Dr. Kathryn Bollin outlines evolving role of immunotherapy as well as the efficacy and role of traditional systemic treatments for melanoma.
we'd like to move from metastatic evaluation to the treatment of advanced melanoma. And we're very fortunate this morning to have Dr Cathryn Bolan MD. Who completed her medical degree at texas A. And M. So she should have some uh huh kudos from that from Dr ross and dr barrett in texas. She then went to a residency that's at the Mayo Clinic and then a fellowship here uh at Scripps Clinic. She's currently associate fellowship program director. She's part of our scripts. M. D. Anderson Cancer Center and helps direct our medical oncology melanoma program. Catherine has been a real pleasure to work with you these last few years and have you with our patients and our various programs. And thank you again for participating in the course this year. Right. It's an honor to be here. Thank you dr Greenway and good morning everyone. Um Congratulations to the team for arranging the virtual meeting. I think it's gone beautifully well and I've really enjoyed the speaker so far. So I'm very pleased to be here and take part. Thank you. All right, so I have no disclosures and today would all be covering um really is the treatment with some updates in the setting of uh NRA sectoral and metastatic melanoma. Um And I won't focus on adjuvant therapy. There's not a lot of new data here and that was covered partly. Um And dr ross is talks already when he mentioned neo adjuvant in comparison with what we know about care and the adjuvant setting. So we do have treatments in this realm um That looked very promising. We don't have survival data but survival data is really going to be the point of my talk today. Um I'll highlight a few special considerations and some things in the pipeline and hopefully along the way address the burning questions that come up in the clinic setting for me on a regular basis. So one thing that I'd like to point out is melanoma has really been the model tumor type to bring us forward into what my colleagues are calling um really the enlightenment era in cancer treatments and that's meaning that we've progressed with our technologies. After learning about uncle genesis and the different elements involved in tumor production to help bring us forward to designing novel therapies that target are cancers more specifically and more tolerable and efficacious manners. Melanoma has really been the model that's allowed us to see the potential for curing patients with very advanced disease. Um whereas before um this was truly a death sentence for the majority of patients. So on this slide, I just wanted to highlight something that dr Wysong beautifully covered with which is the role of UV damage and melanoma and other skin cancers. So UV light itself can induce genetic damage um and suppress the immune environment in the realm of our skin um and pigment cells. And so this can lead to an array of phenomenon within the cell that leads to um anti hepatic uh elements and and pro proliferation changes as well. Um There can be very specific patterns of genetic damage as a result of UV damage to the genetic code. Um And there's something that we call the UV signature which has been identified as you can see in the graph on the right by the blue elements within these bars. Of these four various cancer types with cutaneous squamous cell carcinoma harboring the greatest degree of UV signature damage melanoma next, in line with mucosal had annexed squamous cancers next and lung squamous cell following that. Um And so what uh we also like to measure aside from just the degree of UV damage to the genetic code is ultimately the somatic mutation burden. So the number of mutations within genes can be identified um And quantitative as you see here in this scale with cutaneous squamous cell carcinoma harboring the greatest somatic mutation burdens within a cell. Um And so that has been helpful in recognizing which cancers um may have such a high degree of a neo antigen load on the surface of tumor cells, which is critical for interplay with the immune system. That knowledge has been helpful for us to predict which cancers are going to respond better, perhaps to our immune therapeutic agents. So the next slide is going to just show us that aside from the types of genetic damage as a result of UV exposure. Um There are other psychogenic driver mutations that occur by some unknown mechanisms in certain situations. So we're all well aware of the wrath and rast mutations within the raft raft pathway that are common among cutaneous melanomas. Um And then there are other alterations in melanomas that originate in different sites of the body, such as the mucosal realm where we can see um an apple melon number where we see secret alterations. And then within the U. V. A. Of the eye we see a very distinct set of alterations in the genetic coupling proteins which has also been identified and left a manageable disease that behaves very similar to you or to you feel melanoma but distinctly different from those melanomas that start at cutaneous sites. So understanding the different androgenic driver mutations has brought us forward and designing therapies that can target these um proliferated mechanisms and shut down cancer growth within cells. So again melanoma has been a model cancer for helping us understand and develop technologies and treatments across the cancer spectrum. So this is just outlining um really the advancements that we've seen and I have another slide to show that as well. But kind of the breakpoint in my mind is the year of 2011 