The first of a new kind of lab test and a first-in-the-class therapy have been approved by the FDA. Zelboraf (vemurafenib) was approved by the FDA under the priority review program. It is a novel--yet possibly essential approach to melanoma as it targets a specific gene (BRAF V600E) which 40-50% of melanoma patients have. The drug has been approved with a diagnostic lab test to show if the mutation is present (cobas 4800 BRAF V600 Mutation Test). The good news is a mean 5.3 month progression free survival. The disappointment has been a 0.9% complete response rate and drug resistance.
Approval date: August 17, 2011
Let’s take a closer look at the concepts involved in this medicine. One of the newest concepts in oncology is the idea of genetic therapy. It’s been recognized that certain genes or mutations of those genes have a role in how aggressively melanoma can spread, how quickly some cancer cells can grow and other aspects of cancer.
Serine/threonine-protein kinase B-RAF or B-RAF is involved in cell growth and in sending signals in cells. If the BRAF gene is mutated, the normal way that this protein works can be changed. Looking a little deeper, this protein is important in a signaling pathway called MAP kinase/ERKs. The importance of this is that this complicated name has a role in cell secretions, cell differentiation, and cell division. Mutation of BRAF was found to cause Hairy cell leukemia only this summer and has been known to a problem in 40-50% of people with melanoma.
The FDA took a novel step when it approved both the drug AND a test called the cobas 4800 BRAF V600 Mutation Test (Roche Molecular systems). What this means is that now people can be tested to see if they have the V600E mutation (if they have melanoma) and if that is the case, Zelboraf is indicated for treating unresectable melanoma as well as metastatic melanoma. Zelboraf blocks the way the mutated BRAF protein works.
In the studies that lead to approval, Zelboraf was compared to an older medicine (dacarbazine) and in that population, gave a 74% decrease in risk for progression or death. Only 0.9% of the people in the pivotal approval study (2 of 219) gained a complete response—yet the outlook for melanoma has been so dismal, this rate, coupled with the median time that the disease was halted (progression-free survival) of 5.3 months is a breath of fresh air in melanoma treatment. One investigator noted that Zelboraf and the companion diagnostic test were a great example of more personalized therapy.
The emergence of resistance and the adverse events are sobering for Zelboraf. Problems such as squamous cell carcinoma, photosensitivity, joint pain and serious skin rashes lead the FDA to require that a Medication Guide be given to patients receiving the drug. Still it is important to note that despite tumor regrowth and side effects, this drug lead to an earth quaking 48% response rate in the BRIM-3 study…something of great value in a cancer that has been notoriously difficult to treat.
Moving forward, MII believes that this medicine is especially interesting as part of combination therapy. We’ve seen this approach in many disease and conditions over the years. Important examples include heart attacks, infectious disease and high blood pressure. Many of us have heard of Yervoy (ipilimumab) which also demonstrated an important survival benefit. Because Yervoy works in a different way (mechanism of action) and also because Zelboraf is a pill, it lends itself to a combination therapy approach. In fact, a phase one study (the earliest) has started. It will be important to review the possible side effects from this combination however; as both Yervoy and Zelboraf can cause serious skin reactions.
As always, talk to your doctor, review your specific medical history or have such a review undertaken before considering this new medicine or any other therapy. Despite some limitations, of Zelboraf, there clearly is another bullet to load in the guns directed against melanoma. Visit www.fda.gov to see the original press release and more.