Evaluating Immunotherapy as a New Pillar of Multimodal Head and Neck Cancer Care: Where Does Checkpoint Blockade Fit?

Transcription

1 CME Evaluating Immunotherapy as a New Pillar of Multimodal Head and Neck Cancer Care: Where Does Checkpoint Blockade Fit? Course Director and Moderator Robert L. Ferris, MD, PhD, FACS University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania Faculty Quynh-Thu Le, MD, FACR, FASTRO Stanford University Stanford, California What s Inside 3 Introduction Understanding Immunity in SCCHN and the Emergence of Checkpoint Blockade (Part 1) Understanding Immunity in SCCHN and the Emergence of Checkpoint Blockade (Part 2) Integrating Checkpoint Inhibition Into Multimodal SCCHN Management: A Practical, Evidence-Based Approach (Part 1) Integrating Checkpoint Inhibition Into Multimodal SCCHN Management: A Practical, Evidence-Based Approach (Part 2) Audience Q&A Session This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. Participate in interactive questions, download activity slides, and obtain your instant CME credit online.

2 Activity Information Activity Description and Educational Objectives The management of squamous cell cancer of the head and neck (SCCHN) has come to include the integrated use of multiple therapeutic techniques, from surgery and radiotherapy to cytotoxic and targeted drugs. Despite the potential for cure with these approaches, many patients still experience substantial toxicity, including late effects of treatment. New evidence, however, has confirmed the emergence of immunotherapy as an option in SCCHN and suggests that immune checkpoint inhibitors may be active in settings other than recurrent/metastatic disease. Clearly, immune checkpoint blockade may be the next leap forward in head and neck cancer management. In this activity, our expert panel vets the evidence supporting the continued integration of immunotherapy in SCCHN, profile areas of potential synergy with radiotherapy and other established treatment options, and provides a glimpse of the immunotherapyinclusive future management of head and neck cancer. Upon completion of this activity, participants should be better able to: Describe the rationale and mechanisms for therapeutic targeting of the immune system in head and neck cancer Apply efficacy and safety evidence on the use of immune checkpoint inhibitors in head and neck cancer, including recurrent, metastatic disease and/or platinumrefractory settings Summarize potential clinical synergies between immuno-oncology strategies and other modalities commonly used for the management of SCCHN Select patients with head and neck cancer who may be eligible for immunotherapies including enrollment in clinical trials Target Audience This activity has been designed to meet the educational needs of radiation oncologists, medical and surgical oncologists, advanced practice clinicians, and other healthcare professionals involved in managing patients with head and neck cancer. Requirements for Successful Completion In order to receive credit, participants must view the activity and complete the post-test and evaluation form. A score of 70% or higher is needed to obtain CME credit. There are no pre-requisites and there is no fee to participate in this activity or to receive CME credit. Statements of Credit are awarded upon successful completion of the post-test and evaluation form. Media: Enduring Material Release and Expiration Dates: October 25, October 24, 2017 Time to Complete: 90 minutes Faculty & Disclosure / Conflict of Interest Policy Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute, Inc. for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and PVI, PeerView Institute for Medical Education do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME activity for any amount during the past 12 months. Course Director and Moderator Robert L. Ferris, MD, PhD, FACS UPMC Endowed Professor and Vice-Chair Chief, Division of Head and Neck Surgery Associate Director for Translational Research Co-Leader, Cancer Immunology Program University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania Robert L. Ferris, MD, PhD, FACS, has a financial interest/relationship or affiliation in the form of: Grant/Research Support from AstraZeneca/MedImmune; Bristol-Myers Squibb; and VentiRx Pharmaceuticals. Advisory Board for AstraZeneca/MedImmune; Bristol-Myers Squibb; Celgene Corporation; Lilly; Merck & Co., Inc; and Pfizer. Other Financial or Material Support from Bristol-Myers Squibb and Merck & Co., Inc. for research funding for clinical trial. Robert L. Ferris, MD, PhD, FACS, does intend to discuss either non-fda-approved or investigational use for the following products/devices: various novel therapeutics, including immunotherapies such as durvalumab, nivolumab, and pembrolizumab (among other checkpoint inhibitors) in a range of squamous cell cancer of the head and neck (SCCHN) settings. Faculty Quynh-Thu Le, MD, FACR, FASTRO Katharine Dexter McCormick & Stanley McCormick Memorial Professor Professor and Chair Department of Radiation Oncology Stanford University Stanford, California Quynh-Thu Le, MD, FACR, FASTRO, has a financial interest/relationship or affiliation in the form of: Consultant for Merck & Co., Inc. Grant/Research Support from Amgen Inc. and Varian Medical Systems, Inc. Quynh-Thu Le, MD, FACR, FASTRO, does intend to discuss either non-fda-approved or investigational use for the following products/devices: various novel therapeutics, including immunotherapies such as durvalumab, nivolumab, and pembrolizumab (among other checkpoint inhibitors) in a range of squamous cell cancer of the head and neck (SCCHN) settings. CME Reviewer Shaina Rozell, MD, MPH Northwestern University Chicago, IL Shaina Rozell, MD, MPH, has no financial interests/relationships or affiliations in relation to this activity. Medical Director Carmine DeLuca PVI, PeerView Institute for Medical Education Carmine DeLuca has no financial interests/relationships or affiliations in relation to this activity. Disclaimer The information provided at this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient's medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Providership, Credit & Support This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians. The Medical Learning Institute, Inc. designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Providership This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. Support This activity is supported through educational grants from Bristol-Myers Squibb and Merck & Co., Inc. Disclosure of Unlabeled Use The faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience any reference to an unlabeled or investigational use. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our reports. No responsibility is taken for errors or omissions in reports. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView Press or any of its partners, providers, and/or supporters. 2 Go online to complete the post-test and evaluation for CME credit

3 Evaluating Immunotherapy as a New Pillar of Multimodal Head and Neck Cancer Care: Where Does Checkpoint Blockade Fit? Introduction Robert L. Ferris, MD, PhD, FACS University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania Dr. Ferris: Good evening. Thank you for attending. I d like to thank PeerView for organizing this session. You can see the title here, Evaluating Immunotherapy as a New Pillar of Multimodal Head and Neck Cancer Care: Where Does Checkpoint Blockade Fit? I m very honored to share the podium with Dr. Quynh Le. She s the Chair of Radiation Oncology at Stanford University. I m Bob Ferris. I m a head and neck surgeon and a cancer immunologist in Pittsburgh. So Dr. Le and I are going to discuss a little bit later different facets of immunology, immunity and where immunotherapy with checkpoint inhibitors fit with radiation therapy, and it s a very appropriate session for an ASTRO meeting. Narrator: After completing the activity, access the post-test and evaluation form by clicking the red Get certificate button. I encourage you to download the slides, Practice Aids, and any other activity features that may interest you. Dr. Ferris: So, as I mentioned, I m Bob Ferris, the University of Pittsburgh. I have worked in cancer immunology for the past 15 or 20 years, so it s really an exciting time for us, those of us who believed in it, perhaps against all data and evidence. And so we re very gratified with that. And the goal here is to acknowledge the fact that head and neck cancer therapy is multimodal. We all know that this crossdisciplinary and multimodality therapy has been the hallmark for effective care of head and neck cancer. We know that multimodal therapy can be curative in some settings. We know that traditional therapy with radiation, with surgery, with chemoradiation has toxicities. We ve seen now 10 years since the FDA approval of EGFR-targeting agents such as cetuximab, a biologic agent. I ll try to show you some data to convince you that it has an immune mechanism of action. We have data for the addition of EGFR inhibitors plus radiotherapy, and we have data combining EGFR inhibitors with chemoradiation. It s clear that we have intensified therapy with conventional modalities about as much as we can because of the toxicity. And that s where immunotherapy has come on at a very appropriate time. The RTOG trial adding EGFR inhibition to chemoradiation didn t show what we thought we would see, which was an expected benefit. So the question is, can we add immunotherapy in that setting and see additions to locally advanced disease? So what does the arrival of this new fourth modality mean? We ll discuss what this concept of checkpoint receptors is and checkpoint blockade. The potential, which we ve already seen in the past year, is to improve outcomes for recurrent/ metastatic disease. And the goal now is to combine more effective combinations with radiation and chemoradiation, and perhaps other biologic agents and immuno-oncology, and in some cases, consider whether we can add checkpoint inhibition to radiotherapy and replace cytotoxic chemotherapy altogether. And those studies are underway. 3

