New Horizons in Unresectable Stage III NSCLC: A Case-based Exploration of Evolving Data and the Emergence of Immunotherapy

Join our Expert Faculty, Drs. Joel W. Neal, MD, PhD and Victoria Sherry, DNP, CRNP, AOCNP as they discuss treatment principles across the continuum of care in unresectable, stage III NSCLC. During their presentations and discussion, they will examine the established treatment landscape for unresectable, stage III NSCLC as well as the emerging role of immunotherapy, and practical clinical considerations for anticipating, mitigating, and managing immune-related adverse events.

Presented by Creative Educational Concepts, LLC.
Supported through an independent educational grant from AstraZeneca.

Transcript

 | [Dr. Joel Neal] Hello, everybody out there! Welcome to our program today, and thanks for joining us virtually for “New Horizons in Unresectable Stage III Non–small Cell Lung Cancer: A Case-based Exploration of Evolving Data and the Emergence of Immunotherapy.” This is brought to you by CEConcepts and it's part of the Engage the Experts series, supported by an [independent] educational grant [from AstraZeneca]. I’m Joel Neil from Stanford University. I'm an associate professor of medicine in the division of oncology, a medical thoracic oncologist, running cancer clinical trials, also doing some informatics, and I’m joined today by Vicki Sherry. Vicki would you like to introduce yourself? [Dr. Vicki Sherry] Thanks. Dr. Neil. My name is Vicki Sherri. I have a dual appointment as an oncology nurse practitioner at the Abramson Cancer Center at the hospital at the University of Pennsylvania, where I specialize in the thoracic malignancies. I’m also on the faculty at the University of Pennsylvania School of Nursing where I teach undergraduate and graduate nurses. [Dr. Joel Neal] Thank you, Vicki. So today in our program we'll be going through some of the background in early-stage and locally-advanced non–small cell lung cancer. Then we'll talk about side effects, led by Vicki, and then we'll have some time, hopefully, at the end for questions.
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 | The learning objectives today are to look at the prevalence and pathophysiology of stage three-lung cancer, identify clinical features worthwhile in decision making for immune-oncology, and chemoradiation therapy. We'll think about the approved therapeutics and the landscape. We'll look at ongoing and planned clinical trials in this. We'll look at immune-related adverse events, and hopefully, this will educate everybody in to optimize the treatment of stage three and earlier stage non– small cell lung cancer—an increasingly complicated, yet exciting, part of lung cancer to treat. So with that in mind, we'll go into the background and all of the data we have for treating stage three with the exciting new realm of immunotherapies. So the incidence of lung cancer in general, clearly, there is a relationship to smoking in the tobacco belt that you can see in the darker blue region in the middle of the country—but there still is non–small cell lung cancer everywhere in the United States. When we look at overall incidence, it continues to rise—on an age adjusted basis, it's actually going down, with smoking, going down—but on a per capita on basis, it's going up still because of the aging population. The more people age and don't have comorbidities, such as cardiovascular disease, the higher the risk of lung cancer, both smoking- and non–smoking-related. When we look at the prognosis of lung cancer, this is from the AJCC 8th edition staging criteria article by Peter Goldstraw, and shows us that this new breakdown of IA1, IA2, IA3 very small tumors—less than a centimeter, 1–2 centimeters, and 2–3 centimeters—have a very high 24- and 60-month overall survival, reaching even over 90 percent. There are some very small ground-glass tumors that probably even are close to a 99 percent disease- specific 5 years survival.
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 | On the other hand, when we look at these international data, the median survival for stage IVB non–small cell lung cancer, was still around 6 months back in 2016. Now these are international data—we hope that we're doing better locally, but still there's a lot of work to be done. Lung cancer used to be divided into a couple of major groups over the last 100 years—from pathologists telling us there was small cell lung cancer with small cells, and everything else non– small cell lung cancer. Non–small cell lung cancer was divided into adenocarcinoma, squamous, and large cell, which can sometimes be neuroendocrine, and halfway in between small cell and non-small cell. But until about 15 years ago, all of these were more or less treated the same—with platinum-based chemotherapy once platinums were developed, and then after that usually supportive care. Now we know that there's many more effective treatments, so the development of targeted therapies, particularly for adenocarcinoma among patients who haven't smoked, as well as specific chemotherapies that seem more effective in adenocarcinoma, such as pemetrexed and the use of anti-angiogenics like bevacizumab. And then, of course, the development of immunotherapy that can work in non–small cell lung cancer, and also has a role in small cell. So the treatment modalities of earlier stage non-
 metastatic non-small cell lung cancer, we think
 about as surgery, take it out if it's localized;
 radiation, trying to encompass everything in a
 radiation field; and systemic therapy, which
 historically was just platinum-based chemotherapy
 followed by other single-agent chemotherapies.