which is when we had um success with people um um um on the market or at least soon thereafter available to everyone as a standard of care therapy. And prior to that um we had you know local treatment options with surgery, radiation high dose interferon was being used um And then clinical trials chemotherapy which was never successful really for a long term benefit or I. L. Two which was successful in a very select sub population of patients. And moving forward we've now got these amazing targeted immune therapies, viral therapies sided kind therapies et cetera. So this is just a depiction of that showing kind of the black hole we were in up until the balloon amount entered the market and the explosion thereafter with on top of the screen arrow we've got our immune therapeutics that our checkpoints um and red. We've got our targeted therapies that came on the market around the same time as immune therapies. And we've seen an explosion and development of these agents. And now we're looking at the combination of immune and targeted therapies in traditional therapies here with herpes virus and polio virus that just received orphan drug status for the treatment of melanoma as well. But our technology is really brought us into this new era which is a very exciting time in cancer therapy. So in terms of mechanisms this is just depicting the rash raft pathway which is common in cellular proliferation across malignancies. Um And so we're using our B raft targeted therapies and combination with mec inhibitor therapies to disrupt this growth signaling pathway um in melanoma cells that have these mutations were also targeting this pathway now and other cancers. So we're finding be raft mutations and colorectal cancer, lung cancer and others. And so we're taking the therapies that we learned about and started using in melanoma forward into other cancers that have now been identified to harbor similar mutations. As far as the immune checkpoint therapies go. This slide is showing us really mechanisms of T cell um antigen recognition proliferation and targeting of cancer cells on the left um and then on the right, the two separate immune checkpoint therapies that are on the market. The first one that balloon a mob targets the braking mechanism the CTL A four binding mechanism. Um And then the anti PD L one and PD one molecules targeting those legans um more in the tumor micro environment with the anti C. T. L. A. For being more within the lymph node system. So um targeting anti CTL A four is really unleashing the braking mechanism for proliferation of T cells that have been taught to recognize a certain neo auntie gin. So we're able to produce more of these educated T cells to be released into the body and target cancer cells by by this particular agent. And with the anti PD one and anti PD L one agents. Um here I like to describe to my patients that were interrupting the secret handshake that melanocytes. No, because they belong there. And melanoma also knows the secret handshake protecting them from surveillance of immune cells. Until we break that handshake with these anti PD one or anti PD L one antibodies introduced into the system. So those are the immune checkpoint therapies that we use now across the spectrum of various malignancies dr ross will speak more about our intro to moral therapies. But on the market we have Tyvek which is a herpes virus um that we inject intra to morally. So as long as you can see in palpate a lesion, you can inject this viral therapy which also has a molecule um within this agent um that attracts and helps educate um antigen presenting cells um to target the immune or to listen immune response response locally as we're injecting this agent. What's phenomenal is that we can also see off target benefit in patients. So by injecting a tumor we're introducing inducing an immune cascade of events leading to local cell death of melanocytes um that have become malignant, but we can also see some activation in tumors that were not injecting when we're using these viral therapies. Um And there are now data showing that if we combine um TyveK along with intravenous apple in a mob or the anti PD one antibodies that we can see even a more robust response than with either of the single types of therapies alone. So those are the various agents that we have on the market. Um What I face in the clinic is many layers of complexity beyond just choosing among what's available um I've highlighted really so far on the immune therapies. But certainly I'm always questioning when do I use the targeted therapies? And we've got some data that will go through a little bit helping us to understand what may be the most beneficial. But when I'm faced with meeting a patient in the clinic, there are so many questions that arise, how much cancer is there is relevant for choosing therapy. Should we be doing neo adjuvant therapy when there's one nodal site of disease or respecting it first and providing adjuvant therapy if there's metastatic disease, where all is it located? Does the patient have impairment from cns metastases? Because that has implications in terms of how to treat their brain metastases. Um What is the relevant to our mutation burden within a patient? Um That doesn't typically alter my first choices of therapies but I like to have this information and see what kind of genetic profile is is present in understanding perhaps some information. Prognostic lee about patients as I choose therapies. Um Of course the site of origin of diseases relevant. And then what other comorbidities may exist? Is this a patient that's caught underlying autoimmune