4 So, where [are] we as of September of 2016, the current status of immune checkpoint inhibitors? We have an approved agent, as many of you know. Pembrolizumab, an anti PD-1 monoclonal antibody, was approved for recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-containing chemotherapy regimen. We have nivolumab. That was given FDA breakthrough status in a positive randomized phase 3 trial in platinum-refractory patients who had progressed on or within 6 months of cisplatin therapy, either in the first line or the locally advanced setting. And we have a number of other first-line trials, and second-line [trials], with different combinations of immuno-oncology agents, pembrolizumab and nivolumab and other targeted checkpoint agents, such as durvalumab. Pembrolizumab and nivolumab target the receptor PD-1. Durvalumab targets the ligand PD-L1. And durvalumab is being combined with agents that block a second checkpoint receptor, CTLA-4, and several of these are being evaluated in head and neck cancer. And we will discuss these. But these are now in the phase 3 setting, so there are a great deal of data to be gained in the next year or two. So the agenda tonight we ll discuss why it s important to understand immunity in head and neck cancer, a little bit of foundational evidence for checkpoint blockade. I ll show you a bit of data that we have, and it is consistent with data in the literature, combining radiotherapy with checkpoint inhibitors. We ll explore the future of immune checkpoint blockade in head and neck cancer and discuss practical issues with possible combination approaches, including with radiotherapy. And we really want to answer your questions, your sort of burning issues, and potentially things that you may be concerned about or questioning, and someone else sitting right next to you has the same question. So if you be sure to ask it, I think we would have a good interchange and make sure we demystify the checkpoint inhibitor field and potential issues with integrating with radiotherapy. And this is really getting beyond recurrent/metastatic disease, where we tend to introduce new agents. Multiple studies of checkpoint inhibitors have now emerged, are being designed, or are open, and Dr. Le will discuss the current trials. I will review the basis of immunology and immunotherapy with just a bit of the already presented data. And then what she ll do is really lay out these combinations that I ve been alluding to walk you through some of the populations who are being treated and accrued and the combinations and rationale for those combinations in the locally advanced curative setting, where we have the greatest impact for long-term, durable cures, as well as the adjuvant and neoadjuvant settings. So, really, integrating checkpoint inhibitors into every line of therapy. 4 Go online to complete the post-test and evaluation for CME credit

5 Understanding Immunity in SCCHN and the Emergence of Checkpoint Blockade (Part 1) Robert L. Ferris, MD, PhD, FACS University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania Now, this is a slide from Jerome Galon. This is from colorectal cancer, but this has been reproduced in head and neck cancer. I want to direct your attention to the top of this slide, because this shows the importance of immunity on tumor prognosis. What you can see is that the curves are basically divided up by the TNM stage. Stage 1 patients do well, stage 4 patients not well. But if you take these tumors, whether it s stage 1 or stage 4, and you now quantify them based on the extent of lymphoid infiltrate, the high tumor-infiltrating lymphocyte tumors did very well, even when they were advanced stage, whereas [with] the lowfrequency, low numbers of tumor-infiltrating lymphocytes, even when the patient was stage 1 or 2, those patients did poorly. Dr. Ferris: I think we all are aware that targeted therapies arose over the past 10 or 20 years, and that the integration of targeted therapies was basically after we had already sort of maximized the combinations of traditional modalities, and this promise of understanding the biology, understanding the growth factor pathways and the pathogenesis of head and neck cancers could be harnessed successfully for therapy. And so for many of us, this was the aha moment. We d been working on immunology, immunotherapy, inducing an immune response, but the baseline immunity the de novo immune response during tumor progression is an important prognostic indicator. And as I said, this has been shown now in a number of cancers, including head and neck cancer. The first of those were pathway inhibitors, tyrosine kinase inhibitors. But I think the field has broadened and grown to integrate understanding the targeted agents that target not only the tumor cell, but target the surrounding host immune inflammatory infiltrate. And so we think of this modality as a targeted immunotherapy because of the on-target and off-target effects. So, as I mentioned, there s a de novo immune response; what is happening over time? And Mark Smith and Bob Schreiber helped 5

6 us conceptually with a concept that they coined immunoediting, meaning that the tumor over here that shows up in the clinic, that s symptomatic and growing, has already been edited by that baseline immune response. And so turning the clock back, the immune system is eliminating premalignant cells, the so-called immunosurveillance theory, for months or years. As you have abnormal genomic or other overexpressed antigens, that premalignant cell can be rejected and eliminated by the immune system through a number of mechanisms that we ll describe and discuss. that you could develop a durable response, a so-called tail, a longterm benefit where the immune system could keep the tumor cells in check or eliminate them entirely. And now that we have some of these data that I ll review over the next 15, 20 minutes, what Dr. Le is going to describe to us is, when we have a positive signal, as we do now with a couple of the checkpoint receptor antibodies, how do we integrate this into the standard modalities in the hopes of getting not only early responses, tumor shrinkage, but long-term durability and improve the long-term survival of head and neck cancer patients? At some point over, again, months or years, that premalignant cell goes into an equilibrium phase with the immune system where eventually a clonal population of cells is able to develop alterations, expression of different receptors, some of them checkpoint receptors and ligands, which enable escape from the immune system. So a baseline de novo immune response is beneficial, probably keeps more cancers from arising, but eventually a symptomatic cancer escapes the immune system. And what we have to do is understand the escape mechanisms to turn this clock back. And immunotherapy is the foundation for restoring the elimination phase of this concept. So we began trying to fulfill the hypothesis that I laid out, that many of us had envisioned, whereas there is a baseline immune response against head and neck cancers. And so we took HPVpositive cancers, number one, because they were increasing in frequency, and number two, because it gave us an antigen to track. So we used the oncogene E7 for HPV and looked in a series of head and neck cancer patients that were driven by HPV. And the frequency of HPV-specific T cells was significantly enhanced or expanded compared to HPV-negative tumors or healthy donors, indicating that there is a baseline cellular immune response against head and neck cancers, and in this case, a viral antigen. So this is a great concept. What is the point when we roll this out in the clinic? Well, I think what we were doing for a number of years with targeted agents is taking the effects of chemotherapy or radiotherapy and trying to push this back by adding, in the case of cetuximab, a response rate on top of single-agent radiotherapy, trying to add it to chemotherapy. But what we always saw was that we could push the response rate back, but eventually patients developed recurrent disease and escape. And so in this publication from over 10 years ago, before we had this concept of immune checkpoint receptors and T cell exhaustion, we had a concept of terminal differentiation. This was the phenotype of T cells in the tumor microenvironment, and indeed, these HPV-specific T cells were terminally differentiated, which we now, in 2016, would call exhausted. And we ll discuss a little bit more about that. Immunotherapy was very appealing because it had this concept of memory. We know that the immune system, through vaccines when we re kids, can stick with us for decades. And so the concept was, if one can train the immune system against a malignant cell, 6 Go online to complete the post-test and evaluation for CME credit

