touchEXPERT OPINIONS New frontiers in NSCLC immunotherapy Transcript from a touchEXPERT OPINIONS Funded by an independent medical education request from Novartis. This activity is provided by touchIME. www.touchoncology.com/education/ 1 THE EXPERTS: INTRODUCTION In this activity, international lung cancer experts discuss the current role of immunotherapy in the management of non-small cell lung cancer DR MARINA GARASSINO and outline the most promising emerging National Cancer Institute of immunotherapeutic strategies targeting Milan, Italy infl ammatory mediators, with a focus on the interleukin-1 pathway. Dr Marina Garassino also provides insight into the impact of the COVID-19 pandemic on the care of patients with lung cancer. LEARNING OBJECTIVES PROF. SEBASTIAN KOBOLD Ludwig-Maximilians-University After watching this touchEXPERT OPINIONS, of Munich, Germany you should be able to: • Recognize the remaining challenges in terms of long-term survival for patients with NSCLC despite the availability of checkpoint inhibitors PROF. FABRICE BARLESI • Describe the tumour immune cycle and the therapeutic opportunities it Gustave Roussy, Villejuif, France may provide • Discuss the potential for reduction in cancer morbidity and mortality with IL-1-targeted agents and its implication for early treatment of NSCLC DR EDWARD GARON David Geffen School of Medicine, University of TOPICS DISCUSSED: California, Los Angeles, CA, USA • The current role of immunotherapy in NSCLC and its limitations Funded by an independent medical education • Key features of the tumour request from Novartis. microenvironment in relation to This activity is provided by touchIME. anti-tumour immune responses and possible therapeutic targets September 2020 • The relevance of the IL-1 family of proteins in cancer immunity and emerging IL-1-targeting treatments for solid tumours • The rationale for targeting the IL-1β pathway in NSCLC and the clinical development of IL-1β-targeted agents • The impact of COVID-19 on lung cancer patients, including global epidemiological data and its effect on provision of care www.touchoncology.com/education/ 2 touchEXPERT OPINIONS ASSESSING THE FUTURE OF IMMUNOTHERAPY When are checkpoint inhibitors currently IN LUNG CANCER used in the NSCLC treatment pathway and what are the associated outcomes? Dr Marina Garassino: Now we have several possibilities to use the immune checkpoint inhibitors in the treatment of metastatic My name is Marina Chiara Garassino, I am the non-small cell lung cancer. The fi rst is for patients Chief of Thoracic Oncology at the National Cancer with a tumour expressing PD-L1 more than 50%. We Institute of Milan, Italy. have two possibilities: one is to use single agent PD-1 blockade, which is pembrolizumab, or for this population, potentially we can also use the Which therapeutic targets are currently combination of chemotherapy and immunotherapy, exploited in immunotherapy for NSCLC? and based on recent data, also the combination of anti-PD-1 and anti-CTLA-4. So how can we decide? We don’t know, because We can exploit in 2020 mainly two immune we do not have direct comparisons among clinical checkpoint inhibitors. These two checkpoint trials. So we try to use a chemo-sparing regimen inhibitors are the ones against the PD-1/PD-L1 axis, as much as possible. For the majority of patients, and we are starting now also to use anti-CTLA-4. maybe pembrolizumab alone can be enough, PD-1 and CTLA-4 are expressed on T lymphocytes, but there are some categories of patients, for while PD-L1 is expressed on the tumour, on the example those with a bigger tumour burden or the macrophages and on some other cells. So when never smokers, in whom it may be potentially very you inhibit the PD-1 and PD-L1 axis, you reactivate the important to use it in combination T-cell response. with chemotherapy. Then we have a large portion of patients whose tumour has less than 50% PD-L1 positive cells and for whom nowadays we have approved combinations with chemotherapy that in non-small cell lung cancer can be platinum/ pemetrexed and pembrolizumab or the combination of carbotaxol, bevacizumab and atezolizumab. Recently, data suggested also that for these patients we can use the combination of anti- PD-1, anti-CTLA-4 and two cycles of chemotherapy. Again, also in this setting it is still debatable when to use one combination or the other. What we know is that, both for the grey area between 1 and 49% and for patients who are PD-L1 negative, combination So we know that this kind of pathway is very therapies play a very important role because they important for immune escape and by targeting increase the survival of these patients. Further these pathways, we are able to reverse the immune research will be needed to address whether to use escape. The most relevant drugs that we have one approach or the other. to target immune checkpoints are nivolumab, pembrolizumab and also cemiplimab and targeting PD-L1 we have also atezolizumab, avelumab and