed with Roche, has shown remarkable results in a Phase I trial for melanoma and appears poised for rapid progression through Phase II and Phase III testing with perhaps accelerated FDA approval on the horizon.
Analysis
At ASCO 2009, Dr. Keith Flaherty of the University of Pennsylvania (and now Massachusetts General Hospital) presented data on Phase I testing of PLX-4032, a novel compound from Plexxikon, a privately held company based in Berkeley, CA, that has partnered with Roche to develop this compound.
PLX-4032 inhibits V600E mutated (oncogene) BRAF tyrosine kinase, the most specific such inhibitor to enter clinical testing to date. BRAF mutation occurs in 50-60% of melanomas and to a lesser extent in colorectal, papillary thyroid, ovarian and some other cancers. Over 90% of these mutations are point mutations, the V600E base pair switch. In laboratory testing, PLX-4032 specifically blocks the activity of the mutated but not wild-type BRAF mutation, causing apoptosis or programmed cell death.
This Phase I study examined primarily melanoma patients whose tumors were shown on genetic sequencing to contain the V600E mutation. A total of 21 patients were treated with escalating doses of the drug. The drug appeared to be well tolerated at doses providing projected therapeutic drug levels, although dose limiting toxicity was ultimately reached. A small cohort (3 patients) of papillary thyroid cancer patients was also treated.
The results were remarkable. Of the 16 melanoma patients with the V600E mutation, 9 had partial responses , 6 had stable disease and one had progressive disease as their best responses. None of the 5 non-mutated melanoma patients had any responses. Also, of the three papillary thyroid cancer patients treated, one had a partial response and two had stable disease.
The clinical and radiologic effects were reported as rapid and dramatic. Tumor shrinkage at multiple organ sites were seen, including liver, lung and bone. (No patients with brain metastases were treated in this trial.) Several patients also had dramatic clinical improvement in symptoms associated with their disease, such as pain.
In summary, these trial results represent a dramatic and exciting proof of concept for targeted therapy against a specific identified transforming oncogene in melanoma. Additional trials will be necessary to confirm these early results, and the sponsors appear poised to make both Phase II and Phase III trials happen soon. If these results are confirmed, accelerated approval in a disease like melanoma, with few treatment options available, is a possibility. Like Gleevec treatment for Philadelphia chromosome positive CML over ten years ago, PLX-4032 treatment of melanoma with V600E mutations not only makes genetic sense, it also appears to work exactly as it should.
Analyses are solely the work of the authors and have not been edited or endorsed by GLG.
