Dr. Michael Davies (00:06): Hi. This is Dr. Michael Davies. I am professional and chair of the Department of Melanomedical Oncology at the University of Texas, MD Anderson Cancer Center, and I am the president elect of the Society for Melanoma Research. It is my pleasure to host this series of podcasts discussing some of the key topics in the management of patients with advanced melanoma. And in particular, it's my pleasure to introduce our session today, focusing on the evaluation of the use of immune checkpoint inhibitors in melanoma. Dr. Michael Davies (00:36): Our discussant today is Dr. Michael Postow, who is chief of the Melanoma Service at Memorial Sloan Kettering Center in New York City. Mike, the field of melanoma and the treatment, in particular, of patients with stage 4 melanoma has really been revolutionized by the approval of new immune checkpoint inhibitors. At this point for patients with stage 4 melanoma, we really have multiple immune therapies to choose between, including single agent nivolumab, single agent pembrolizumab, combination immunotherapy with ipilimumab and nivolumab, and recently combination immunotherapy with nivolumab and relatlimab. I'm wondering if you could just sort of provide your perspective of what you think are the strengths and optimal use of each of these different immunotherapy regimens in the management of stage 4 melanoma patients today. Dr. Michael Postow (01:31): Thank you very much, Dr. Davies. It's a pleasure to join for this podcast. As you mentioned, we have a lot of new tools in our toolbox to really treat patients with unresectable stage 3 or 4 melanoma in dramatically better ways than historically. And I think the challenge that we have now is which treatment for which patient and when. When do we use single-agent PD-1? When do we use PD-1 in combination with relatlimab, like nivolumab and relatlimab? And when do we use nivolumab plus ipilimumab? Dr. Michael Postow (01:58): And in thinking about this, one can think about this on a spectrum of kind of aggressiveness in terms of treatment and side effects and also aggressiveness in terms of the patient's disease, and then also kind of a perception on how the patient weighs side effects and expected efficacy. Dr. Michael Postow (02:16): And along the spectrum, I kind of think about single-agent PD-1 is the backbone. And then building on single-agent PD-1, the kind of little bit more side effect combination of relatlimab plus nivolumab, but also more effective than single-agent PD-1 is the relatlimab/nivolumab combination. And then kind of at the most aggressive end with by far the highest side effects is the nivolumab plus ipilimumab combination. Dr. Michael Postow (02:42): You would say, "Well, as you step from single-agent PD-1 to the nivolumab plus relatlimab combination to the most aggressive nivolumab plus ipilimumab, how much incremental efficacy are you getting along the way? And what do you really need for your patients? Dr. Michael Postow (02:57): So I guess I'll start with nivolumab and ipilimumab. That's with the highest side effects. I think that that one is a regimen I'd choose for patients with brain metastases, because we have really great data for efficacy in patients with brain metastases. I'd choose the nivolumab and ipilimumab combination for patients that have really aggressive melanoma, potentially a lot of liver metastases or otherwise sick and symptomatic with their melanoma. Those patients that I really, where I may only have one shot on goal, and if they don't respond to initial frontline systemic therapy, we're going to have some problems. So in those patients populations, I kind of lean toward nivolumab and ipilimumab. Also, it's important that patients have really good performance status and are able to potentially withstand the side effects of that more aggressive regimen. Dr. Michael Postow (03:42): Between the other options of single-agent PD-1 and then the newly approved relatlimab plus nivolumab combination, given the positive phase 3 RELATIVITY-047 study, demonstrating superiority in terms of progression-free survival for nivolumab and relatlimab over nivolumab monotherapy, I tend to use nivolumab plus relatlimab in most patients as opposed to single-agent PD-1. And I think that's where people wonder where is nivolumab and relatlimab going to kind of rest in the spectrum. Dr. Michael Postow (04:11): I think it's going to replace a lot of single-agent PD-1, because we have a regimen that has a higher progression-free survival and pretty good toxicity. The toxicity of nivolumab and relatlimab is just a little bit worse than