Optimal use of front-line immune checkpoint inhibition for metastatic non-small cell lung cancer (NSCLC)

DR LOVE: Good day, everyone. I’m Neil Love from Research To Practice, and welcome to “Striving for Consensus,” as today we talk about the current and future management of metastatic non-small cell lung cancer in patients who progress after having received a checkpoint inhibitor. We have a great faculty today: Dr Corey Langer from the University of Pennsylvania in Philadelphia, Dr Ticiana Leal from the Emory University in Atlanta, Dr Karen Reckamp from the Cedars-Sinai Cancer in Los Angeles, and Dr Jacob Sands from the Dana-Farber Cancer Institute.

Here’s where we’re heading today. We’re going to start out with a little bit of a warmup discussion, then we’re going to jump into some cases from the faculty, and then we’re going to go through — each of the faculty’s going to do a presentation on this topic. We’ll go through their presentations, and then we’re going to finish up with some additional case histories.

But I just want to start out with a little bit of background, and Jacob, the topic here is managing people who’ve progressed on IOs, and we’re going to get into your vision about why people do progress on IOs, but I just thought we could start out with maybe a little bit of — a snippet from your own practice, Jacob, in terms of who are the patients with metastatic non-small cell who don’t get a checkpoint inhibitor up front. Two big categories that you hear a lot about are people with prior autoimmune conditions or transplants who really are not good candidates for IOs, and also people who are getting targeted therapy.

So Jacob, can you provide a little bit more insight into your practice in terms of, again, what are the situations where you’re not using an IO up front?

DR SANDS: Yeah. This is such an important topic, and I’ll just start with pointing out how miraculous these IOs have been for a subset of patients, that I firmly believe that in the next 10 years we’ll be able to have more data that says there are in fact some patients actually cured from what has been an incurable diagnosis by the inclusion of these. And that’s an important first thing to acknowledge because then to not give it is obviously a big deal.

Now you pointed out the classic population, those who have had a transplant. The transplant failure rate is very high, and so of course that is really I think a hard line in not utilizing, and autoimmune diseases. Now initially it was really kind of all autoimmune diseases, although we’ve been able to back down a bit from that. I’d say someone who has really symptomatic autoimmune disease and is on active management of that I tend to not give checkpoint inhibitors for. But a history of controlled, not particularly symptomatic, not requiring active management, some of these patients can get a checkpoint inhibitor. And I often involve their rheumatologist within that discussion if in fact they have a rheumatologist. If they don’t have a rheumatologist then usually that’s pretty suggestive of them not having very severe autoimmune disease, although really that needs to be — that needs to be dived into in more detail.

DR LOVE: So Karen, maybe you can add some comments to what Jacob brought up, but also the issue of people who have targetable mutations. I think in terms of EGFR and ALK it’s pretty clear everybody’s going to start out with targeted therapy, whether they’re even going to get an IO we could talk about. But of course there are so many other targetable mutations. How do you decide whether you’re going to use an IO up front, particularly in people who have potentially targetable lesions?

DR RECKAMP: So I think you’re right, targetable lesions there’s some differences that we look at, and I usually think about it mainly as kind of smoking-related targetable alterations versus nonsmoking-related targetable alterations, so when we think about EGFR, ALK, and ROS1, I put RET into that also, and NTRK, which is exceedingly rare. But those are patients where I’m thinking we know from the second-line data that generally monotherapy immunotherapy is about a 5% response rate or less for these patients. We’re getting some indications that in EGFR patients adding immunotherapy to chemotherapy may not be beneficial. So immunotherapy in these patients I think is less of an exciting treatment at this moment in time until we can figure out how best to use immunotherapeutics in these patients, and so I would definitely choose the front-line targeted therapies for these patients.

And then there’s a unique aspect, especially of osimertinib, where we know that patients who receive immunotherapy may have higher risk of even Grade 3 toxicities, especially interstitial lung disease, so we want to avoid toxicities, otherwise we may lose a very good drug like osimertinib if we give immunotherapy first. So it’s about toxicity and the lack of efficacy.

When we think about KRAS and BRAF, I think those are a little bit different, and I think there’s more discussion. And obviously treating KRAS is a second-line treatment anyway, so those patients generally will receive immunotherapy up front. And then MET I think is a big outlier. Some patients may respond and other patients may not, but I tend to use targeted therapy in those patients first.

DR LOVE: So Corey, it’s really amazing that we’re going to spend 3 hours talking about this topic, which kind of really didn’t exist 10 years ago. There’s a little video that circulates on the internet from about 7 years ago of me at a GU conference saying, “I think things are about to change,” because I knew that the nivo was up for approval in the FDA. That was only like 7 or 8 years ago. And on that video I go, “Things are about to change. Your infusion rooms are going to be looking a lot different.” Any thoughts about this revolution that has occurred, Corey, and also, again, any other thoughts about this issue of who doesn’t get an IO up front?

DR LANGER: I agree with both Jacob and Karen. Immunotherapy has irrevocably altered our therapeutic landscape. We see long-term survivors now out 4, 5, 6, 7, 8, in my case at least a couple people 9 years and beyond, many of whom were originally on the Phase I and II studies, or the second-line trials. This is unprecedented. Non-small cell, at least in our youth, was not like this at all.

I worry that we may have reached a plateau, and hopefully we can ease above that, and certainly the topic of discussion today will hopefully give us pointers in those directions.

To expand on the patients who are appropriate or not appropriate, one caveat that needs to be mentioned, all patients — I would say all patients with adenocarcinoma regardless of smoking history, and certainly all never or remote former smokers regardless of histology, need to have their molecular workup done before initiating immunotherapy.