 More recently, is targeted therapy for particular
 patients—and now we have actually 10 different
 molecular driver oncogenes with FDA-approved
 targeted therapies, the most recent one being a
 trastuzumab deruxtecan a couple of days ago for
 HER2-mutant non–small cell lung cancer. That's the
 tenth. As well as immunotherapy, which can work
 for many patients and is more likely to work with high PD-L1 expression. So to figure out which of these is most appropriate, at least in terms of the systemic therapies, we think about disease stage performance, status, histology, the tumor genetics, and PD-L1 expression, which isn't found in next-generation sequencing and has to be done based on immunohistochemistry tests. So what about surgical considerations? Our surgeons will tell us, at our tumor boards, and I agree with them, that any patient that's potentially eligible for surgical resection should be determined by the surgeon, right? A medical oncologist generally shouldn't say if you’re eligible for surgery or not, and the patient should hear about the options of surgery before deciding on radiation, chemoradiation, or just therapy for metastatic disease. If it seems like the disease is not metastatic, then our multidisciplinary tumor board is very effective in having these discussions.
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 | So some of the considerations for surgery. A mass that is not invading into the mediastinum or major vessels, ideally localized to a lobe and not requiring a pneumonectomy in order to remove all of the tumor, because pneumonectomies have particularly more morbidity and mortality associated with them. Larger tumors may be less resectable, the tumor location, and then, of course, the lymph node involvement. So is it single station, are there any left nodes involved? If no, surgery is a great option. N1 lymph nodes in the hilar space, surgery still will oftentimes get those out with a lobectomy procedure. And then N2 lymph nodes, ipsilateral, if there's only one station of N2, surgery is on the table. If there's multi- station N2, then [surgery is] less feasible, because there could be other nodal stations and even contralateral ones. And then bulky lymph nodes and N2 stations of 4 cm or greater, is a relative contraindication. So for a full surgical workup, patients need the usual staging, including brain MRI for anything over a centimeter or two, history and physical pulmonary function tests, and ultimately to see a surgeon, or at least have them hear the story. For non–small cell one cancer, these small tumors
 that are node negative are often surgical resectable—
 N1 tumors, or occasionally, N2 tumors with relatively
 small tumors in the primary area. On the other hand,
 stage IIIB and IIIC, T4N3 disease, is not generally
 surgically resectable just because of the high chance
 of nodal involvement and lymph nodes and other
 tumor being still residual after the surgery. So
 surgeons can access the N2 nodes on the same side of the chest relatively easily during a lobectomy but contralateral nodal disease is less feasible to address during surgery. And then, of course, metastatic disease, we would save surgery and radiotherapy mainly for palliative approaches. So our first patient case, a 43-year-old woman, no past medical history of smoking presents with this 4 to 4 1⁄2 cm tumor, core needle biopsy had no carcinoma, EBUS showed ipsilateral in two nodes, diagnosed with stage III disease. And what do we do? In stage III disease, we do recommend neoadjuvant chemotherapy before going to surgery. It wouldn't be inappropriate to refer the patient to a thoracic surgeon, but the question would be: can I give chemotherapy first before you do surgery, or should we just think about chemoradiation for this patient?
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 | So here's another way of looking at the same thing. Now there have been a development of a number of other adjuvant therapies beyond just platinum- based chemotherapy, usually cisplatin-based chemotherapy in the adjuvant setting. So first we have the ADAURA study, with adjuvant osimertinib for 3 years after surgical resection for EGFR exon 19 or L858R EGFR-mutant lung cancer. This does include 1B because the trial had 3–4 centimeter tumors included under the old IB categories, and then for IIA all the way through stage III, adjuvant osimertinib is also approved. More recently we have the approval of adjuvant immunotherapy for stage II and III non–small cell lung cancer adjuvant atezolizumab following platinum-based chemotherapy specifically for PD-L1 greater than 1% and that's also an approval in stage III. We can also for stage IIIa and IIIB consider chemoradiation, and chemoradiation always has consolidative immunotherapy with durvalumab afterward. That's been an approval for the last 4 years or so. So stage III, non–small cell lung cancer. It's around a third of lung cancer. The goal is cure, and I think it's important to point that out to patients. It's heterogeneous disease, so every patient is unique, and I think the personalized treatment approaches should be considered. Surgical resectability can only be determined by a surgeon. Sometimes we know as medical oncologists, when patients clearly are not surgical candidates, but the patients that were borderline should be evaluated, and chemoradiation is always appropriate as a backup For stage III, though, that's getting the surgery, these patients should get neoadjuvant therapy, and we'll talk about some of the data. So when we think first neoadjuvant and then adjuvant treatment of stage III non–small cell lung cancer, the terms me neoadjuvant and adjuvant suggest the patient is going to get surgery or has already gotten surgery. That's how we use those terms.