single-agent PD-1, but the efficacy is also a little bit better. And so most of my patients, when they're thinking about single-agent PD-1 or a combination with nivo and relatlimab, they'll tend toward thinking about nivo and relatlimab for that reason. Dr. Michael Postow (04:37): How we decide between nivolumab and relatlimab and ipi-nivo combination, that's a lot of challenging considerations, some of which are the patient factors that I brought up earlier. But I think that's how I kind of think about these three frontline immunotherapy regimens in unresectable stage 3 or 4 melanoma. Dr. Michael Davies (04:55): That's a really great overview, Mike. Thanks so much for doing that. I think one of the things that you and I have talked about, too, is one of those other factors, as much as we focus on where the disease is, how much disease there is, I think the other thing that's really important, as we think about the relative risk-benefit ratio for these, is the support network that patients have. Dr. Michael Davies (05:14): I tend to think about patients, again, who have a good support network and good access to medical care as being different from those patients that we see who come from very isolated areas or with very limited sort of support in terms of what the relative risk would be of some of our more toxic regimens. Dr. Michael Postow (05:32): I absolutely agree. I think that's incredibly important, especially for the nivolumab and ipilimumab combination where patients frequently have to have immunosuppression and need to retain a lot of close contacts with the medical team. And it's really, really telling when a patient comes in for an initial visit, who comes with them to the visit. Who might be on a telemedicine visit with this patient? How can the patient identify their care team and support structure? Dr. Michael Postow (05:58): A lot of times, this really is a parent. It's so important, I think, to have that team, because this is really a team sport, and especially with regard to toxicity management, clear communication, and involving other loved ones, family, caregivers. It's critical to the success of this treatment in especially some of these more aggressive combinations. Dr. Michael Davies (06:16): Yeah. That's a great point. Dr. Postow, one of the questions I often get asked about by fellows, by other physicians, and all importantly by patients, is for patients who have a BRAF mutation, they have not only all of these immunotherapy options, but also FDA approved targeted therapy options that can be very effective. Dr. Michael Davies (06:36): This is really sort of an area where we haven't really had prospective clinical trial data until recently. I think, as you and I have talked about, this is some of the most important data that we've seen in a few years. Would you like to talk about sort of, again, what we know now about the comparison of upfront immunotherapy versus targeted therapy in stage 4 melanoma patients with a BRAF mutation? Dr. Michael Postow (07:02): Absolutely. This has been one of the long debated issues in melanoma. Do you start a BRAF mutant patient with BRAF plus MEK combination therapy? So that's either dabrafenib plus trametinib or vemurafenib plus cobimetinib or encorafenib plus binimetinib. Or do you start that patient with some form of immune therapy? Dr. Michael Postow (07:20): And we have data now from a randomized study called the DREAMseq study that was run by Michael Atkins. And it was a cooperative group study, so really great success for the cooperative group model here. And it really showed that two years overall survival is better ... Starting patients with nivolumab plus ipilimumab compared to dabrafenib plus trametinib. These were all BRAF mutant patients, and they either had randomization to dabrafenib plus trametinib targeted therapy or nivolumab plus ipilimumab. And this was the standard FDA approved dose of nivolumab and ipilimumab, at the ipilimumab dose of 3 milligrams per kilogram and nivolumab, one milligram per kilogram. Dr. Michael Postow (08:00): And so at two years, the survival is dramatically better for nivolumab plus ipilimumab of 20% better. So I think this really helped resolve the issue of what's the best frontline treatment for these BRAF mutant patients between targeted therapy and at least the ipi-nivo combination. I think the answer is ipi-nivo. Dr. Michael Postow (08:19): Now, there are a couple of subtleties still from that trial that came out. One of the interesting issues was that there was a crossing of the curves and that there were some early deaths in the ipi-nivo group. Dr. Michael