Hi, this is Dr. Michael Davis, professor and chair of the Department of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center, and the president elect of The Society for Melanoma Research. It is my pleasure to welcome you to our discussion today. The use of adjuvant and neoadjuvant approaches in patients with melanoma. Our expert discussing today is Dr. Tara Mitchell. Dr. Mitchell is associate professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia. Dr. Mitchell, thank you so much for joining us today. Dr. Tara Mitchell (00:38): Thanks for having me, Mike. I'm happy to be here. Dr. Michael Davies (00:40): Very good. Well listen, so we've done a couple of other podcasts that have really focused on how the new immune therapies have really revolutionized the treatment of patients with stage four, an unresectable stage three disease over the last decade. And over the last few years, these treatments have also been tested in multiple clinical trials and patients with earlier stages of disease. And so now the Anti-PD-1 immunotherapy Nivolumab is approved as adjuvant therapy for patients with surgically resected stage three disease. The Anti-PD-1 antibody Pembrolizumab is approved for adjuvant therapy, for surgically resected stage three, and more recently stage two disease. And finally targeted therapy with Dabrafenib and Trametinib is also approved as an adjuvant therapy for stage three disease. So this is an area, multiple different treatment options, but also lots of questions and controversy. So just to start out, if we think about stage three patients, based on the currently available data, what is your approach to adjuvant therapy for these patients? Dr. Tara Mitchell (01:43): I think it starts with a detailed conversation with each patient. It's a shared decision making that starts with what is your individual and personalized risk of recurrence, whether you have high risk stage two or stage three melanoma, I have a conversation with the patient of what is their risk of recurrence in the next three to five years, whether it's stage 2B and their risk may be still as high as 30 to 40%. Or stage 3D with a high risk of 70% or higher, they need to know what their risk is going into it and on the opposite side of that, what their chances of being cured with surgery alone. And so, once they understand that, it's really a personal decision, which we help walk them through the information about, how can immunotherapy lower that starting point risk. And on the other side of it, what are the risks of toxicity associated with immunotherapy? Dr. Michael Davies (02:44): Yeah, very good. No, I think it is one of those parts, as you said, it's shared decision making. And so making sure patients have the information that they need to make that decision. As we talk about it again, we've been doing this for a few years for patients with stage 3 disease. So now recently we've had this approval in high risk stage 2, is that conversation that you have with stage 2 patients any different? Dr. Tara Mitchell (03:09): It is different. It's different because their starting point risk is high in some, but it's a bit lower than in stage three still overall. It's also different because of the pattern of recurrence. In the patients with stage 2 disease, I usually tell them it's about a 50/50 chance that if it comes back, it's either going to be local or regional. In which case they may be cured again with surgery. And then the other 50%, which is translates to a small number of patients, will have distant metastasis. That's their first site of recurrence. Whereas, in stage 3 disease, also high risk, there's a higher chance of stage 4 disease at the time of initial recurrence. Though, some of those patients also will have regional or local disease that can be resected with curative intent, though that's a higher number in stage 2. So what really, it comes down to, I think in stage 2 is focusing on that rate of distant metastasis [inaudible 00:04:16] survival, for which they've shown about a 6% decrease in the rate of developing metastatic disease, with adjuvant Pembrolizumab in those patients, which we have to weigh against the high risk of toxicity on the order of about 15% of patients will have severe toxicity or even life threatening toxicity. So again, it comes back to a shared decision making, and where does the patient's personal preference and risk tolerance lie? Dr. Michael Davies (04:49): That's a great summary. I think, one of the other interesting parts about this is the fact that we're still unsure, knowing that these same treatments can be very effective in stage 4 patients and even curative. The real question is whether using these treatments at this earlier point in time will be more effective and will ultimately result in a higher long term survival rate. Do you want to sort of talk, what do we know at this point about the impact of adjuvant therapies on overall survival? Dr. Tara Mitchell (05:19): That is such a great question. And this is one that I bring up with all of the patients when we're having this conversation. Really, there's no definitive data that suggests any survival advantage of adjuvant therapy in all patients at risk, versus watching and waiting with close observation and treating those at the time who develop stage 4 disease. And that's not because there hasn't been tremendous progress and incredibly effective therapies that have been developed for stage 3, it's just that these therapies are very effective in stage 4 with many patients being cured of stage 4 disease, including patients with metastatic disease to the brain, the liver, the bones. And high volume symptomatic disease can have durable, complete responses after stopping therapy. And so, in the current era of highly effective therapies for stage 4, is how I would really put it. It is unclear that there's any survival advantage in treating patients in an adjuvant manner. Though, there's clearly been proof of reduction in recurrence with either Nivolumab, Pembrolizumab or Dabrafenib, Trametinib in patients with BRAF mutation. And that has been statistically proven and shown in longer and longer follow up between three, four and five years now, for adjuvant therapy at stage 3, that the recurrence rates are reduced. But the way I describe it to patients is that we don't really know whether treating you today, versus watching and waiting and treating you if your disease comes back, will result in a better chance of you being alive and cancer free in five years or 10 years. And that's really what we need longer follow up, but we may never really see that clear survival advantage given how effective these therapies are in stage 4 and the continued progress we're