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Understanding and Overcoming Resistance to Anti-PD-1 Immunotherapy in Melanoma

  • Authors: Michael Davies, MD, PhD; Jason Luke, MD, FACP
  • CME / ABIM MOC Released: 8/31/2022
  • Valid for credit through: 8/31/2023
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Target Audience and Goal Statement

This activity is intended for oncologists, dermatologists, surgeons, and other members of the melanoma care team.

The goal of this podcast is that learners will be better able to understand resistance pathways in melanoma and strategies aimed at overcoming them.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Recent clinical trial data evaluating regimens aimed at overcoming immunotherapy resistance in the management of patients with melanoma
    • Practical considerations in managing patients with melanoma who have progressed after immunotherapy 


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  • Michael Davies, MD, PhD

    Professor and Chair, Department of Melanoma Medical Oncology
    Professor, Translational Molecular Pathology, Genomic Medicine, Systems Biology
    Anne and John Mendelsohn Chair in Cancer Research
    University of Texas MD Anderson Cancer Center
    Houston, Texas


    Michael Davies, MD, PhD, has the following relevant financial relationships:
    Consultant or advisor for: ABM Therapeutics; Apexigen; Array; Bristol Myers Squibb; Eisai; Iovance; Novartis; Pfizer; Roche/Genentech
    Research funding from: ABM Therapeutics; LEAD Pharma

  • Jason Luke, MD, FACP

    Associate Professor of Medicine in the Division of Hematology/Oncology
    Director of the Cancer Immunotherapeutics Center
    UPMC Hillman Cancer Immunology and Immunotherapy
    Pittsburgh, Pennsylvania


    Jason Luke, MD, FACP, has the following relevant financial relationships:
    Consultant or advisor for: 7 Hills; Abbvie; Actym; Alphamab Oncology; Arch Oncology; Bayer; Bright Peak; Bristol Myers Squibb; Castle; Checkmate; Codiak; Crown; Day One; Duke St; EMD Serono; Endeavor; Evaxion; Exo; Flame; Fstar; Genentech; Gilead; Glenmark; HotSpot; Ikena; Immunocore; Immutep; Incyte; Inzen; IO Biotech; Janssen; Kadmon; Kanaph; Macrogenics; Mavu; Merck; Nektar; NeoTx; Novartis; Onc.AI; OncoNano; Partner; Pfizer; Pyxis; RefleXion; Regeneron; Roivant; Servier; STINGthera; STipe; Synlogic; Synthekine; Tempest; Xilio
    Research funding from: AbbVie; Astellas; AstraZeneca; Bristol Myers Squibb; Corvus; Day One; EMD Serono; Fstar; Genmab; Ikena; Immatics; Incyte; Kadmon; KAHR; Macrogenics; Merck; Moderna; Nektar; Next Cure; Numab; Palleon; Pfizer; Replimmune; Rubius; Servier; Scholar Rock; Synlogic; Takeda; Trishula; Tizona; Xencor
    Owns stock (privately owned) in: Actym; Alphamab Oncology; Arch Oncology; Kanaph; Mavu; NeoTx; Onc.AI; OncoNano; STipe
    Owns stock (publicly traded) in: Pyxis; Tempest


  • Deborah Middleton, MS

    Senior Medical Education Director, Medscape, LLC 


    Deborah Middleton, MS, has no relevant financial relationships.  

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  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Yaisanet Oyola, MD, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Developed through the collaboration between Society for Melanoma Research (SMR) and Medscape Oncology.

In support of improving patient care, Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

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Understanding and Overcoming Resistance to Anti-PD-1 Immunotherapy in Melanoma

