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Dr. Michael B. Atkins was recently appointed deputy director of the Georgetown Lombardi Comprehensive Cancer Center. He was formerly the director of the cutaneous oncology and biologic therapy programs and the cancer clinical trials office in Beth Israel Deaconess Medical Center's division of hematology/oncology and was the leader of the kidney cancer program at Dana-Farber/Harvard Cancer Center. His research interests include immunotherapy of malignancy—specifically, using cytokines, understanding and overcoming cancer-associated immune suppression, novel treatments for melanoma and renal cell carcinoma, and antiangiogenic and targeted therapies. He is currently investigating the potential of CTLA-4 and PD1 pathway antibodies, and mechanisms of enhancing sensitivity of melanoma to selective RAF pathway inhibitors.
CancerNetwork: There seem to be two principal promising avenues of therapy now for patients with metastatic melanoma: targeted, oncogene-directed therapy, and immunotherapy. The mechanisms of action involved in these two approaches are very different. Could you briefly summarize what you see as the greatest strengths and weaknesses of the two approaches?
Dr. Atkins: The benefit of immunotherapies is that they can produce durable responses in a small subset of patients off the treatment and appear to work in patients with both BRAF-mutant and BRAF-wild-type melanomas. The benefit of the molecularly targeted therapies is they produce a high level of tumor shrinkage and survival benefits in a large proportion of patients with BRAF mutant melanomas. Those responses are likely short-lived, on a median of 6 to 8 months progression-free survival, but for patients with symptomatic disease who need a response, the high degree of response is a major benefit.
CancerNetwork: I believe a phase I/II trial of the combination—ipilimumab and vemurafenib—is now underway. Last year at ASCO there was excited speculation about the beneficial synergies that might result from using these two approaches together. However, a poster presentation this year, by James Harding and colleagues at Memorial Sloan-Kettering, reported an increased rate of grade 3 skin rash in patients who received vemurafenib after ipilimumab; the increase was most marked in patients who started vemurafenib within one month of completing treatment with ipilimumab. So clearly there is also a potential for negative interactions between targeted agents and immune-enhancing antibodies. What is your take on how successful this combination treatment is likely to be?
Dr. Atkins: Well, I think many of us are still hopeful that immune therapy and molecularly targeted therapy with a BRAF inhibitor will produce the benefits of both classes, meaning maintaining a high response rate and increasing the number of patients who have durable benefit. But the questions that remain are which agents should be given first if you're giving them in sequence and which agents to use for both BRAF inhibitor and immune therapy. The abstract that was presented from the group at Memorial Sloan-Kettering suggests a potential problem if you give an immune therapy first—which is if you start the vemurafenib afterwards you can have increased skin toxicity from the vemurafenib. That might not be an issue if you wait longer and allow for the antibody to clear from the circulation or if you use dabrafenib, which is a BRAF inhibitor that doesn't cause as much skin toxicity. There are equal if not more problems with starting with vemurafenib and trying to switch to ipilimumab, as an abstract that was presented in the poster session by Allison Ackerman suggested that very few patients are able to get immune therapy after progression of disease following a molecularly targeted therapy, and those that did receive it were unlikely to benefit. So the hope is that potentially by giving them simultaneously we might reduce some of those issues—but once again it may require using immunotherapies that are more selective, such as the PD1 blockers, and molecularly targeted agents that may have less overlapping toxicities with the immune therapies, such as potentially dabrafenib.
CancerNetwork: One of the hot areas of research in melanoma right now involves the discovery of other inhibitors on the surface of T cells, in addition to the CTLA-4 protein that ipilimumab targets. One of these, programmed death 1 (PD1), was discussed in an oral abstract presented at ASCO (#8507). How might targeting PD1 be different from targeting CTLA-4 and what might be the advantage (if any)?
Dr. Atkins: CTLA-4 is a very early checkpoint inhibitor, and when you target it, the interaction is likely blocking an interaction between antigen-presenting cells and immune cells that takes place in a lymph node, and therefore the effects are not selective to the tumor and you can release immunity not just against tumor antigens but against host antigens. The blocking of PD1 or the PD1 ligand (PDL1) appears to take place more peripherally because PDL1 and PD1 only seem to interact in peripheral tissues, and so providing an antibody that blocks that interaction might limit the effects to the tumor site. So that means that there's potential for more selectivity and less toxicity.