disease, neurological, autoimmune disease, organ transplant or is it a world traveler that I'm not sure I want to let out of my sight for that trip that they have planned um If I'm giving them combination checkpoints which can be dangerous for instance, would they have access if they're going somewhere else for their therapy and have come to us just for an outline of care. So lots of different questions arise in the clinic. Unfortunately we have lots of options available these days, but this just kind of highlights a few of the questions that I have to ask and what I always like to highlight is how important it is now in treating these patients with melanoma to really involve my expert colleagues um as I'm treating them because of the various complications that can arise from our treatments. So for the remainder of the talk, one thing that I'm going to be focusing on is the latest data demonstrating survival benefit among the different therapeutic options and the un respectable and metastatic setting. Um so this is again kind of a break point in the year 2005 year overall survival for patients with un respectable metastatic melanoma. Um was about 6%. There were those few lucky patients that got L. Two and they're still alive decades later. Um But now we've made tremendous strides with checkpoints and be wrapped targeted therapies. So just pay attention to the survival curves as we go through. Um We've hit above the 50% mark in certain populations of patients for five year overall survival. So, incredible strides have been made. What I'll go through are the landmark clinical trials for therapeutics in this setting. And this is just a list of the landmark immunotherapy studies um And I kind of marched through these. So this is the survival curve for people um Ahmad when it first entered the market as the first checkpoint therapy available to us. This was a fairly large phase three randomized study for patients that had disease refractory to other therapeutics available at the time. And this was comparing Apple UMA mob in combination with essentially placebo which was a peptide vaccine for G. P. 100 versus people. Um Ahmad alone versus a. G. P. 100 alone. And so the two cohorts with people um a map where equivalent essentially. And what we gleaned was that in these groups the media and overall survival was about 10 months. Um and toxicity is something that's a theme throughout the talks we will discuss that um there were seven-related deaths to a balloon a mob itself on this study. And in terms of the latest update which they didn't put on the side. We have a 2015 pooled analysis of this study and others where people. UMA mob was used either on a protocol or as an expanded access provisions to patients. And the three year overall survival data from that 2015 publication was such that about 22% of patients were alive at three years after a couple. Um um um Next we're heading into the anti PD one therapy is with the volume ab and the checks mate oh 66 study. Um So we have five year data on this here and what we're seeing are in significant improvements and some fluctuation in the overall survival curves at the five year mark on this slide, What we're seeing are some differences between the level of um LDH uh in these patients with metastatic disease um and their five year overall survival and some differences between those and their Pd L. One status. So greater PD L one status, patients treated with anti PD one therapy do have superior outcomes, but we can certainly see benefit in patients even without Quantifiable PDF one. So that's not a marker that we use and deciding about which therapy we're going to provide. So this just highlights data from this particular study. This was a study comparing um no volume abv versus the car Visine. So, chemo therapy at the time. Um And that's why you see such a significant difference between those survival curves because we know that chemotherapy was not significantly beneficial for our patients and uh anti PD one therapy has made a huge difference. So the five year overall survival from this study, this 39% for and volume versus 6 17% for Dakar Visine and what we're seeing is benefit in progression free survival. A pretty incredible overall response rate of 42% versus 14%. Um And one thing to highlight here because this signal is what we're seeing in the Neo adjuvant realm as a marker of expected durable response to neo adjuvant therapy is the notion of complete response. So if we can induce a complete radiographic remission for patients with metastatic disease treated with this therapy they have better outcomes. So live at five years with a complete response. 37% of patients um Sorry 47%. Whereas 33% with those that had a partial response, stable disease less and certainly progressive disease less. Yes mm. So next I'll advance to pay Embolism mob. So here you don't see as wide a separation and survival curves and that's because of this study. This is Pebble is a massive in comparison to people in a mob for patients in the metastatic setting. And this is demonstrating five year data. The difference between the top and the bottom slide here is whether or not the patient received there Therapy 1st Line or 2nd Line. And so all of that is depicted here. This is a phase three study with five year overall survival data now showing us that with pebble is a mob. Um 40% are alive at five years versus 30% of patients treated with people. Um Ahmad were alive at five years. Um Certainly still toxicity and there was a death in attributable to Pemberley is a mob in this particular study. Um And the toxicities is typically we'll see