7 and neck cancer cell, this would be an HPV, say, E7 antigen driven response. And you turn the signal 1 the T cell receptor on. Signal 2 is a costimulatory signal. It turns out there s about 8,000 signaling events that are required for the T cell receptor to turn on a T cell. When you have a costimulatory signal 2, that number can decrease down to 1,700. And so you get a basically additive beneficial signal from this signal 2 that enhances the T cell receptor. And so it s important to understand, I ve already introduced, head and neck cancer is really two different diseases, both biologically and clinically. You have carcinogen-exposed, highly mutagenic tumors, traditionally associated with tobacco and alcohol exposure, and then you have virus-induced cancers. Of course, before HPV in the Western world, we have nasopharyngeal carcinoma in Southeast Asia that s EBV-driven. So this has been really the dichotomy of head and neck cancer for many years. And then cytokines, in the tumor microenvironment, they shape the phenotype and the function of those T lymphocytes and determine whether they re going to be suppressor cells or activated effector cells to kill the tumor. So we need to have these three signals, and these are the signals that tumor cells harness and use to avoid immune attack. So what s the evidence for immune escape in immunoediting against signal 1? This is the most obvious immune escape, because if you can avoid the key going in the ignition and turning on the engine of the car, you re not going to roll down the hill, you re not going to pull out of the driveway. So downregulation of HLA and the antigen processing machinery by the tumor cells is a very common mechanism of immune escape. And so, from the standpoint of immunity and immunotherapy, are the immune escape mechanisms of immunoediting the same in both of these tumor types, and is the response likely to be similar for HPV-positive versus -negative head and neck cancers? So to discuss a little bit about the signals that turn on a beneficial T cell response, we know that these can be broken down into signal 1, signal 2, and signal 3. The first signal, that has been likened to getting in your car and turning on the gas, starting the engine, is the T cell receptor. You have to have signal 1. You have to turn on the engine. And this is triggered by the HLA peptide complex. In an HPV-positive head Here is some evidence from our laboratory. You can see the staining on the left-hand part of the slide, nice staining for different components of the antigen processing and presentation machinery, which result in the HLA class I complex at the cell surface. If you look in the same patient, on the left, this is the surrounding normal mucosa; on the right, is the tumor cell. And you see downregulation of the antigen-presentation machinery and the HLA class I. The savvy eye will pick up some staining here of HLA class I, but this is the infiltrating fibroblasts. The epithelial cells have downregulated HLA because they re escaping immunity. 7

8 And if you take an HPV-positive head and neck cancer cell and you reintroduce antigen-processing machinery, you can actually restore T cell recognition. So this is a bona fide, although theoretical, escape mechanism. So then we had a publication last year. Neil Hayes and The Cancer Genome Atlas, TCGA, published the mutational landscape of head and neck cancer. And what you can see here in the red box is an area that I helped contribute to this committee, where we looked specifically at mutations in the HLA antigen processing machinery and the interferon pathway and found really a not insignificant frequency of mutations of HLA, antigen presentation, and interferon pathways. So I ve talked about signal 1 being important, and I ve talked about the importance of signal 2 being a costimulatory molecule. Well, tumors have figured out how to use the flip side of that coin. You can create a negative signal 2 or a co-inhibitory signal. And this is where the checkpoint inhibitors come into play. There is a big family of checkpoint inhibitors, as I ll show you in a later schematic, but the simplest one to understand is the programmed death 1, the PD-1 pathway. So, as we know, tumors mutate pathways that are necessary for them to persist. And so this was additional good evidence that baseline immunity against head and neck cancer was important, and I would suggest, in an era of effective immunotherapy, this may be a barrier as we go forward and may explain why some patients do not respond if they ve lost the HLA processing machinery, because then they don t have signal 1. And we can add the checkpoint inhibitors all we want, but we need to evaluate this in patients. Now, PD-1 is a normal activation receptor. When we get infected with influenza, our flu-specific T cells expand, and as they re activated, they express PD-1. And if you keep expressing influenza antigen, PD-1 gets higher and higher. But it turns out, acute viral infections do not repetitively stimulate. We clear the flu. We get better. The antigen goes away, and the PD-1 goes away. But now you can think and realize how cancers are different, because the HPV doesn t go away; the tumor antigen doesn t go away; and the T cells in the microenvironment are repetitively signaled and triggered, and the PD-1 levels go higher and higher and higher because the antigen doesn t go away. It s a repetitive signaling, and that s the essence of T cell exhaustion, is you have excessive co-inhibitory signal 2. 8 Go online to complete the post-test and evaluation for CME credit

9 This is a dampening mechanism that the immune system has, and the tumors now can leverage it and harness it, because they ve figured out how to express the ligand, PD-L1. So PD-L1 on the tumor can then trigger PD-1 on these exhausted T cells in the tumor microenvironment and promote the dysfunction and flip those cells off. Think about the same car analogy. You ve got the engine turned on, the key in the ignition, but you re pushing on the brakes, so the car s not going anywhere. So we need to push on the gas and take the foot off the brakes, and that s the analogy we re going to show you clinical evidence for. So the mechanism of action of anti PD-1 antibodies is to disrupt this PD-1/PD-L1 interaction, to take off the brakes, and to reactivate the cytokines associated with T cell activation and allow proliferation and a lytic activity. And so we began to look not just at a binary HPV-positive and -negative, but quantifying the highest levels of PD-1 level PD-1 expression. And in a series of patients that are HPV-positive and -negative, we could look at the disease-free survival based on the fraction of T cells that were PD-1 high and those patients did poorly, when you had a lot of PD-1 high cells, the must exhausted. And the patients who did very well had the PD-1 low. Those are the activated, competent, functional T cells. And we could quantify this in terms of a relative risk of recurrence. The more PD-1 high cells, you had a linear increase in the risk of recurrence, and the more PD-1 low cells conferred a better prognosis. So I think going forward, we need to understand what PD-1 is doing in head and neck cancer and how anti PD-1 therapies or PD-L1 therapies can reactivate this somewhat complex population of cells in the microenvironment. So in head and neck cancer, is PD-1 expressed on tumor-infiltrating lymphocytes? Here are some data published earlier this year. And you can see, we re quantifying the number of PD-1 positive T cells in the tumor microenvironment. This is looking at peripheral blood lymphocytes and comparing them to tumor-infiltrating lymphocytes from a series of head and neck cancer patients that are either HPV-positive or HPV-negative. And what was interesting to us is that there is an enrichment of PD-1 positive cytolytic T cells in the tumor microenvironment, but they were higher in the HPV-positive patients than the HPVnegative patients. Now, this was curious, because most of you in the room probably know, HPV-positive patients do better than HPV-negative patients. And so we didn t understand how you have more exhaustion receptors on the good-prognosis patients than the poor-prognosis patients. In this report, we also reported the PD-L1 expression. You can see here, about 60% of head and neck cancers that we stained in collaboration with Gordon Freeman over here at Dana-Farber using his antibody, 60% were PD-L1 positive, 40% PD-L1 negative. And this was related to HPV status. The HPV positives were about 70% positive for PD-L1, and about 43% of HPV negatives. 9

10 Understanding Immunity in SCCHN and the Emergence of Checkpoint Blockade (Part 2) Robert L. Ferris, MD, PhD, FACS University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania Again, there s complexity to this, particularly with regard to those patients who have the highest levels of PD-L1, and that s shown here on the left portion of your slide. And we actually were able to link PD-L1 expression to overexpression and EGFR-driven pathways in head and neck cancer. This is consistent with lung cancer, where activated EGFR mutations actually are associated with higher PD- L1 expression. So there is a linkage between oncogenes like EGFR in head and neck cancers and immune escape through PD-L1. Dr. Ferris: So the first positive data from initially a phase 1B study that was expanded into a single-arm so-called B cohort from the KEYNOTE-012 trial [with pembrolizumab] was presented by Tanguy Seiwert at the ASCO This was a very exciting set of data that was presented, and the paper was published just a few months ago in Lancet Oncology. We saw a few very interesting and intriguing results a high frequency of partial and complete responses in a heavily pretreated population. And what we saw was, with follow-up presented at the time, we had this concept of a tail. And this was intriguing, because if you look at the same sort of population treated with cetuximab, response rates were about half in this cohort: about 13%, versus 20% to 25% in this KEYNOTE-012. And you can see that the cetuximab group has some initial responses. The median PFS might be similar, but it goes to zero asymptotically; whereas [in KEYNOTE-012] we have this tail, this very intriguing potential durability that had been hypothesized for immunotherapy. 10 Go online to complete the post-test and evaluation for CME credit

11 A follow-up phase 2 trial, the KEYNOTE-055, was testing pembrolizumab in recurrent/metastatic head and neck cancer. This was presented at ASCO 2016 by Josh Bauml at Penn. You can see here, Dr. Bauml presented patients who were platinum and cetuximab resistant, a large number of patients. And this was flat dosing, going away from weight-based dosing. These patients were followed for safety and oncologic outcome and got 24 months of treatment, assuming they did not progress. The best overall response was 18%, as you can see here, in the first 50 patients and then those with greater than 6 months of followup. So 17% to 18% in terms of overall response rate. This was primarily partial responders in this group. Whether we can have atypical or delayed responses, I think we ll see with further data and longer follow-up. But one could see objective responses in the 17% to 18% rate. Here is the cohort and its characteristics. Median age and demographics similar to what we tend to see. About 70% ECOG 1, 28% performance status of 0. So a relatively robust population, but similar to what we tend to see in this population who has already gotten platinum and cetuximab. And you can see here, by HPV status, 41% [of the overall population] were HPV positive, and the response rate was 22% versus the other 60% that were HPV negative [of the overall population], and the response rate was a bit lower, 16%. So already starting to see a hint that the HPV-positive patients may do better, even though these numbers [are] a bit small. Forty-one percent were HPV positive. I think that is important, because we ll discuss the differences between these two subgroups of head and neck cancers. And you can see the number of prior lines of therapy two and three prior lines of therapy, heavily pretreated group. 11