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 | So we had some exciting data out earlier this year with the CheckMate 816 study. This was a phase 3 study of nivolumab in addition to platinum-based chemotherapy that could be cisplatin or carboplatin plus pemetrexed or a taxane-based therapy. Almost 200 patients got nivolumab plus platinum-based chemotherapy for up to 3 cycles before surgical resection vs almost 200 patients got platinum- based chemotherapy alone. It was interesting that this got FDA approved almost before we even saw the data. When we look at the subset analysis, there was definitely more benefit in patients who had a better performance status, looks like younger patients in general had a better benefit, and then there was a PD-L1 association where the higher the PD-L1 seemed to have a trend toward more benefit overall. Tumor mutational burden has been put out there as another biomarker for response to immunotherapy, and tumor mutational burden didn't look like it had a strong predictive factor. Interestingly, carboplatin looked like it was better than cisplatin. Now the patients with carboplatin, there was no randomization there—so I've wondered whether this reflects patients that are poor performance status, had to settle for carbohydrate, or maybe carboplatin didn't have as much effect, so immunotherapy could rescue that somewhat more. Regardless, it looked like there was a trend toward benefit through many of the subgroups that were analyzed, as presented by Patrick Ford. Then we looked at the disease-free or event-free survival, and looking at both 1 year and 2 years, there was more than a 10% benefit at a year in terms of preventing disease-free survival, and almost a 20% improvement in disease-free survival close to 2 years, with the data immature at this point and still ongoing. So this looks like it's definitely preventing cancer coming back, and is now an FDA-approved option, regardless of PD-L1 status, together with neoadjuvant chemotherapy. So for those stage III patients getting neoadjuvant chemotherapy, I think it would be the standard of care to give this, with the exceptions of probably not for ALK or ROS or other mutations, positive tumors that don't respond very well to immunotherapy. And I'd be a little more hesitant in the very low PD-L1 tumors—although it is technically approved in that subset, I'd anticipate potentially less benefit.
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 | We also saw data that said that the pathological complete response, so the amount of tumor left afterward, was much lower, so much less tumor left after nivolumab plus chemotherapy, than chemotherapy alone. And we saw data recently at the World Conference in Lung Cancer, in Vienna, on NADIM II. So the interesting thing about CheckMate 816 was it did not have adjuvant therapy—so it was just 3 cycles of nivolumab plus chemotherapy, and then done. So this phase 2 study NADIM II enrolled patients with clinically resectable stage IIIA lung cancer, no EGFR or ALK, and had the same nivolumab, paclitaxel, and carboplatin versus just carbo- paclitaxel. And so the primary endpoint was pathological complete response, and then also progression- or disease-free survival. Pathological complete response, again, much higher in patients who received upfront immunotherapy and progression-free survival significantly higher at 24 months
 immunotherapy with hints of overall survival benefit as well, at least of this early look, very strong hazard ratio here. Again, the PD-L1 expression higher in the tumors, and of course, EGFR and ALK were excluded from the trial, predicted more benefit. So moving on from the neoadjuvant setting, where we do have one standard of care with nivolumab plus platinum-based chemotherapy doublets in the neoadjuvant setting from the CheckMate 816. What about if patients don't get neoadjuvant among the patients who got immunotherapy, what are the data for adjuvant immunotherapy? So these come from the IMpower010 study. This was a phase 3 study led by my colleague, Heather Wakeley, at Stanford, almost 500 patients on each arm, with atezolizumab following standard platinum-based chemotherapy. So 1–4 cycles, up to the investigator how many cycles to use. When we look here, the disease-free survival, again at 24 months, almost 10% higher, with a benefit that looks like it goes out to 36 months.
