 Jeffrey S. Weber, MD, PhD, discusses the background for the KEYNOTE-942 trial, which was conducted in resected high-risk melanoma

Dr Weber on the Background of the KEYNOTE-942 Trial in High-Risk Melanoma

Jeffrey S. Weber, MD, PhD, deputy director, codirector, Melanoma Research Program, New York University (NYU) Langone Perlmutter Cancer Center, Laura and Isaac Perlmutter Professor of Oncology, NYU Grossman School of Medicine, discusses the background for and rationale of the phase 2b mRNA-4157-P201/KEYNOTE-942 trial (NCT03897881), which was conducted in patients with resected high-risk cutaneous melanoma.

presented data from the clinical investigation

 of the addition of a personalized mRNA neoantigen vaccine to standard-of-care (SOC) pembrolizumab (Keytruda) in patients with resected stage IIIB, IIIC, IIID, and IV cutaneous melanoma. Findings from the investigation indicated that this treatment strategy enhanced survival outcomes compared with pembrolizumab alone in this patient population. These data supported the inference that monitoring circulating tumor DNA can offer valuable insights into the extent of benefit patients may derive from receiving an mRNA vaccine plus pembrolizumab.

The rationale for this study stemmed from research conducted over the past 7 years, which demonstrated that neoantigen treatment approaches, including RNA vaccines, could effectively trigger neoantigen-specific T-cell responses, he explains. These treatment approaches also induced epitope spreading to other antigens and sustained responses, Weber notes.

Additionally, clinical responses were observed in a subset of patients with metastatic diseases, particularly melanoma and lung cancer, Weber continues. Based on this background information, a randomized phase 2 trial, which randomly assigned patients with high-risk melanoma 2:1 to receive the RNA vaccine with pembrolizumab vs pembrolizumab alone, was conducted to assess whether the combination could produce recurrence-free survival and distant metastasis–free survival benefits in this patient population, he states. Positive outcomes from this trial, which enrolled 157 patients, would provide the rationale for proceeding to investigating this combination in a larger, more costly, more extensive phase 3 study, with minimal risk associated with advancing to the larger trial, Weber concludes.

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Jeffrey S. Weber, MD, PhD, discusses the background for the KEYNOTE-942 trial, which was conducted in resected high-risk melanoma.

Dr Weber on the Prognostic Utility of ctDNA Dynamics in Melanoma

Jeffrey S. Weber, MD, PhD, deputy director, codirector, the Melanoma Research Program, NYU Langone Perlmutter Cancer Center, Laura and Isaac Perlmutter Professor of Oncology, NYU Grossman School of Medicine, discusses the use of circulating-tumor DNA (ctDNA) dynamics when guiding treatment decision-making in melanoma, according to data from the phase 2b mRNA-4157-P201/KEYNOTE-942 trial (NCT03897881).

This randomized study compared the personalized mRNA-based neoantigen therapy mRNA-4157 (V940) in combination with pembrolizumab (Keytruda) vs pembrolizumab alone in patients with resected, high-risk melanoma.

Findings from the study were presented at the 

, and showed that patients treated with mRNA-4157 and pembrolizumab experienced improved recurrence-free survival and distant metastasis-free survival compared with pembrolizumab alone, regardless of baseline ctDNA status. Notably, baseline ctDNA expression was identified as a potential negative prognostic factor for treatment outcomes in the study.

The crucial consideration for any biomarker lies in its impact on patient care, Weber begins. Generally, a test should not be conducted unless it will substantially influence disease management strategies, Weber states. If patients have negative baseline ctDNA that remains negative throughout treatment, they are more likely to respond well to therapy, he details. Accordingly, ctDNA serves as a predictive marker at baseline, providing valuable information about the patient's prognosis, Weber explains.

Although positive baseline ctDNA expression suggests poorer outcomes, the utility of ctDNA is limited by its potential to become positive during the course of treatment, Weber continues. The current utility of ctDNA is therefore primarily prognostic, he clarifies, stating that positive baseline expression may indicate poorer outcomes on treatment, and negative baseline expression is generally associated with positive outcomes.

Monitoring ctDNA over time can provide valuable insights, Weber adds. For instance, if ctDNA was initially negative and later increases, it could signal the need to switch therapy, he suggests. In scenarios where patients opt for a specific treatment, such as pembrolizumab alone, monitoring ctDNA becomes crucial. If ctDNA levels rise, it may prompt the addition of a vaccine or another drug to the current regimen, especially if studies on combining LAG3 antibodies with PD-1 antibodies show positive results, Weber says.

Ultimately, the influence of ctDNA on patient management is dynamic, requiring continuous monitoring and response adjustments based on its changing status over the course of treatment, Weber states. Further investigation is needed to better understand and leverage ctDNA monitoring to guide treatment decisions and disease management strategies in melanoma, he concludes.

Jeffrey S. Weber, MD, PhD,  discusses the use of circulating-tumor DNA dynamics when guiding treatment decision-making in melanoma, according to data from the phase 2b mRNA-4157-P201/KEYNOTE-942 trial.

Dr Weber on the Prognostic Utility of ctDNA Dynamics in Melanoma  

Jeffrey S. Weber, MD, PhD, deputy director, codirector, the Melanoma Research Program, NYU Langone Perlmutter Cancer Center, Laura and Isaac Perlmutter Professor of Oncology, NYU Grossman School of Medicine, discusses findings from the phase 2b mRNA-4157-P201/KEYNOTE-942 trial (NCT03897881) of mRNA-4157 (V940) in combination with pembrolizumab (Keytruda) in resected high-risk melanoma. 

The open-label, randomized trial assessed the personalized mRNA-based neoantigen therapy with pembrolizumab vs pembrolizumab monotherapy in patients with stage IIIB, IIIC, IIID or IV cutaneous melanoma who underwent surgical resection within 13 weeks of their first dose of pembrolizumab. Patients were randomly assigned 2:1 to the combination or monotherapy arms. The median duration of follow-up was 23 months for the combination arm and 24 months in the monotherapy arm. In addition to the primary end point of recurrence-free survival (RFS) and secondary end points of distant metastasis-free survival (DMFS), safety and tolerability, the analysis focused on the longitudinal dynamics of circulating tumor DNA (ctDNA) and its association with clinical outcomes.

Results showed that the combination of mRNA-4157 and pembrolizumab produced significant RFS and DMFS benefit vs pembrolizumab alone, Weber reports. Moreover, patients with minimal residual disease (MRD) at the beginning of treatment had shorter RFS. Of the patients with available ctDNA data and recurrence events, a higher proportion of molecular non-responders experienced recurrence compared to molecular responders. Local recurrence was more common in molecular responders, but non-responders had a higher incidence of distant events. This trend was more pronounced in DMFS than in RFS.

Although there was a trend toward improved efficacy with mRNA-4157 plus pembrolizumab in both 

 wild-type and mutated subgroups, patients who were ctDNA-negative experienced more consistent efficacy with the combination regardless of 

Overall, patients experienced improved survival outcomes with the combination vs monotherapy irrespective of baseline ctDNA status. However, preliminary findings suggest that baseline ctDNA dynamics may a negative prognostic factor for treatment outcomes in patients with high-risk resectable melanoma, Weber emphasizes. Accordingly, the combination regimen may provide superior benefit to patients across other positive biomarkers such as PD-L1 status, interferon expression signature, pr tumor mutational burden, he adds. The results support the need for further investigation in upcoming studies to better understand and leverage ctDNA monitoring for improved patient management in this challenging disease.

Jeffrey S. Weber, MD, PhD, discusses findings from the phase 2b mRNA-4157-P201/KEYNOTE-942 trial of mRNA-4157  in combination with pembrolizumab in resected high-risk melanoma.  