I agree with Karen, you start immunotherapy on a patient who may have a high PD-L1, but you have not completely classified their molecular phenotype, you’ll do them tremendous disservice if they do turn out to have ALK or EGFR. So whether it’s liquid testing or tissue or ideally both that needs to be accomplished a priori and it’s frustrating because the turnaround for NGS is still exceedingly long, which is another issue we didn’t deal with 10 or 15 years ago when we empirically started everybody on the same regimen.

As far as the patients who should not immunotherapy I think we’ve gotten a bit more liberal over time. Certainly an individual with a past history of Crohn’s that’s no longer active, while they might have been excluded from clinical trials I would definitely treat that individual. Patients with a history of hepatitis or HIV that’s now controlled with appropriate medication and have appropriate T cell counts, I would consider strongly that population. That may not be a consensus, but I think there are data now showing that it is relatively safe.

I do draw the line, as Jacob said, at active collagen vascular disease that’s requiring ongoing treatment. And whether or not a rheumatologist is involved in their care I think is a good checkpoint as to whether that patient should get treated.

When it comes to transplants, I draw the line at cardiac and liver transplants. You can’t go to the store and get a new liver or heart. However, kidney transplants I have started giving that because you can always go back to dialysis, and there are regimens that are compatible with that. So it’s a gamble, but if you’re really out of options or if that looks to be the best option I think a shared decision-making discussion in that venue is reasonable.

DR LOVE: We had a famous case presented, I remember it was the beginning of the pandemic, of a patient with multiple sclerosis, metastatic disease. They didn’t want to give her a checkpoint inhibitor. She’s running out of options. Very intelligent patient, went for a second opinion, wasn’t fulminant multiple sclerosis, I think it was actually not even being treated at that point. They decided to go ahead and give her a checkpoint inhibitor. She had a complete response and is going great. Not saying whether it was a good decision or a bad decision, but the thing I always love about the case was that the PD-1 level was 0.

Anyhow, just to finish this out, Ticiana, I’m curious about your thoughts. It’s interesting, Corey brought up a really important point that we’ve been talking about a lot, which is the patient who’s sick and needs to be treated right away, they’re in the ICU, they may be in respiratory failure, and this issue that Corey brought up of holding off on giving the IO until you make sure that you have your NGS or whatever you’re going to get to look for targetable lesions.

Any thoughts, Ticiana, about patients in your practice who aren’t getting checkpoint inhibitors up front?

DR LEAL: Yeah. So I agree with everything that’s been said so far, and I think regarding the ICU patient, that’s an extremely challenging case, but I feel like that’s the case where NGS is really of the utmost importance because that’s the treatment that has the quickest time to response. So I think the role of liquid biopsy in getting faster turnaround times for our NGS results is essential in that patient with a critical need, and those are the patients that I am seeing coming out of the ICU. They have a targetable mutation, you can initiate with targeted therapy, and hopefully then those patients are the ones that turn around the quickest. IO doesn’t turn around that quick, so I think still getting NGS liquid and tissue essential up front.

Whether these patients receive IO inside that hospital admission that’s extremely rare, not only because of cost and ability to give those patients IO in the inpatient setting, and again will they benefit quick enough. I don’t think so, so I think, again, for those patients we really have to individualize care, and once we can hopefully stabilize them, get them to the right treatment, and if that is IO or IO combinations we do that as quickly as possible.

One thing that I think is increasingly a challenge in terms of the patient that is being treated up front I would say are the patients who have a recurrence. And so these are now metastatic setting but that have received IO, and increasingly we’re using the neoadjuvant strategy with chemo/IO, and so identifying which patients are going to be benefitting from standard of care IO, IO combinations I think is also another challenge, and obviously those patients that are chemorads and have progression on durvalumab. So adding another challenge in terms of IO resistance or who’s still IO sensitive up front in the recurrent setting with metastatic disease is something that we’re also learning more about.

DR LOVE: That last point was so important.

Case: A man in his late 60s with NSCLC, no actionable mutations, PD-L1 20%, who received second-line datopotamab deruxtecan as part of a clinical trial

DR LOVE: That was very interesting. Let’s move on now and talk about some real-life cases. We asked you to present cases that are relevant to the scenario that we’re talking about today and also a little bit about the patient and what it was like to take care of this particular person.

So Jacob, can you tell us a little bit about your 69-year-old man?

DR SANDS: Yeah. So this is a guy who was healthy, active, working as a lawyer at a high level, also doing like a whisky club on Fridays with his friends, just a real character, but suddenly was having some shortness of breath that really worsened over months, as often happens initially treated as a pneumonia. Had a little bit of improvement but then no resolution, and then as symptoms worsened his wife ended up just bringing him down to the emergency room downtown.

He was admitted to the hospital for a workup. You can see on the right there his CT scans showed pleural effusion, pericardial effusion, and really just findings throughout both lungs. Some of the fluid was drained and unfortunately did end up showing a lung adenocarcinoma. It has no actionable alterations. PD-L1 was 20%.

He did, I’ll point out, have a smoking history. It was somewhat moderate, so had kind of transitioned to pipes, so wasn’t really smoking multiple packs per day, but kind of an occasional pipe, although with a prior smoking history.

Now as you can see, the picture on the right there, I learned about this guy from him. So he was on — he did go on our clinical trial with datopotamab deruxtecan, and in his case he did lose his hair, and when he did he pointed out that now he looks like Kojak, who as I said I had to look up. But he would walk around with a lollipop and sunglasses just to really bring it home.

So I saw him in the hospital, and relative to our prior discussion around checkpoint inhibitors, he was extremely anxious about his diagnosis, understandably of course. And I find one of the most challenging aspects of being a medical oncologist is to really get a sense of where the patient is coming from psychologically to guide them in their expectations around their treatment and such in an individualized way. And in his case we talked a lot about starting chemotherapy. This was in the inpatient setting, getting cycle 1 inpatient, and then adding in pembrolizumab with the second line as an outpatient.