Authors: Michael Davies, MD, PhD; Jason Luke, MD, FACPFaculty and Disclosures

CME / ABIM MOC Released: 8/31/2022

Valid for credit through: 8/31/2023


Dr. Michael Davies (00:04): Hello, this is Dr. Michael Davis. I am professor and chair of the department of melanoma medical oncology at the University of Texas MD Anderson Cancer Center. And I am the president elected of the Society of Melanoma Research. It is my pleasure to host this discussion today, focused on understanding and overcoming resistance to anti-PD1 immunotherapy and melanoma. It is also my distinct pleasure to introduce our discussant for this podcast, Dr. Jason Luke, who is associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh Medical Center, Hillman Cancer Center in Pittsburgh, Pennsylvania. Jason, thank you so much for joining us today. And just to start off, can you actually talk about how prevalent is resistance to anti-PD1 immunotherapy in melanoma patients? Dr. Jason Luke (00:52): Well, thanks so much for the opportunity to participate. I think this is going to be a great conversation, albeit on a difficult topic. Dr. Jason Luke (00:59): So when we think about resistance to anti-PD1 immunotherapy in melanoma, and actually in other tumor types, we tend to kind of split it into sort of resistance that develops immediately on treatment, as opposed to resistance that develops over time. And I guess what I mean by that more granular is if you're treating a patient and on their first scan, they progress, that's kind of different than if they're on treatment for a long time before they eventually the effect seems to sort of wear off. And we sometimes refer to these as refractory or resistant and there's sort of some different nomenclature. But those are the two concepts that we think about. Dr. Jason Luke (01:33): So on the former, when we think about how common is it that patients don't benefit at all from anti-PD1, we're fortunate that it's not super common, but it's not uncommon either. It's probably in the range of about 30% of the patients who really derive absolutely no benefit and just progress right on through the initial therapy. And then you have gradation out over another 10 to 20% of patients who have some level of maybe stable control of the tumor for a period of time. And then a larger number who actually have treatment response, especially as we get into combinations of therapies. Dr. Jason Luke (02:04): And so those patients who have no benefit whatsoever are clearly a high unmet need, and those patients have a poor prognosis, obviously, if they derive no benefit whatsoever. And if we think about the development of resistance over time, that's sort of a different biology probably, and it's a different clinical problem. So they are upwards of about probably 60 to 70% of patients eventually will progress on anti-PD1. And while there is that subfraction who do very, very well and who never have survival events on our clinical trials, we know that unfortunately, most patients eventually will progress on PD1. Dr. Jason Luke (02:40): But again, differentiating that clinical course is going to be quite a bit different in terms of how we think about mechanisms of resistance, which I'm sure we'll get into here in just a little while and how we might think about therapeutic approaches for developing new treatments also would be sort of different when we think about how we would want to attack those two problems. And so that's broadly how I'd sort of set the clinical parameters of thinking about resistance. Fortunately, most of our patients do derive benefit off the bat, but most patients unfortunately, eventually, will develop resistance to anti-PD1. Dr. Michael Davies (03:11): That's a great overview, Jason. One other question that often comes up is now that we have anti-PD1 immunotherapy sort of approved in the adjuvant setting as well, we're seeing patients who are treated with immunotherapy for a defined period of time. And at some point after they stop their treatment, we see evidence of disease progression. How do you think of that as you've talked about sort of the different categories of resistance to immunotherapy? Dr. Jason Luke (03:35): Yeah. So this is a really important discriminatory point to make. And it's been actually a problematic area in some of our clinical trials as we've tried to develop novel therapies. And I think broadly in the field, there's become a consensus that patients who progress while on adjuvant therapy, or within six months of completing adjuvant therapy, really are those that we sort of consider to be outright resistant, meaning deriving no benefit from the adjuvant therapy. Whereas if patients get adjuvant anti-PD1 and are off of treatment for more than six months, we tend to think of those patients as potentially having the ability to benefit if you were to treat them again with anti-PD1 thereafter. Dr. Jason Luke (04:15): And it's an important point because I think when we sort of think about, "Well, what about this patient," this is a very important thing to think about. In my practice, a patient who progresses on adjuvant therapy, or quickly after stopping it, I'm really thinking of them as PD1 resistant and really escalating to combinations or novel therapies very quickly. Whereas patients who have a durable period of time where they're off of that adjuvant therapy, you really then can think about possibly going back to anti-PD1 monotherapy, albeit that the world is sort of shifting around what all these therapeutics are that are available and that may or may not be what you choose to do anyway. Dr. Michael Davies (04:49): That's great. No, thank you so much for clarifying that. So as you mentioned, Jason, that a lot of what really has driven our field forward in many ways is understanding the biology and immunology of this disease. Dr. Michael Davies (05:01): And one of the areas that you've done a lot of work is trying to understand what are some of the different mechanisms that underlie resistance to anti-PD1-based immunotherapy. Could you talk about sort of, in broad terms, what are some of the mechanisms of resistance to PD1 that have been identified to this point? Dr. Jason Luke (05:18): Yeah, that's a great question. And I think it goes back to sort of our discussion before about what is clinical resistance and how do we marry that to the actual biology in the tumor? And I'll start by saying that we have a lot of work to do to fully understand this area, but we are starting to understand it to some degree, which is to say that maybe if you flip the question around at first, it might make it slightly easier.What are the mechanisms that actually allow anti-PD1 to work in the first place? Dr. Jason Luke (05:44): And some of the fundamentals there we do understand, I think pretty well, which is that some patients, and fortunately most with melanoma, have a spontaneous immune response against the cancer where your immune cells will go there and actually get into the cancer. And that's associated with the upregulation of a molecule that everyone's going to be familiar with, PDL1, which in melanoma is less of a biomarker and more of an indicator of biology, because we don't tend to use it to stratify which treatments we give. But it's very important that some patients who have immune cells go in there and PDL1 goes up, therefore, if you give PD1 blocking drugs, you can get a treatment effect. Well, now if we start to think about resistance then, and put the question back around the way we started, you can lose the expression of PDL1 or other recognition mechanisms of those immune cells for the cancer. Dr. Jason Luke (06:34): And if that ability to recognize the cancer is lost, well, then those immune cells can't kill the cancer. And so how do we think about, in a granular way, what those resistance mechanisms can be? Well, I talked about PDL1, so loss of interferon signaling... And interferon signaling, we don't have to get into all the details, but that's what drives the upregulation of PDL1. And that tracks back to that recognition. And so if your immune cells lose the ability to see the tumor, they can no longer kill the tumor. And so some genomic mechanisms of resistance... So loss of expression of certain genes by mutations, such as the major histocompatibility complex 2, MHC class 2. And you don't have to remember that folks. Just remember there can be mutations or a loss of genes like [inaudible 00:07:19] signaling or a beta 2 microglobulin, which, again, these are molecules that allow the immune cells to see the cancer. These are known and described in mechanisms' resistance. Dr. Jason Luke (07:28): Now that being said, those defined genes have actually only been seen in a relatively small number of patients who have developed resistance. So we know that's true, but how widely relevant it is in our practice actually is an area that we're actually not so sure about. Rather I think what we're coming around to think in the field is that there's actually a host of other reasons that immune cells can become dysfunctional in the tumor micro environment. And that can have to do with regulatory changes within T cells that cause them to lose their function or the upregulation of other inhibitory receptors, which might be drug targets. It can be the interaction of other immunosuppressive cells that are near the immune cells trying to kill the cancer. And then on a fundamental level, both in the context of primary resistance where patients never derive any benefit And in some patients on treatment, there can really just become a fundamental inability of the immune cells to actually get into the cancer. And we refer to this as immune exclusion. Dr. Jason Luke (08:29): And there have certain sort of pathways in cancer cells, and in the tumor micro environment, that have been strongly associated with this and a famous one is one called wnt signaling or wnt beta catenin. And another that's maybe a little more familiar would be P10 signaling so the AKT P10 PI3 kinase signaling pathway. When these pathways get turned on, immune cells seem to be unable to get into the tumor. So I'd summarized all this by saying that there are actually a diverse set of mechanisms that can drive the resistance that we see in clinic. And I think we're only starting to learn now about how would we use that information actually to design better therapies? Because we are starting to make some progress there.But I think we're really actually only in the infancy of our use of these kind of translational data to inform the treatments we might give to our patients. Dr. Michael Davies (09:20): That's a great overview, Jason. And just to add on what we've also come to appreciate is certainly again the importance of the tumor itself or the tumor micro environment. But even other factors that we never thought of before, like the microbiome and other factors potentially being important determinants, maybe not driving resistance themselves, but really sort of driving some of the factors that you talked about. But really interesting again, how we're converting that information now into new therapeutic approaches for patients who've progressed on anti-PD1. So as a clinical investigator, what are really sort of, again, to use some of the most interesting and exciting sort of approaches or clinical trials that are ongoing to really overcome resistance to PD1? Dr. Jason Luke (10:02): Yeah. And so I think this is the brass tax for our patients and how are we thinking about where the field going? And again, I would separate this into at least two categories. One would be on the upfront side of things, how would we want to avoid resistance from ever developing in the first place? And then on the second side, well, what do we do if it does develop? Well, how do we attack that? And I'll focus mostly on the latter, but point out some success on the former, which is we have a recent approval of a new doublet combination of checkpoint blocking antibodies, nivolumab, and relatlimab, which both block inhibitory receptors and increase the benefit. And so that's a way we think about avoiding resistance on the upfront and that therapy is recently approved and now available for our patients. If we focus though on patients who start on anti-PD1 and develop resistance, however, in terms of thinking about what treatments we would give, it a