that there's greater toxicity in patients that receive the anti C. T. L. A. Four but not always. Um in these clinical trials. And here on the right. What we're seeing is those patients treated first line with embolism ad had better outcomes with a median overall survival of 38 almost 39% and a five year overall survival rate of 43%. And when I'm talking about first line versus second line therapy, one distinction to be made between this study and that with the volume OB. Was that on this study they enrolled patients that had be raft mutated status. So some of these patients had actually received targeted therapy prior to getting immune checkpoint therapy which was not the case on the volume app study. So there are differences between these patient populations um that really do relate to the statistical differences that we're seeing. Um I'll show this overall survival curve from the landmark study, the checkmate oh 67 trial. Um Which was the combination of immune checkpoint therapy with both anti C. T. L. A. For an anti pD one therapy. Um So the study wasn't powered really to compare the combination which is the green line on top and it's five year overall survival um tuna volume Ab alone which is the blue line here but was to compare to people um um Abalones. So superior five year survival with the combination versus apple. Umum Avallone most certainly. And I want to go back to just give you the print and then highlight another little tip here but from this very large study with the combination of people um ahmad and the volume of these were treatment naive patients. Again with un respectable disease. Um some of them did have mutation status that was positive, but again, treatment naive And what we see here is that the combination of the two checkpoints, the five year overall survival across all comers of patients was 52%. Um for Nevo it was 44% and it d it was 26%. Um And then those that had a complete response to therapy um did better. Again, so that's a thing that we see throughout these studies, significant within the realm of toxicities that the combination afforded greater much greater toxicity than either of the other two therapies alone. There were deaths and all um aspects of the all different cohorts. Um And the discontinuation rate, which is something that comes up is a bit higher in the combination, although significantly high for the hippie group as well alone. So, in the pie chart here on the right, what's really remarkable is here, with the combination versus the volume, a balloon or ip aluminum Avallone. Those patients that were alive at five years. Many more of them were no longer requiring any kind of therapy at all. Here we had 74% of patients treated with the combination of five years were no longer requiring therapy. That number dropped significantly to 58% For those of the patients alive at five years that received anti pd one therapy alone Or less, 45%. So this is, you know a remarkable outcome for these patients and the signal is that we're curing probably more patients. That's the way I like to think about it with the combination. But that is yet to be born out in long term data. And some of the other studies which will go through next. Let's see. Okay so overall survival crew. So now what we're asking is is it possible really to reduce the toxicity of the combination? We've seen beautiful outcomes with the checkpoint therapies in general. The combination seems to have Perhaps the long term durability best outcomes for patients but it is a more toxic regimen. And can we improve upon the safety in these studies. So this was a really nice study looking at pebble is um um so still early phase but in combination with a lower dose of aluminum. So the keynote nine study We now have three year data from this demonstrating again in a remarkable overall survival rate at three years of 59%. At a very nice complete response rate as well. There have been no deaths on the study discontinuation rate about the same as the other checkpoint combination studies. Um and so this is really remarkable that a lower dose of aluminum before it's less toxicity. It's been proven. But what's interesting about the comparison between anti C. T. L. A. For an anti PD one is there's not a dose response relationship really it doesn't appear or maybe there's some signals emerging right now but we haven't understood it to be the case so far for the anti PD one therapies. So the dose is less relevant in the anti PD one realm in terms of toxicities but with people um Ahmad we certainly know that higher doses are more toxic. Initially we were using the 10 mg per kilogram dose in the adjuvant setting and that was highly highly toxic. So we dropped it down to a three megs per kilogram dose in the checkmate oh 67 study where it was combination immune therapies. Um And now for this combination therapy we've dropped it down to one minute per kig have seen still remarkable outcomes with less toxicity. Um This is another study also with the combination of people um a mob and the volume of the checkmate 5 11 study. Looking at this alternate dozing schema. So this is um now I phase three for randomized study. Um The one with Pedro I think were treatment naive patients and here prior adjuvant therapy was allowed in this cohort. Um And so what we've got here is relatively early data um But looking at the differences between what we were calling the standard dose of I PS three versus a lower dose of it be. So the Nevo doses also changed but that's less likely to be significant. Um And so can we alter the dose of the combination therapy and see great outcomes. Um So here I just