And in his case, really in most cases, I do talk about the potential for very long-term disease control for years with a checkpoint inhibitor. I’ll just point out as an aside I think that within medical oncology we — there tends to be a discussion about worst-case scenario with patients, but I find that when patients come in they don’t seem as aware of possible best-case scenarios, and so I think that’s important to round out that conversation.

And I think in some ways there’s this idea out there that well, if patients understand the worst-case possibilities and then things go dramatically better that then they’ll be happy because it’s better. And I don’t know that I entirely agree with that. I think sometimes people just clench up so much, and then they live their lives in such a tense state not being aware of the real great potential outcomes that can happen.

And so in his case we talked quite a bit about best-possible-case scenarios. Of course I stressed that there is no promise here that this is a subset of individuals that really have this, but it’s possible.

Now in his case he did get 10 months of disease control, really continued his practice of law, continued teaching law students, as well, was active, would still have his whisky clubs, and then had progression 10 months in. And so he was really cruising along, I think, doing quite well, and then of course at progression that was another really big event for him, understandably so. And again, the room’s spinning around him as we’re trying to then discuss next-line therapy.

I’ll admit that now that the checkpoint inhibitors have gone into the first line, I think gotten used to having this second-line option that has potential, amazing outcome benefits with little side effect profile, to now go back to having docetaxel as a second-line therapy is a different experience. Patients end up with quite a bit of toxicity. The benefits of it, although I’d say are real and absolutely a preference to use it rather than not in the majority of patients with a good functional status, it’s not an exciting option.

And so he was enrolled actually on the Phase I, so early, within the DS-1062, now called datopotamab deruxtecan trial as second-line therapy. He tolerated it extremely well. As you can see, he did lose his hair. He also ended up having some of the eye toxicity. So he’d have some irritation in his eyes, and being the character that he was he really would not — didn’t like using eyedrops. He just had a real aversion to it to the point where it was actually quite difficult for him to really force himself to do it. So he frankly just didn’t until I told him, “Hey, if your eyes get any worse on your ophthalmology exams you might actually not qualify for continuing therapy on trial.” And that was what made him then use the eyedrops consistently, which worked well for him.

This controlled his disease really for 21 months with ongoing disease control with datopotamab deruxtecan. Unfortunately at progression we then did use docetaxel, and then when he had progression on that used gemcitabine. And unfortunately neither of those really did a lot for him, so ultimately he did pass, but was really an absolutely beloved individual within our institute. And he and his family were very grateful for those 21 months on trial, although obviously it’s still not enough, and so ongoing research continues to be very important.

DR LOVE: So one of the themes I’d like to get into with your cases is what value do you think was provided to the patient and family by the treatment that was given. Trying to find the time at which you hold off on treatment is a real challenge, and when you look back on this man’s course first of all I’m curious what you think the value of the therapies were, also curious how he did on the dato. Did he have any tolerability issues, any mucositis?

DR SANDS: No mucositis, really just the loss of hair, which for him was not distressing. For some individuals it really is. I think that’s a toxicity that sometimes we don’t fully appreciate how meaningful that is for patients, but for him it was fine. And then the eye toxicity, which was really mostly found within the ophthalmology exams. He did have some irritation, although it wasn’t really impactful to his life in any real way.

And so on the therapy I’d say he is one of the great success stories with the drug getting 21 months of disease control with ongoing working his profession and continuing to live a very good quality of life.

DR LOVE: So we know — I think I saw a press release, that says that there’s going to be a positive Phase III trial of dato presented. I’m guessing it’s probably going to be at ESMO. And Karen, it could be that in the near future, this next year, this antibody-drug conjugate may be coming in to practice as second-line therapy. I’m curious what you’re thinking how this is going to affect quality of life, for example, compared to what you’re currently using, whether it’s docetaxel, docetaxel/ramucirumab, or something else. Any thoughts, Karen, about what’s going to happen if and when these ADCs start coming into practice for lung cancer?

DR RECKAMP: I agree. This is an exciting time, and the ADCs are definitely the area where we are looking to provide better therapies for our patients, especially in this second-line and subsequent-line therapy. With the data that we have is a press release that we know there’s an improvement in progression-free survival over docetaxel. I think we — it will be interesting to see the data and look at the toxicity and tolerability of these agents because we know that they have a unique spectrum of toxicities and adverse events that occur that are not just based on the cytotoxic that’s used, not just based on the antibody, but multiple contributing factors from the ADCs.

So I like to see that we’re getting improvement in progression-free survival, which is definitely meaningful for patients, as we see with Dr. Sands’ patient, but I think we need to start to understand the toxicity, and we’re really looking forward to seeing those results presented so that we can start to understand those and compare those. But we all want something better than docetaxel.

DR LOVE: So Ticiana, I’m curious about your thoughts on this. I feel like every time we do a program now in solid tumors we’re talking about ADCs. Bladder cancer has 2 approved ADCs in the metastatic setting, and 1 of them has now just moved up into the first-line setting. One of the issues that comes up with these, Ticiana, they are targeted therapies, but more and more — and of course you’ve had T-DXd for HER2-mutant lung cancer, so now you’re starting to see this, that you still do often see chemotherapy-like side effects certainly with T-DXd. I’m not sure to what extent you see that with dato. Again, any thoughts, Ticiana, about how you see these antibody-drug conjugates fitting in and what kinds of chemo-like GI effects, cytopenias, et cetera, can we see in this situation?

DR LEAL: I think the ADCs are for sure exciting in development therapeutic strategies across the board for all solid tumors, and we have that study here at Emory as well, and we’re treating patients with solid tumors, including small cell lung cancer.

As we think about second line and beyond, this is a population of high unmet need, so having patients on trial in second line is very exciting to patients. They want to be a part of having a novel strategy, and a lot of our patients also want to contribute and help others as well.