12 Looking at a biomarker, patients want to understand, am I likely to benefit? Physicians want to know whether this is a worthwhile therapy. Looking at PD-L1 positives, these patients tended to do better, about double what the response rate was for the PD-L1 negatives in this study. This was safe. Fatigue was the highest reported event. Hypothyroidism, what we tend to see is often some symptoms if you query the patient of hyperthyroidism early on, and eventually likely autoimmune attack on the thyroid, leading to future hypothyroidism. So this needs to be monitored. Lower rates of diarrhea, anorexia, nausea, some nonspecific GI symptoms. In general, a very tolerable drug, as you can see here. Grade 3 to 5 events were relatively uncommon, about 12%. One can see here, in the swimmer s plot, the kinetics of response, as shown here in the orange triangles, and one can see the durability of some of these. Over half of the patients had a decrease in target lesions, as one can see here, and those below on this waterfall plot, below the 30% threshold. So many patients benefited, and of course, we look forward to updated data. Now, another study was presented at ASCO Actually, the initial data were presented by Maura Gillison. I was one of the cochairs on this study. Maura presented some initial oncologic data at AACR in April, and I was able to present the follow-up data from the CheckMate 141. This was a randomized phase 3 trial of nivolumab in recurrent/ metastatic head and neck cancer patients who had progressed within 6 months of platinum-containing therapy. That could have been either in the locally advanced setting or in the recurrent/ metastatic setting, and the patients were stratified by prior cetuximab treatment. 12 Go online to complete the post-test and evaluation for CME credit

13 Patients were randomized 2:1 to nivolumab at 3 mg/kg every 2 weeks or investigator s choice single-agent chemotherapy with either methotrexate, docetaxel, or cetuximab. The primary endpoint was overall survival. Here s the overall survival curve. You can see in this Kaplan-Meier plot, the curves begin to separate about month 4, and remain separated. One can see that there s a doubling of 12-month overall survival, 36% versus 16.6%. And again, what we re seeing, which was hinted at from the pembrolizumab data, is this durability, a flattening of the curve and potentially a tail. The hazard ratio of 0.7 reflects a 30% reduction in risk of death in this study. There were select adverse events that we began to quantify related to potentially immune-related issues. Skin was one of them. We have rashes, which are not uncommon, with checkpoint inhibitors. Endocrinopathies, whether this is hypophysitis or direct thyroid attack, and others. Other GI, hepatic, and based on lung data, there was some concern for pneumonitis and pulmonary toxicities this was relatively low. It was a bit higher, 2%, in the nivolumab group versus about 1% in the investigator s choice. There were two patients, one of whom who had pneumonitis and died; the other patient got a pneumonia. So this wasn t any new signal, but clearly we have to monitor these select adverse events. Similarly, the treatment-related adverse events were relatively uncommon compared to the investigator s choice control arm: about 13% grade 3 and 4 adverse events versus 35%. So almost a third lower frequency. Separating by PD-L1 positive or negative, using a threshold of 1% greater or lesser, those with PD-L1 expression greater than 1% had an earlier separation of the curves. You can see the hazard ratio for the whole trial improved from 0.7 down to With PD-L1 negatives, the hazard ratio of 0.89 modestly benefited the nivolumab-treated patients, but you can see the confidence interval quite liberally crosses 1. The curves did appear to separate at month 8 to 9, and perhaps there is a bit of a tail. Longer-term data are certainly warranted 13

14 for us to see what the effect of the PD-L1 negative group is, but clearly the PD-L1 greater than 1% derived greater benefit. an 11% overall response rate. And if one selects PD-L1 positive patients this is from ESMO from 2 years ago, we re looking for additional updated data in the near future but by selecting PD- L1 positives, durvalumab-treated patients had an 18% response rate. PD-L1 negatives, it was really not negligible. This is an 8% response rate, similar to what we saw with pembrolizumab and nivolumab in the PD-L1 negative, or less than 1%, population. So we need to think hard about what is best for the PD-L1 negatives, because they still do derive some benefit. One can see that the disease control rates are portrayed there, and responses appear to go on for quite a while. Now, going by HPV status, using p16 immunohistochemistry as the biomarker, you can see, again, an early separation of the curves. As early as 1 to 2 months, the HPV-positive patients did better. Again, the hazard ratio at 0.56, was very favorable and really, a doubling of the median overall survival. HPV-negative patients still did pretty well. The hazard ratio for the whole trial was 0.70, and so the HPV-negative hazard ratio was 0.73, relatively comparable. And you can see that this curve separates at about 6 months and remains separate. There were six complete responders on this trial. Two of those were PD-L1 negative, so I think we do need to discuss the use of the PD-L1 biomarker and HPV status, and [for] any trial that gets reported in head and neck cancer, we need to understand the frequency, the enrichment for HPV positivity, because that to some degree drives better responses. This portrays the depth and the durability of those responses in a spider plot showing here. You can make out that the top curve in this purple [brown] is the PD-L1 negatives. The blue curves are the PD-L1 positives. And the orange is not tested. But you can see the responses occur in the PD-L1 positives or the PD-L1 negatives, and these persist for quite a while below the RECIST threshold. And you can see the PD-L1 positive and negative over here, responses in both groups. Durvalumab is another agent targeting the ligand; it targets PD- L1 itself. Its previous name was MEDI4736, and durvalumab has 14 Go online to complete the post-test and evaluation for CME credit

15 So we ve talked about targeting the receptor and targeting the ligand from the PD-1 pathway. I ve alluded to another checkpoint inhibitor, CTLA-4. We have still other co-inhibitory signal 2s. These are all inhibitory signal 2s, pushing on the brakes. And you can see all of these targets are now therapeutically being evaluated. We have positive costimulatory signals, a beneficial signal 2 that we liken to pushing on the gas and driving an immune response. And we have antibodies that are agonistic and can trigger a positive signal 2, that s through OX40 or GITR or CD137, CD27, and we can ramp up an immune response. in the recurrent/metastatic setting, and we begin to see agents combining PD-1 with CTLA-4 as compared to monotherapy against PD-L1 or monotherapy against CTLA-4. And then, in the EAGLE trial, which is a population similar to the CheckMate trial, where you could get on this trial progressing within 6 months of cisplatin, either in the locally advanced or in the recurrent/metastatic setting. And these patients are randomized in a 1:1:1 between standard of care chemotherapy at the bottom (investigator s choice chemotherapy), durvalumab anti PD-L1 monotherapy, or targeting anti PD-L1 plus CTLA-4. This is a large trial, about 700 patients, and has stratification based on PD-L1 status, so we can really understand whether the combination of two checkpoint inhibitors benefits the PD-L1 positives or the PD- L1 negatives better. And so immuno-oncology combinations can add two co-inhibitory [signals] say, PD-1 and CTLA-4, those are the most obvious. But it can also add a PD-1 inhibitor with a costimulatory signal 2. And a number of these agents are now being tested in head and neck cancer, and I ll just briefly mention them. I want to describe a little bit of radiation therapy combination in a preclinical model using anti PD-1. Response rates are modest, and so we wanted to see what happens in a mouse model of head and neck cancer that s HPV positive, and we give radiation just to the head and neck where the tumor is, so that we don t give full-body radiation and we allow the immune system to have secondary lymphoid organs that are not radiated. This is in collaboration with Andy Clump, a great radiation oncologist at our center. And we ve taken this cell line, and we knocked out PD-L1. And so if you take this tumor cell line this head and neck cancer model that is a tonsil epithelial cell transfected with HPV and you knock out PD-L1, you can see if you radiate these cells at baseline, they overexpress PD-L1, either based on radiation or treating with interferon gamma. Durvalumab, I gave you the monotherapy data from a couple years ago. This led the company to launch a series of trials they call the raptors, from a number of birds. The HAWK trial is shown here. It was monotherapy with durvalumab. The CONDOR trial was in second-line head and neck cancer after platinum therapy But if you knock out the gene, you can eliminate the PD-L1 expression. And so this allowed us to ask whether radiation therapy rejection of these tumors was PD-L1 dependent. Interestingly, you can see they still upregulate HLA class I, so you can eliminate the co-inhibitory signal 2 while maintaining a good signal 1. 15

