CancerNetwork: Do you think a combination of a PD1 antibody and a CTLA-4 antibody will be a promising approach, or might there be an unacceptable increase in autoimmune-related adverse effects?
Dr. Atkins: Well I think there's a lot of rationale for combining them from a therapeutic standpoint because when you activate the immune system with a PD1 antibody or a PDL1 antibody, those cells might still express CTLA-4 on their surface, and it's possible that the CTLA-4 expression—particularly if those cells are circulating—may limit their effectiveness. And blocking CTLA-4 at the same time may therefore enhance their efficacy. In addition, when immune cells that have been activated by shutting off the CTLA-4 inhibitory interaction reach the tumor, if the tumor is expressing PDL1, then those cells which likely also have PD1 on their surface may not be able to kill the tumor. So there's a strong rationale for putting these together. There is a concern, given the autoimmunity side effects related to ipilimumab, that you might enhance those. That's why many of us would recommend that if a combination be tested that it should be built off PD1 rather than using a full dose of CTLA-4 antibodies.
CancerNetwork: Do you think immunotherapy will soon become another area in which a "personalized medicine" approach will prevail, with some tumors responding better to one of these antibodies and some to another?
Dr. Atkins: There is some data that was presented that I would view as very preliminary suggesting that patients in their tumors PDL1 expression were more likely to benefit from a PDL1 inhibitor than those that did not have that expression and so that doesn't mean that PDL1 is actually a target of the antibody in the typical sense; it means that PDL1 is a biomarker of a immune reaction that's taking place where the immune system is recognizing something on the tumor. But because it's an inducible marker, its expression at even a low level, 5% or so, is sufficient to suggest that an immune reaction is taking place. It could be very difficult or possible to miss the expression with the type of pathology review that's typically done. So a lot of work has to be done to both figure out what specimens should be used, how to get a more reliable antibody, and to try to make certain that enough samples are looked at to accurately report whether a tumor is expressing PDL1 or not, so that we can address the question of whether this is a true predictive biomarker of response. For that reason I don't think that it's appropriate right now to restrict PD1 antibody treatments to patients whose tumors have the expression of the PDL1 ligand.
CancerNetwork: What progress has been made in melanoma with regard to the problem of patients developing resistance to targeted agents such as vemurafenib and dabrafenib? What have we learned about the mechanisms of acquired resistance—and have we learned enough to design ways to prevent or minimize it?
Dr. Atkins: There was a very nice oral presentation from a group led by Jeff Sosman in the melanoma oral session at ASCO that looked at analysis of tumor specimens pre- and at-time-of resistance in a number of patients receiving vemurafenib. And their conclusion was that the majority of resistance mechanisms involved reactivation of the MAP kinase pathway and specifically phospho-ERK, and they reported a number of mechanisms by which that can happen—a number of these have been published—but what they also mentioned were the frequency of mutations in NRAS and in MEK that were seen in their population. Some of those mutations were bypassed pathways that may be sensitive to MEK inhibitors—but not all of them—and therefore one of the proposals for prolonging the benefit to selective RAF inhibitors could be to combine them with a MEK inhibitor, and there was some data presented in the MEK inhibitor session that suggested that a combination of a RAF inhibitor and MEK inhibitor was tolerable and may produce a longer progression-free survival—although once again, resistance does develop. In addition, I think with more sensitive assays we may be able to pick up these mutations in the pretreatment specimens because they likely did not develop as a result of treatment but were there to begin with and were selected for. And that may allow one to choose whether a patient should receive a RAF inhibitor or a combination of a RAF inhibitor and a MEK inhibitor or some other treatment approach.
CancerNetwork: And have there been lots of adverse events associated with MEK inhibitors as well?
Dr. Atkins: The MEK inhibitors do have toxicities because they're less selective when they're given at high doses, but they don't seem to add toxicities to the selective BRAF inhibitors. Particularly when the MEK inhibitor from GlaxoSmithKline was added to dabrafenib, there seemed to be less skin toxicity and less typical toxicity associated with the MAP kinase pathway bypass, but there may have been more pyrexia.
CancerNetwork: Are there any targeted agents in the pipeline for melanoma patients who do not have the V600E mutation?
Dr. Atkins: I think the MEK inhibitors also show value in NRAS-mutant melanomas although they're not selective inhibitors of the mutation so they're limited by their toxicity because MEK is pretty important even in normal cells. There's been data that's presented for a while about c-kit inhibitors particularly in mucosal melanoma. But we don't really know what's driving the rest of the tumors that are classified as BRAF wild-type, and hopefully some research into that may uncover some driver mutations that potentially could be targeted.
CancerNetwork: Most of the buzz at ASCO is about therapies that involve drugs that can be mass-produced by pharmaceutical companies. What about other approached to melanoma therapy that do not involve a drug, such as adoptive cell transfer? Are any of these promising?
Dr. Atkins: I think the adoptive T-cell therapy approach has always been promising but very impractical and limited to sites like the National Cancer Institute which has the financing to be able to do these research studies or to a few institutions that have taken the effort to gather the resources to have a program. The trouble with adoptive T-cell therapy is that a randomized trial has never been done to prove the value of the adoptive transfer of the T cells above and beyond the selection of the patients that take place at multiple steps along the way in their process. Until that happens, I think it's going to be hard for programs to enthusiastically endorse this or for insurance companies to pay for it. There is a company that has developed some interest in trying to move this effort forward to perform that phase III trial and so it's possible that such a phase III trial with a company having some intellectual property rights to the process of preparing the cells. If and when the trial is done, and assuming the results show benefit for the use of the cell. Regarding other approaches, I think most of those are within the pharmaceutical industry, although some places are still looking at their own developed vaccines, alone or in combination with dendritic cells or fused to dendritic cells—and there's a new opportunity for vaccine approaches combined with some of the more novel immunotherapies, so we may see some of those move forward again.
CancerNetwork: Dr. Atkins, thank you very much for your time.
Dr. Atkins: You're very welcome, Ian.