So with datopotamab DXd specifically I think the overall strategy with showing improved progression-free survival in the TROPION-Lung01 study, I agree, we’ve got to see the data and see what kind of magnitude of benefit we’re seeing in terms of progression-free survival. And then this is a dual primary endpoint, so we’re still holding out for overall survival as well, depending on that magnitude of benefit and comparison in terms of toxicities. So having patient-related outcomes and quality-of-life outcomes in these studies to compare the differential toxicities I think will be very important.

We all know the side effect profile of docetaxel, but we’re also very accustomed to managing the side effect profile of docetaxel. And now we have a new agent which does have GI toxicities, the mucositis that you mentioned, the eye toxicities, myelosuppression is also seen, so I think we’re going to also have to learn how to manage these side effects more proactively, how to educate patients about managing these side effects. As Jacob was saying, it was really hard for this patient to really get onboard with managing the ocular toxicities, so I think we have to factor that in, as well, depending on the patient’s perspective on these therapies.

DR LOVE: So a final comment from Corey. I was just thinking, I’m not sure how many people even know who Kojak was, but when I saw that picture I was flashing on when I first started doing videos in the mid 1980s at the University of Miami one of the first patients — I started interviewing patients, and one of the first patients I interviewed was a Miami policeman who sat there during the entire — of course this was a while back, sat there during the entire interview with me, with metastatic disease, smoking, literally smoking during the interview. Anyhow, in those days you could do it indoors.

But it also brings up the issue, Corey, of how these patients affect us. I think you could hear in Jacob’s voice the feeling he had about this man. He’s dealing with metastatic disease, and he’s bringing humor into the situation. So in addition to your thoughts about the case I’m curious also about your thoughts about how patients affect us and how we learn from them.

DR LANGER: It’s really a heady time for patients, but particularly for us. We’re suddenly parachuting into the lives of people we’ve never known at a point that is most critical in their lives, on a crash course basis getting to know them and usually their families. And if a family was dysfunctional beforehand they become twice as dysfunctional when confronted with a cancer diagnosis.

So in addition to being clinicians and oncologists we often become family therapists and social workers. We really — it’s imperative, and I’m sure this happened with you, Jacob, that you enlist the support of other team members. You can’t do this alone. It would absolutely completely discombobulate us. We’d be exhausted both mentally and emotionally.

So if patients are having trouble or if the caregivers are having trouble I make sure they get counseling. I make sure they’re introduced to our entire care team, including our advanced practice nurses, our nurse practitioners and PAs, that they know who the patient navigator is. Communication is key.

And then unfortunately when they die it’s as if the curtain comes down and we’re suddenly disassociated from it all. I do maintain contact with some patients’ family members afterwards, but that’s pretty rare. It’s a hard time for them, and I think many family members view this experience negatively. They want to get as far away from the problems that they encountered as they can. But it is life altering and in many ways life-altering for us, and if we don’t learn how to compartmentalize our own lives it can absolutely drag us under.

As far as this specific patient, I’m impressed that his response to the ADC was more than twice as long as his original response to KEYNOTE-189, and I echo Ticiana’s concerns. The chemo — the typical chemo toxicities, we have lots of training. We know how to deal with those. We know how to manage myelosuppression. We can get inventive about managing mucositis. Nausea and vomiting is not a big deal for us. We’re quite flexible in agents that we can introduce.

ILD for me is the big concern. If the patient gets severe ILD it can be a game changer, can be fatal, so this is a toxicity we really need to know more about how to manage it successfully, ideally how to prevent it. I don’t know if there’s much work yet in that regard, but certainly that’s an unmet need. I think it’s the thing that frightens us the most, and certainly with trastuzumab deruxtecan we’ve seen ILD rates of any grade of 20, 25%, Grade 3 8, 10% or higher, and yet it’s an amazing drug that works in mutations where other drugs haven’t.

My final point, and this goes to the question we always get, “How long have I got?” We don’t know. I always answer that with I have no idea. I can quote you numbers, but I always tell them, as Jacob has pointed out, both worst and best-case scenarios, and then I emphasize the fact that we’re going to try to do everything we can to get them beyond the median.

DR LOVE: So yeah, oncology 2023. Earlier this year we did a program on ophthalmic issues in oncology, ophthalmic issues in — because all of these — so many of these ADCs, even beyond ADCs, other — erdafitinib causes central serous retinopathy, so being in oncology now you’ve got to be a renaissance physician, I think, Karen.

Case – A man in his early 70s with metastatic NSCLC, PD-L1 30%, who received first-line chemotherapy with pembrolizumab followed by maintenance pembrolizumab and second-line ramucirumab/pembrolizumab after disease progression

DR LOVE: Anyhow, let’s hear about your 72-year-old man. What happened with him?

DR RECKAMP: So this was a gentleman, and as a little background this is a person who’s actually kind of been able to go with the flow throughout the diagnosis and treatment and is kind of a person who says, “Doc, tell me what to do, I’ll do what you want me to do,”’and not highly anxious. He comes with his wife every time, they have appropriate questions, and just wants to keep moving forward. And they plan ahead when they can, and they are able to take a breath and step back when they can.

But he was 72 and came in with cough and chest discomfort for a few months. He did have a 40 pack-year smoking history and had quit about 10 years ago, had not had CT screening as we see with many of these patients that may have benefitted him, and had a large left upper lobe mass extending to the left hilum and hitting the pericardium with mediastinal and right hilar lymphadenopathy, and again multiple pulmonary masses and a left adrenal mass.

The PET/CT confirmed uptake in the lung masses and the left adrenal and multiple lymph nodes, also in the bone, in several places in the bone. And MRI of the brain did not show evidence of metastatic disease. So we see some of the PET scan here showing multiple pulmonary nodules and the larger mass on the left-hand side.

