Better ways to use BRAF inhibitors for melanoma!!!

In 2011, the FDA approved vermurafenib (Zelboraf) for the treatment of late stage melanoma patients with BRAF positive mutations. (About 50% of all melanoma patients will test positive for the required mutation...though with new, more refined testing perhaps that number will rise...as patients already tested and found negative with older tests have been found to be positive using the newer techniques.)  BRAF positive melanoma patients who respond to Zelboraf (about 70-80%) experience a rapid and miraculous decrease in their tumors that lasts for about 7-8 months.  At that point, most patients' tumors cease to respond to the drug and develop a lethal form of drug resistant tumors.  There are amazing exceptions to this however, from patients themselves reporting a durable and constant response to Zelboraf of more than 13-35 months.  (You rock Dick_K and jmmm!!!!!)  Sadly, they are the exceptions.

Sooooo, how are we going to make 2013 better??

On January 9, Sciencedaily.com reported (with info largely from a report in Nature, 2013) that researchers in California and Switzerland have discovered that when melanoma cells develop resistance to vermurafenib (Zel) they have simultaneously developed an addiction to it.  Once "addicted", the melanoma cells actually use vermurafenib to foster rapidly progressing, drug resistant tumors.  The teams began a study of dosing mice with melanoma in an "on-again/off-again treatment schedule" and found that this method of dosing prolonged the lives of mice with BRAFi resistant melanoma tumors.

Specific studies in humans with this sort of on-again/off-again dosing pattern are being formally planned. Additionally, doctors have gradually been noting that in their patients who developed resistance to BRAF inhibitors and went on to other therapies, but were then reintroduced to Zel later, did, in fact, RE-respond.  Now, medical opinion is heading toward the idea of reducing tumor burden in patients with Zel then, before tumors develop resistance, switch to a different therapy like ipi or anti-PD1.  Or, as noted in the article, use an interrupted pattern of dosing with Zel in the first place.  Another way of trying to maintain the response of Zel is to combine it with MEK (more on that later) or with other drugs.  Furthermore, there is recent evidence that the use of BRAF inhibitors increases the amount of melanoma specific antigen present and may be a rationale for making the tumor cells more susceptible to immune therapy. Thereby, providing a rationale for planned sequencing of BRAF inhibitors followed by immunotherapy.  However, the proof is in the pudding and that remains to be proven.

Bottom line....better.  Keep up the research...AND...hang in there ratties!!!! - c