16 And this is the curve that I think is most telling. In the PD-L1 knockout tumors, you see a small bump of tumor growth until about day 6, and then the immune system and the radiation rejects these tumors, whereas you continue to grow without that. And what we saw is that you decrease the regulatory T cells here when you knock out PD-L1, and you shift the ratio of cytotoxic, good T cells to the regulatory suppressive cells when you eliminate that signal 2 escape by knocking out PD-L1. So this is a good model to give us an idea for how anti PD-1 therapies could potentially be combined by getting rid of that PD-L1 escape and combining with radiotherapy. So in the last few minutes, I want to just bring back the fact that we have a therapeutic antibody that s been FDA approved targeting EGFR, and the immune effects of cetuximab are intriguing and may make a good partner with a checkpoint inhibitor. EGFR is overexpressed in a large number of head and neck cancers, but cetuximab is only effective in a small fraction of them. So then, as far as dosing and schedule, in studies that we ve done and now reproduced, we looked at concurrent PD-1 antibody plus radiation, sequential PD-1 antibody coming after radiation, or getting anti PD-1 antibody on board first, prior to the radiation, and continuing it in a concurrent fashion. And that initial antibody prior to the PD-L1 upregulation that I just showed you was so deleterious appears to have the best antitumor activity. Cetuximab can trigger downstream immune receptors and, on the natural killer cell, can trigger the NK cells to activate both innate and adaptive immunity, expanding and stimulating T cells. And so we had published this in a couple of papers over the past few years that cetuximab can induce an adaptive immune response. And yet, the response appeared to be dependent on the frequency of suppressive T cells that expressed CTLA Go online to complete the post-test and evaluation for CME credit

17 chemoattraction, to shape them with the right cytokine milieu, to overcome and take off the brakes of these negative checkpoint receptors that are co-inhibitory, and not forget that the tumor has been selected or edited for downregulation in the HLA antigen processing pathway, with the ultimate goal of reactivating that endogenous immune response or inducing a de novo one. And so this is a study that we just completed in collaboration with Julie Bauman, a medical oncologist that I collaborate with frequently. We performed a phase 1B study now moving out of the recurrent/metastatic setting into high-risk or intermediate-risk head and neck cancers in the locally advanced setting, where we enroll patients that are previously untreated, that were HPVpositive smokers or any HPV-negative patient. They received cetuximab-radiation, which, as you know, is an FDAapproved regimen in locally advanced head and neck cancer. And at week 5, the final 3 weeks of the cetuximab-radiation, we added the checkpoint receptor ipilimumab, which targets CTLA-4, and then continued for three more doses after the chemoradiation. We did have to dose-reduce. We started at 3 mg/kg, and we had two patients out of the first six with pretty impressive autoimmune dermatitis, very impressive rashes. So we came down to 1 mg/ kg and accrued the next 12 successfully. This will be presented at ESMO in a couple weeks by Dr. Bauman. So tumor immune escape takes on signals 1, 2 and 3 to evade any of the triggering mechanisms that activate the immune system. The key is to increase the tumor-infiltrating lymphocytes with 17

18 Integrating Checkpoint Inhibition Into Multimodal SCCHN Management: A Practical, Evidence-Based Approach (Part 1) the high-risk postop setting, or with radiation alone to replace chemotherapy or cetuximab in patients who are unfit, for elderly patients. And touch a little bit on radiation alone to replace chemotherapy [or] cetuximab in good-risk patients or other rare cancers in head and neck. Quynh-Thu Le, MD, FACR, FASTRO Stanford University Stanford, California So, moving on to the first-line setting, there are several ongoing phase 3 trials that are testing PD-1, mainly checkpoint therapy or combination, in patients with recurrent/metastatic head and neck cancer. Dr. Ferris: Now it s my pleasure to turn it over to Dr. Quynh Le. You can see all of her titles. In addition to this, she chairs the Head and Neck Committee of the RTOG. In that context, we ve gotten to collaborate a great deal. And she didn t even know as a radiation therapist that she s been an immunotherapist for many years. So, Quynh. So that s the KEYNOTE-048 trial. It randomized patients to standard-of-care chemotherapy, which is the combination of cetuximab, platinum, and 5-FU, compared them to either pembrolizumab with the combination chemotherapy (platinum plus 5-FU) or pembrolizumab alone, given at the fixed dose that you ve seen you heard the data from Bob. This is an 800-pluspatient trial. Dr. Le: Thank you, Bob. That was a fabulous talk. And I m not an immunologist. I ve learned quite a bit from Bob, and I actually dabbled on a molecule in the lab, and it turned out to have an effect on the immune system. So I m learning quite a bit nowadays. But my part of the talk is more clinically oriented, talking about what clinical trials we are developing or [have] under development, moving from the second-line metastatic setting into the first-line metastatic setting, talking about how we can integrate radiation with immunotherapy, especially in the oligometastatic setting. And then talking about the trial developments that are either currently about to be activated or active in patients with locally advanced head and neck cancer, either in definitive setting, in Another trial, going on with the bird theme, is the KESTREL trial. And this is the early first-line setting. And again, comparing the EXTREME regimen that you can see [which used to be] considered the standard of care for the first-line regimen in 18 Go online to complete the post-test and evaluation for CME credit

19 head and neck cancer in the metastatic setting compared to durvalumab, which is the anti PD-1, or a combination of durvalumab and tremelimumab, which is a combination anti PD-1 and CTLA-4. months. Toxicity is pretty mild, and you can see a few grade 3/4 pneumonitis and hepatitis, mainly in hepatitis B carriers. Here s a waterfall plot showing the response, and the spider plot showing durability of the response. CheckMate 714 is a phase 2 randomized study comparing patients who either relapsed from the locoregionally advanced setting or [had] first-line metastatic disease. And the comparison is singleagent nivolumab versus nivolumab and ipilimumab, which is a PD-1/CTLA-4 combination. So that has triggered some randomized studies. I know the one that s currently active and accruing patients right now is the KEYNOTE-122, and that s a phase 3 randomized study comparing pembrolizumab versus standard of care investigator choice of either docetaxel, gemcitabine, or capecitabine. These are active second-line agents in NPC. And it s a phase 3 study comparing progression-free and overall survival as the primary endpoint. One other head and neck cancer that Bob hasn t touched on, but it s presumably very active, is nasopharynx cancer, because it s a virally driven cancer So there s a bunch of early, second-line studies that have been completed in Asia. This is a collaboration between North America and Hong Kong, and this is, I think, a Taiwanese study, where patients in the second-line setting were treated with single-agent nivolumab or pembrolizumab. And, as you can see, the overall response rates are very similar, so I m just going to show data from one trial, with overall response rates about 26%, which is very similar to what you ve heard before for HPV-positive tumors. The median duration of response is 10.8 So the question is, how can we bring radiation in earlier in these metastatic patients? This is a study that was presented at ASCO by the Gomez group. It s a first-line randomized study [looking at] the role of radiation in patients with oligometastases. So these are lung cancer patients with three or less metastases after front-line systemic therapy. So they actually started with front-line systemic therapy. They have to have stable disease. 19