put on toxicity and discontinuation rate. Um There seems to be a greater hepatitis when we're using the combination with higher doses of IT geneva which I referenced by higher dose of it. Be putting it be up front. So 48% of grade 3-5 toxicities but a much lower toxicity rate and the reverse dozing with the lower dose of epi in comparison. Um And then when we look at responses, complete responses in the Nevo with low dose EPI group We're 27 24 complete responses and the higher dose of it be so very similar. Um and I'll show the overall response rate seems to be a little bit different. But the curves which I show here um for 12 months overall our. Sorry? Yeah 12 month PFS here progression free survival and overall survival here the curves overlaps significantly. So it seems to be that there's enough similarity between the low dose sippy and the high dose epi but significantly less toxicity with the lower dose of EPI. That we may be settling upon a different does things fema to improve safety with similar outcomes in these combination studies. So I just want to highlight because it's always the case that we do need to be careful about cross trial comparisons among you know the checkpoint studies or and the keynote studies um Checkmate in keynote versus the targeted therapies as well because there are different patient populations among the patients in each of the studies to wrap up with the immune checkpoints. I want to talk just briefly about cNS metastases because this has always been a refractory group of patients to treat. Um But many patients with metastatic melanoma will develop brain metastases. So up to three quarters of them will have brain metastases at the time of death and more than a third at the time of diagnosis of their metastatic disease. Previously median overall survival was on the order of months. Um and then only 5% alive at the five year mark. And so this can be a very complicated scenario with many um difficult side effects as a result of having cns metastases. And prior to within the last couple of years these patients weren't really included on clinical trials. So we weren't aware of how best to treat them. But we did see now in 2019 some nice results of patients in a highly selected population that actually benefited significantly with a one year overall survival of 82% of patients that received the combination with traditional dozing of people. Um Ahmad and a volume mob Again important to highlight these are patients that were identified to have only a few small brain metastases and we're completely asymptomatic not requiring steroids. So we demonstrated benefit. But in a subsequent analysis we saw that patients with the worst performance status requiring steroids didn't benefit from therapy. So we have to be careful about what we're looking at. Released just this year at ASCO was data from a nice Phase one study from MD Anderson showing those patients who had left um an angel disease um where the median overall survival was traditionally less than three months. And we had no approved therapies could benefit significantly from providing traditional intravenous no volume ab but also interacting the volume ab intra ethically so with into the spinal fluid. And the data so far shows us that these patients of which there are only a few on study had a median overall survival of 46 weeks. So this is really exciting. Um and I can't wait to see evolving data from this type of study quickly. I'll go through it Get in trials because here we also have five year overall survival data which is remarkable. But the combination be roughneck inhibitors. We now have among all patients included in the study, five year overall survival of 34%, which is fantastic. And those in a select population of 55% which is also remarkable treatment discontinuation Of 18% and no deaths on study. Um And then then Kobe combination with the roughneck targeted therapy, we have four year data with overall survival, achieving 34% in this cohort um discontinuation around 20%. Um And a low number of toxic, high grade of grade 34 toxicities in that study. Um A third combination regimen and paraphernalia and Betty met in it. We now have three year data Looking at overall survival of 47% in this cohort. Um or the study we see the highest overall response rate among the targeted therapies. Um so this is exciting data. Um and then this is just a slide to let you know that we have to manage toxicities of these patients who typically cannot come off of their therapy. Um And it's variable among the different b raf met combinations and may play into how we make decisions. Yeah. Um We also have good data demonstrating efficacy in the setting of brain metastases using combination be roughneck therapy um with this Phase two study uh Debra fine nib and trauma tonight with overall survival at the 12 month mark. Looking at the different cohorts of patients and whether or not they had a good performance status, a worst performance status or a history of radiotherapy to target their lesions in addition to Oral agents. These are the response rates at 12 months. So also very good between 40 and nearly 70%. So this just really highlights how far we've come and treating these patients with un respectable and advanced melanoma. Um Now we've got five year incredible data with the combination of above 50% higher in some populations. Um for instance, with Deborah funded and tormented and only a few sites of disease and low LDH et cetera. Um um And then single agent therapy is also pretty remarkable in these patients with our five year overall survival data at this point in time. And down