The patient underwent a CT-guided biopsy of the lung mass and showed squamous cell carcinoma negative for the adenocarcinoma markers but positive for p40. There were no alterations on molecular testing. We did do molecular testing despite being squamous cell. PD-L1 was modest at 30%. So this was a metastatic Stage IV. Normal liver and heme function and performance status was 1.

And so the patient went on and did get front-line therapy with a combination of carboplatin/nab-paclitaxel and pembrolizumab due to the PD-L1 of 30% and went on to maintenance pembrolizumab with continued response for 18 months. Of note, the toxicity was relatively mild that the patient experienced but did develop an interesting side effect of cellulitis, which we treated with antibiotics, and it was refractory to antibiotics yet then improved on a steroid taper, and so we thought it was more related to the immunotherapy rather than an infectious cellulitis. So that was something that I hadn’t seen in many patients before.

But he was able to tolerate therapy, and we had to hold several times because the cellulitis would kind of recur, but overall he did well for those 18 months then developed progression in a hilar lymph node and in the adrenal gland.

And so in this patient I had a question about what we do next, and I put in there afatinib because officially for squamous cell carcinoma this is an option for patients, not one that I use or believe in because the trial that got the approval compared it to erlotinib, which also doesn’t really work in patients without EGFR mutations or patients with squamous cell, but I put that on the list. And then we have our standard docetaxel, docetaxel/ramucirumab, and then the option that I put in that we’ll talk about later, pembrolizumab/ramucirumab from our S1800A trial, a trial that is ongoing.

DR LOVE: So what’s the follow-up on the patient?

DR RECKAMP: So the patient did start on the Pragmatica trial, Pragmatica-Lung trial, with pembrolizumab and ramucirumab, and he just recently started on this trial and was randomized to pembrolizumab and ramucirumab. But with the initial response to immunotherapy and lack of significant toxicity we thought this was a good option. If the patient was randomized to standard of care we would have given him docetaxel/ramucirumab.

DR LOVE: So you actually continued the pembrolizumab? He was on it, and you added the ramucirumab?

DR RECKAMP: Well, this is on clinical trial, so we added —

DR LOVE: Right, but —

DR RECKAMP: — and he got pembrolizumab with ramucirumab as the next-line treatment.

DR LOVE: Interesting.

DR RECKAMP: Correct.

DR LOVE: So I’m going to ask Ticiana for her thoughts about the case, but first I have to ask you. I was fantasizing that the man was a farmer, but tell me, what kind of work does he do.

DR RECKAMP: He has worked — he worked as an engineer, but he’s an outdoors kind of guy, and so he enjoys clay-pigeon shooting and likes to be close to the earth, so I think you’re correct in that kind of mindset.

DR LOVE: That kind of vibe. And the other thing is, can you talk a little bit more about the cellulitis, like what it looked like? I personally have never heard that as a complication of immunotherapy. Maybe the rest of you have. But where was it, and what did it look like?

DR RECKAMP: It was on his lower extremity, one more than the other, and it was swelling and erythema and looked very much like your standard cellulitis, but did not respond to antibiotics, got admitted for IV antibiotics, did not really respond until we started the steroids. And then it became somewhat clear that it was related to the immunotherapy rather than an infectious cause. But I had not seen it before that.

DR LOVE: So Ticiana, I’m curious. First, have you seen anything like this cellulitis? And also how do you think outside a clinical trial today you would be managing a patient in this situation?

DR LEAL: So regarding the cellulitis, I’ve seen it, and I’ve seen it with immunotherapy, but I’ve actually more commonly seen it with the taxanes. It’s like a pseudo-cellulitis. I’ve seen it with pemetrexed as well. In the cases that I’ve used taxanes or pemetrexed I’ve done short courses of steroids peri-chemotherapy, and it gets them through that bind, and then they’re able to do okay because there’s no infection, and it depends on how severe it is. But I’ve gotten some patients through by giving them dexamethasone peri-chemotherapy, kind of like you would do for nausea. I just extend it again for the pseudo-cellulitis.

I haven’t had it a lot with immunotherapy, mainly taxanes and pemetrexed, I actually had a recent case with pemetrexed which was a pseudo-cellulitis, and we managed that with steroids, so…

But regarding this patient I think standard of care I would give docetaxel. If there’s no contraindications for a VEGF agent, which this patient didn’t have, I would use docetaxel/ramucirumab. I haven’t really been using afatinib in the squamous population, although there is an approval. I just feel like the activity isn’t meaningful enough for the potential toxicities for patients in this line of therapy.

I think pembro/ram being part of Lung-MAP conflicted I think would have been a great option, as well, on trial. And I think seeing the data from the Phase II study the tolerability was favorable compared to docetaxel and docetaxel/ramucirumab.

But I think standard of care, definitely going with docetaxel, and then informed decision-making about the add of ramucirumab in terms of benefits and the adds of the toxicities.

DR LOVE: So Jacob, I’m curious how you generally would manage a patient like this, again, outside a clinical trial. Also the issue of would you add on as another option palliative care and not giving aggressive therapy? And when you get into this situation is that a realistic consideration that maybe you’re going to end up doing more harm than good? And tying into that also I’m curious, a couple years back we had the incredible work from Jennifer Temel and her group looking at early palliative care and the benefit that that had, and I think there was a message in there. I’m curious what the message you read out of that work and in general how you think through this clinical situation in your practice, Jacob.

DR SANDS: Yeah. The point of Dr Temel’s paper is an important one, that early involvement of palliative care actually led to longer lifespan along with better quality of life. I think the better quality of life is the obvious expected part, the living longer was a little more surprising to me but further makes the point that involving palliative care earlier can lead to better outcomes.