20 And they were randomized to continue on chemotherapy by physician s choice versus local therapy. And the local therapy can either be surgery or radiation, but all the patients ended up getting radiation but one patient; only one received surgery. And then this is allowing for crossover. If the patient progressed, they can go onto local therapy, or they can continue with chemotherapy. We also know that radiation synergizes with the anti PD-L1 blockade in this preclinical study. So here, as you can see, this is data from Chicago. So the primary endpoint of this trial was progression-free survival. The trial was actually terminated early after an interim analysis showed an impressive result when adding local therapy to these patients. Twenty-four patients in each group, the median progression-free survival shifted from 4 months up to 12 months. As you can see here, overall median survival has not been reached. And exploratory analysis, interestingly enough, showed that local therapy increased time to progression to a new site, not the local site you treated, but also a new site, as well. So there are data suggesting that local therapy does matter in prevention of progression of microscopic disease. When you take that radiation and you combine it together with blocking the PD-1/PD-L1 pathway, you can see synergism in the irradiated tumor, but you also see synergism in the unirradiated contralateral flank tumor. That s what we call the abscopal effect. And it appears to be mediated by CD8 T cells, because if you deplete the T cells from the mice, you lose that effect, and the tumors start growing again. And the main mechanism, they think, is, as you know, radiation can induce a number of suppressive T cells, including T-regulatory cells, and also the MDSC, which is the suppressive macrophages, myeloid-derived cells. And so you can see that when you add PD- L1 blockade with radiation, you do decrease the MDSC number in this preclinical study. So because of that, there s very strong interest in trying to incorporate radiation into the systemic treatment. So there are trials looking at adding radiation to immune checkpoint therapy, mainly the PD-1 pathway. This trial here including head and neck cancer, but also allowed for non-small cell [lung cancer] and renal cell carcinoma, is testing the different 20 Go online to complete the post-test and evaluation for CME credit

21 fractionations of radiation. So pembrolizumab is combined with either 8 Gy versus 20 Gy of radiation. A trial is ongoing that has been activated this year at Memorial Sloan-Kettering Cancer Center by Dr. Nancy Lee using nivolumab plus/minus radiation, so that s the randomization. It s 27 Gy in three fractions, the fractionation that Silvia Formenti uses. And they treat only to one lesion, and the question is, [what is the] abscopal effect on these patients? Hopefully, this trial will allow us to be able to test a randomized study comparing incorporation with radiation once we know what is the main for the control arm, which is what systemic agent? Is it a single-agent PD-1 path blockade, or is it a combination in this patient population? What do we know when radiation is treated to head and neck cancer? We know when the radiation is delivered to head and neck cancer, we see an increased CD8 level in the blood, but at the same time we see increased deregulatory cells and MDSC cells. And these are data that just came out from the Harvard group, and the T cells are upregulated. They tend to be exhausted. They have a positive for Tim3, PD-1, or a combination of Tim3/PD-1. So it makes sense to bring in something such as an immune checkpoint therapy to combine with radiation. So we know that it synergizes with large-fraction radiation. That s what a lot of people looked at. The question is, does it synergize with fractionated radiation? And, you know, there s a controversy out there. So I think you ve seen Bob s data, which is 4 Gy per fraction times 5 fractions. Here s the data from the UK group. They used 2 Gy per fraction for 5 fractions, so this is kind of similar to the fractionation that we use in the clinic. And you can see that it actually synergizes the radiation synergizes with either anti PD-1 or anti PD-L1 antibody in terms of improving survival in mice. So that led to many proposed phase 3 randomized studies that I will mention. One of them is the one that s chaired by Dr. Ferris, sitting here, through RTOG Foundation. This is a phase 3 randomized study comparing chemoradiation plus/minus nivolumab in patients with intermediate- and high-risk locally advanced head and neck squamous cell carcinoma. 21

22 But before we move into a very large phase 3 study, we actually have to get a signal on toxicity of the patients, so I m going to show you the schema of the phase 1 lead-in. I think some of you were in my talk this morning about what the best chemotherapy regimen is for patients with locally advanced head and neck cancer, and there s a lot of controversy out there. And so one of the things we think that we can contribute to the literature and to the community is to actually lead several phase 1 studies to see what toxicity we see when you add immune checkpoint therapy into different combinations of chemoradiation in head and neck cancer. In addition, there are two other randomized studies that are either activated or about to be activated using chemoradiation backbone, and that s with avelumab, which is now called the Javelin Head & Neck 100, a PD-1 inhibitor, and pembrolizumab, which is another PD-1 inhibitor, and possibly more. So it s a very active field right now, and it s a very crowded field, as you can see. That s for the definitive setting, chemoradiation setting. So this is a complicated phase 1 schema, but I think we ll learn a lot, and then we ll contribute a lot to the community. Patients will be randomized to either chemoradiation with weekly cisplatin as a backbone with nivolumab, or chemoradiation with highdose cisplatin as a backbone with nivolumab, or cetuximab and radiation with nivolumab. We also have a separate arm, a fourth arm study, which is patients who are elderly that cannot get chemoradiation or are cisplatinunfit. They will get radiation plus nivolumab and [we ll] get some toxicity data out of that. After that phase 1 trial, we will move forward into a phase 3 trial comparing chemoradiation with nivolumab, and that s RTOG 3504 Foundation. In the postop setting, these are patients at high risk, patients with extracapsular extension, patients with a positive margin. We know that when we add chemotherapy to them, we still have about 40% risk of failure and death in these patients. So the question is, can we do anything better? And so this is that phase 1 NRG oncology study that will be activated hopefully next month. But patients will get combined chemoradiation with cisplatin with pembrolizumab adding onto the backbone of that. The first dose will be given before, and then will continue during the treatment and after. 22 Go online to complete the post-test and evaluation for CME credit

23 a randomized study with radiation plus pembrolizumab versus radiation-cetuximab in cisplatin-unfit patients. And NRG Oncology is proposing a similar study, but using durvalumab, which is an anti PD-L1, versus RT and cetuximab in this patient population. This is Julie Bauman s study, and it s an interesting way to de-escalate if need be. We hope that we won t have to deescalate, but if we have to de-escalate, we will not decrease the dose intensity. What we do is we minimize the overlapping of pembrolizumab with the combined chemoradiation. We have less overlap or no overlap at all. And hopefully some of you who have NRG Oncology membership will activate this trial. Other clinical trials have been in planning stage or have been proposed. So either single or combination immunotherapy with radiation in good prognosis. The question is, can we replace chemotherapy? I think a well-known theme in head and neck is everybody hates cisplatin, and the question is, what can we do to improve that? So chemoradiation with checkpoint inhibitor for anaplastic thyroid cancer there s a strong activity in that. And also Merkel cell carcinoma, as you know, is very highly active in patients with metastatic disease, with over 40% response rate. And so there s an interest in moving it into an earlier setting. So there s another group of patients out there that we don t know what do with. And these are the patients [who are] cisplatin-unfit. And if you look at the LORHAN [Longitudinal Oncology Registry of Head and Neck Carcinoma] database and we actually asked the membership what people do with them, and we get all sorts of answers. But these are patients treated off study, and with the elderly population growing more, that cannot have cisplatin, this is a growing population in the head and neck cancer community. So there is very strong interest to see how we can move this nontoxic type of systemic therapy into [treatment] with radiation. So there, here are the trials that are either active or about to be activated. So there s a phase 2 study, that I think was just activated now at UNC, looking at pembrolizumab and radiation for cisplatin-unfit and elderly patients. The GORTEC just started 23

24 Integrating Checkpoint Inhibition Into Multimodal SCCHN Management: A Practical, Evidence-Based Approach (Part 2) Quynh-Thu Le, MD, FACR, FASTRO Stanford University Stanford, California The less common immune-mediated toxicities, you may see some hematologic changes. You ve heard a little bit earlier on about cardiovascular toxicity. There is potential PD-1 activation and cardiovascular event. Rare ocular toxicity, and rare renal toxicity. Dr. Le: So when we bring these treatments with combined chemoradiation, we re going to have to learn how to manage the side effects in these patients that we treat. When you talk about immunotherapy, the immunotherapy is present throughout the body, so any organ system can be impacted any time throughout the treatment. Dermatologic, GI, hepatic, endocrine, and other inflammatory events can occur in patients, and it tends to be the more common ones, so the ones that are highlighted here, which are endocrine dysfunction, either pituitary or thyroid or adrenal; GI toxicity; skin reaction; pneumonitis; hepatitis; pancreatitis; rare motor and sensory neuropathy; and arthritis. So if you look at the treatment-selected adverse events I m just highlighting what Bob has shown before the data are pretty consistent. If you take the PD-1 antibody, be it nivolumab or pembrolizumab, you will see about 8% endocrine toxicity [or] hypothyroidism. 24 Go online to complete the post-test and evaluation for CME credit

