Dr. Jeffrey A. Sosman
One misconception about vemurafenib therapy is that everybody is going to have a relapse in 6-7 months and die. The progression-free survival has a median of 6.8 months, but we are seeing impressive median overall survival, with a 15.9-month median in BRIM-2, probably the longest in any similar trial. The 63% relative reduction in the risk of death in BRIM-3 with vemurafenib benefited nearly all subgroups but was most impressive in patients having high lactate dehydrogenase (LDH) levels or M1c disease. We are unlikely to get good long-term survival data from this trial because of the early favorable result and allowance of crossover.
Another misconception about vemurafenib therapy is that most patients will have aggressive disease at relapse, and there will not be an opportunity for a second therapy. In fact, many patients have a localized relapse, undergo resection, and can continue on the vemurafenib. My experience has been that the patients having an aggressive relapse are those who enrolled in the trial with aggressive disease, and would not have been appropriate for other treatments. They did have a great improvement in their quality of life, albeit not for as long as hoped.
With all the limitations of comparisons between trials, vemurafenib compared with ipilimumab has been associated with better rates of overall survival at 1 year (54%-58% vs. 46%) and 2 years (33% vs. 24%). And there is a huge improvement in the disease control rate (86% vs. 44%).
Unquestionably, some patients have highly durable remissions with immunotherapy, but a major frustration is our inability to pick out this small subset of patients up front – prior to therapy.
Vemurafenib is probably the only effective therapy we have ever had for symptomatic patients with a high LDH level, who need rapid improvement in their performance status. I honestly had never seen a patient with those characteristics respond to anything until vemurafenib.
Finally, there may be some science suggesting that giving vemurafenib after ipilimumab is better, but there is not one bit of data to show that you are not able to achieve a durable remission to ipilimumab after failure of a BRAF inhibitor. More research on the sequencing of therapies is needed. In BRIM-2, only about 5% of patients had previously received ipilimumab. And although an analysis is being done among the 24% who got ipilimumab after stopping vemurafenib, it is a post hoc analysis, and the goal is simply to ascertain any contribution to the overall survival result.
In conclusion, in this era of targeted agents, it is essential that all melanomas be genotyped. It is my view that patients with symptomatic bulky disease or an increased LDH level should get vemurafenib. Patients with indolent disease, asymptomatic M1a or M1b disease, could get either; I can’t make any passionate argument that they all should get vemurafenib. But if you’re trying to put a patient into remission for as long as you can with a good quality of life, then vemurafenib is much more likely to do that. Ultimately, we need trials evaluating the issues of sequencing and combination therapy.
Dr. Sosman is professor of medicine and director of the melanoma program at Vanderbilt-Ingram Cancer Center, Nashville, Tenn. He disclosed that he is a consultant to, and receives research support from, GlaxoSmithKline (manufacturer of investigational targeted therapies for melanoma) and Roche (manufacturer of vemurafenib).