As far as palliative care, I still — I guess from that I’m more inclined to involve them, but that doesn’t mean I just blanket involve palliative care with every — for every patient. I think someone who’s having symptoms we work to control those symptoms, but if that simple — if that’s not resolved it’s better to have others involved in that discussion and evaluation, and I’ll involve palliative care. In someone where I anticipate high risk of early clinical decline I’m more inclined to involve palliative care as well. And one could say now in the second line of non-small cell lung cancer that is a scenario where things can clinically really change quickly.

As far as the therapy, docetaxel alone is more commonly what I use. There are select patients where ramucirumab is something I may consider more so in younger patients with excellent performance status, but it’s not something I use across the board in everybody.

I am very interested to see what comes of Pragmatica because I frankly was very surprised by the results of pembro plus ramucirumab in that initial single-arm study, and I would love to see that really play out longer term. And it really speaks to the fact that we still have so much to learn about pembrolizumab that by adding VEGF we may really extend the benefits of it, and so I’m very hopeful that the Pragmatica trial will demonstrate that.

Case – A man in his mid 60s, PD-L1 60% and no actionable mutations who received first-line single-agent pembrolizumab followed by the addition of chemotherapy and chemotherapy/immunotherapy maintenance for NSCLC

DR LOVE: Yeah. I’m really looking forward to, when Karen goes through that data, chatting about your thoughts concerning it.

Well let’s move onto another case. Corey, you have a 65-year-old man. What happened with him? A former smoker, 20 pack years.

DR LANGER: This was a gentleman with comorbidities including diabetes. He had presented with progressive cough and dyspnea. He was originally treated, you could say misdiagnosed for pneumonia, but did not get better, found to have a huge right pleural effusion. He was admitted outside to another institution, ICU, required a lot of oxygen, but after draining the fluid and 7 days of antibiotics, steroids, and nebulizers he finally got better, at least to the point that he could be discharged on nasal cannula.

The drainage showed adenocarcinoma, TTF-1 positive, was negative for p40. And again, when it comes to markers those are probably the only 2 you need to do to just differentiate histology. Doing an excess number of other markers starts to deplete the tissue, and we want to avoid that.

Unfortunately cytology was QNS for PD-L1 or NGS. He had a second tap, the same problem.

He was finally transferred to Penn. Brain scan was negative. PET basically lit up along the pleura with diffuse nodular hypermetabolic activity and hilar and mediastinal nodes with no evidence of extrathoracic metastasis.

And finally, because we really needed to know his PD-L1 and NGS, he had a VATS where he had guided pleural biopsies, intraoperative talc pleurodesis. This was further complicated with a persistent air leak, so he needed a special Heimlich valve. It took 2 to 3 weeks before the air leak finally resolved, and his lung was back up.

PD-L1 was positive at 60%. NGS and fusion panel were negative for any actionable molecular abnormalities.

And just by way of background he is always accompanied by his wife. I have never seen him alone. She often answers the questions I pose to him. We see that dynamic commonly. And he is a retired electrician.

Here’s his scan. You can see the pleural uptake. This actually predated the VATS procedure. A CPA angle node. And the initial dilemma we were faced with, how would we manage him. Would it be single-agent pembro? Remember, his PD-L1 was 60%. Would we be more aggressive with KEYNOTE-189? Would we use a 9LA regimen? Ipi/nivo with pem/carbo? Enroll on the INSIGNA trial or other?

So he got single-agent pembro, at which point he developed progression in the right lower lobe and retroperitoneal nodes. You can see the involvement on the right in the retroperitoneum. He continued pembro, and at this point we grafted pemetrexed and carbo onto that regimen, and then ultimately shifted to combination pembro/pemetrexed maintenance.

The progression occurred within 10 months, similar to Jacob’s case, but his response to the KEYNOTE-189 approach lasted over 2 years, and he stayed on maintenance pem-squared is what some call it, for 42 cycles, profound PR, but eventually developed worsening renal insufficiency. His creat I think ultimately hit 2.5, so we stopped initially the pemetrexed in December ’21 and then discontinued pembro earlier this year when his creat hit 3.

And again, you can see the improvement. A lot of disease here in the right lower lobe, consolidation, and if we go from right to left major decrease in the amount of involvement.

So he was observed off antineoplastics, placed on steroids for his presumed immune — checkpoint inhibitor mediated nephritis. His creat gradually improved to 1.7. Amidst all of this he developed CNS metastases. He underwent stereotactic therapy for that. He also developed chest pain and shortness of breath, so the comorbidities were starting to rear themselves. And again, these are smokers, or past smokers, so other medical issues don’t disappear. He required stents for coronary insufficiency.

Unfortunately, 4 months ago he developed recurrent shortness of breath. He was back on intermittent O2 with exercise, and his CT showed progression, you can see here on the right, with new right lower lobe masses.

So again, what’s the next step? Do we go back to pembro with or without pemetrexed now that his creat’s improved, perhaps with some steroids onboard? Do we use Karen’s approach, the S1800, resume pembro and add ramucirumab? Do we start docetaxel or docetaxel/ramucirumab? Or, particularly after this 2 1/2-year hiatus, is there a role for resuming carbo and adding a taxane, which he’s never been exposed to, and then adding either bevacizumab or ramucirumab?

Well, here’s the answer, at least what I did. We actually have an in-house clinical trial where we’re doing that, carbo with nab-pac, nanoparticle albumin-bound paclitaxel, carbo dosed at AUC of 6 with the nab-pac at 100 per m² days 1 and 8 every 3 weeks. Combined on trial with ramucirumab it’s specifically geared for patients who have had at least 6 cycles of maintenance pem/pembro. So it’s basically you could say a salvage regimen, a combination salvage regimen, in individuals whose disease progressed on KEYNOTE-189 maintenance.