durvalumab. Moving to the anti-CTLA-4, we have the possibility now just to use ipilimumab. www.touchoncology.com/education/ 3 What are the limitations of current How do you envision immunotherapy for immunotherapies in the treatment NSCLC will evolve in the future? of NSCLC? The future of immunotherapy is very challenging There are some problems that are for example, because we are now in a sort of a plateau. I think the lack of biomarkers for these patients. We have that in the future, we have to promote as much nowadays only PD-L1 as a biomarker. So in the as possible the neoadjuvant setting, where it beginning, we are unable to understand who are seems that with immunotherapy we are able to the patients who will benefi t from single agent, have also major pathological responses that were combination therapies and who will benefi t from unseen with chemotherapy. We will have to wait immunotherapy in general. The second big point for the adjuvant trials, after the surgical resection is that we need to work on the primary and on the and clearly the next wave of immune checkpoint secondary resistance; we don’t really know very well inhibitors will be very important. So all the pathways what the mechanisms of resistance are. Potentially targeting the microenvironment and also all the they can be multiple and overlapping and they can pathways overcoming the mechanisms of primary rely on low antigen expression, they can rely on a resistance. There are some pathways that are microenvironment with a very immunosuppressive more interesting than others but it will be crucial component from the beginning. So it is possible that to understand what are the biomarkers behind, to it is not just a single mechanism of resistance, like for foster proper research for the future of the targeted therapies, but we have a combination non-small cell lung cancer. of multiple mechanisms of resistance. The next step will be very important to select the population that will better respond to immunotherapy and to increase the outcomes in the primary and the secondary resistance. www.touchoncology.com/education/ 4 touchEXPERT OPINIONS UNTAPPED POTENTIAL IN THE There are a variety of these cells, and I just want TUMOUR MICROENVIRONMENT to name some examples here such as regulatory T cells, myeloid-derived suppressor cells, immune suppressive macrophages, also called M2 macrophages, and many others. The interplay of these different types of cells, together with the Prof. Sebastian Kobold: tumour cells, in the end determines whether, in the fi rst place, you will ever go to an active disease, My name is Sebastian Kobold, I am Professor of because we know that many of those cells are also Medicine and Experimental Immunooncology already able to control the disease, or progress to and Vice-Chair of the Department of Clinical a clinically apparent disease, which is what we see Pharmacology here at the University Hospital of the in the clinic. I think what is also important to bear in Ludwig-Maximilian-University in Munich. mind for the next topics is simply that the balance of these cells can make the difference between an active, ongoing immune surveillance and immune What is the tumour microenvironment? response, or just a progressive disease. How does the tumour microenvironment So, the tumour environment or microenvironment is infl uence the tumour immune cycle? an overarching term that in the end describes the environment of a tumour. It is a conglomerate of cellular structures and non-cellular structures that encompasses and surrounds the tumour. I think I will start out to answer this question by maybe that one of the essential aspects for today that briefl y introducing the tumour immune cycle, which are present within the tumour microenvironment in the end, describes the interaction of the tumour are really immune cells, and cells that will then and how it gives rise to an immune response and communicate both with each other and with the how this immune response can, in the end, fi ght tumour cells. cancer. So this starts out, as many times when it comes to specifi c immunity, with the release of I just think what is important to bear in mind is that tumour antigens that are then being taken up either this tumour environment is typically constituted locally or to more distant sites, like in lymph nodes of cells that are both in favour of an anti-tumour by so-called antigen-presenting cells that take up immune response, that can contribute to an the antigen and then present it or cross present it anti-tumour immune response, such as cytotoxic to surrounding T cells, specifi cally also CD8 T cells. cells, NK cells, particular types of myeloid cells Whenever a specifi c CD8 T cell hits its antigen on an that are pro-infl ammatory, but at the same time, APC, it becomes activated, starts recirculating out of and I think this is also the essence of why you the lymphatic structure and can go to the tumour to have a cancer disease, there are also a lot of eliminate it.