New Treatment Paradigms for Advanced Melanoma - Episode 10
Jeffrey S. Weber, MD, PhD: Let’s shift gears a bit. We haven’t talked much about the other approved treatment. We keep forgetting about the other approved treatment, which is T-VEC. Robert, you’re literally a world’s authority on T-VEC. How do you use it? Do you just use it alone or do you incorporate it off label with ipilimumab, or nivolumab, or pembrolizumab? How have you been using it in your practice?
Robert Andtbacka, MD, CM: T-VEC was approved over 2.5 years ago, Jeff. In our practice, we have had a number of clinical trials with T-VEC that have enrolled with combination studies. The approved T-VEC is really monotherapy, and it’s for patients with no visceral metastases. We’ve often used it as a standard of care in patients with more limited disease, at least in patients with stage 3 disease or limited stage 4 M1a disease. It can be very effective in that first-line setting, especially in patients who are older who may not be candidates for some of these other therapies or who have limited disease. It can be very effective, having a good, very durable response in patients. We have also used it in clinical trials in combination. T-VEC seems to be able to improve the effect of the backbone of the checkpoint inhibitor. Whether that is with anti-CTLA4 therapy, with the ipilimumab, we know that adding T-VEC to that sort of doubles the response rate from about 18% or 19% to almost 40%.
Jeffrey S. Weber, MD, PhD: Which is not trivial. This is with ipilimumab, which we know never seems to have more than a 20% response rate. But what about with pembrolizumab? That has been a published study.
Robert Andtbacka, MD, CM: For pembrolizumab, we published a study where we looked at 21 patients. I think we really have to be cautious in trying to sort of extrapolate from that. But in that study, we know that the response rate with pembrolizumab was over 60%. But, again, I really caution us to make any long-term statement from that. What we did learn from that study was that an intralesional agent, such as T-VEC, may be able to modulate the immune system. The discussion we’re really having is, do we go for that monotherapy PD-1 inhibition or do we go for ipilimumab/nivolumab? There are patients who would have a low probability of responding to PD-1 inhibition, but maybe an agent such as T-VEC or another intralesional agent could modify the immune system in those tumors and make those potentially low responders into high responders.
Jeffrey S. Weber, MD, PhD: There was an article by Antoni Ribas, who could be one of my favorite oncologists. He had a very nice article in Cell not that long ago, last year. What is it that he found in those tumors? I guess he did biopsies pre and post?
Robert Andtbacka, MD, CM: That study was part of the phase Ib study with T-VEC plus pembrolizumab. We looked at the interferon signal, and we also looked at tumor infiltrating lymphocytes. We know that patients who have a kind of high interferon signal in their tumor with a high level of CD8-positive T cells are more likely to respond to PD-1 inhibition or anti—PD-1 therapy. We found that tumors that had a kind of low tumor–infiltrating lymphocyte CD8-positive T-cell population, with a low interferon signal, responded when we gave T-VEC first with 2 injections followed by pembrolizumab.
We also found that there was an upregulation in in these CD8-positive T cells in the tumor when we initially gave T-VEC and then started pembrolizumab. Again, I caution that this was a small number of patients, but it’s an interesting observation.
A subsequent study is the large phase III randomized clinical trial in which we use pembrolizumab as the backbone. Patients are randomized to either receive intralesional T-VEC or an intralesional placebo option. That study has enrolled over 660 patients. Data from that will be forthcoming. We are really trying to understand whether there is a difference in those patients who get the combination.
Jeffrey S. Weber, MD, PhD: When is that expected to read out for its progression-free survival endpoint?
Robert Andtbacka, MD, CM: It will probably be about a year or so before we get the readout.
Jason J. Luke, MD, FACP: I think that’s great, but I think this experience with intralesional T-VEC is really just the beginning of this whole sort of... Robert’s done pioneering work. He’s really pushed this whole field forward, but I think all of us have finally caught up with him. It’s not just an injectable virus. There are a number of approaches that are emerging very rapidly in clinic to try to sort of shift the tumor microenvironment to be more favorable to immunotherapy, putatively to try to use individual tumors that are injected as a vaccine to try to augment systemic immunotherapy. In these refractory patients, we could inject things and see responses. Then, second line to PD-1, calling back to what Mike had said about whether it should it be PD-1 or ipilimumab... I think all of these data sets are emerging, but I really think it’s important to highlight that this field is very young. We have a lot of work to do in this area. I think that there are oncolytic viruses, Toll-like receptor agonists, STING agonists, and radiation combinations. There are many different ways that we’re going to need to think about this, especially in these refractory patients.
Robert Andtbacka, MD, CM: I agree. I think that I would also caution all of us to look at these [sorts] of small trials and data coming from them. They are interesting, but what we don’t know, in many of the studies, is what the true tumor burden was in the patients before they went on these therapies—the kinetics of their disease. Those factors are really important, and I think many of the studies have not necessarily reported on that. So, I think that those are things that we need to learn more about. We need to determine what will be best, to change that sort of cold tumor microenvironment into a hot one. I think that is going to be different from patient to patient. This is just emerging. However, having said that, having been a part of this for about 12 years—and you said that you caught up—we did that for many years and no one believed us. I’m happy to see that people are finally saying that there may be some value to these intralesional therapies as an adjunct to some of these other things.
Jeffrey S. Weber, MD, PhD: What about neoadjuvant therapy? I actually wasn’t aware that there was a neoadjuvant trial. I recently learned about this. Is that an ongoing trial with T-VEC?
Robert Andtbacka, MD, CM: Quite a few years ago, I did a multicenter international clinical trial in patients with resectable stage 3B/3C and stage 4 M1a metastatic melanoma, according to the AJCC 7th edition. We randomized patients to receive surgery up front, which would be the standard of care—and I would still maintain that this is the standard of care—versus T-VEC, intralesionally, for 12 weeks, and then surgery. The primary endpoint for this was recurrence-free survival. We’ll be presenting some of that data a little bit later on this year or maybe early next year. Right now, we are presenting data asking, is there a potential benefit to giving T-VEC in this setting?
All of this really stemmed from data that we received from the original T-VEC study, which showed that patients who receive T-VEC may potentially have a lower risk for developing visceral and bone metastases. That then led us to asking the question of, could we do this in the early-stage patients who have resectable disease? We’ll be presenting some of the safety data. What is also interesting is that with only 12 weeks of T-VEC, we have a very robust pathologic complete response rate in these tumors, something that I think is a bit surprising to many of us. Determining whether this will improve recurrence-free survival, we will have more information a bit later on this year.
Transcript Edited for Clarity