But I think certainly any of the last 3 options could be reasonable, whether it’s docetaxel/ramu or the carbo combination. Resuming pembro and even pemetrexed in this gentleman with renal insufficiency is dicey, and I was not particularly disposed toward that. I think if push came to shove, and he started to have progression here, I would at least at some point perhaps contemplate going back to an IO.

DR LOVE: So you don’t know whether he’s responding yet to the current regimen.

DR LANGER: He is, actually. So the panel in the middle —

DR LOVE: Really? Huh.

DR LANGER: — on the right is the baseline. In this middle this is follow-up scans as of June, and you can see the nodules are starting to diminish. His pulse ox is back in the 90s, and he’s resumed most of his ADLs.

DR LOVE: So I’m going to ask Karen in a second to respond to the case and also preceding a little bit about her getting into the data your vision about whether there’s a difference in efficacy when you combine bev/ramucirumab, or a VEGF/TKI with an IO.

But first just 1 more comment from Corey. I was reflecting back on your comment about how you feel like you’re parachuting into a patient’s life, and I think in this case it sounds like you were parachuting into a war. What an incredible story to have to deal with all these complications. What’s it been like to — how has he and his family responded? I mean he’s been through a lot already.

DR LANGER: And we have constant discussions of whether it’s worth continuing, whether the continued toxicity, and also the — I guess the burden of his comorbidities is something that he can confront even as he continues to confront his cancer.

It’s a little bit like Karen’s patient, do or die, keep going until I say otherwise, and he generally cuts those conversations short. How can you not treat my cancer? Of course we’re going to go ahead. So I don’t tend to delve further.

If patients start to express some degree of ambivalence or particularly if family members do, then I will explore that conversation in much more detail.

He’s weathered the storm. He’s successfully gone through SRS for the brain. His heart seems to be functioning a lot better.

Fortunately or unfortunately we often end up becoming the de facto internist for these patients, and that’s probably not our role. I think ideally we need to keep the primary care doctor and other disciplines involved because we can’t manage it all. We can barely manage the oncologic issues, so the phrase it takes a village really applies to this gentleman, and he has a care team that includes at least 4 or 5 other physicians, and of course nurse practitioners.

DR LOVE: There were so many complications and things that you were just talking about, but has he had periods of time, even now, where he has a good performance status and feels good?

DR LANGER: Oh, yes. Absolutely. Before his kidney function started to deteriorate he was quite active. His big joy is going out to local diners having coffee, going to local bakeshops. I’m a big guy. He’s a much bigger guy. He’s pretty heavy, and food and eating are high priorities.

DR LOVE: Yeah. I’m still stuck on that whiskey club. I don’t know what a whiskey club is exactly. But anyhow, Karen, any thoughts about the case in general, and also my question about this, to me, a mystery of why antiangiogenics seem to potentiate IOs and which one works better?

DR RECKAMP: So yeah, I think this case gives us a lot of — a lot to talk about from the — I think the first thing that strikes me as you talk about, Dr Langer, with needing the village, and often with these patients who have multiple comorbidities and get diagnosed with lung cancer most of their physicians step away and say okay, you’re oncologist has got you now.

And there’s still a lot of nihilism associated with a diagnosis of metastatic lung cancer even though we’re in this era where people are living for years and years, which didn’t happen 20 years ago but is definitely happening now. So we absolutely need the primary care doctors and the whole group of specialists that the patient may have needed before getting diagnosed with lung cancer. So I think that’s important.

And I think, again, the importance of seeing that the patient got reintroduced to a carbo-based regimen after recurring I think is also really important. A person with this type of comorbidities you may see people thinking oh, let’s give him weekly docetaxel or something for somebody who is more frail. And I like the idea of going back to a platinum-based regimen after somebody has a prolonged period off because this is kind of what we would have done before the era of immunotherapy when we had a patient who did really well on the initial chemo, came off for a period of time. We would have reintroduced it, and so I do like that strategy.

And the question whether I would even think about potentially using the IMpower150 regimen and giving both immunotherapy and VEGF therapy for this patient in addition to the chemotherapy. But I like that, and I think we need better treatments than docetaxel and docetaxel/ram, and so I appreciate that this patient was able to get, again, more of a front-line regimen after a period of time off of therapy.

And so speaking of the VEGF piece, it seems to me so far as we get more and more of the Phase III data and negative trials that are coming out, that we do see a difference between VEGF-TKIs and VEGF antibodies. And this may be due to enhanced immunomodulation that we get with the antibodies. We see most of the VEGF combinations with TKIs and immunotherapy are active in diseases where the VEGF-TKIs are already active as single agents, which we don’t have in non-small cell lung cancer. So that may be part of it too. So I think there are multiple reasons why we have been less successful in combining VEGF-TKIs with immunotherapy in lung cancer.

DR LOVE: Just to follow up on that, Karen, what about the difference between ramucirumab and bevacizumab? Obviously they have slightly different mechanisms. From the point of view of potentiation of IOs do we know whether one is more effective than the other?

DR RECKAMP: I really can’t speak to that. I mean there may be some — the subtle differences may be important, but I don’t have — I think we’ve used more ramucirumab, especially in the refractory setting, because that’s kind of where it’s approved and where we’ve used it on patients. But I don’t have a good explanation for that at this point, and I don’t think we have the biology for that.

DR LOVE: Maybe Jacob — I’ve asked that question a million times. Nobody has any answers. But maybe, Jacob, you do.

DR SANDS: No. I don’t have an answer to that, but I did want to point out that in each of these patients they qualify for lung screening, and it likely was not done in these cases. And when we talk about what can be done to impact cancer mortality, not just lung cancer mortality, but cancer mortality, there’s probably not anything that exists that can impact cancer mortality as much as lung screening as the potential to do so just given the very high numbers of lung cancer fatalities.