Dr Weber on Survival Outcomes With mRNA-4157 Plus Pembrolizumab in High-Risk Melanoma

Jeffrey S. Weber, MD, PhD, Laura and Isaac Perlmutter Professor of Oncology, Department of Medicine, NYU Grossman School of Medicine, deputy director, Perlmutter Cancer Center, codirector, Melanoma Research Program, NYU Langone Health, discusses unmet needs in ocular and mucosal melanoma.

Despite significant advances in the treatment of patients with melanoma, such as the integration of nivolumab (Opdivo) plus ipilimumab (Yervoy), around half of patients treated need additional therapy, Weber says. As such, therapeutic development is important in melanoma, particularly for the ocular and mucosal subtypes. 

In August 2021, the FDA granted a priority review designation to the biologics license application of tebentafusp (IMCgp100) for the treatment of adult patients with HLA-A*02:01–positive metastatic uveal melanoma. Data from the phase 3 IMCgp100-202 trial (NCT03070392) demonstrated a median overall survival of 21.7 months with tebentafusp vs 16 months with investigator’s choice of pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine in this patient population. 

However, beyond this agent, no therapies are approved for use in patients with metastatic uveal or ocular melanomas, underscoring the need for novel therapies. Moreover, clinical trials evaluating adjuvant therapy in ocular melanoma are needed, Weber adds.

Similarly, novel therapies are needed in mucosal melanoma where the combination of nivolumab and ipilimumab is not as effective as it is in cutaneous melanoma, Weber says. Although most melanomas and melanomas of unknown origin are likely cutaneous, the 5% of patients with ocular, mucosal, or acral lentiginous melanomas that are characterized by low mutation burden and are less sensitive to immunotherapy represent an area of significant unmet need, Weber concludes.

Jeffrey S. Weber, MD, PhD, discusses unmet needs in ocular and mucosal melanoma.  



Dr. Weber Discusses Unmet Needs in Ocular and Mucosal Melanoma 

 Thanks to all of you for this rich and informative discussion. Before we conclude, I’d like to get final thoughts from each of you. Dr Chandra?

 This is a great time to be a melanoma medical oncologist. I think with our group of colleagues, it’s really been at the forefront of the field of immunotherapy. The more we’re learning, I think the more questions we have. We’ve discussed a lot today about how to best plan algorithms. Should we do sequential? Should we do combinatorial? Which combinations for which patients? Should we do IO [immunotherapy], or targeted therapy? We have so many options.

I do think we need to be thoughtful as a community in moving forward. We have limited patients, limited resources. Throwing the kitchen sink at patients doesn’t make sense. We need more biologic rationale and more scientific rationale in the trials that we do design and put our patients on.

Today, we haven’t even talked about some of the unmet needs besides melanoma brain metastases, such as uveal melanoma, and mucosal melanoma, in which there were some great data presented at ASCO [the American Society of Clinical Oncology annual meeting] this year. I do think we have a long way to go. I’m very excited about how far we’ve come.

 To take up on what Su was saying, I think we’ve made a huge amount of progress. I look forward to having more than just 1 tool in our immunotherapy toolbox. Right now, for lack of better description as just PD-1, I feel like we need to understand how to really stimulate effector T cells. We’ve used IL-2 [interleukin-2], but most of us, when push comes to shove, don’t really want to get up in the middle of the night and make those IL-2 decisions. I still have PTSD [post-traumatic stress disorder] from those times. Jeff, I’m sure you do.

 I think in terms of medical oncology friendly tools that we can actually give in the here and now, I think it would be nice to have some more maybe inhibiting Tregs [regulatory T cells]. I think there’s a lot of exciting preclinical data. I feel like we haven’t really been able to exploit Treg inhibition, unless you consider ipilimumab to be a Treg suppressive drug. I feel like the next 5 years will be exciting also.

 I would quickly say that I think as we talked about with lifileucel, trying to identify the patients who are not going to benefit from the therapies that we have. We have these outstanding 5-year data for some patients. Realize that 50% survival, when you flip it over, it means 50% not survival, right? We don’t have time to talk about it here, but a lot of next-generation genomic approaches are starting to inform our ability to know who’s going to respond to some of these treatments. We ought to think about designing trials to go after those populations of patients who we know are not going to respond because that’s really the big unmet medical need. Those are the patients we stay up all night thinking about.

 I don’t have a whole lot more to add. It’s been said, but finding out which patients are going to benefit, and more importantly as Dr Luke said, which patients aren’t, is critical. Despite all the progress, we still have a lot of progress to make. That means we have a job for a while, and we haven’t fixed this disease and are ready to move on to another one. We can cure some patients, and that’s amazing, but we’ll keep working at it until we can cure all.

 Great. Well, thank you again. Thanks to our viewing audience, and we hope that you found this 

® discussion to be useful and informative.

Treatment Optimization for Patients With Melanoma

 Ryan, bring us home. Tell us about what you think are the more promising emerging approaches. We’ve heard about TILs. We’ve heard about triple therapy, BRAF-MEK, immunotherapy. What do you like?

 What I like and what I think is coming next are probably in line, and then there may be some of the things that I think could also be in the future. If the data with TIL therapy, for example, which in an, albeit selected population, 66 patients, they obviously had to have a tumor that could be resected. They had to be able to grow the TILs. They had to be well enough 3 or 4 weeks later to receive lymphodepleting chemotherapy and then get the TIL product and the IL-2.

The response rate in a heavily pretreated population, everybody who had PD-1 inhibition, three-quarters or more had had CTLA-4 inhibition, with a 36%, 37% response rate. It’s totally respectable. The waterfall plot definitely inflected past 50%, meaning most patients had some tumor regression.

There’s a 75- or 80-patient cohort. If there’s a similar response rate seen in that cohort, I would anticipate that that would be FDA-approved. That’s exciting. Anytime there’s a new potential drug that could be approved, it’s exciting. At centers, Jeff, you’re obviously an expert at giving TIL therapy. Most of us aren’t. Fortunately, CAR T-cell therapy has forced all of our institutions to rethink delivering cells to patients. Ten years ago, this would have been a hard thing to roll out. Now it would be a relatively easy thing to roll out. That’s one thing that came out of this. It was reinforced data that were updated from last year, but data nonetheless that are encouraging and likely speak to a near-future change in the way we manage patients in the refractory setting.

 Ryan, can I make one more comment quickly?

 The other data that I was impressed by in this update were that when you looked at the responding patients to lifileucel or the TIL product, they disproportionately were people who were outright refractory to PD-1. When we go back to what Adil said earlier about wringing out all the T cells, these are patients who do very poorly. The idea that they have a disproportionately more active agent for that population of patients, to me, makes this a high priority. I’m actually really excited about this because I feel like these are the patients who we have not advanced the field for. We’ve done really great for some of the patients. But for these patients, we have not made progress. Maybe this is it. We’ll have to wait and see. We still need more data.

 Yes. The other point that Adil made was that we need to see how durable the responses are. In fairness, the duration of response with 18 months of follow-up hadn’t been met yet. Certainly, some of these responses were very transient, and by 4 or 5 months, the response was gone, and patients had progressed and were either on to something else or unfortunately not onto something else. In the majority of patients, those responses were lasting 18 months or longer. It’s a commercial product. It’s something that we might be able to use if it gets approved, as soon as it gets approved. They are exciting data for a population of patients who don’t have a lot of exciting data.

The triple therapy, so BRAF-MEK/PD-1 or BRAF-MEK/PD-L1,, this is a decade in the making with phase 1 and phase 2 trials that many of us were part of. Then to see an idea that BRAF-targeted therapy causes changes in the tumor microenvironment, maybe adding immunotherapy would be useful. Ultimately, it seems like it might be. In the frontline setting, there seems to be an improvement in progression-free survival. There seems to be an improvement in duration of response. That’s not just in a randomized trial that we talked about before, the IMspire150 or the trilogy study, which is vemurafenib/cobimetinib lead-in for 28 days and then you add atezolizumab.

There’s also a dabrafenib/trametinib/pembrolizumab study that was randomized and showed an improvement in progression-free survival and a trend toward an improvement in overall survival in patients who received triplet therapy versus doublet BRAF-targeted therapy.

Also updated at ASCO this year was the COMBI-i study. It’s a randomized trial and that part hasn’t been updated yet. That data have not been released, and are not mature yet. The nonrandomized phase 1/2 data show a complete response rate of 44%. That’s a remarkable number. If in the randomized data you get a complete response rate in the 35% or 40% range, that’s dramatic. We anticipate that that would meet the primary end point of progression-free survival.

Ultimately, where that fits, I don’t know. That’s not comparing against PD-1 inhibitor therapy. That’s not comparing against ipilimumab or nivolumab. We’ll at least have things to argue about at our meetings for the next 5 years until somebody does that type of study. It’s still another option. There are patients who are 

 mutated that we give BRAF-targeted therapy to because we think they’re going to die 2 weeks from now. Now we can offer those folks BRAF-targeted therapy plus a PD-1 inhibitor with some hope that they’ll do well. If we have BRAF-MEK, PD-1, and PD-L1 studies, I think that seems likely that that’s another thing that could get to the clinic. We obviously can all do it off-label. That’s something that could be approved in the next year or two as well. The more options we have, the better.

In terms of other things, I think there are first-line cancer vaccines plus PD-1 inhibitors. We’ll see where that goes.

 What about the thing that Jason mentioned? He talked about pembrolizumab plus a nontoxic partner. What about NKTR-214?

 IL-2 is an old drug. Bempegaldesleukin is a modified version of an old drug that has a bunch of PEGylations on it, which have been shown that it seems to preferentially target the receptors on the T effector cells and the NK cells, as opposed to T regulatory cells.

The data in single agent are compelling in terms of you can see changes in tumors. It’s not so compelling in terms of single-agent efficacy. In combination with PD-1 inhibitors, it seems like there’s something there. Whether that’s so much there that you end up with a positive phase 3 trial, I don’t know, but we’ll find out, because that phase 3 trial is ongoing. It’s nivolumab plus or minus bempegaldesleukin.

There are other IL-2 analogues that are out there now too. We’ll have to see where that part of it goes. It’s a compelling concept to use IL-2 because it did set the bar for potentially curative therapy in melanoma. It just was a low bar. The question is, if you add that to PD-1, do you really raise the bar further, or are you just treating the same patients who were going to do well with PD-1 inhibitor? I guess we’ll find out. It’s exciting that these trials are out there and that they’re asking these questions, and hopefully will answer them.

Future Treatment Landscape for Melanoma

 Let’s turn to Su. Can you tell us what you think are the more promising phase 3 strategies? We acknowledge they’re not going to be mature. What do you like? I hear there’s at least a half a dozen studies going on.

 Absolutely. Most of these studies haven’t given us real mature data that we can hang our hat on. There are certain approaches that are being looked at that look fairly promising. One thing that’s being looked at is targeting the toll-like receptor 9, which is also known as the TLR9 agonists. There’s a trial out there with SD-101. Jason, I think you were involved in one with CMP-001. These agents are intratumoral injections that are supposed to stimulate dendritic cells, for example, which are antigen-presenting cells. They release more interferon-alpha. They cause more maturation of these cells, which can lead to an augmented T-cell response.

The notion behind some of this is how to make these tumor microenvironments more inflamed, more hot, more potentially amenable to T cell-mediated responses. The problem, though, at least in my experience, is that in my practice, I don’t see a lot of patients with injectable disease. A lot of my patients end up having visceral disease, and that may not be injectable. I certainly don’t want to inject into the liver very easily or the lung. Even with radiographic imaging guidance, it’s a tricky situation.

Even patients who do have injectable disease, which I said was few and far between for me, it is a challenging situation in administering the drugs. They’re not the easiest drugs to give. I certainly think that it opens doors for this particular patient population.

The ipilimumab/tilsotolimod trial is also the same kind of scenario. That’s attractive because, as Jason said, let’s say you start out with nivolumab alone or pembrolizumab alone or nivolumab plus X, where X is not ipilimumab, if you progress, then you can go to ipilimumab plus Y. That has some attractions that we don’t have any data on. There were phase 1/2 data, correct, Su, if I’m not wrong?

 Yes. The phase 1/2 data there showed a response rate of a little less than 40%, I believe. It was a small number of patients. Some were between 25 and 30 patients. The data are quite early.

 That’s now in phase 3. Jason, there’s the lenvatinib/pembrolizumab trial. I’ve heard some good things about that. I don’t know if those are publicly known. I’m not sure that that’s been presented, but I like the idea of this pan-TKI [tyrosine kinase inhibitor] plus pembrolizumab.

 There are VEGF TKIs, sort of these dirty TKIs, lenvatinib or cabozantinib or axitinib and many of them, which across a number of disease states now actually look quite promising in combination with an anti–PD-1. They’ve been approved in some indications that are obvious, like kidney cancer. That’s where VEGF agents are super-active. Even in other diseases that are epithelial in origin, and you really wouldn’t expect VEGF blockade to have that much activity, cervical cancer and now colorectal prostate, and now melanoma.

 Yes. It’s looking very exciting that these combinations may actually be able to overcome some of the resistance mechanisms that we’ve suggested. I wonder to what extent they are targeted therapy and to what extent they’re chemotherapy because they do a lot of things. All the same, when we’re thinking about salvaging patients who have progressed on PD-1, I think it’s all hands on deck. Certainly the initial results do sound promising.

Promising Late-Stage Trials in Melanoma

 Can I make a comment quickly to follow up on one thing that Adil mentioned about checkpoint blockade in the refractory disease setting? I want to highlight quickly, because we didn’t talk about it yet, the data for using ipilimumab in the second line, and adding it onto PD-1 because there were 2 big abstracts on that, that I don’t want to say are practice-changing, but I definitely think will influence people’s thought process. One was a second-line phase 2 study of adding low-dose ipilimumab after initial PD-1 failure. That study showed a 27% response rate in 70 patients. That was augmented by a retrospective study from the MIA [Melanoma Institute Australia], where they looked at the experience of giving ipilimumab/nivolumab after nivolumab or PD-1. They got a 32% response rate in a group of 180 patients. Those are 2 reasonably large data sets to suggest that you could get more activity by continuing PD-1 and adding ipilimumab than you would of just giving ipilimumab because the response rate we would expect for ipilimumab alone in that setting is about 13% to 15%. This looks to be almost double that.

It was mentioned before that you’re wringing all the T-cells out. I think that’s true to some extent, but in the immediate post–PD-1 monotherapy space, it’s looking more and more like giving that combination therapy may be better than giving ipilimumab monotherapy. There is more work to do there. There is a SWOG trial that’s specifically randomizing patients to look at that. I think that’s worth being cognizant of, because if patients are having rapid progression after PD-1 monotherapy and they’re 

wild type, I personally would recommend continuing the PD-1 and adding the ipilimumab on top of it. It is an open question. Now reasonable-sized data series support that.

 I think a lot of people do that as their routine standard if they’re not in a protocol setting. On the other hand, how often in your practice, or Adil, Ryan, or Su, do you give someone single-agent PD-1 blockade? How often do you do that versus giving them the combination?

 In my practice, I tend to be pretty aggressive. I do use a lot of combination immunotherapy. One thing that’s changed recently with the coronavirus disease 2019 pandemic, however, we felt, perhaps scaling back a little bit. The responses with anti–PD-1 alone are actually quite remarkable. To stave off some potential AEs [adverse events] that would put people at risk by bringing them into the hospital, etc, we have been using a little bit more anti–PD-1 alone. In general, I would say I use a lot of combination, and certainly for patients with brain metastases.

 I don’t want to pretend to be consistent on this issue because I have argued all kinds of sides of this. In this instant, listening to you guys talk, I feel like a lot of the time, I do use combination therapy up front, unless I can be almost positive from looking at the T cells, that somebody will have a response, or if somebody has very low-volume disease, or is older and doesn’t want to come in a lot, or is quite worried about toxicity. But I’ve been very easygoing in terms of stopping combination therapy after 2 or 3 cycles. Once somebody has a response, that heavy lifting with PD-1 blockade seems to be done pretty early, and what you’re getting a year or 2 years out probably isn’t a whole lot. I’m quick to stop combination therapy. So far, I’m sticking to the 3 mg of ipilimumab, but really there are data on either side.

 I wouldn’t argue with anybody’s perspective. I tend to still be somebody who uses clinical factors for selecting patients for ipilimumab/nivolumab combination, which is high-risk disease, so high LDH [lactate dehydrogenase], liver, bone metastases, and brain metastases. In patients who don’t have those features, I tend to still defer toward PD-1 combinations in clinical trials. I tend to give monotherapy there. That’s why the data for bringing in ipilimumab in the second line, to me, was, I don’t want to say reassuring because every patient’s different and it’s hard to know, but it’s still possible to salvage some of the patients to get responses in the second line by adding the ipilimumab. I might be biased toward being less intensive up front unless there are clear clinical factors that really push me that way.

 I would agree that the Daniel Olson, MD, article from your former institution from Chicago. Then the Ines Pires da Silva, MD, PhD, which is Melanoma InstituteAustralia. Olson’s was prospective. I think it was something like 70 patients. Then da Silva was retrospective with 355. I would say those are important. For me, they’d be practice-affirming, as opposed to practice-changing. Ryan, are they practice-changing for you or affirming?

 No, I tend to agree more with Jason here. I don’t know if it’s a competition, but I probably give more single-agent PD-1 in the front line than most. My rationale is, it comes from when we worked together on the CheckMate 064 study, which randomized patients either starting with ipilimumab or nivolumab, and then they switched to nivolumab or ipilimumab. Then they went to maintenance nivolumab. The results of the trial were interesting. Obviously, starting with nivolumab was better.

What helped me understand the impact of these 2 drugs together was that when you gave ipilimumab soon after nivolumab, a lot of patients who weren’t having clinical benefit started to have clinical benefit. They all started to have toxicity, but that cemented into me that if there are patients for whom you can wait 3 months to see if PD-1 monotherapy is effective, you might as well, because you probably are salvaging most of the patients that you’re treating with combination up front who are going to get the benefit of ipilimumab. The da Silva and the Olson studies affirm, as you say, that bias that giving ipilimumab afterward is probably OK. More importantly, giving it with a continued PD-1 inhibitor is a reasonable way to go.

If you’re aged 60 or 70 or 80, or 20, it’s hard to argue with younger patients getting combination with survival benefit that may be better by that few percentage points. In older folks who have comorbidities, even if they’re not autoimmune comorbidities, getting a 30% or 40% chance of having durable remission with the PD-1 inhibitor, and if they don’t have that, you might be able to make up the durable remission rate with second-line ipilimumab/nivolumab. That’s a reasonable way to go for patients who don’t need a response right away. If you need a response right away, you’ve got to give ipilimumab/nivolumab. If you have brain metastases, you’ve got to give ipilimumab/nivolumab. There is more wiggle room now that those data are out. I knew about that wiggle room because of Jeff Weber and CheckMate.

 Jeff, if I can just make a quick comment, too. When I designed that study for the low-dose ipilimumab in the second line, the rationale at the time was that we thought we had PD-1 plus X combinations that were going to look really hot and give us less toxicity. We haven’t really gotten there yet. I still hold out hope for a future where that would be true. One could even imagine with the ongoing studies of relatlimab or bempegaldesleukin or other novel molecules in the front line that that could still be a play, a PD-1–based nontoxic regimen that increases response rate. If you don’t get that very quickly, then you flex over to give CTLA-4 combination. We’re thinking into the future now, but that was actually the rationale when we designed that study back when. I’m still hopeful that someday, we’ll be able to get there with the idea we can limit the toxicity of ipilimumab.

Targeted Therapy Versus IO for Relapsed/Refractory Melanoma

 Let’s turn to refractory disease. We’ve gone through resectable disease, adjuvant, neoadjuvant, frontline, and then comes the tough nut to crack. This is always the biggest challenge. What do you do with a patient who’s been through your frontline therapy, or a frontline and second-line therapy? Now you’re in third-line therapy, or if they fail adjuvant therapy, and then they get, say, combination immunotherapy [IO], then they fail, then what do you do? Adil, let’s come back to you. How do you approach patients who progress on IO if they’re 

 wild type, or if they progress on IO, then they get 

, if they’re mutated, and now you’re into third-line therapy, then what do you do? What can you tell us about resistance and about how you choose what to do next?

 This is a challenging population, and it’s a hard nut. I have to say that the last couple of years haven’t been super encouraging. From what I can tell looking at the PD-1 refractory tumors, most of those patients don’t have a lot of T cells left. That probably is why we’re seeing disappointing results with additional checkpoint blockade. Once you’ve wrung out PD-1, you’re not going to get much more from other checkpoints, simply because there are not a lot of T cells left in those tumors.

There might be exceptions to that rule. Maybe 10% or 15% of the time, you could restart treatment if you haven’t had it for a while. Your question really goes to the heavy-duty PD-1 refractory field. One encouraging signal we are seeing is getting a new bunch of T cells to come into your tumor. I personally like interleukin-12, but I think you are seeing some encouraging data from these TLR [toll-like receptor] agonists—there was the CheckMate trial that was reported at SITC [the Society for Immunotherapy of Cancer meeting] last year. There are also some intriguing responses, where you’re getting T cells coming into your tumor. You’re turning some lukewarm tumors to a little bit less lukewarm tumors. Then once you add PD-1 to that, you can get responses to it.

With the targeted therapy field, 5 or 6 years ago, there were papers showing that 

 mutation might be responsible. I don’t think they panned out enough in the data that today we can say we really understand what’s happening with BRAF resistance. It’s a challenging field, and you’re probably going to rely on things like the…study where they’re looking at adoptive T cells where, outside of the immune suppressive microenvironment, maybe you can get some fresh T cells to ramp up and then put them back in. You might get some response, although I think the jury is still out on how long term those responses are and whether those are really immune responses, or whether it’s the preparative regimen that’s doing some of the heavy lifting for you in that setting.

Novel Approaches for Relapsed/Refractory Melanoma

 Let’s head back to Jason. The ipilimumab-nivolumab track record in brain metastases really did change my practice. Those are pretty recent data that have come out over the last year or 2. What can you tell us about your approach in treating melanoma patients who have brain metastases in frontline therapy? How do you decide ipilimumab-nivolumab, pembrolizumab, or nivolumab alone versus 

 This has been an evolving area that still remains the toughest spot in melanoma to deal with. What has really come forward is that there’s just no question anymore that the standard of care for patients with brain metastases that are asymptomatic or low-volume where you don’t have to intervene immediately is ipilimumab-nivolumab. I would even go farther to say nivolumab plus ipilimumab-3, although maybe you guys want to argue with that.

The reason for that is 2 trials. One was out of Australia and led by Georgina Long, the ABC-X trial, as well as the CheckMate204 study that Hussein Tawbi led. If you look at patients treated on these trials, this is a selection of patients with brain metastases. This isn’t the run-of-the-mill patient. The people who present with small-volume or asymptomatic lesions, the landmark 1-year survival is 80%. You think about dating back 5 to 10 years, the median survival for these patients was 6 months, and now we have 80% of them alive at a year. They’re durable. It’s response in the body. It’s response in the brain. It’s really quite impressive.

In my practice, that is enough that I don’t even radiate these patients. I give them ipilimumab-nivolumab, and then we watch and monitor. If we have to, we radiate later. These data really do change the game.

I mentioned that that isn’t every patient. In fact, it’s not even a majority by any means of patients with metastatic melanoma. Many patients present, they need steroids, they’ve got shift, and they’re sick. In those patients, it’s a barrier to think you’re going to give ipilimumab-nivolumab there because if they’re on steroids, it will blunt the effect, and/or they’re already too sick to think you’re going to stress them.

It’s really all hands on deck. That’s where 

mutational analysis is super important. Certainly, BRAF inhibitors are active and 

 combination in CNS [central nervous system] metastases. Mike Davies presented the COMBI-MB study some years ago showing that you get responses as you would expect in the brain. The caveat is that they are not as durable as they would be otherwise in the body. Whereas the median PFS [progression-free survival] for 

 in the body is on the order of about 11 months, in the brain it’s about 6 months. For patients who present with symptomatic brain metastases, I try to think about if there a way we can get them to ipilimumab-nivolumab, because the data for ipilimumab-nivolumab are so impressive.

It’s worth noting as a follow-on that Hussein Tawbi updated last year’s ASCO [American Society of Clinical Oncology Annual Meeting] with the symptomatic population, where they used ipilimumab and nivolumab and got not nearly the same kind of results. They had a response rate of about 20%, perhaps. Even those 20% were outliers who had weird stories and weren’t representative of the usual patient you would see if a patient is symptomatic with these high doses of steroids or has a shift or something like that.

The quick is that ipilimumab-nivolumab, if you can do it, is for sure the right answer. If not, use everything you can get, with the 1 caveat being not whole-brain radiation. At ASCO last year, there was a nice study looking at adjuvant whole-brain radiation after resection. The results were equivocal. There was no difference between the whole brain and not using whole brain.

If you looked at the numerical data, whole-brain was actually worse than doing nothing. All of us have treated patients and given whole-brain, and whole-brain is awful for patients, and in melanoma, it does not add anything. Please don’t use whole-brain radiation. We need to SRS [stereotactic radiosurgery] some lesions, we can use the 

, but try and get to ipilimumab-nivolumab. Do not use whole-brain radiation. Call everybody you know to try to get as much advice as you can because these are hard patients to manage.

 Su, will you forgo stereotactic radiosurgery in an asymptomatic patient who presents front line?

 That’s an excellent question. We usually always discuss these patients at our multidisciplinary melanoma tumor board. We have radiation oncology there, obviously medical oncology, surgical oncology, etc. If they’re asymptomatic and they are up to 3 cm or so, we usually wait. Three is probably pushing it in terms of sizes, but we try to forgo radiation therapy and give them some time on ipilimumab-nivolumab. We follow them very closely with respect to symptoms and radiographic imaging. We’ve had situations where their lesions have responded beautifully, and they haven’t required radiation. With SRS, although it’s fairly well tolerated, there can be adverse effects. We’ve seen radiation necrosis. It’s certainly not a benign modality.

 One last interesting thing is, in the trilogy or the IMspire150 trial, there were some data about the time to CNS metastases. This was presented prominently at AACR [American Association for Cancer Research] 1 month or so ago. Ryan, what can you tell us about that? You know that study pretty well.

 The study randomized patients to receive a triplet of vemurafenib, cobimetinib, a BRAF-MEK inhibitor, for 28 days, and then after 28 days, to fold in atezolizumab therapy. The comparator was vemurafenib, cobimetinib, and atezolizumab placebo. The data for the primary end point was progression-free survival. There was a progression-free survival advantage to giving triplet therapy versus doublet therapy.

It didn’t allow patients with active brain metastases, but there was a subset analysis looking at the time to develop brain metastases in patients who received doublet versus triplet therapy. It seemed to be a numerical difference, meaning the patients who got doublet therapy had a shorter time and were more likely to develop brain metastases than those who got the triplet therapy, though it didn’t meet statistical significance. It was a subgroup analysis. It wasn’t a ton of patients. I can’t really say that’s the way to go in terms of treating patients in frontline with brain metastases that are asymptomatic and overtreated. That’s a different experiment, so to speak.

There will be those types of trials. Already, there are a couple of trials, including a trial in SWOG that’s looking at triplet therapy.…That will be an important trial to understand whether targeted 

 and combining that with PD-1 is as effective in patients with brain metastases than just nivolumab.

Management of Brain Metastases in Melanoma

 Let’s turn back to Ryan. Jason had alluded to a couple of scenarios where alternate doses and schedules of immunotherapy were used. At this ASCO [American Society of Clinical Oncology annual meeting], there was at least 1 very interesting oral presentation by Mike Postow. What can you tell us about the different doses and schedules? Tell us a little more about how you treat your patients in real life, off protocol.

 In real life, off protocol, I tend to treat patients as my colleagues do and often give single-agent PD-1 or combined immune checkpoint inhibition. The reason I don’t give combined immune checkpoint inhibition to everybody is the high toxicity rate. That’s obvious. It’s probably also why the difference in overall survival between 52% and 44% at 5 years isn’t 70% and 44%. Because the toxicity is high, a lot of patients need corticosteroids. It’s not a high percentage, but some patients certainly die from the toxicity more with combined.

There’s been a push in the field to look at alternative ways of delivering combined immune checkpoint inhibition. One way of doing it is to lower the dose of ipilimumab. Jason alluded to the CheckMate 511 study, which was comparing alternate dosing of 3 mg and 1 mg ipilimumab-nivolumab versus 1 mg and 3 mg ipilimumab-nivolumab times 4 doses and then maintenance nivolumab.

What’s clear is the toxicity is less with the flipped dose. What’s also interesting is it’s probably a little early. There was only about 18 months of follow-up to see a real difference in overall survival with that. When you think about when the overall survival advantage was seen with ipilimumab and nivolumab versus nivolumab in CheckMate 067, it was actually 2 and 3 years when you started to see those curves separate, not 1 year, not even 18 months. We can feel good about the fact that it was less toxic, and the relapse-free survival looks about the same. I don’t think we can comment much on overall survival with alternative dosing of ipilimumab until you have longer-term data.

At this ASCO, Michael Postow and his colleagues at Memorial Sloan Kettering Cancer Center presented data on a trial where they thought they could get away with 2 doses of ipilimumab and nivolumab for patients and then do a scan. If the scan looked good, meaning there wasn’t any growth, then that would be it, and they could switch to maintenance nivolumab. If patients were having some additional growth of their disease, then they would continue to receive the final 2 doses of ipilimumab and nivolumab. This is the standard dose of 3 mg/kg of ipilimumab and 1 mg/kg of nivolumab.

What was interesting about the data is essentially 2 doses was about what you’d expect with 4 doses, meaning the majority of patients had no progression at 2 doses. In fact, the 12-week response rate was slightly less than 50%. But the total response rate, when we looked out further, was 57%, which is in line with what you’d see with when you intend to give 4 doses of ipilimumab and nivolumab.

Of those patients who may have had some evidence of tumor progression after 2 doses, none had a response. That was a minority of patients. That was about one-third of the patients who fell into that category. It suggests that continuing with ipilimumab-nivolumab when you’re not seeing benefit may not actually be the right thing to do. Although quite frankly, it doesn’t seem it was the wrong thing to do, because the toxicity rate was virtually the same you would expect if you were intending to give 4 doses.

What it ultimately shows us is that response is an early phenomenon with these drugs. So is toxicity, particularly in combination. Thinking about how we can optimize therapy, just thinking about a lesser number of doses, would be fine. It’s hard to say we should change our standard of care based on that. We certainly should feel OK if all we can do is give 2 doses because the patient is not tolerating it.

This is 1 of those types of questions that can be done only at an institution, and then ultimately maybe in a cooperative group to try to change the amount of dose that we give to be less than what’s standard. It certainly is something that may be considered in the future to do a larger trial, just comparing the 2 doses.

 The amazing thing is that 19 of 60 patients had more than 4% growth. Why they chose 4%, I don’t know. That’s a good question. That means any evidence of growth, as opposed to stability or regression, but none of them responded. Those were all the patients who are going to do badly. I was absolutely struck by that. The median survival is not reached. They haven’t even reached median PFS [progression-free survival], as I remember.

 It is pretty interesting, although I assume they met median PFS, but actually, that’s surprising if they had 20 months of follow-up, and they haven’t seen the median PFS.

 It’s 60 patients, so it’s hard to lean on even the PFS and the OS [overall survival], but certainly the response data are fascinating, as is the toxicity.

 Eighty percent of patients who were alive at either 18 or 24 months. That’s pretty impressive.

 Those investigators may be onto something. We’ll see. Maybe less is more.

 There also were the correlative data. They mentioned that they looked at T-cell activation and cell proliferation, and the parameters didn’t change after 2 doses. The increases they saw after 1 seemed like that was sufficient. That that data also support biologically what’s happening.

 They chose the 2 classic pharmacodynamic sine qua nons of getting PD-1 blockade alone or ipilimumab alone: Do the T cells proliferate, so Ki-67, and do they upregulate ICOS? I was blown away by the fact that 2 weeks later, it happened. Then you can keep going for as long as you want. Nothing changed. That’s a pretty early indication. Very interesting data.

I/O Dosing Schedules in Metastatic Melanoma

 Let’s talk about the data. Let’s turn to Su. There have been some relatively long-term follow-up studies of at least ipilimumab plus nivolumab-pembrolizumab, eventually nivolumab alone, and 

. The longest would be the dabrafenib-trametinib story. What can you tell us? Do you feel there are enough data to drive you in metastatic first-line disease in a 

-mutated patient to want to choose 1 or the other? Sorry to put you on the spot, but those are the data.

 Absolutely. That’s an excellent question. First, I have to point out that the options we have in front of us today have really blown the field wide open for melanoma, right? The response rate we see with anti–PD-1 alone is somewhere around 40%. The response rate we see with combination anti–PD-1 and CTLA4, is probably somewhere between 55% and 60%. There’s certainly a survival benefit, which I’m happy to get into. Then the response rates with targeted therapy are probably somewhere over 70%, potentially with less of a durable response.

It’s important to note that we have so many choices in front of us in terms of anti–PD-1 alone, combination, targeted therapy for those who have a 

 mutation. I do use a lot of I/O [immuno-oncology], even in the first-line setting. That is certainly a little a bias. The COMBI-d and COMBI-v trials have now 5 years of data. The 5-year overall survival is 34%, which is not insignificant by any means. Compared with that, for example, the CheckMate 067 data, where over 900 patients were randomized 1:1:1 to ipilimumab plus nivolumab, nivolumab alone, and ipilimumab alone with matched placebos. The response rate was almost 60%. I believe it was 58%, albeit the grade 3/4 adverse-event rate was also almost 60%. The overall survival at 5 years was 52%, meaning 1 of 2 people are still alive at 5 years.

The data are really exciting. I had alluded to the fact that I do use a lot of I/O in the first-line setting for the 

metastatic population. Part of it is because I have seen in my practice that if I use targeted therapy in the first-line setting—and once they become resistant, I barely have time to get them onto an I/O regimen, because their disease seems to just be accelerating—the performance status declines. There are just a lot of factors that prohibit me from then trying a second-line therapy. Now I know it’s doable. I’ve certainly been able to do it in some patients. That is a worry that I always have.

 I wonder, do your colleagues agree with that? Jason, do you agree that if someone fails frontline targeted therapy, then the immunotherapy becomes a difficult scenario?

 My bias is to say yes. I also think that patients who fail any therapy in the frontline are also harder to manage. I look for the high upside, and because of that, those ipilimumab-nivolumab data look quite impressive. It’s worth noting that we certainly have not figured out the optimal regimen in terms of immunotherapy in the front line, or even combinations with targeted therapy. All this is evolving.

In the last couple of years, we’ve had some discrepancy around the most appropriate dose of ipilimumab become an issue in the field, with CheckMate 511 showing potentially no difference in the benefit between nivolumab 1 mg/kg–ipilimumab 3 mg/kg and nivolumab 3 mg/kg–ipilimumab 1 mg/kg, but that’s in contrast to previous randomized studies. There are data for ipilimumab plus pembrolizumab with a lower dose of ipilimumab. All this is to say that we have a lot more to do. When I think about which treatment to use in the front line, I am somewhat biased toward immunotherapy as well, going into long-term overall survival with PD-1 around the low 40s and doublet I/O in the low 50s. I like those data. That is usually what drives my perspective.

I’ll also note that you have the BRAFinhibition in the back pocket, so if you don’t get the kind of long-term sustained benefit you want, you can get disease stability, which allows you to regroup and think about future options. All those are ways I think about it. I will note, just for the record, that the best patient with 

-mutant disease to treat with a BRAF inhibitor, though, is the patient with low-volume disease who is almost always going to be the person in the front line. On some level, we are putting ourselves behind the book when it comes to using targeted therapy if we do it that way. Probably everyone here is going to, generally speaking, agree with that sentiment.

Novel Therapies for Metastatic Melanoma

 Let’s move on from adjuvant to neoadjuvant. Let’s talk about systemic approaches. Back to you, Adil. It’s the same question that we think about in the adjuvant mode. How do you make decisions in choosing therapy, 

 versus immunotherapy, based on if it’s a 

 wild-type patient? What are the biomarkers that help you to make the choice?

 That’s a great question, and I loved the previous discussion that Jason Luke and Sunandana Chandra were having about adverse events. In terms of neoadjuvant, I lean toward immunotherapy. That has to do with some biases from trials in terms of thinking that immunotherapy will have more lasting benefit. I have to say, parenthetically, that we understand a lot more about immunotherapy response, and we understand the mechanism of immunotherapy response a lot better than we understand 

-mutated patients who will have a lasting response versus who won’t have a lasting response. There’s been some interesting biomarker work done in 

-mutated patients too. Today I would say that none of us can really predict, given the 

-mutated patient, who’s going to have a lasting benefit versus who’s going to have some kind of bypass pathway.

I feel like in the neoadjuvant space, unless somebody has a history of previous adverse events—colitis, multiple sclerosis, or some major issue—I lean toward using immunotherapy. Then the choice between using single-agent or double-agent immunotherapy comes down to what I think is likely to work, how bulky the tumor is, and how urgent the treatment seems to be. Most of our neoadjuvant patients today are not organ sparing. As Jason was mentioning earlier, you’re not really converting non-surgically resectable to resectable. You’re just basically trying to see what works better. Some of the ASCO [American Society of Clinical Oncology] trials are interesting in the sense that they are suggesting 2 cycles or a shorter duration of treatment is enough. Alex Huang’s trial also suggested that 1 single dose might be enough.

I treated this 1 patient—and I mention this because it just happened. I gave her 6 months of treatment with single-agent nivolumab. She had a complete response, pathologic complete response [CR]. Then we had a long discussion. I was like, “Yeah.” She was like, “It’s really important for me to have maximum survival.” I was like, “OK, we’ve given 6 months. Why don’t we give you 6 months more adjuvantly afterward?” In the 6 months, her sugar started rising, and then she developed type 1 diabetes. Now I’m just cringing inside, and I’m thinking maybe I should have stopped with the path CR and not done that extra few months of treatment. Maybe she wouldn’t have type 1 diabetes. I feel like 1 lesson for me from this year’s ASCO Annual Meeting is that maybe shorter duration is OK. I hope I don’t overlearn that lesson and have the opposite problem. Maybe the 1 advantage of neoadjuvant therapy is that we can get by with shorter, less intense treatment.

 Do you feel the same way about metastatic therapy? Meaning, do you tend to lean to immunotherapy first, rather than targeted therapy?

 I do. I just want to check my biases here. I feel like the data are maybe not fully supporting my position. I feel like immunotherapy offers longer-term success.

Systemic Therapy for Metastatic Melanoma

 Su, how do you talk to patients about the toxicity issues? Jason just started to get into that. Maybe you could continue. In other words, in front of you is the stage IIIA patient with some minimal amount of disease in the lymph nodes, and they don’t have ulceration in primary. I just saw such a patient yesterday as a new patient. It’s a tough discussion. How do you handle explaining the relative toxicities to them?

 First of all, I do go over the data somewhat with the patient. For example, if they have less than 1-mm focus of tumor in their lymph node, then based on the trials, they probably don’t even need therapy, right? That’s something worth considering if they truly are eligible for adjuvant therapy based on the trials we have.

It’s really a balance between the 2 paradigms of therapy, 1 being targeted, and 1 being immunotherapy. By balance, with targeted therapy, you can certainly see adverse effects. They can be pretty life-impactful in the sense that you could have pyrexia, for example, with a particular combination of BRAF and MEK inhibition. You can see transaminitis. There are certainly adverse effects that can be impactful for the patient, impactful for whether we can continue treatment. As opposed to immunotherapy, where there are certainly also adverse effects, these adverse effects may actually, in some cases, be permanent. They may lead to endocrinopathies requiring lifelong supplementation. They can sometimes be life-threatening adverse effects, albeit very rarely.

I just have a frank discussion with our patient population in terms of this is what we can expect. They both have rigorous data. We have overall survival benefit now that has been shown specifically with the combination approach. Together, we come to a decision. The nice thing is that they’re both very valuable and efficacious options. It’s just a matter of going through the nitty-gritty and trying to figure out what kind of toxicities are acceptable to the patient and their family, as well as us.

 Jeff, can I follow on that really quick, just because I’ve thought about this toxicity question? It’s important to note, and none of us has alluded to it yet, that escalation of cancer therapy has been associated with improved benefit in general. We’ll talk about the metastatic—the data where ipilimumab and nivolumab together really do appear to have the best long-term overall survival advantage. In the adjuvant setting, we already have a study now, the CheckMate 915 study, that actually does not seem to suggest that we have an added benefit by adding double I/O [immuno-oncology] therapy.

The reason I bring that up, to dovetail into what Su just said, was that the toxicity associated with ipilimumab and nivolumab is not insignificant in the metastatic setting, let alone in the adjuvant setting. That’s a really important consideration when you think about choosing adjuvant therapy. The toxicities that we would tolerate, potentially in the metastatic setting, are not the same toxicities that we would tolerate in the adjuvant setting. Being very aggressive up front to educate patients—to let us know so we can interrupt therapy, we can intervene very quickly, whether it’s I/O or targeted therapy—is truly an important part of the care of adjuvant patients.

 It’s going to be even more important. I was about to turn to you, Jason. I know you’re the PI [principal investigator] of the KEYNOTE-716 trial. It’s going to be even more important because now we’re treating stage IIB and IIC patients. If that’s a positive study, which I assume it will be, you’d better bet that there will be a lot of stage IIA patients who get treated in the community. Your point about having a different threshold for stopping and a different threshold for choosing based on toxicity will become even more important because if those studies, the KEYNOTE-716 and the BMS [Bristol-Myers Squibb Co] CheckMate76K trials, I’m assuming they’ll be positive. Assuming they are, that opens a lot of patients to adjuvant therapy. It’s like, 20,000 patients in addition a year.

 The number of patients with stage II melanoma who would be amenable if the approval comes through would be approximately the same as the stage III population. We would essentially be doubling the number of adjuvant patients. But again, as we talked about in the beginning, the risk of those patients for relapse is actually as high as for the ones we already treat. It makes sense to potentially extend that to those patients, but yes, it will be many more. Being cognizant of that toxicity is important.

Adjuvant Therapy for Melanoma: Safety and Efficacy

 Let’s take another turn, and let’s go back to Jason. Jason, let’s talk about treating our patients with the higher risk—the stage IIIB, the IIIC, and the IIID by the AJCC [American Joint Committee on Cancer]. Those are really the bad actors, because frankly those with stage IIIa, by the current AJCC ratings, do pretty well. They have only a 20% risk of death at 10 years. It’s those with stage IIIB, IIIC, and IIID who do badly. How do you decide I/O [immuno-oncology] versus 

-adjuvant therapy? What’s the deal? Even add IIIA if you want.

 It’s an important thing to think through. You mentioned earlier, do you test for 

 in neoadjuvant? It becomes the same question. Do you test for 

 in adjuvant? When you think about trying to make these decisions, you have to have that data to make such a decision. It’s very common that we get the patients referred to us through the usual referral channels, and they haven’t had the test. That actually often limits our ability to make that discrimination between therapies, and sometimes you need to delay that conversation.

I would emphasize that for anybody viewing, because that’s a really important need, that test. That should almost be reflexively routed by the pathology department at this point. If you have that data, then you can set up this question about which therapy you want to choose. It comes down to patients’ perspectives as well as doctors’ perspectives. Ryan Sullivan, MD, was just alluding to some people who use 

, some people use I/O. The data, as you just mentioned, look pretty similar going out. There are some caveats that I would just note. One of them, around the 

-mutated patients, is that 1 slide from KEYNOTE-054 was interesting to look at the disproportionate improvement in the hazard for relapse in the 

 population, specifically relative to the total. Pembrolizumab in the adjuvant setting worked better in 

-mutant patients than it did in the total population.

I don’t want to exaggerate that more than anything else, except to say that it definitely works in 

-mutant patients as well. You can see that in some other I/O trials also. In terms of which stages to treat, for all of us here, there would be no question that we would try to get a patient who’s stage IIIC or IIID melanoma to take adjuvant therapy. In stage IIIB patients, most of us probably would say that. The stage IIIA population, as you alluded to, that’s the tough one. Their absolute benefit from adjuvant therapy, while it could be improved by 50%, ends up being single-digit improvement and absolute improvement.

When you think about the toxicity spectrum of these drugs, that’s a consideration, because there are long-term irreversible endocrinopathies that develop on I/O therapies—the thyroid, diabetes, etc—and I have difficulty with that population, stage IIIA especially, for using immunotherapy in the adjuvant setting. In those patients, I tend to defer, which I think you were alluding to in general. If they want adjuvant therapy, that’s where I would definitely tend to go for BRAF inhibition.

The data from COMBI-AD really highly support that. The data look really good in the stage IIIA setting as well. In that consideration point, you have to put it in front of the patient and think about what’s meaningful to them: coming for an infusion every 4 to 6 weeks or taking the targeted therapies each day?

I’d also summarize by noting that these—I won’t call it extreme benefits that we’ve seen with these hazards for improvement in the stage III setting—are likely going to be extended into other disease settings as well over the relatively near term. Due to idiosyncrasies in our staging system, all of you are aware that stage IIB and IIC melanoma is, in fact, higher-risk than stage IIIA. That really goes to the biology of the disease we treat, which is that the primary depth of the melanoma is actually more important than the involvement of single lymph nodes.

Because of that, we have this oddity where we have the on-label ability to treat that stage IIIa population that I just said I wouldn’t usually treat with immunotherapy, yet we do not have on-label usage of the drugs for a higher-risk population of stage II with deep primaries. Two trials are being investigated in that space, the KEYNOTE-716 study with pembrolizumab and the CheckMate76K study with nivolumab. The former study, KEYNOTE-716, is likely to read out much earlier. We’re really hopeful that we’ll be able to extend this benefit of adjuvant therapy into earlier stages of melanoma.

When you marry that to our previous discussion around neoadjuvant, we’re starting to get to a place where medical management of melanoma over the next 5 to 10 years may come forward as the primary modality for managing patients. That’s really interesting to think about. It would have been heretical to say that 10 years ago, but these data really do support that, as the field has brought all these data forward, moving into different disease settings. It’s really exciting.

Adjuvant Therapy for Melanoma: Ongoing Studies of Interest

 Speaking of adjuvant, let’s go back to Ryan. I think at ASCO [the American Society of Clinical Oncology annual meeting], there were 2 presentations, both of which were updates. They were not new trials. One was COMBI-AD, and that was excellent. The other was the readout of Lex [Alexander] Eggermont, [MD, PhD,] for KEYNOTE-054. What can you tell us about updated data? Does that change your mind about using one versus the other at all?

 I think the way to set the context is for so long, we had interferon, and there were people who would use interferon. There were people who wouldn’t use interferon. They would draw sabers at conferences and fight each other about this. Then thankfully, we had more effective therapy in the metastatic setting that was able to be brought forward into the adjuvant setting.

You know full well, Jeff, that the CheckMate 238 trial, which is nivolumab versus ipilimumab, but even before that, there was the EORTC study comparing ipilimumab versus placebo. That was a positive trial with regard to relapse-free survival [RFS] and overall survival, really resetting the template, if you will, for adjuvant therapy. Interestingly, what was presented last year, ipilimumab versus interferon, is not a slam dunk for ipilimumab. We would have anticipated that ipilimumab would have been way better than interferon. Interestingly, there were 2 doses of ipilimumab looked at, 3 mg/kg, 10 mg/kg. If you had to choose one of those from a toxicity standpoint, you would choose 3 mg/kg because it’s much less toxic. Remarkably, against interferon, the difference with 3 mg/kg versus interferon was better than the difference with 10 mg/kg, suggesting that the toxicity may actually be influencing the ultimate benefit because of presumably the immunosuppression utilized to counteract that toxicity.

Then bringing forward the more contemporary, even though that was probably the most recently first presented adjuvant trial, the CheckMate 238, that is nivolumab versus ipilimumab, showing clear improvement in relapse-free survival. I believe you presented the 3-year data last year showing about a 60% relapse-free survival for nivolumab.

This year, Lex presented the KEYNOTE-054 3-year update, again showing about a 60%, I think the number was 58%, 3-year relapse-free survival for pembrolizumab, comparing that to placebo, which was in the mid-40% range. I’m not sure those data help us to distinguish between those 2 drugs, but it’s comforting that the relapse-free survival is pretty solidly above 50% at 3 years.

The COMBI-AD study, which is now for something completely different, BRAF-MEK inhibitor therapy versus double placebo, so dabrafenib/trametinib versus double placebo. I think the most remarkable part about these data is they continue to show, really for the first time in an adjuvant study with a molecularly targeted therapy, continued improvement in relapse-free survival of the treatment arm versus the placebo arm. Most of those studies look like this, where there’s an initial benefit and then it comes back together….

Suggesting that you haven’t actually cured patients, you’ve just delayed when their disease is going to come back. The data with COMBI-AD, 5 years down the road now, suggest that they’re probably curing patients with BRAF-targeted therapy, or if you’re not, you’re delaying those relapses by 5 or 10 years. Interestingly, the 3-year data look almost identical to the nivolumab and pembrolizumab data, 59% relapse-free survival, the 5-year data, 52%. There’s a little bit of decay in the relapse-free survival curve. It’s not a complete plateau, and we’ll have to see in the future whether we see complete plateaus with nivolumab and pembrolizumab in those respective studies. I think the bottom line is if you were somebody who would think about targeted therapy for patients with stage III melanoma, you’re still going to offer that. If you were somebody who wanted to go up-front PD-1 inhibitor therapy for patients with a 

 mutation, you’re still going to offer that. The data from KEYNOTE-054 and COMBI-AD reinforce what you’re previously thinking of doing. Then if patients are 

 wild type, the data from KEYNOTE-054 and most recently last year, CheckMate 238, again support the use of nivolumab or pembrolizumab in patients with high-risk stage III disease.

 Yes, certainly it looks like the KEYNOTE-054 and the CheckMate 238 curves are very close at 3 years. I was absolutely fascinated by the fact that COMBI-AD looks like it’s coming to a plateau. The urban legend was that the targeted therapies would have an early high RFS, and then it would dip down below immunotherapy, but that hasn’t really happened. Actually, they have the longest follow-up of any of the current adjuvant trials. I was actually quite impressed that the patients on COMBI-AD who got treated with dabrafenib/trametinib did very well in the long term.

Adjuvant Data Explored for Locally Advanced Melanoma

 Jason, there are other neoadjuvant trials out there. As I said, there’s been a flood of interest in this. Can you tell us about any of the other trials? I think there’s been one with pembrolizumab alone.

 There are some very interesting results. Going to that question about the pace of the responses, when you start a BRAF inhibitor, you get rapid responses. We know that. The study that you are alluding to by Alex Huang, [MD,] et al, from University of Pennsylvania, it’s very interesting that they gave a single dose of pembrolizumab prior to surgery. They got roughly similar results to giving 3 or 4 doses of nivolumab. A single dose of PD-1 can generate a substantial treatment response. I think that’s really interesting as we think about kinetics of response and a long-term benefit that we can see in some of these patients. As we start thinking about the feasibility of combination regimens, especially, we don’t necessarily need to think about long durations of treatment prior to neoadjuvant approaches. I think that’s exciting.

I also want to note quickly, there are some other intratumoral injection studies that are also starting to come forward. We’ve seen some data for TVEC [talimogene laherparepvec] that look interesting. I’m not sure I would do that, but there are combinations of PD-1 antibodies with other sorts of innate molecules that we’re going to talk about a little bit later that do look quite promising, and again, I think do have the potential to come forward as a strategy in the future.

 OK, I like the TVEC idea. But again, that’s a tough one. What about BRAF-MEK? One would think with the excellent response rate that BRAF-MEK would be the perfect neoadjuvant strategy. What can you tell us about the data? I think there was a presentation probably last year. I don’t think it was updated this year. I believe it was summarized in Alex Menzies, [MD’s,] review that he presented last year.

Jeffrey S. Weber, MD, PhD, NYU Langone Health

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