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 | And when we look at the PD-L1–positive cohorts more than a 10% benefit at 24 months in terms of disease-free survival. We saw hints of an overall survival analysis presented, which looked like the PD-L1 greater than 1% in the intention-to-treat population. The stage II and IIIA population had overall survival hazard ratio of 0.71 that just barely did not cross one when they excluded the EGFR and ALK positive patients. And the most significant overall survival benefit looked goes on, there will be other trials maturing, and some of these other trials that are going to mature include ones combining chemotherapy with immunotherapy in the adjuvant setting, as well as other neoadjuvant trials. like it was in the PD-L1 greater than 50% population. So my takeaway here is, if patients did not receive neoadjuvant immunotherapy together with platinum-based chemotherapy, and we're offering platinum-based chemotherapy, then they should get adjuvant atezolizumab unless the chance of a response to immunotherapy is very low, with targeted alterations or undetectable PD-L1. As time the ah RTOG 9410 study. In this study, the patients got sequential chemotherapy or concurrent chemoradiation or tumor radiation twice daily. There was a primary endpoint of overall survival. Really concurrent chemoradiation is better than sequential chemotherapy plus radiation. Although I was really interested in what other countries do, to find out that oftentimes they only have a few So then we'll move on to think about unresectable stage III non–small cell lung cancer, so not surgically resectable. What do we do? Well, historically, some of our best data come from
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 | radiation sites across the country, so patients get local chemotherapy and then have to go for radiation elsewhere. So beyond concurrent chemoradiation, what are the more recent developments? Well, the biggest breakthrough, after trying a bunch of different things, including the addition of cetuximab to chemoradiation, testing 60 Gy versus 74 Gy, and even trying a number of different adjuvant consolidative approaches, such as consolidated docetaxel, consolidated gefitinib, even despite lack of EGFR mutation testing. Only one trial has yet been positive in a phase 3 way for consolidated therapy, and that's the PACIFIC trial. So in the PACIFIC trial, patients were randomized in a 2:1 ratio to after finishing chemoradiation with a scan that did not show progression, after any chemoradiation regiment it was dealer's choice on having durvalumab for a year afterward versus placebo for a year afterward. And what we saw now that the 5-year results that have come out, there's a significant decrease of the probability of death or metastasis lasting on through many, many years after the receipt of immunotherapy in a consolidative fashion and an overall survival benefit. So this got first approved almost 5 years ago, 4 1⁄2 years ago now, and in 2020 got an additional dosing regimen, which is much more convenient—every 4 weeks for these patients. Here's the 5-year update, and we can see the tail on the curve continues to separate, as we often see for patients that benefit from immunotherapy. This can be a very durable response over time, even though I'll point out again that patients only received the durvalumab for 12 months.
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 | PD-L1 1% or higher expressing tumors, and there didn't seem to be a benefit in EGFR or ALK patients, even though some were included in the study. So one exploratory analysis that was done here was in N2-positive patients, because there's many different ways to have stage IIIA large tumors, for And the overall survival looks similar with almost a 10%, even a greater than a 10%, benefit and overall survival that does seem to be durable. What do we look at subgroup analysis? Certainly, the stage IIIA patients look like they did a little bit better. Higher PD-L1 did better than low PD-L1, even though in the United States this is approved regardless of PD-L1 status. I believe, in Europe, European countries mostly, it's only approved for example, a T4N0 tumor is also surgically resectable. But the N2 is a more homogeneous kind of typical of what we think about stage IIIA non–small cell lung cancer, It looked like this benefit of patients was from chemoradiation followed by durvalumab consolidation was particularly high in this group. This was an interesting group, because it was the group of patients that also might be considered for a surgery. Now, at the time that these data came out there were no neoadjuvant or adjuvant approaches with immunotherapy in this patient population, but since this time, as we talked about at the beginning, there are other treatment options. So it'll be interesting to see if the receipt of any immunotherapy anytime can then do some of this benefits seen at stage III. Safety signals from immunotherapy, so far we haven't gotten into this, but we will here, because it's important to know how to manage
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 | immunotherapy. Generally, very similar to what we see in the metastatic setting. Of course, all of us were concerned when we're giving chemotherapy radiation, and then followed by an immunotherapy afterward, the pneumonitis may be much higher than we would expect otherwise. It did appear to be slightly higher in the durvalumab group than the placebo group, but not significantly so. And my experience has been relatively unusual to have higher grade, grade 3 or 4 pneumonitis reflected by these data that say that the serious pneumonitis is not higher compared with placebo. So currently the guidelines say that definitive chemoradiation followed by durvalumab is the standard of care for unresectable stage III non– small cell lung cancer. There is a trial ongoing through the [EGOG-ACRIN Cancer Research Group], which I'm a member of, studying