25 And you will see about 6% GI toxicity, be it diarrhea or you classify as GI, and about 2% pulmonary toxicity. So this is kind of interesting, when I see that the trials [have] different populations, different agents, but you see a very similar rate of toxicity. So grade 1, you do supportive care and continue treatment. Grade 2, you withhold treatment, re-dose if resolved to grade less than 1, or you consider low-dose corticosteroids if symptoms do not resolve in 1 week, and usually it s oral. When you go grade 3 or 4, you discontinue the treatment, you use high-dose corticosteroids, usually IV. Rarely, you have to bring in immunosuppressive therapies, such as infliximab, for these patients. So how do you manage these? This is often a diagnosis of exclusions. Other causes could be ruled out, but immunotherapyrelated toxicity should always be included in the differential. Early recognition is the key, because you can avoid it or you can reverse it. So patient education and physician education is the key. Management usually requires corticosteroids and rarely immunosuppressive treatment if it s a very high-grade toxicity, and discontinuation of therapy. If appropriate, immunosuppressive treatment is used. Patients generally recover from these AEs, so that s why early recognition is important. And what s interesting is that, you know, we try to avoid corticosteroid use in these patients, but there are data retrospective data, as well as retrospective data of the randomized trial in melanoma suggesting that if you even use a corticosteroid, it does not appear to impact the response to the checkpoint blockade. So I just want to touch on a couple things that may overlap with radiation and chemotoxicity, so others can be aware. One of them is skin toxicity rash. This is a type of rash you ll see; you ll see with CTLA-4 and you ll see with PD-1. It s over the face, it s over the back, and it s over the trunk. The severe skin adverse reaction is rare. If it s grade 1 and 2, which is defined as less than 30% of body surface area, use antihistamine and topical steroid. You consider a derm referral or oral steroid if it persists, and biopsy the rash. If grade 3 and 4, which is more than 30% body surface area, then you get a dermatology consult right away. You start on IV steroid, and switch over to oral. You do a long taper. You educate the patient. 25

26 And then, we know that from Bob s study with CTLA-4 with ipilimumab, you actually can increase skin toxicity of chemoradiation, or at least from their phase 1 data, they have to dose de-escalate. It s unclear whether PD-1 blockade will enhance in-field reaction, and we re waiting for data from our phase 1 study, as well as other phase 1 studies coming in, to take a look that. Other potential toxicities that may appear, especially when you do SBRT for patients with metastases these can occur anywhere, around the bone, the lung, or the GI are the pulmonary, GI, and hepatic toxicity. If you look at risk of pneumonitis for all grades, it s double, higher in lung cancer, 4%, compared to 2% for melanoma, and it s more common when you do combination immunotherapy than monotherapy. Endocrinopathy: in head and neck cancer, about 8% of any grade. And the problem is we irradiate a bunch of endocrine organs in head and neck cancer, including the pituitary and the thyroid. Radiation alone can cause hypothyroidism in 20% to 60% of the patients. It s not clear if SBRT for metastatic disease to these sites will increase the toxicity, and we need randomized trials to hopefully address these issues. So far, the retrospective studies have suggested it has not been. And the factors associated with hypothyroidism [risk] related to the radiation include the gland volume the smaller glands tend to be more likely to have side effects; the mean dose of a thyroid; the volume received, more than 30 Gy, or the inverse of the volume spare. It s unclear if you add the two of them together whether you re going to have additive or super-additive effect on thyroid function. So it needs to be studied prospectively, and we actually will have to identify that as part of our phase 1 and look at dose volume and be more careful in the thyroid constraint. So there are many unanswered questions today with checkpoint inhibitors in combination with radiation or radiation and chemotherapy. These are listed here. I m not going to address all of them. I think Bob has been touching on patient selection with biomarkers. When and how is concurrent better than adjuvant? You see preclinical studies; I ll show some more preclinical studies. Radiation dose. For fractionation, what is the optimal dose and fractionation? And will prophylactic nodal radiation which we 26 Go online to complete the post-test and evaluation for CME credit

27 do quite a bit in head and neck cancer mitigate the benefit of radiation therapy? So here, if you look at the preclinical data this is from the UK group. So they dosed 2 Gy per fraction for 5 fractions. They gave anti PD-L1 antibody either at the beginning of the 5 fractions, at the end of the 5 fractions, or adjuvantly after 5 fractions. They show that if you give it concomitantly at the beginning, you get better outcome than if you give it at the end or you give it adjuvantly. And this is very consistent with Bob s data. What about in humans? Do we have any data in humans? The only glean that I can get from data in humans is in these patients with melanoma brain metastases. It s a group at Yale that published. So they take a bunch of patients who will get immune checkpoint therapy, either PD-1 or CTLA-4, and these patients get stereotactic radiosurgery. And they define concurrent as within the week of either before or after stereotactic radiosurgery. And nonconcurrent is any window outside of that. And they showed that if you give it concurrently, you get better response to the brain tumor. This is not survival. This is response, tumor shrinkage. The PD-1 appeared to get more tumor shrinkage than CTLA-4. And survival, the concurrent seem to do better on the survival. So at least the human and the mouse data suggest that concurrent treatment may make sense. However, it s dependent on the agent. So if you look at CTLA-4, just like PD-1, it makes it better if you give it before the radiation. This is day minus 7. But if you look at an activator, like an OX40, the preclinical data suggests it may be better if you give it after radiation. So again, it s very agent dependent. But we re going to have a study that hopefully addresses some of that. This is a randomized study that s activated at Pittsburgh, where people with locally advanced cancer get IMRT with weekly cisplatin, and they re randomized to either adjuvant pembrolizumab versus concurrent pembrolizumab. And hopefully that s going to give us some information on efficacy, a glean on efficacy data. 27

28 What about dose and fractionation? This is a nice meta-analysis, actually, in all the preclinical studies that have been published with radiation. And you can see, it ranges anywhere between 2 Gy per fraction at 5 fractions to multiple 20 Gy in single fraction. And the administration of the immunomodulation antibody, either concomitant [or] postradiation, and all the different types of tumor models that were used. So here, if you look at abscopal response in patients with immunotherapy, metastatic melanoma, fraction size less than 3 Gy [and] fraction size greater than 3 Gy, and you can see similar waterfall plots between the two fractionations. Here are data that came out from Silvia Formenti in Lancet Oncology looking at GM-CSF as an immunomodulator, and she used 35 Gy in 10 fractions, so a fraction size of 3.5 Gy, and she still does see abscopal effect with that. So it s unclear to me whether you actually have to use huge, large doses fraction in order to get abscopal effect. I think the most exciting study is the one by Silvia Formenti. As you can see, they give 20 Gy in one fraction versus 8 Gy times 3 versus 6 Gy times 5. And they looked at the response with the primary tumor, and you can see that the response of the primary tumor seemed to be a little bit better with the fractionated approach. And the response of the abscopal tumor effect tended to be more with the fractionated approach, and that s why a lot of people use 8 Gy times 3 or 9 Gy times 3 in the SBRT type of approach. If you looked at abscopal response you know, there s a dogma out there. One camp says you need a really large fraction to get abscopal effect. The other camp says you may not. So I just want to see whether we have abscopal effect when just fraction size is smaller. So the last thing I just want to touch on is, what about the lymph node, treating the lymph node? You know, you use immunotherapy. You prime the tumor, you prime the lymph node, and if we wipe out the lymph node, we cannot wipe out the effect of immunotherapy. And so in radiation treatment, I think we do need the lymph node. This is a preclinical model. It s a beautiful paper, actually, not very well cited. It came from the Japanese group, where they irradiate the lung cancer, but they have either surgically removed the draining lymph node for this tumor, or they use genetic deficient mice that knocked out the draining lymph node. 28 Go online to complete the post-test and evaluation for CME credit