continuing to see in stage 4, as well. Dr. Michael Davies (07:19): Yeah, no, it's a great summary. And that being said, I think that there can be real benefit for quality of life, of preventing disease from recurring. And so that absolutely supports the rationale and why it's a shared decision. And would just say that, for those of you who are wondering, the approval of Pembrolizumab in the adjuvant setting for stage 2, we don't have any overall survival data yet for that trial. We don't actually have negative data or positive data. We just have an absence of overall survival data. And I think one of the special groups of patients, are those patients who present with high risk stage 3 disease. The majority of stage 3 patients are diagnosed these days, by a sentinel lymph node biopsy that detects microscopic disease. But on the other hand, those patients who present with clinically apparent bulky lymph nodes have always represented a really high risk group. And this is an area where we've started to look at, as a field at the neoadjuvant therapy approach. And indeed you've led some of the interesting research in this area. Wondering if you can talk about, what the rationale for neoadjuvant therapy in those patients is, and what have been the results of some of the important trials over the last few years? Dr. Tara Mitchell (08:29): Absolutely. I think it's an area of huge momentum in melanoma research. And I think that the clear benefit, and I'll talk about some of the results that have shown us this, is the prognostic value of the pathological response at the time of resection, after treatment with neoadjuvant therapy. So what we're faced with in stage 3 disease is that we really don't know who is benefiting from adjuvant therapy. We know that some patients are going to recur regardless of therapy. Some patients are going to be cured with surgery alone. And then there is that small percentage who are actually benefiting from the adjuvant therapy, and are being cured because of the therapy. But we don't know who they are, and we don't have a good biomarker for that. With neoadjuvant approach, we can with a short course of therapy in one to two doses of immunotherapy in the immunotherapy trials, meaning treatment given over approximately six weeks, and then followed by the curative intent resection and lymph node dissection, we can see an early and complete pathological response in a high percentage of patients. And what we've shown and what's been published in an international pooled analysis, is that those patients with a complete response, meaning no viable tumor at the time of surgery or a near complete response, what we call a major pathological response, meaning less than 10% viable cells at the time of resection, those patients have a very low rate of recurrence, and most patients are cured at the time of surgery. In the studies, most of those patients went on to complete up to a year of adjuvant therapy as well. So we know that both the pathological response that they get from neoadjuvant therapy is prognostic of survival, but the completion surgery may still be necessary. And the adjuvant therapy to completion of up to a year may still also be contributing to that excellent outcome that we're seeing in those patients with a complete or near complete response to neoadjuvant immunotherapy. Dr. Michael Davies (10:43): Yeah. I think that the data's been so compelling and it's also supported by preclinical laboratory experiments that really supported that in animal models, that giving immunotherapy before you resected the tumor gave you a much better chance of generating an immune response with immunotherapy, than taking the tumor out first and trying to treat micrometastatic disease. And trials have also shown better T-cell diversity after a neoadjuvant approach. That being said, to this point, we haven't proven that this results in superior clinical outcomes compared to adjuvant therapy alone. And so this is where there is a clinical trial ongoing at this point, comparing those two approaches for clinical benefit. But I would say again that for a high risk group of patients, it's really been very impressive results over the last few years. And so something that again, we certainly try to recommend clinical trials to our patients who present in that setting. I guess one final question for you is, again, as we are seeing these changes over the last few years and even new approaches, for you, what do you think are some of the most interesting areas of research or important questions or trials that are really addressing adjuvant therapy in the field right now? Dr. Tara Mitchell (11:58): Well, I think the answer to that comes back to the neoadjuvant therapy clinical trials, because I think there's a lot to be learned from that clinical trial model. As you said, we still, though we have the preclinical rationale, I think that the ongoing randomized clinical trials of adjuvant versus neoadjuvant will show whether there's actually a biological improvement in giving neoadjuvant therapy compared to adjuvant, and that improves outcomes. But the other things that we can test by using a neoadjuvant approach are mechanisms of response and resistance. So by having paired tissue collection at the pretreatment biopsy, and then several weeks later at the time of surgery, you can actually interrogate the T-cells, the tumor infiltrating lymphocytes, along with the pathological response, look at the phenotype and look at what could be mechanisms of response or resistance that are leading some patients to have such an early and complete pathological response, while others have nearly no tumor infiltrating lymphocytes at the time of surgery, no pathological response, and have a higher rate of recurrence in the coming one to three years after resection for curative intent. So I think that there's a lot to be learned about mechanisms that could lead ultimately to individualizing therapies for patients, based on their tumor biology and immunology. So there's a lot to be learned from that type of study design, even in smaller numbers of patients. And I would also emphasize what you mentioned, that all of the neoadjuvant therapy currently is all investigational. So there's no FDA approved pathway to neoadjuvant therapy right now, pending larger randomized trials, but there's a lot of promising research that's ongoing, that'll give us more information to shape the individualization of patient care. Dr. Michael Davies (14:04): Well, Dr. Mitchell, thank you so much. Again, it's really a fascinating space and a true pleasure to talk to you about these different treatments and clinical trials. So thank you so much for joining us today, for this discussion.Thanks, Mike.