Transcript Details This is a transcript of an educational program accessible on the ReachMD network. Details about the program and additional media formats for the program are accessible by visiting: https://reachmd.com/programs/medical-industry-feature/immuno-oncology-perspectives-currenttherapies-future-developments/9502/ ReachMD www.reachmd.com info@reachmd.com (866) 423-7849 Immuno-Oncology: Perspectives on Current Therapies & Future Developments Announcer Open: Welcome to ReachMD. This program entitled Immuno-Oncology: Perspectives on Current Therapies & Future Developments has been developed with funding from EMD Serono, Inc. and Merck KGaA, Darmstadt, Germany. Current Attitudes Toward IO I think the main attitude toward IO or immuno-oncology is excitement and promise. In everybody's mind now that we are on the verge of a new age of therapy for cancer. And, in fact, even a new way to look at cancer from the perspective of how we treat it. We need to learn about immunotherapy; we need to learn about the side effects, what works, what doesn't, which patients are best served, and we also need to understand that there are patients now with advanced disease, metastatic disease, who are enjoying long-term remissions when these patients we would have considered incurable. For instance, metastatic non-small cell lung cancer or bladder cancer, or head and neck cancer, these are results that we would have never dreamed imaginable in the past. So, opportunities with respect to how we go forward and how we begin to learn to best use these agents, but also challenges, because, clearly, 2018 ReachMD Page 1 of 7
right now not everybody is benefitting and we want to continue raising that bar. Well, in the academic community, at least, there is a great deal of excitement about the immunooncology products because they are active across a broad range of malignancies, and in some patients you get durable responses, maybe even cures in a small subset, in diseases where we have never seen durable responses before. Well, I think immuno-oncology is really changing the face of oncology treatment for patients, and so, what is particularly exciting about this therapy is the duration of responses. So we sometimes refer to this as, you know, being on the tail of the curve and what that really means is that patients are alive longer and longer, and so, this is the real benefit. Role of the Community Oncologist Well, community oncologists are, basically, the connection between the patients and their care. They play huge roles in educating their patients about the benefits of these therapies, in following their patients in order to identify toxicities early, in moving these patients from initial IO that is approved in the community to the clinical trials looking to unlock the answers to primary resistance, to a good partial response that is not durable, or when we can stop giving this therapy. They are our partners in the community and in academia. I think for community oncologists it becomes challenging because this is clearly a new paradigm; it is a new type of therapy and, with that, we need to learn how to use it. We need to learn, again, which patients are best served by these types of therapies. In some instances, we need to learn how to use the biomarkers associated with those therapies, and it is now very confusing because there are some diseases where a biomarker applies and there are some cancers where a biomarker doesn't. And then, furthermore, and perhaps most importantly, the community oncologist needs to understand what the different side effects are because it is clear that there is different adverse event profile with immunotherapy versus traditional cytotoxic chemotherapy or targeted therapy. It is also clear that early recognition is critical in the management, and so, we are now moving into that new area of immunotherapy and the community oncologist is faced with learning quite a bit in a relatively short period of time. James Gulley, MD: 2018 ReachMD Page 2 of 7
They are often the ones treating the patients with these IO agents and certainly the ones that are seeing them if they run into problems with these agents. So, it is very important for these community oncologists to be aware of the potential side effects that one might see with IO agents as well as the differences in responses one might see with the IO agents, like pseudo-progression before the disease actually goes away. Promising Treatment Developments Kunle Odunsi, MD There are a number of promising treatment options and I will put them in three categories. The first category is the use of immune checkpoint inhibitors. 2 The second category of IO that is really very promising is the adoptive T-cell therapies, whereby, patients' own immune cells are taken out of the body, reengineered or reprogramed and turned into cancer fighting cells. 3 The third group are the vaccines, whereby you can actually prime an immune reaction against a tumor with cancer vaccines, so that you can generate immune cells, again, these are the soldiers, the foot soldiers, generate these cells and then sometimes combine the vaccine approach with all of the other strategies including the immune checkpoint inhibitors. Well, anti-pd1 and anti-pd-l1 has been the most successful oncology agent that I have ever seen. It really is active across many different malignancies and produces long durable responses in a small subset of patients. So that, by far, is the most active agent out there. There are other agents that are in development. The immune therapies like CAR T-cells, for example, for lymphoma and some of the cell therapies are very exciting. Those are probably next online. There are other immune checkpoint inhibitors that are being developed. But right now, the backbone of all that we are doing is really the drugs, the antibodies that block either PD-1 or PD-L1. So, the most promising options right now, I think, really revolve around the T-cell checkpoint inhibitors. Again, these have shown promise in a large number of different types of tumors and we already have some early data, particularly for melanoma, that combination of the checkpoint inhibitors can be synergistic or additive in terms of efficacy. Although there are some additional toxicities that occur when you start doing the combinations, we are particularly interested in some of the newer combinations where the toxicity profile may be more acceptable. For example, there have been studies using oncolytic viruses as a general approach with checkpoint inhibitors and are showing fairly dramatic response rates without any increase in monotherapy toxicities. So, I think, time will tell whether these will lead to approval and improvements for patients, but we are really very excited about 2018 ReachMD Page 3 of 7
the combination strategies that are now in clinical development. Unique Toxicities of IO Well, since you are stimulating the immune system, the unique toxicities of IO is anything that can be inflamed can become inflamed. And what we see can depend a little bit on the specific drugs being used, but, essentially, we see inflammatory reactions to normal organs. So, it could be pneumonitis, colitis, endocrinopathies, hepatitis, dermatitis or a rash. And what the practitioner really needs to do is be aware of a couple things, first of all, the timing of these different side effects. They tend to be fairly predictable in terms of their onset. Not 100%, but fairly predictable, and the fact that they can mask themselves as either side effects or manifestations of the cancer or side effects that could be dismissed by the patient. It's really autoimmunity, inflammatory and then the way you manage it, is by giving an antiinflammatory, a steroid or a secondary immunosuppressive. But you just have to understand how these toxicities present and then treat them appropriately and know when to treat. But, clearly, we are understanding more, and I think that is the role of all of the investigators that are in IO, is to educate our colleagues, whether they be community oncologists, or gastroenterologists, or neurologists, cardiologists, about the fact that a patient on this type of therapy can have these toxicities that are immune-mediated and require immunosuppression. Exciting Combination Treatments James Gulley, MD: So, my interest in immunotherapy really comes down to a simple theory that you first need to get the immune system engaged in recognizing a tumor, and then, you need to allow those immune cells to work at the level of the tumor. So, I really like the combinations that can get both the immune system engaged, the T-cells or, perhaps, other immune cells engaged in the tumor, and then, allow them to work better within the tumor microenvironment. Kunle Odunsi, MD: The most exciting for me is the use of adoptive T-cell therapy and based on the fact that you can deploy large numbers of these cells and there is already data indicating that this approach can lead to 2018 ReachMD Page 4 of 7
regression of large, established tumors. However, we also understand that the tumor has a way of fighting back, developing a counter-regulatory measure against the T-cells. So, what is exciting for me is to be able to combine the adoptive T-cell therapies with strategies to counteract negative regulation by the tumor. Those are the most exciting, as far as I am concerned. Predictive Biomarkers So, I think, the Holy Grail for immuno-oncology would be to identify a predictive biomarker that would allow us to select a patient for one therapy or another one. At present, I don't think we have any biomarkers that are universally acceptable for this purpose. We do know that PD-L1 expression seems to be a very important marker for better responses in patients with non-small cell lung cancer, and there have been trends toward better responses in tumors with high PD-L1 expression in other types of cancer, as well. I think that the research in the field is particularly interesting around things such as looking at the total mutation burden in the tumor cell and looking for interferon gamma-related gene signatures, and various factors in the interferon pathway that seem to be very important in terms of either allowing or suppressing anti-tumor immunity. So, I think, the next few years will be interesting as several of these factors are now being prospectively validated in large patient cohorts and, hopefully, we will be able to identify a biomarker shortly. Personal Perspectives So, I primarily treat melanoma and kidney disease. We are very interested in combinations just like everyone else. And we have been focusing, for example, on combinations with VEGF receptor inhibitors. We are very interested in metabolic alteration of the tumor microenvironment, and we are very interested in things that alter the function of monocytes and macrophages and myeloid-derived suppressor cells within the tumor microenvironment. We are actually very interested in cell therapies also, and we are starting a cell therapy program at our institution, and we hope to be working on ways to improve the cell product and the ways that we modulate those cells after we give them back to patients. So, at the Angeles Clinic and Research Institute where I work in Los Angeles, our interest now has gone onto biomarker work. That's, I think, is one of the most important fields in IO right now, due to the fact that some of these combination therapies do have significant toxicity. We are also looking at clinical trials for patients who have failed first-line PD-1, PD-L1 in multiple solid tumors. And those have to do with other checkpoints that are coming forward like GITR and that family, also looking at adoptive 2018 ReachMD Page 5 of 7
T-cell therapies and failure, antibody drug conjugants and combinations of all of those. What we are really focusing on at the University of California San Diego, a very robust pipeline of clinical trials using immunotherapy agents, mostly checkpoint blockers, and now, there are really dozens of agents with hundreds of clinical trials. The next is developing a personalized vaccine portfolio. James Gulley, MD: So, I've done a lot of work with vaccines for cancer in various different cancers. We have a prostate cancer vaccine that we hope to get data on later on this year. But, I think, that vaccines are great and they can help get an immune response. The problem is in the patients their tumor microenvironment may be so overwhelmed with negative regulatory influences that the cells generated by the vaccine may not be able to work optimally. I think that the best way to get both the immune checkpoint inhibitors to work and the vaccines to work is to combine them together and then you are going to be able to take patients that don't have an underlying immune response and give it with the vaccine in patients that get the response, but the immune response is not working at the level of the tumor; help them with the checkpoint inhibitor. And so, we have a trial in prostate cancer that has just opened and we are treating patients with vaccine and checkpoint inhibitor. So, my own work has largely been focused on the use of oncolytic viruses and we have been very interested in using these agents as a way to turn lymphocyte poor, or what we sometimes call "cold tumors" into hot tumors, so you bring in the lymphocytes which are often coming because there is a viral infection and then we try to trick those T-cells into fighting the cancer as well, because the virus will release tumor antigens. And we are especially excited about the potential for using oncolytic viruses as a cornerstone of combination immunotherapy since they appear to have a very good safety profile so far. Kunle Odunsi, MD: So, over the years, we have developed vaccine approaches, but more recently, adoptive T-cell therapy approaches targeting this NY-ESO-1 antigen. Very exciting for us. We have discovered unique and novel receptors targeting NY-ESO-1 T-cell receptors, that we believe are likely to help patients who have NY-ESO-1 expressing tumors. That is very exciting to us. Announcer Close: You've been listening to REACHMD. This episode has been developed with funding from EMD Serono, Inc. and Merck KGaA, Darmstadt, Germany. If you have missed any part of this discussion, visit 2018 ReachMD Page 6 of 7
ReachMD.com/IOInsights. Thank you. 2018 ReachMD Page 7 of 7