29 If you give the radiation with the draining lymph node intact, you actually have more response. But if you remove the draining lymph node, you actually have less response. And the same thing with the mouse that removed draining lymph node. I m not sure if any of you folks were in the immunotherapy session today. There s a study where they actually randomized the mice to either 12 Gy to the tumor alone versus 12 Gy to the tumor plus draining lymph node. And the question is, do you have a different effect on the tumor growth, and also a T cell effect? survival and overall survival is excellent in this group of patients with a median of 3 years follow-up, and in HPV-positive patients, you re still in the order of 90% progression-free and overall survival. So the question is, can we do something like this with some sort of immunotherapy? And that s something that, you know, people are starting to think about as well. They see that there s probably less effect on T cells when you irradiate all the lymph nodes. But the PD-1, they have not seen a differential effect on the tumor response. So either treat the tumor or the draining lymph node. They see a similar response. For the CTLA-4, they actually see a differential effect where, if you irradiate the tumor, you have more response than if you irradiate the tumor and the draining lymph node. We hope to get a little bit better data when this is published, and we also have asked them to do more a more fractionated approach, which we do in the standard treatment, because 12 Gy to the whole big lymph node is not what we normally use. So, in conclusion, immune checkpoint therapy, specifically, PD-1 pathway blockade, improves survival in patients with metastatic second-line head and neck squamous cell carcinoma. And I think it s being tested in the earlier setting. As you can see, it s an exciting time for us as radiation oncologists. But several questions remain. Does adding immunotherapy to chemoradiation improve survival in patients with nonmetastatic disease? Can immunotherapy replace chemotherapy in certain settings? Are there unanticipated toxicities when combined with chemoradiation? And what is really the optimal dose, fractionation, and field size in these patients? So can we cut down further? And I think this is just intriguing data. I m not advocating this, but I want you folks to hear about this, because there is a camp out there pushing, and their possibility is because our toxicity is not just from the dose of the radiation, but the volume of the radiation that we treat these patients. And we hope we can answer that and I hope that this session will get you excited enough to start enrolling patients in trials. And being the Head and Neck Committee Chair of NRG Oncology, I hope that you will be participating for an NRG trial. And that s it. So the Chicago group did this nice study where they actually did response-adapted volume de-escalation. This is not with immunotherapy, but they used induction chemotherapy with cisplatin, paclitaxel, and cetuximab. For two cycles, those who have a good response, they just treat the tumor plus a 2-cm margin. Those who have less than a partial response, they treat the tumor plus the draining lymph node. And if you can see here, the outcome in terms of progression-free 29

30 Audience Q&A Session Robert L. Ferris, MD, PhD, FACS University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania Quynh-Thu Le, MD, FACR, FASTRO Stanford University Stanford, California that gives a suggestion [that] if you develop it, you might do better, and we might want to push them to continue this toxicity profile, even if they needed to end up in the hospital with the appropriate medical care, in order to achieve better complete responses? Dr. Ferris: So, great question, Steve. Steve himself was doing immunotherapy before it was cool, with Steve Rosenberg at the NCI. So I don t know if you wanted to be a surgeon, a radiation oncologist, or both. But he s immunotherapist first. So I want to address that question, because we often get asked, when you have an adverse event and many of you out there were thinking, when Dr. Le mentioned to give steroids when you have an adverse event that s immune-related, aren t you just kind of cutting off your nose to spite your face? Aren t you taking away the benefit? So the data would suggest that when you use steroids to manage an adverse event, that you don t eliminate the benefit of immunotherapy. So coming back to Steve s question, once you generate that immune response, which in some manifestations is an adverse event, inducing an antiself or autoimmune effect that affects both the tumor and the skin or your thyroid gland, it appears that that triggering of the immune response is durable, and even coming with steroids to dampen the adverse event does not appear to remove the response and the benefit of immunotherapy. Dr. Ferris: Thanks, Quynh. Outstanding talk. We have a question here from microphone number one. Steve Finkelstein: Thanks. Steve Finkelstein, NRG Immunotherapy and Immunomodulatory Co-Chair. So I want to say thank you to both of you, because, you know, I ve had the pleasure of meeting and knowing Bob for about two decades, when he used to be the International Society of Biological Therapy. And I can remember back then, if I could imagine that we d be sitting in a room like this, which is packed, to study the combination of immune phenomena in general, and now with radiation, it s really mind-boggling how much we ve advanced. With the toxicities that we develop when we create immunotherapies for cancer in the old days, when we gave IL-2, we used to put one out of three patients in the intensive care unit. We had to line them, Swan them. And there was a suggestion that maybe if you had immune phenomenon toxicities that people would do better. With the findings that you re finding, is there any specific toxicity It does appear, through some anecdotal data that are still emerging, and I think, not yet convincing, but the hint is that if you develop an autoimmune adverse event that you tend to do better, not worse, and that is somewhat consistent with the fact that the host, the patient, was immune responsive. This comes back to this concept of having inflamed tumors and having the capacity to respond to immunotherapy. So that would be my best answer, Steve, to a very good question, which is not only do you not necessarily have to re-treat, or not re-treat going backwards but treat again, which is that once you ve triggered an immune response, all of the good effect may be baked in, and you don t necessarily have to continue treatment with an adverse event. There are data from Jim Allison, who is really one of the fathers of checkpoint inhibitor blockade, that one of the first patients who got anti-ctla4, got a single dose, the tumor went away, and is disease-free 15 years later. So it may be just taking off those brakes sufficiently. Dr. Le: I can add Dr. Ferris: Please. Dr. Le: a follow-up on that, though I think would be kind of 30 Go online to complete the post-test and evaluation for CME credit

31 intriguing to see you know, how [with] cetuximab, we had a rash, people tend to do better? Right? So the question is, if you look at these studies, and if they have certain immune-related events, can we you know, in a value situation, can we stop the treatment, and do they do better, and do we have to continue for longer? Dr. Ferris: It s ASTRO, so we ve been talking about sequencing and regimens with radiotherapy. But the elephant in the room is even monotherapy, for which we showed you nice data, how long does that treatment need to go? You know, at present, we feel uncomfortable, when the patient does well, removing the therapy. But as I just alluded to, it s possible that the benefit has already been induced. And so without studies, I think everybody s uncomfortable removing the therapy. That was what most of us thought until ASCO 2016, where in lung, we saw that the PD-L1 positives appeared to benefit from the combination. Is head and neck cancer more like lung than melanoma? That gives you a sense of where we might be going. But I would say at present, although it s an outstanding question, we don t yet know if the combos will benefit the PD-L1 positives or negatives better. I m going to select a couple of these, because I think they re very good questions that probably a lot of people are asking about. Dr. Ferris: Another question is asking about, given the regression patterns of successfully treated immune checkpoint blockade, and assuming the RECIST criteria don t fit, is there a need for a unique set of criteria for this class of therapy? So, many of you know Jedd Wolchok and others had an immune response RECIST for this concept of atypical or delayed responses, or we bandy about the word pseudo-progression, where the tumor may grow before it responds and shrinks. Dr. Ferris: In which head and neck cancer patients do we think PD-1/PD-L1 combinations may provide the most benefit? My first answer is that HPV positives just appear to do better with any type of treatment we ve ever thrown at them, whether that s radiotherapy, surgery, [or] chemoradiation, and immunotherapy appears to be the same. So my guess is, combo treatment will do better for HPV-positive patients than -negative, just because of everything we ve seen. Now, in terms of a biomarker that s a biological, like PD-L1, we have conflicting data. So in melanoma, the combination of ipilimumab with nivolumab seems to be best, or most rational, in the PD-L1 negatives. The PD-L1 positives appear to be driven by the PD-1 pathway, so you didn t really see a detectable benefit by adding CTLA-4 targeting when they were PD-L1 positive. It seemed like you found the signal 2 escape mechanism it was the PD-1 pathway and blocking that was sufficient. You didn t get a benefit from the combo. I have to say that the data in head and neck cancer for pseudoprogression or unconventional responses that might rise to the level where we really need to implement a widespread unique RECIST or immune response RECIST is relatively uncommon. The fact of the matter is most patients who respond do so within the traditional kinetics and timeframe. The data out there are somewhat flawed, because the trials that have so far been reported haven t usually allowed treatment beyond progression, so then you re stuck with whether the treatment up until progression at the point that it s stopped led to a delayed tumor shrinkage. There may be data with treatment beyond progression down the road, but at present it seems that the specialized immune response criteria, at least in head and neck cancer, are not very much additive over the traditional RECIST without the immune response criteria. The immune response criteria permit scarring of nontarget lesions as well as target lesions. [They] permit a scan 1 month after to look for that shrinkage after tumor growth. So I recommend that paper in Clinical Cancer Research. Jedd Wolchok s the first author. [Wolchok JD et al. Clin Cancer Res. 2009;15: