Highlights from the Society for Melanoma Research (SMR) Congress: New Research in Anti-Tumor and Combination Therapies

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1 Transcript Details This is a transcript of a continuing medical education (CME) activity accessible on the ReachMD network. Additional media formats for the activity and full activity details (including sponsor and supporter, disclosures, and instructions for claiming credit) are available by visiting: Released: 12/07/2015 Valid until: 12/07/2016 Time needed to complete: 30 Minutes ReachMD info@reachmd.com (866) Highlights from the Society for Melanoma Research (SMR) Congress: New Research in Anti-Tumor and Combination Therapies Welcome Dr. Flaherty. Thanks for taking time to participate in this educational program related to the events here at SMR Many listeners of our conference coverage from SMR 2015 may have a pretty good foundation on checkpoint inhibitor pathways, but could you discuss the mechanistic differences between anti-ctla-4 and the anti-pd-1 and anti-pd-l1 agents? Yes, well I think probably the easiest way to start is to cluster CTLA-4 and PD-1 as both being normally 2018 ReachMD Page 1 of 12

2 expressed on the types of T-cells that we are trying to activate to unleash an anti-tumor response. And I think several years ago, before these agents had sufficient clinical experience, I don t know that really anyone was predicting which would have greater efficacy, toxicity, but functionally they behave in a similar fashion in terms of impeding T-cell activation. Now we ve learned and we ll delve in, I m sure, to some of the evidence based around those therapies. PD-L1, that s the ligand, and that s actually normally expressed on immune constituents that regulate T-cell activation and really push cells into inactivation, and the phenomenal aspect of cancer biology, as it pertains to immunology, is that tumors have essentially co-opted expression of PD-L1, and also PD-L2, for that matter, on their surface and can directly impede immune function and activation at that level. Should remind listeners that there s also a PD-L2 ligand that can also be expressed by tumors as well as immune cells, of course, and when you re targeting PD-1 you block both of those interactions, PD-L1, PD-L2. When you target PD- L1 with an antibody, you leave alone that PD-L2/PD-1 interaction and that s just something to earmark for years to come, because as we really dig in with nuances of combination and safety, it may emerge that there s a difference at that level. Just lastly, on the topic of these new agents which we re now starting to see some combination data with, IDO is an enzyme that produces tryptophan and that seems to be particularly important in the tumor micro-environment because it can impede T-cell entry as well as activation. And so, it seems to be one of the factors that is gating to whether T-cells can gain access to a tumor and we know that s probably one of the pieces we re missing with the immune checkpoints. Oncolytic virus is quite a different concept in that these are partially replication incapable viruses. The one that s been now most heavily developed and just FDA approved, so-called T-Vec, is engineered to produce GM-CSF, and in any case, the virus itself, when instilled into a tumor and producing GM-CSF thereafter, causes inflammation that s quite substantial, almost multifactorial from an immunologic perspective. It s very different than these drug-like approaches otherwise, but it may accomplish something that is part of this missing piece of the puzzle to really get an immune response initiated and then potentially set the stage for a knockout blow, if you will, from the immune checkpoints. So, in summary then, the mechanisms of these different agents may be different but they could potentially be synergistic in terms of the cancer immune cycle? 2018 ReachMD Page 2 of 12

3 Yes, exactly. I mean, that s the hypothesis. I think we obviously have to prove that that s the case and I think one of the ready opportunities is to think about pairing something from the CTLA-4, PD-1, PD-L1 class with one of these other approaches and, as many listeners may be aware, if they ve been hunting down clinical trials for individual patients in their practice, they ll see this proliferation of PD-1 antibodybased combination trials. We re seeing some emerging evidence now from some of those early studies but the rationale, I think, is pretty clear that if you could use one of these other agents to really try to improve entry of T-cells that otherwise are capable of recognizing tumors first, then help fortify their activation with an immune checkpoint blocking antibody, that might be an ideal combination. So, has anything new emerged out of this year s SMR that gives us some insight as to sequencing or combination therapy related to these different immunotherapeutic approaches? The past couple of conferences, more general cancer conferences, as well as SMR, we ve started to see some interesting activity emerge, particularly around this PD-1-plus strategy. So, PD-1 plus IDO inhibition as well as PD-1 plus oncolytic virus have at least Phase I level evidence in melanoma patients, so of course you can then start to pay some attention to emerging efficacy data as well. And, it s clear that the safety is manageable as one would have expected from the single-agent experience with either oncolytic virus, which really has injection site reaction as the predominant feature of it, IDO inhibition which has quite a modest toxicity profile as a standalone. When you put them together, it doesn t seem to be too much of a problem from a safety perspective, and the first handfuls of patients treated would suggest that anti-tumor activity could be superior to PD-1 antibody therapy, but we certainly need larger datasets to explore that. So, that s all very interesting and we re all excited about the future of combination therapies related to immunotherapeutic approaches. Let s move on to some interesting data related to biomarkers and there s certainly a lot of interest in biomarkers in the treatment of melanoma, whether its markers for response to immunotherapeutic agents, or other targeted agents. Has anything new emerged from SMR this year that would give us some very important insights as to potential new agents or a 2018 ReachMD Page 3 of 12

4 combination of various agents that we actually have used in the past? Yes. This issue of biomarkers is, I think, going to be critical for future success of melanoma therapeutics. And by that, I mean we know there are patients who derive longterm benefit from the current therapies and sticking with the immune agents, CTLA-4 antibody therapy, of course we know that very convincingly for a subset, PD-1 antibody therapy emerging, how large that subset might be, but of course we do have patients now who are several years out and counting, so we know they exist. The question is, how frequent? And then, the interest becomes, is there a way to predict them, rather than having to wait 3 years for things to emerge in terms of their clinical benefit or loss of clinical benefit? So, this is really a huge area in the field and I would say the same for the combination of CTLA-4, PD-1. We d ultimately like to navigate patients to effective maximally tolerable single-agent therapy, if we know that longterm outcome could be achieved, if we could increase the confidence from the very beginning that we have a patient like that in front of us. So, the data that s been emerging and was added to at this meeting with a couple of key presentations including the keynote from Tony Ribas, it falls into two categories. There is increasing evidence that if you look in a tumor sample right before treatment is initiated, you can score PD-L1 expression on tumor cells, yes, but that seems to be certainly not enough of a story to assign patients to PD-1 antibody therapy unto itself. You can also score the presence of CD8 T-cells, the ones we re most rooting for. You can go further than that and actually look at markers of their state, their activation or inactive state, and those layers seem to be adding also to the ability to predict. Which is to say, if you see the T-cells in the tumor, you see PD-L1 on the tumor surface, you see markers that suggest that these T-cells are active, and of course you re dealing with a patient with metastatic melanoma so something s not quite right, but those patients seem to be the one that may really just be one drug away from mounting an early and ultimately longterm response. The combination strategies, I think, we all recognize, at least with PD-1, CTLA-4, do invoke more toxicity, but we would all feel more confident in using them if we knew we had a patient in front of us who was predicted not to get the benefit of single-agent therapy; I think we and our patients would be much more willing to say, Okay, we ll roll up our sleeves and deal with the relatively short-lived, several-month period of increased toxicity with combination therapy. So, this idea of at least allocating patients to single-agent therapy with these emerging biomarker strategies, I think, is exciting. Just lastly, mention that there s really intriguing data but very much unsettled as to whether you can look in the tumor at its mutation makeup. I don t mean BRAF and RAS, these things that we use to deploy targeted therapy, but rather the overall mutation burden. Are there specific mutations that actually could be recognized by the immune system? Could you score tumors in some way to say, Yes, this is 2018 ReachMD Page 4 of 12

5 one where the immune system likely has a good and unique handle on it? It s very intriguing scientific work and we ve seen some recent evidence this fall as well as at this meeting that continues to increase our understanding, but we re a long way away from really being able to use that in some precise medicine way. So, in making predictions for response to therapies or lack of response to therapies, it s probably going to be a combination of different biomarkers. So, like you mentioned, mutational burden is another possibility in combination with PD-L1 expression as well as the type of T-cell infiltration there is in the tumor. But what about the biomarker for anti-ctla-4? Is there really a good biomarker for that? There, I think, we have less evidence or confidence that PD-L1, for example, is going to be an important feature and so you pivot to the rest of the story, in other words, these measures of inflammation within the tumor at baseline, as well as mutation makeup. All of those features are still on the table and are hypothesized to play a role. There s an interesting paper just published actually in Science, Dirk Schadendorf and Levi Garraway s groups partnered together to look in a very deep way at the patient s tumor in terms of mutation, so visiting that hypothesis, as well as getting a little bit of a look at the expression, at least on tumor cells, of various markers that might be relative to impeding an immune response. And that paper, although high impact and published in Science, still doesn t give us that reduced-to-practice type biomarker strategy. I guess I would make a prediction that we re going to come up with somewhat tailored biomarker platforms for each individual therapy, probably borrowing several components though. So, I would envision a day where we actually have this multi-marker platform. I m making up numbers here, but you know, 8 or 10 analytes on it that we use to take the temperature of a tumor. We may only pay attention to 5 of those factors in terms of deploying any one of these therapies. But unfortunately, still a good bit of work to do and not any validation effort yet, until we really get at least the test data to support the idea that we ve got really high predictive value. Great. Let s move on from immunotherapeutic agents and talk a little bit about some of the targeted agents in the treatment of melanoma and what has emerged at SMR in terms of supporting the 2018 ReachMD Page 5 of 12

6 combination therapy of BRAF plus MEK inhibition in BRAF-mutant patients. BRAF-inhibitor-based therapy continues to be the most impactful by far and that lead was established with just BRAF inhibitors alone. It s become wider with BRAF-MEK combination therapy in the BRAFmutant population. Just to remind listeners that all of the evidence we have really hones right in on the V600 mutant BRAF population. We know that there are maybe 5% of melanomas that have other types of BRAF alterations, but we still don t have a targeted therapy strategy yet for those. So, this is just in the V600 population where that s about 45% of advanced melanoma patients. In that group now we have 3 randomized trials and at SMR we saw the updated results of the most recently FDAapproval of these strategies. So vemurafenib, the first approved BRAF inhibitor, but now paired with cobimetinib, substantially improving overall survival is what we ve now learned from that combination, as well as progression-free survival and response rate. Dabrafenib and trametinib, FDA approved almost 2 years ago, also offer those features based on 2 large randomized trials and the benefit of that dataset, even though we ve known of the results for some time, is we re seeing longer-term outcome data now, 3 year outcome data; and a nice abstract presented by Georgina Long at this meeting is starting to tease apart, you know, who are those patients who get 3-year benefit and maybe beyond, versus those you get a short, maybe intermediate-term benefit, and it s quite clear that rather simple features, like patient s disease burden, or serum LDH which doesn t always align with burden, but let s say aggressiveness. Patients with high LDH can certainly benefit but they re really unlikely to be those long-term responders, or patients with just long-term survival, whereas low-disease-burden patients can have an exceedingly good outcome. Unfortunately, what I just said isn t a unique feature for the targeted therapies; it s true for the immunotherapies as well. Yes, it looks like the LDH question is a really important one and while we used to think of it that it paralleled burden of disease, it may not be that simple. There may be something specifically aggressive about patients that have a high level of LDH that may not necessarily parallel with the burden of disease ReachMD Page 6 of 12

7 Yes, and I think what we re seeing now, it was suggested several years ago, but now in the era of much more impactful systemic therapies, this clear prognostic feature almost gets amplified in its importance when you re now talking about patients in the setting of treatment. So, yes it s a prognostic factor, but it almost picks up a little bit of predictive ability because you just have these patients who are deriving years-long and maybe indefinite benefit from immunotherapy and even a subset with the targeted therapies in this low LDH group. The other population, the large LDH group and the higher you go, the more concerning. We have a lot of work to do for those patients if we re going to find regimens, multi-agent regimens that can really wrestle down or dial back the aggressiveness of their disease to try to induce remission. That s still the aspiration, but we re not there yet with most of these treatments. So, you mentioned that about 45% of the BRAF-mutant population, or the one that we re focused on which is the V600, are the ones that are classically described. But what about the ones that have mutations that are V to K as opposed to V to E? It s a smaller patient population but do you we think that we have enough data to suggest that they respond in a similar way to combination therapy? I mean, respond well enough to have been included in the FDA approvals, but all of the data we have suggests that they have a modestly lower response rate, maybe modestly shorter progression-free survival as well. To remind listeners, this V600K cell population, it s mostly older patients, whereas V600E tends to skew towards the younger end of the distribution and, maybe not surprisingly then, if you look at the makeup of these patients tumors as has been done and published this year in the TCJA data, they had more mutations, so beyond just the BRAF V600K mutation, so they re more genetically complex and maybe that has a lot to do with opportunities for resistance to manifest to therapy. Again, this is, I wouldn t say, a reason to think completely differently about offering such a patient BRAF-based therapy, but recognizing that maybe you have a little less confidence that this is a patient who s going to respond or maintain that response. What about the patient population that we don t really have a lot to offer to right now in terms of 2018 ReachMD Page 7 of 12

8 targeted therapy; the patients that are NRAS mutant? Is there anything new related to those patients? I know there have been some studies in the past with MEK inhibition for those patients, but there are other agents that have been looked at as well. Couple of key points; one is that we still lack direct RAS-targeted strategies which is what we all would prioritize as the most impactful. I d also add to your question the group with NF1 mutations. It s another 10, maybe 12-13% possibly, we have yet to see a clinical cohort really well characterized, but suffice it to say that we have NRAS mutant patients, about 25% of the total, and therefore a very large group amongst those who don t have a BRAF mutation, and then this NF1 group. NF1 is normally a negative regulator of RAS, in other words, impedes RAS signaling. So, if we had an effective RAS strategy that would play across a large population of patients. Lacking that, our attention has been focused on the so-called RAS effector pathways and that s where the MAP kinase pathway comes back in. So, BRAF, MEK are components of that pathway. But RAS has other opportunities. It doesn t only signal through the MAP kinase pathway. What we know from Phase II level evidence with 3 different MEK inhibitors is that the NRAS population, if you just focus in on those, has about a 20% response rate, maybe a hair less, to MEK inhibitor by itself. Again, we know that that MAP kinase pathway isn t the whole story in those tumors, but some of those tumors seem to be reasonably sensitive to it. Now that s actually being sought, if you will, in validation in a Phase III trial of MEK inhibitor versus chemotherapy, but we know from the Phase II evidence that if that trial is positive it s not going to be like a BRAF inhibitor. It s not going to offer that level of activity. But if disease control and overall survival are improved, I think we d obviously be encouraged. What I would say is we continue to focus on the idea of trying to elaborate combination strategies to add up to something like a BRAF inhibitor; in other words, trying to intercept these RAS effector pathways in a more complete way. We re going to face challenges in terms of toxicity, we already know that, with some of these strategies, but there is emerging results that have been on the table now for more than a year with a MEK inhibitor combined with another cell cycle inhibitor, CDK4 inhibitor. Interesting strategy, does have some toxicity concerns, and highlights the fact that in all of this targeted therapy combination work beyond BRAF-MEK, for which we got away with one there in terms of the ease of combination, we re probably going to have to not give all drugs all the time and really revisit this issue of how do we use these drugs for their optimal cytotoxic effect and emphasizing that word cytotoxic, because of course listeners know that we don t give the taxanes or, you know, Adriamycin on a continuous schedule. And so it may be that some of these drugs we actually have to learn how to use them in a different way ReachMD Page 8 of 12

9 Talking about combination therapy, I think the real 64,000 dollar question is this biomarker discovery. We could really hone down on risk-benefit ratio, but really, the question right now, moving forward in terms of the clinical management of patients, is combining targeted therapies with immunotherapeutic agents. So, what have we learned from SMR this year that gives us some insight for future directions? We swung and missed in the field with our first attempt to do this with the first BRAF inhibitor, vemurafenib combined with ipilimumab. That was as big as the toolbox was at the time and there were some concerns. We participated in that study, my group, and shared those concerns that there might be some interaction in terms of toxicity there. We never quite chased down exactly why but we have some theories by that. Having said that, CTLA-4, ipilimumab, brings more of a risk in terms of autoimmune toxicity than the PD-1/PD-L1 antibodies, and that s where the focus has shifted. It is now still leaning on the BRAF-inhibitor-based approach now with PD-1/PD-L1 antibodies. And very interesting data is beginning to emerge. Dr. Hamid presented some updated results of BRAF inhibitor monotherapies, and not BRAF-MEK yet, with a PD-L1 antibody. That looks to be quite manageable in terms of the toxicity profile and the early efficacy data also looks quite promising. Now, going to the more relevant and current BRAF-MEK combo backbone, that trial is now moving in that direction in terms of looking now at the triplet. We need to understand the safety, obviously, first and foremost. We need to understand whether you need to give all the drugs all the time, or whether there are alternative strategies to minimize toxicity while maintaining efficacy with those types of strategies. And, as you alluded to, in terms of the biomarker focus, it could well be that we re going to be left with a population of patients where we just can t find that factor that predicts good outcome, long-term outcome, with either targeted therapy or immune therapy and where a combination becomes maybe a default for those folks, similar to the discussion we had about CTLA-4/PD-1, maybe being directed to a population who just wouldn t get the benefit of the individual components. So, it s an intriguing concept and I ll just close that by saying that we do have some evidence that tumors, if they can be attacked, disrupted, even killed to some degree with molecularly targeted therapy, they may actually be more vulnerable to immune attack. These might really be potentiating effects of these therapies. And there are multiple strains of evidence that support that. So this may not just be the clinical imperative of having a patient in front of you for whom you really feel like you need a response in the near term and you re willing to throw multiple agents at them, should we credential these regimens as being useful of 2018 ReachMD Page 9 of 12

10 course. It may really be that we have some synergy ahead of us. Let me just mention though as, just to underscore that last point, that we shouldn t be doing this in practice just yet. Yes, we have these drugs available, this whole menu if you will, but they re best use, as we know them now, are as standalone treatments. I wanted to expand a little more discussion about the adverse events, but before we do that, I wanted to bring up the issue about resistance to the targeted agents. While it s pretty clear there s a group of patients that can have long-term survival without having relapse, most of the patients ultimately will fail, and do you think the immunotherapeutic agents addresse some of the resistance or will it be mostly molecular-based therapies that would have an impact on the resistance approaches? Yes, it s a huge question and has a lot to do with the optimal sequencing of these therapies, of course. One of the things that we re focused on now is just trying to figure how these tumors re-wire and recover, and it s becoming clear that there are some recurrent themes there that give us some insights into how we might build additional even higher order combination therapies; so BRAF-MEK as a backbone, adding additional drugs. So there are Phase I trials testing those concepts now, and so, obviously, not ready for primetime. The immune combinations are interesting, but the immune sequence is, of course, that s what s happening in the clinic and we look at patients with BRAF mutations and wonder which of them should start with immunotherapy and be watched closely, reserving the targeted therapy strategy as a backup, or vice versa. This issue you re raising about, what do these therapies do to set each other up, or not? This is a great focus of several groups right now in terms of the translational medicine. We do have evidence that supports the idea that the targeted therapies can have a positive immune consequence on tumor recognition early in the course of therapy, but we also have evidence to suggest that goes away when tumors develop resistance, and Roger Lo gave a nice presentation here at SMR looking at patient tumor specimens, and not just describing that phenomenology but really getting into the details of why that seems to happen in terms of the way in which the tumors have achieved resistance and how that relates to escaping immune surveillance, yet again. And so, I think this issue is not a simple 2018 ReachMD Page 10 of 12

11 one. It s certainly not one size fits all, but I think, for now, we really lack an effective approach that s mechanism-based or has precision medicine principles to it, in terms of how best to deal with patients, especially coming off the targeted therapies. We focus so much of our effort in the field right now in terms of devising strategies to better treat them upfront, because most of the evidence that we have is that when the tumors come out resistant to this treatment, it can be hard to tackle in terms of the tools of the drugs that we have now. In the short term, moving forward, it sounds like you d be pretty supportive of the Intergroup Trial that randomizes patients to upfront targeted therapy versus upfront immune-based therapy? Yes, I think it is critical trial to step in the direction of trying to get some better understanding. If we characterize these patients tumors, particularly in a deep way, could we then look at the outcome of this trial and define optimal sequences for subsets? That s my major, sort of scientific, motivation behind that trial. The only problem is it s a 300-patient trial. I would have argued that this might need to be a continued exercise and focus in the field, and in cooperative groups it would be a good use of our time and resources, so you could argue that if we really wanted to learn all of these principles maybe we need a bigger, broader platform. We re certainly getting some information about some novel adverse events that we ve never seen before. Any good markers for who would get the immune-related adverse events, and any possibility to change how we manage them or maybe even actually prevent them? We all wish we had true predictive markers, so before you started treatment do some sort of test to know who are the patients you have to watch most closely, or have a low threshold for starting either corticosteroids or infliximab TNF antibody therapy even, if needed, but unfortunately we don t have 2018 ReachMD Page 11 of 12

12 that. So, I think the focus then shifts. Do we have better monitoring tools? Can we do things other than just advise patients to look out for rash and diarrhea and look at our serologic tests for liver function and endocrine gland function as the backbone or safety net, if you will, that we use now? There s some intriguing data emerging in terms of some of the blood-based methods that, really research, focusing on watching immune activation happen. I think really much of the motivation behind that research was to focus on the anti-tumor aspect of that, but it s clear that one can start to see shifts, even in immune cell populations in blood, preceding either an anti-tumor or anti-normal-tissue effect of these therapies. So, one wonders, given that signal, could there be something to track in terms of markers of inflammation, in particular, shifts in immune cell population even in the blood, to put you on higher alert? I d be cautious about the notion that earlier and earlier pre-symptomatic intervention with steroids is a good idea, or for that matter infliximab. You know, I think one of the things about the learning curve of these therapies is to educate doctors, patients, the entire care team, frankly, about the nature of these side effects, the need for realtime communication, but judicious use of immunosuppressive therapy. We know with that approach that all the clinical trial data supports you don t erode the benefit of the treatments. Trying to get a bit more aggressive which is tempting in some ways, to think about the idea of intervening before a more serious manifestation emerges, that could begin to undermine therapy. I think all of us have concern that if you were to give preventive immunosuppressive therapy from day one, you probably would prevent the tumor response in a great many patients as well. So, there s something magical that we still haven t quite worked out about the time course, the kinetic, when to intervene to eliminate the autoimmune component, maintain the antitumor part, but you re raising an important point about the need to really hone on that strategy, particularly for combination immune therapy, PD-1, CTLA-4; big benefit but also some multiplication of the toxicities. Dr. Flaherty, this was great, very fascinating, and I thank you for your time. We covered a pretty broad landscape related to the evolving treatment of melanoma. So, thank you very much. Thanks again for having me ReachMD Page 12 of 12