here at the bottom looking at reduced dozing of people um Ahmad, we don't yet have five year data. So it's going to be interesting how that does compare to the higher dose of epi as time goes on. Um as these data mature and then our cns data is all relatively new but um incredible differences that we can make in that realm as well. Again hard to compare and inappropriate to compare across the trials. But these are the questions that come up in my clinic. Am I going for that, you know, potential cure in a patient with immune therapy which we can achieve and less likely with targeted therapy. Um That's that's what I'm always hoping for is looking for the right patient for the right treatment. Um and then I just wanted to highlight again with the combination immune therapies. Remember the large percentage of patients who were no longer on therapy at the five year mark, whereas we really can't say that it's acceptable to stop their targeted therapy um released this year at ASCO were really um several different early studies looking at how we can fine tune the therapies to improve um efficacy and reduced toxicity. We looked at dozing alterations as I mentioned but also shortening the court. There is a nice study looking at only two doses of combination therapy to really help us understand if that may be sufficient rather than the typical four doses of combination therapy that we give in our patients and then trying to understand um when white might we use targeted therapy first and switch to checkpoints versus the other way around and patients. So various alterations in the dozing schema that we can see. Um The big questions that still exist are what do we do in the setting of refractory disease. And there are nice data for those patients with refractory disease to anti PD one alone. Can we then later add hippie or switch to E. P. And C. Benefit. And it looks as though yes if we do the combination so they've failed pd one. But let's throw in some hippie can we get a nice response and indeed we can. Um So the combination is superior to just switching over to petaluma mob with PFS of 27% versus 13%. When that's done there's some exciting new therapies on the market. We'll hear more about some of them later. But this is an aisle 12 that's introduce generally provided to patients along with some electricity. So electric parading this into the micro environment and combining with anti PD one therapy And seeing amazing responses overall response rate of 30% in patients that had previously refractory disease. I look forward to data for the polio vaccine that's been used in glioblastoma within melanoma. As I mentioned, it now has orphan drug status in this disease entity. This is just a poster. I'll skip over with the benefit from the L. 12 and electro operation. And then on the market for the future. Is this more personalized type cancer care? So this is a patient here. You had refractory disease. To what's available on the market, harvested one of her tumors and extracted the T cells from the tumor. And these T cells can then be engine mirrored in the lab to recognize those neo antigens present on melanoma cell surfaces and then expanded so that there is a larger quantity that can be reinjected into patients after some manipulation of their immune system. And then we see that those activated T cells in abundance can eradicate their disease. So this has been done at the NIH for many years. And D. Anderson has some beautiful data and this was an article that was just published this year In a Phase two study of 10 patients with an overall response rate. With what we call till therapy or tumor infiltrating lymphocytes therapy Of 50%. So remarkable outcomes in the refractory setting with some of these therapies. What else can we do? Well there have been combinations of immune checkpoint and targeted therapies. This in my mind is still a little bit controversial because we've had three studies that haven't moved forward and one that has gaining FDA approval for the combination of anti Pd L. One therapies materialism along with very refined and Cobham. Attentive Um where we can see some benefit in the median progression free survival. But in some of the other studies what we're seeing here in grade 3-5 toxicity of 58% for instance. Um and this study that didn't meet its primary endpoint with a different combination schema for progression free survival. So I think the jury is out on how to apply triplet therapy and the metastatic setting it this point. Um And then always were wondering about special populations, how to re challenge patients that had toxicity, what to do in the oligarch metastatic disease setting for those patients that have an organ transplant where we can't use checkpoints most of the time. And then those subsets of melanoma such as mucosal. That's been more refractory to treat. We've got some data showing combination checkpoints can be useful or different targeted therapies in this environment. And then we've had some nice data in the U. V. A. Realm more recently. Um And this disease has been more difficult to treat than cutaneous smell it. No mind. So I'll stop there. This is a photo a patient of mine sent to me on his travels to Vietnam. He was one of those folks that received it also surgery um targeted therapy immune therapy and I had a hard time letting him travel which is what brought him happiness in life. But finally he's been in remission now for several years and was able to go. So thank you everyone. I'll answer questions. Catherine. Thank you. We'll hold the questions and forward those to you so everybody can participate at the answers.
