Oncology Frontier: So with the BRAF inhibitors， is that the only treatment that we are going to use and then we stop that and we are at a good place?

　　《肿瘤瞭望》：BRAF抑制剂会是将来的唯一选择吗？我们需要抛弃现有的手段吗？

　　Prof. Flaherty: This is a great question about what is the best time in the management of a patients’ metastatic disease to deploy BRAF inhibitor based therapy. Immunotherapy has emerged as an option for patients regardless of mutation type， it’s fairly clear when looking at ipilimumab <https://www.google.com/search?newwindow=1&es_sm=93&q=ipilimumab&spell=1&sa=X&ei=ummeVIXfKNb8oQTemoJ4&ved=0CBwQvwUoAA>or PD1 PDL1 antibodies that the ability of those agents to produce responses and durable response is really independent of the underlying mutation status. Whether it’s a BRAF mutation or any other type of mutation that might be driving a melanoma; so if you were to focus then on the BRAF mutant population they have immunotherapies emerging as treatment options as well as BRAF inhibitor based treatment. A complicating factor is that both immunotherapy and BRAF inhibitor based therapy seems to work more powerfully in terms of durable responses in patients with low disease burden. In high disease burden patients’ immunotherapies historically and particularly with a balloon map tend to have their least ability to able to induce a durable response compared to lower disease burden patients. BRAF inhibitors can work in that setting but not particularly durably and so it’s in low disease burden patients where we have multiple arguably good options and it’s a great challenge currently to know what the optimal sequence is， BRAF inhibitors followed by immunotherapy or vice versa. The absent definitive data from clinical trials are purposefully testing that question. Many investigators and clinicians prefer to start with immunotherapy in the low disease burden population and watch patients closely if they have a BRAF mutation and at the first sign of disease progression initiate BRAF inhibitor therapy. I think that is a relative generalized statement preference absent more definitive data regarding optimal sequence.

　　In high disease burden patients we tend not to have so much of a choice; we really need to lean on BRAF inhibitors to be able to gain disease control much more reliably than immunotherapy can offer us and that patient population unfortunately many of those cannot then bridge to immunotherapy once they fail the BRAF inhibitor. If they were high disease burden at the initiation of the BRAF inhibitor based therapy even they respond generally their disease remains aggressive once they are coming off BRAF inhibitor based treatment.

　　This issue of optimal of deployment of BRAF inhibitor based therapy is still a bit of a conundrum but our hand is somewhat forced based on the clinical situation currently. We do recognize the need to investigate this issue and really dive more deeply into the problem of understanding predictive biomarkers for the BRAF inhibitor based therapy on one hand and immunotherapy on the other hand to have a more precision basis of deploying these treatments as opposed to purely clinical parameters.