the use of durvalumab together with chemotherapy and radiation. So starting about 6–8 weeks earlier than it would otherwise, compared with following with durvalumab after chemoradiation is complete, we'll look for both signals of the survival benefit as well as safety signals of giving those therapies concurrently. So, going to patient case 2, this is a 52-year-old man with newly diagnosed, unresectable stage IIB squamous lung cancer, PD-L1 5% in the tumor, treated with carbo-paclitaxel and radiation, after completion of definitive chemoradiation follow-up CT scans confirmed a partial response. All right, so after chemoradiation shows a partial response and nonprogression, what's the next step in therapy? We just talked about it: start treatment with development for a year. durvalumab completely, but we may start to integrate it more with chemoradiation in the future and starting it earlier. So, future directions. There's many trials ongoing in unresectable non–small cell lung cancer. PACIFIC2, with the concurrent chemoradiation-durvalumab strategy, the ECOG-ACRIN study that I mentioned. And then some pembrolizumab-olaparib studies, Ipili-nivo versus nivo, and then other pembrolizumab studies, and a durvalumab split course for poor performance status stations. So many other trials maturing. I think it would be hard to envision that any of these would displace
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 | So now we get into management, one of the
 toughest parts of our job—because it's nice to say
 that the data show benefits, and we can offer these
 agents, and we're giving overall survival and
 disease-free survival benefits, but the truth is, there
 are side effects for immunotherapies, and as we've
 all experienced in the stage IV metastatic setting,
 the early stage is no different. But I think for me,
 one of the major challenges is that this is a patient
 population that would be otherwise potentially
 cured even without immunotherapy. So we have to
 be cautious in using these drugs, particularly for
 patients with very small tumors, very low likelihood
 of tumor recurrence. These are the patients that
 may stand to lose the most from a life-threatening or very morbid immune-related adverse event as opposed to a metastatic patient that's facing a battle with cancer right now. So, I think Vicki, who's one of our experts and works closely with the thoracic oncology medical staff at University of Pennsylvania, would like to share thoughts on what we do during chemoradiation, what we do to manage the adverse effects from immunotherapy, and maybe share any personal experiences that you have in this realm. [Dr. Vicki Sherry] Thank you, Dr. Neil. So on the next few slides, I will be going over the adverse events that patients experience from the treatment modalities that Dr. Neil just explained to us and went over in detail. We'll start with chemoradiation. Chemoradiation can affect really all organs of the body, which is why supportive care during treatment is really of utmost importance, and the goals of supportive care are really multi-factorial. So they include reducing acute toxicity, reducing late effects, and really improving overall quality of life. When I first meet a patient who is going to be starting chemoradiation. I give them my Vicki Sherry hydration, nutrition, and exercise speech, and I explain to them that I can help support them with almost any side effect that they throw at me, either with medications or with a referral to a specialist. However, I cannot eat for them, I cannot drink for them, and I cannot exercise for them—so I put this onus on them. So patients must stay adequately hydrated, preferably water or some sort of electrolyte drink—about 64 ounces a day is the target that I give them. I also stressed this, the drinks should be non-alcoholic, non-caffeinated drinks—so they can drink caffeine, they just cannot include it in the 64 ounces that I asked them to drink every day. And then I stress the importance of exercise. So doing some mild exercise about 2–3 times a week for at least 30 minutes, really just to keep up their strength and reduce their fatigue. And I tell them that I know this seems really counterintuitive. But all the data on treatment-related fatigue really just reinforces the importance of exercising. And then I also like to get physical therapy in sooner rather than later. Sometimes it's nice, because it likes a little bit of fire under them and gets them moving. And then, if patients are really struggling with fatigue throughout treatment. I will sometimes prescribe a low-dose of betamethasone, but I like to reserve this for severe fatigue. I discuss the importance of maintaining their weight for treatment with high protein, high calorie snacks, meals, shakes, small, frequent snacks or meals throughout the day. And then I also ask my patients to front load the calories in the first two weeks of treatment, because that's usually when they're feeling good, the radiation hasn't kicked in yet, and that way toward the end of treatment, if they experience esophagitis or dysphagia, they have a little bit of wiggle room for weight
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 | loss. I always consult our nutritionist to speak with the patient really about optimal nutrition and just different shake options that they can get. And then, as far as radiation-induced esophagitis, it typically begins during the third week of chemoradiation and reaches a peak approximately 2 weeks after the end of chemoradiation. Prophylactically, I start my patients on a PPI just to reduce any gastric acids, and then at each weekly visit make sure you ask your patients about difficulty swallowing and pain, because what patients describe as a sore throat is typically the beginning of a radiation esophagitis. And at this point, I usually start sucralfate before each meal and at bedtime, just to give their esophagus a little layer of protection. And then, as the pain progresses, I'll add in an opioid—I usually add in oxycodone—and I tell them to take it about 30 minutes before they eat anything. And then these patients can experience esophageal candidiasis. It can occur frequently in this patient population, so make sure that you examine their mouth and oropharynx every time that you do a physical exam. For patients who have delayed recovery of the esophagitis—so it's taking longer than that typical 2 weeks—you should suspect candidiasis and either start an anti-fungal therapy, or you could refer to GI and they will like they scope them. Another side effect from radiation is dermatitis at the radiation portal site, and I always encourage my patients to moisturize that radiation site with a thick emollient several times a day to prevent the skin becoming dry, and then the skin will break down—they should continue this throughout treatment. And this also requires a weekly reminder to them, because in the beginning they're applying lotion to skin that's not erythematous—it's not painful—and if these patients are religious about putting this lotion on, then they can usually avoid skim breakdown and sometimes avoid radiation dermatitis completely. Another important aspect of supportive care during chemoradiation that I want to mention, that's not on this slide, is smoking cessation. Smoking cessation before or after chemoradiation really can increase their performance status and their quality of life, and lead to improved survival. So at Penn, we have a smoking cessation program that uses both pharmacologic and behavioral therapy. 1-800-QUIT-NOW is another great resource. So just make sure you always ask your patients if they smoke, whether they're interested in quitting, and the importance of quitting. So now we are switching from chemoradiation to immunotherapy. So because we are enhancing the
 immune system and immune checkpoint inhibitors
 can lead to auto-inflammatory side effects that are
 referred to as immune-related adverse events or
 imAEs, or irAEs, these are sort of the same thing— immune-mediated and immune-related are really interchangeable—and the precise path of
 physiology underlying the immune-mediated
 adverse events is really unknown. It's believed to be
 related to the role that immune checkpoints play in
 maintaining immunologic homeostasis, and
 because immunotherapy can affect the any organ in
 the body, I tell my patients that it can cause an -itis
 in any organ—so uveitis, pneumonitis, arthritis, colitis, dermatitis. So I tell my patients it's really important—today is your baseline, and any change after today you need to call me. Maybe it's mild, maybe it's their itchy skin, they have stiff, sore joints, or their arthritis feels like it's flaring, or maybe something that's more serious, such as shortness of breath or watery diarrhea. But either way you need to stress the importance that they call you immediately with any changes in the baseline.
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 | Immuno-mediated adverse events can occur at any time. They usually say within the first few weeks, to months after treatment, and then they begin to wax and wain over time. Most immune-mediated adverse events exhibit a characteristic pattern and timing of their occurrence. So you can see here on the slide skin-related adverse events can be expected after 2–3 weeks; GI after 6–7 weeks; and then endocrinopathies occur on an average at about 9 weeks. On the slide, you see the beginning and the end of each curve represents the median time and onset and median time to resolution. And it’s very important that we, as providers, tell the patients and caregivers, give them up-to-date education about immunotherapies, telling them to call with any change in their baseline, letting them know this mechanism of action, and letting them know the clinical profile of possible imAEs that could occur during therapy throughout treatment and even survivorship. I've seen more than I want to of DIREs—which are delayed immune-related adverse events—that are occurring years after patients come off of immunotherapy. So it's something we always need to be aware of if a patient is on immunotherapy or has received it in the past. And then, if identified early, again, stressing early, a
 patient reports it in. ImAEs are almost always
 reversible with the initiation of immunosuppression
 using steroids, and this is where immunotherapy
 and chemotherapy differ greatly. If the irAE goes
 unrecognized, these events can lead to significant
 morbidity, they can lead to organ dysfunction, and
 even death. So we base our management on
 grading guidelines. Generally, a grade 1 we can
 continue immunotherapy; a grade 2 will hold the
 immunotherapy and may or may not initiate
 corticosteroids; grade 3 we are holding, and we are
 starting high-dose corticosteroids; and then grade 4
 you want to permanently discontinue the immunotherapy. The one exception to this is endocrinopathies— endocrinopathies are controlled on hormone replacement therapy, so as long as they're receiving HRT, you can actually continue these patients on immune checkpoint inhibitor therapy. And then at the bottom, you can see that there's a little, sort of disclaimer about rechallenging with ICIs and I do want to note that you do not dose reduce immunotherapy like we do with chemotherapy. If they're having side effects, we don't dose reduce. Dr. Neil mentioned rechallenging in his discussion and you can rechallenge if you do have an imAE—you hold the drug, you give steroids, and then it reverts to a grade one, you can rechallenge. But they are advising that we use caution when we are rechallenging with these patients, especially in those with the early onset irAEs. So here is the final question. So the patient is started durvalumab consolidation after definitive chemoradiation. Three months after initiating durvalumab, the patient-developed diarrhea. Following a negative, infectious workup grade 3 immune-mediated colitis is suspected.
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 | So which of the following are appropriate management strategies for this immune-mediated adverse event? Hold durvalumab and add prednisone with a slow taper is the correct answer. And I think we're all finished. Dr. Neil, I welcome you back, and we can open it up for questions with the ah audience. [Dr. Joel Neal] Thank you, Vicki. I learned a lot from the supportive care. I like telling people that they're First question is, do I do molecular testing, or do we do molecular testing on stage III, stage II early-stage disease. I'll tell you that our institutional practice is pretty much any tumor over a centimeter, we'll do PD-L1, EGFR, ALK, ROS rapid, just because historically we've done that and then go ahead and do next-generation sequencing because if the tumor recurs, I'd rather have the information at my fingertips. Other academic centers, though I've heard often for early-stage disease, only do PD-L1 and EGFR. I think we're not learning everything about the response to immunotherapy if we do that limited a panel. Um, Vicki, what do you do in terms of testing at Penn? [Dr. Vicki Sherry] Our practice at Penn is exactly how your practice is set up. We do NGS testing on all of our patients, actually. So. [Dr. Joel Neal] I think we're moving in the direction of doing NGS and PD-L1 testing on all tumors with lung cancer. But there may be cost and reimbursement issues for particular patients out there in the community, which we can appreciate. Most of the time with central testing or the testing providers, if it's not covered, because it's too early stage, oftentimes the companies can work something out. So I'd encourage the NGS just because it gives me a good idea of if this patient likely to respond to immune therapy. So TP53 mutations are interesting because they occur in probably 60%–70% of non–small cell lung cancer. As of right now, they're not actionable. They occur across all different kinds of cancer. There have been a lot of different approaches to try and treat them, including a P53-deficient cell oncolytic retroviral therapies and all kinds of fancy things; but as of right now, I consider TP53 to be a generic mutation in lung cancer and wouldn’t treat it any differently. [Dr. Vicki Sherry] Dr. Neal, going back to your biomarker question, we also do liquid biopsies, which I’m sure your institution does the same. I know we can't pick up on PD-L1 with a liquid biopsy, but that's another great way to do NGS testing on these patients. [Dr. Joel Neal] I know that the Charu Aggarwal there has really been a force of liquid biopsies, even encouraging the pulmonologists, I think, to order liquid biopsies as they're doing bronchoscopies. in charge of exercise and eating and drinking, and I’m going to use that one in my clinic—I like that a lot. Yeah, I always say they're in charge of the day- to-day decisions that they make about their body, and I only see them infrequently. So those things definitely help people live longer and better, regardless of what the treatments are in the early stage or the metastatic setting. We did have a couple of questions. The first one was, how do we manage a stage III non–small cell lung cancer with a tumor with the P53 mutation. So we'll see these on the next-gen sequencing reports.
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 | [Dr. Vicki Sherry] Yes, they do. [Dr. Joel Neal] So ordered, not by the medical oncologist, but by other providers. So I’m not sure I’m there yet, and there's often no reimbursement unless you have a diagnosis. So you can't. Yeah, in the real world, outside of a research study, it's hard to get testing for liquid biopsies unless you say this patient already has known cancer. So I would do them second, after finding the histologic diagnosis for the community. Let's see what else we have. Somebody commented, as to both of our patients presented being non-smokers. I think that's an artifact more than anything. Lung cancer does have a stigma, and I think it's important to talk about where lung cancer has historically been mostly smoking-associated. In California and elsewhere around the country, we're seeing that there's less and less immediate proximal smoking–associated lung cancer that's developing. We are seeing adenocarcinomas, we are seeing squamous. For me, it comes down to the molecular testing more than it has the smoking issues. The person who asked the question also said “what about eliminating tobacco options from consideration.” I think there were many lawsuits against the tobacco companies and now it looks like the nicotine substitutes and e-cigarettes are falling out of favor—very fortunately, because they seem to be a gateway drug to tobacco itself. For people who want to learn more, there's a great website tobacco.stanford.edu, where they've recorded for posterity all the marketing that tobacco companies have ever put out, so that they don't go away, including how 30,000 doctors recommend certain brands of cigarettes from the 1930s at the American Medical Association meeting. So, yes, tobacco.stanford.edu is a powerful tool, in addition to what you mentioned, Vicki, about all the smoking cessation resources. If you tell people that they were marketed and they were tricked to start smoking, they get really mad about it, and that's another tool that you can use, especially for the younger folk. Another thing we were talking about is the management of esophagitis. You talked about a bunch of useful tools, Vicki. I was curious. So I completely agree, and I think it's under-recognized how often candidal super infection probably happens with esophagitis. So part of my triple mix or quad mix, or whatever it is, is often nystatin based. I tend to shy away from the lidocaine as part of the mix that I use, and instead of putting it all as a mix, I say [to the patient] here are like four different things you can compound it yourself—you want to take it all at once, but they're way cheaper if you prescribe them individually, than if it's some compounded mix. And then and then sucralfate, too, is something that our radiation oncologists recommend—these pills that you have to crush out or compound, and then swallow. How do you deal with this? Because I think this is this is one of those subtleties that those of us in practice, the compounding, and the expense, and everything else. What's your practice use out of all these tools, the ones that you like, and the order you use them in? [Dr. Vicki Sherry] Sure. So “magic mouthwash” is another one of those compounds of the lidocaine, diphenhydramine, and antacid liquid, and anytime a provider prescribes it, it always get to kick back to us from pharmacy—like, what do you mean by this, what are we doing? So it's just sometimes easier to tell them to take them individually. My sort of go-to is the sucralfate, and then I'll add on sometimes a topical lidocaine, but I don't like them to swish it in their mouth or swallow it. I'll tell them to put it on a cue tip and if they have a sore use like that. But I’m not a big fan of the lidocaine, just because it's numbing them out, they can't taste anything. It's just not my go-to. I like your nystatin perspective. I don't do it upfront. It is really difficult to diagnose esophageal candidiasis. You usually can't see it if it's in the esophagus. So it's usually GI sending them to get scoped, so I don't do it upfront, but if they're having persistent pain, despite the sucralfate, despite the oxycodone, I will add it on. [Dr. Joel Neal] Yeah, I think the supportive care through chemoradiation is really incredible to get people through. We're fortunate over the dozen or so years that I've been attending and practicing, to see the development of all these very focused radiation techniques like IMRT. I think esophagitis has gotten a lot better. All of these radiation side effects have gotten a lot better overall. So I’m appreciative of the improvements in radiation technologies, even though we don't have the randomized controlled data to show you the survival benefits. We just know that it's better because it is. [Dr. Vicki Sherry] Right, absolutely. And to answer a question about super-hot or super-cold liquids, I would say to avoid the super-hot liquids, just because also they're probably very uncomfortable going down if you have open sores in your esophagus. That's another reason that the magic mouthwash with the lidocaine worries me—if they do take a sip of a hot drink and their mouth is numb, they can burn their mouth. Super cold, I think is fine. It's actually usually appealing to patients. The colder temperatures, like milkshakes or ice cream.
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 | [Dr. Joel Neal] Beyond that, I know our radiation oncologists say no alcohol, no spicy foods, no acidic foods. During chemotherapy, sometimes the infusion nurses will say no sushi, no raw foods. For me, I say it's what you tolerate. If you want to eat it, it's probably okay. If it doesn't agree with you, you'll figure it out. [Dr. Vicki Sherry] Right. I even say as far as the alcohol, if you're feeling well enough to have a drink, then that's actually a good thing. I don't encourage it, by any means, but that means they're feeling well’ [Dr. Joel Neal] Yeah, it is a good sign. I think we reviewed a lot of exciting things about the use of immunotherapy in the treatment of earlier stage non–small cell lung cancer now. I would emphasize, again, that molecular testing can show us which patients are more likely to respond to the immunotherapies and which ones may be more appropriate for targeted therapies, even though for EGFR, which is really the pioneer of molecular testing and treatments that are directed against EGFR, there is an early-stage indication for osimertinib. As of right now we don't have a stage III chemoradiation approval, but the LAURA study—locally advanced AURA study—is predicted to read out which gives osimertinib indefinitely after chemoradiation, actually. So I think we'll have another niche there, and then hopefully look forward to the use of other targeted therapies, which may be more cytostatic than cytotoxic in this locally advanced setting over the next couple of years. So I want to thank all of the learners out there. I saw definite improvements—and maybe it was because of my hints of the answers—but, hopefully, everybody learned something that's relevant to their practice, or the people that you collaborate with. And I want to thank you, Vicki, for joining us today. It's always really interesting to have other members of the multidisciplinary team. We provide cancer care as a village, you know, even though there's an attending of record, and the PIs and everything else, I couldn't deal without my APPs, my medical assists, my medical scribes even, and all of my research coordinators and the research team. So really appreciative of everybody out there who's helping us make lung cancer care better. [Dr. Vicki Sherry] Absolutely. I couldn't agree more with what you said. It takes a village, and we all work collaboratively together to give our patients best outcomes, and I just want to thank you again for being here today. [Dr. Joel Neal] It's been a pleasure.
[Dr. Vicki Sherry] Thank you, everybody. Have a good night. 
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