little bit depends on what happens to the patient and what the distribution of the disease is at the time of resistance. Dr. Jason Luke (11:01): So for example, if a patient gets anti-PD1 monotherapy and progresses, but doesn't have a rapidly progressive disease, we still might think about going on to another immunotherapy, as opposed to maybe transitioning to targeted therapy. And in continuing immunotherapy, our group and others have shown now that combining ipilimumab with continuance of anti-PD1 can actually augment the activity such that about 30% of patients can have treatment response, which can be very durable even in that second line setting. And so that's important to be cognizant of because that's a pretty effective therapy for patients in that setting. Now, obviously if patients get, say nivolumab and ipilimumab up front as their combination, you wouldn't want to switch them to another combo just the same. But for patients who got anti-PD1 monotherapy, that certainly could be an attractive combo. In the more novel setting, however, in refractory disease, there's a lot going on that looks quite exciting. Dr. Jason Luke (11:58): And so one of the sort of "drugs" you might think about that's coming forward, and we actually hope might get approved this year, is the use of tumor infiltrating lymphocytes or till as adoptive cell transfer. And what do we mean by that? Well, we know based on what I kind of told you at the beginning about why immunotherapy works in the first place is that some immune cells can get into the cancer. And in fact, if we cut the cancer out, we can find those immune cells and decades of research have gone into efforts, such that we can now harvest those immune cells out, augment and grow them in the laboratory and then give them back to the same patient. And they're basically getting back sort of an anti-cancer transplant of sorts. So we call it adaptive cell transfer. Dr. Jason Luke (12:41): And in clinical trials of PD1 refractory patients, we've seen response rates on the order of about 30-ish% for till therapy. And that could be really quite exciting. It's a complicated therapy as I just kind of explained, but it's really a differentiated immunotherapy mechanism relative to the checkpoint inhibitors that were more commonly seen. And I think what's most exciting about till therapy is that to date, it seems to be the most effective in those patients who derived the least amount of benefit from anti-PD1. So going back to what we talked about with mechanisms of resistance, these were the patients who were outright refractory, who had no benefit to anti-PD1. They're the patients who seemed to benefit the most from till therapy. So we're really looking forward to that potentially being approved broadly so we could give it to more patients outside of just clinical trials. Dr. Jason Luke (13:31): But beyond that, there are a couple of other approaches definitely worth highlighting, a handful of them, actually. Some of them include the intratumoral injection of sort of immune stimulatory molecules. And one that's garnered a lot of attention are toll-like receptor 9 agonist in a molecule called vidutolimod. Again, for the non-melanoma aficionados, don't worry about it. Eventually, you'll have to be able to read it, but not say it. So we call it Vito, but this is a treatment. And really, you can kind of think about it just like a flashing light for the immune system that you're injecting into the cancer to make immune cells see the cancer and the TLR9 agonist will trigger early immune responses. And so we kind of talk about it like heating up the tumor to try to get the immune cells to go there. Dr. Jason Luke (14:11): And in clinical trials of patients who have progressed on anti PD1, injecting the toll-like receptor agonist, or combining it with PD1, can get a response rate of about 25 to 30%. Again, potentially useful in a third of patients. There are a number of approaches now trying to leverage cytokine approaches. And so people may remember the days of interferon or maybe interleukin 2 and IL2 still around. And we're trying to find more novel or interesting ways to give these molecules to sort of leverage the benefit that we know that they can have. And early clinical trials are suggesting that there may be a benefit to some of these newer cytokine-based therapeutics. And finally, I would just call attention to the development of VEGF inhibitors in combination with PD1. This'll be an area that most healthcare professionals in oncology be aware of due to the results in kidney cancer and hepatocellular carcinoma. Dr. Jason Luke (15:03): But it's clear that in anti PD1 refractory melanoma, if you combine lenvatinib and probably other VEGF TKIs with anti-PD1, you can get response rates again around 30%. And so that can be, again, a very useful therapy utilizing a treatment approach that we're very well aware of in oncology. And I think the big picture question in my mind, actually, after sort of raising all these different treatments. We have tills, and we have intratumorals. And we have cytokines and we have VEGF inhibitors. Are the same patients benefiting from these therapies or are these actually different groups of patients in the PD1 refractory setting who could benefit from these? Dr. Jason Luke (15:42): And I think that question remains unknown, but is a very important one for our research community to understand. Because if we get all these different treatments approved, which one do we use for which patient? And I think we're still working on that, but it's exciting to think that we, at least, have options. Because even just a few years ago, the options were much more limited. Dr. Michael Davies (15:59): It's a great overview, Jason. And I would just sort of add that we also sometimes see patients who present with progression, but only in a solitary lesion. And in those patients, we often think about local approaches, including surgery or radiation as well. Well, Jason, as you said, this is a complicated but exciting topic. I really appreciate the expertise and perspective that you've provided today. Thank you so much for participating. Dr. Jason Luke (16:23): Thank you.