Postow (08:29): And so one of the questions comes up, "Well, now that we have superior two-year overall survival for starting patients with ipi-nivo over BRAF-MEK, would you start everyone with BRAF mutant melanoma with ipi-nivo instead of BRAF-MEK?" And I think the answer is most patients certainly, yes, however there are still some of these people that have these early deaths with ipi-nivo. And those are the patients that are really, really sick, and you may want to consider, at least in my feeling, BRAF-MEK inhibition in some of those patients. These are people that might be on steroids for brain metastases. That could be another group of people to think about BRAF-MEK inhibition. Dr. Michael Postow (09:04): So I think there still is some role for BRAF-MEK in the front line in very, very selected group of patients, but I think the vast majority should have immunotherapy in the front line based upon the DREAMseq data. Ongoing questions about different, you know, "How good is nivo-rela in this setting, and single-agent PD-1 versus BRAF-MEK?" We don't really have data on that. But I think that the nivo-ipi superiority over BRAF-MEK is really telling. Dr. Michael Davies (09:31): Thanks, Mike. That's a great review of those results. Are there any other sort of recent trials or advances that you have found particularly interesting or impactful in our field? Dr. Michael Postow (09:42): One of the other areas that's been really kind of a logical consideration is, well, what about triplet therapy, and what do we think about BRAF plus MEK plus immune therapy? We've just spent some time talking about immunotherapy or targeted therapy. I wanted to highlight this just for a second because the FDA has approved vemurafenib, cobimetinib, and atezolizumab. I think my general take on this, and I know there are some different opinions around the field on this issue, but my general take is that's been a little bit disappointing overall. Dr. Michael Postow (10:12): There was one positive phase 3 study with them, cobi and atezolizumab over vemurafenib and cobimetinib along for investor-assessed progression-free survival benefits. Although, the independent review on that progression-free survival benefit didn't really bear out. And there was another negative randomized phase 3 study of dabrafenib and trametinib and spartalizumab in this space. Dr. Michael Postow (10:34): So how much concurrent PD-1 or PDL-1 therapy really adds to BRAF and MEK is a little bit unclear. And certainly, there's more toxicity. So I haven't been finding myself using triplet therapy in most of these patients, but I did want to kind of mention that that has been an active area of investigation in melanoma treatment. Dr. Michael Postow (10:52): And whether there are roles for triplet therapy in high-risk patient populations like patients with brain metastases, I think that kind of remains to be seen. There was certainly some data at ASCO on that particular population. I know brain metastases will be the subject of a different podcast, so I won't get into all these details. But I think that's one area that we really have explored. The results aren't all that fantastic. I still generally think about doublets for my patients in the clinic. Dr. Michael Davies (11:20): Yeah, I think that's a great point. As you pointed out, there's this new data about sort of the vem-cobi-atezo in patients with brain mets, particularly those with symptomatic brain mets, which are patients who haven't actually responded very well even to the ipilimumab-nivolumab combination. And again, ongoing trials are also looking at those triplets in patients who have already progressed on PD-1. So that question, "Do we switch from immunotherapy to targeted therapy or do we add?" and I think those are some of the continuing questions that we have in the field and that we wait for more data on. Dr. Michael Davies (11:51): As we talk about sort of groups of patients maybe that don't get as much benefit from immunotherapy, clearly one of the areas of challenge has been patients with non-cutaneous melanomas, and particularly those patients with uveal melanomas that arise from melanocytes in the eye. And there, we have a new immunotherapy option, as well. Do you want to talk a little bit about that? Dr. Michael Postow (12:11): Absolutely. This is a fantastic success in the melanoma field, especially for uveal melanoma, which traditional has been a harder type of melanoma to treat. And even these immune checkpoint inhibitors that we've talked about don't work as well in advanced uveal melanoma as they do for cutaneous melanoma. Dr. Michael Postow (12:28): Tebentafusp is a new drug that has come out and is FDA approved for uveal melanoma. It has to be a certain subtype of patients that have a certain type of immune characteristic called HLA-A2. And that's a way that the patients present the antigens. And so if the patients are HLA-A2, and you can do that testing on peripheral blood, and they have metastatic uveal melanoma, they could be candidates for tebentafusp. Dr. Michael Postow (12:56): Tebentafusp is a new drug that kind of works like a matchmaker. It has two different arms to it. One arm grabs a T-cell through something called CD3. And the other arm grabs an antigen called gp100, which is highly expressed in uveal melanoma cells. And essentially, it just, as a matchmaker, brings these T-cells in close proximity with uveal melanoma cells with the idea that the T-cells kill these uveal melanoma cells. Dr. Michael Postow (13:20): So it has demonstrated an overall survival benefit in the randomized phase 3 study against investigator choice of treatment. Ipi-nivo was not the control arm in that randomized phase 3 study, so one question comes up, is ipi-nivo better than tebentafusp? We don't know the answer to that formally. But I think with the overall survival benefit of tebentafusp over other single agent immunotherapy options for patients with uveal melanoma, I do think tebentafusp is a frontline treatment option for patients with HLA-A2 uveal melanoma. Dr. Michael Postow (13:50): It's great to show that we can improve overall survival in uveal melanoma. We can run randomized phase 3 studies in this disease. And tebentafusp is really a first-in-class of these T-cell redirecting therapies in solid tumors to get an FDA approval. So a real big success in a way that melanoma's been the leading the field, and great for these uveal melanoma patients. Dr. Michael Davies (14:09): Yeah, no, that's a tremendous step forward. And so maybe just one last question for you, Dr. Postow. As I sort of alluded to earlier on, we're really focusing here on the treatment of patients with unresectable stage 4 or stage 3 disease. We do know that immune checkpoint inhibitors are now also approved in the adjuvant setting for patients with earlier stage of disease, for surgically resectable stage 2 or stage 3 disease. And we're increasingly seeing now patients presenting with stage 4 after receiving adjuvant immunotherapy. And just wondering what your thoughts and perspective are on how this will impact or influence your thinking about the management of our stage 4 patients. Dr. Michael Postow (14:48): So great question. This is an area that we need certainly a lot more research about efficacy of some of these new combinations after prior PD-1 exposure, especially in the adjuvant setting. Is there different efficacy expected if patients are progressing right on adjuvant PD-1? Or what if they've been off of PD-1 for three months, six months, one year, two years, five years ago? Is there differential efficacy for some of these combinations? Dr. Michael Postow (15:15): I don't think we know a lot about this, but one thing I would say is if I have a patient in the clinic that's progressed on adjuvant PD-1 or very soon after discontinuing adjuvant PD-1, I'm a bit more inclined to treat that patient with nivolumab plus ipilimumab rather than kind of going back on single-agent PD-1, or even nivolumab and relatlimab. And that's because my feeling, in general, and based upon the SWOG 1616 study, is that nivolumab and ipilimumab combination therapy has a higher response rate in PD-1 refractory melanoma than nivolumab plus relatlimab or even re-challenging with single-agent PD-1. Dr. Michael Postow (15:50): So in that context, I would think about nivo-ipi a little bit more for frontline treatment in metastatic disease, especially if the adjuvant PD-1 was given recently. But whether a break-off of adjuvant PD-1 restores some additional sensitivity to nivo-rela or even single-agent PD-1 after certain amounts of time, I think we need more data on that. And hopefully as time goes on, we'll collect that information and know how best to treat the patients in that new setting. Dr. Michael Davies (16:16): Well, Dr. Postow, thank you so much for joining us today. And really our conversation really does actually work as a great lead in to the other podcasts that we're going to have in this series, including podcasts focusing on immunotherapy resistance, the management of CNS metastatic disease, and adjuvant and neoadjuvant therapy. So thank you again so much for joining us today. Dr. Michael Postow (16:38): Thank you very much. I appreciate it.