And so I just wanted to take an opportunity to make the point that we see so many patients with Stage IV disease and really the majority of them likely could have been diagnosed in Stage I had they been getting yearly lung screening, which is USPSTF guidelines now for a decade, and this is just a really important message for us to continue to get out into other centers.

DR LOVE: That’s a really great point.

One other question I have before we get to this last case from Ticiana, to you, Corey. Every time I hear the word carboplatin nowadays I immediately think of the current shortage that’s going on, also with cisplatin. This comes up in every solid tumor program we do nowadays. I’m just kind of curious in non-small cell lung cancer, Corey, I don’t know if you’ve had a problem accessing carbo, but if you do or for those many people who do, what are you recommending? What’s ASCO recommending first-line therapy with — as an example?

DR LANGER: We’ve been hit by the carbo shortage. Fortunately we’ve just recently got a big shipment in that’s going to last us at least a month, but they’re scrambling. It’s been a big problem. It looks to be an ongoing problem, and it’s constantly blamed on supply line, but at the end of the day it’s health economics. There’s very little profit margin in making these generic agents, and I suspect it’s going to take more than just our pharmacies and our hospitals. It’s going to take legislation of some sort to make sure that lifesaving drugs, drugs that are used in the adjuvant setting with improved survival, that they’re adequately available.

In metastatic setting we do have the ipi/nivo combination, so there’s at least something we could potentially fall back on. I have on at least 1 occasion done that, but that patient had other potential indications, squamous histology, and I believe a PD-L1 that was not measurable, so a patient you might have considered going that approach regardless.

But it’s a huge challenge and something that’s always been there, but it seems to be a lot more pervasive than persistent at this point.

DR LOVE: So just to clarify, though, a little bit more. Karen, what do you recommend to someone who cannot access carbo?

DR RECKAMP: So yeah, if we cannot access carbo, and these are patients with refractory disease, they are going to be the first to not receive it. We’re going to save it for patients who are potentially curable, so more in the adjuvant or potentially neoadjuvant setting or in diseases that have more curable outcomes. So for that patient I think I’d be moving — you’d have to move to something like docetaxel/ramucirumab or something like that.

DR LOVE: Interesting. Well maybe we can — if you have any more thoughts about that we can talk about it later.

Case: A woman in her late 60s with NSCLC, PD-L1 60%, with complete response in the liver and lung to second-line tumor treating fields with atezolizumab

DR LOVE: But let’s do 1 more case. Ticiana, you have a 68-year-old woman. What happened with her?

DR LEAL: So this is a 68-year-old female. She’s a retired accountant, presented with loss of appetite, 20-pound weight loss over the past 4 months, fatigue, and shortness of breath on exertion associated with a cough. Her past medical history was significant for hypertension, which was well controlled, and hyperlipidemia. She had a diagnosis of microscopic colitis, collagenous colitis, and she had had like a mild flare 3 months prior to her diagnosis that did require management with lower-dose budesonide.

So on physical exam she has good performance status. She had mild wheezing on exam at initial encounter, and she ultimately underwent a liver biopsy. She had evidence of lung disease with a right hilar mass, hilar adenopathy, mediastinal adenopathy, and liver disease as well. Negative brain MRI. And she underwent a liver biopsy that demonstrated squamous cell carcinoma.

Her PD-L1, I’ll tell you about it in the next setting. She was treated at an outside hospital. But given her diagnosis of microscopic colitis outside consultant did not want to treat with immunotherapy up front so she actually underwent treatment with plain old carboplatin/paclitaxel for 4 cycles and then went on to observation; additional treatment was limited by development of neuropathy. And then imaging after that demonstrated progression.

The inflammatory bowel disease, the microscopic colitis, she had follow-up with GI, had been well controlled, hadn’t required any systemic immunosuppression beyond budesonide with the local effects and lower-dose budesonide for about 8 months.

So here is the imaging at progression. She’s had now evidence of progression with worsening disease. You can see some cavitation in that lung with associated adenopathy, and the liver metastases are shown on the right.

Her PD-L1 was done at consultation with a PD-L1 of 60%, and here no genetic testing was performed with the squamous cell carcinoma. She did initiate treatment now. We had this long discussion about did she qualify for the LUNAR study given her prior diagnosis of well-controlled inflammatory bowel disease. And given the mild flare that she had, after discussion and meeting criteria for the trial, she actually enrolled with the choice of atezolizumab, the PD-L1 inhibitor, as the systemic therapy associated with tumor treating fields therapy.

She did well, and she achieved a CR with response rate in the liver, as well as in the lung, although she had the residual cavitation there.

Her main side effect with the treatment was Grade 2 rash, and this was associated with tumor treating fields therapy, and it was associated with the adhesive bandages and was not a widespread rash. Given the Grade 2 nature this was managed with holding tumor treating fields therapy for 1 week, and then we used topical steroids and educated her on skin care. You have to rotate the adhesive bandages about 2 cm every 3 to 4 days making sure that the skin was dry and clean and also just applying emollients. And she did well and stayed on therapy for a total of 8 months and then went off for progression.

DR LOVE: What’s her current status?

DR LEAL: So this was a patient that I treated at the University of Wisconsin, and the study actually was done a long time ago, so I don’t have the follow-up for her, but the standard of care for her at that time would have been docetaxel plus/minus ramucirumab.

DR LOVE: So interesting. So Corey, I’m curious what your thoughts about this case. I guess one thing would be the outside oncologists decided not to use an IO in spite of the fact that she had a PD-1 level of 60%. I’m curious, given what you heard about her autoimmune history, what you — do think you likely would have also held off, or you maybe would have gone ahead with an IO, Corey?

DR LANGER: I would have been conflicted, but I think I might have gone ahead assuming the outside consultants, rheumatology and GI, were following the patient along with me. The patient’s collagenous colitis was under good control. We will often institute immunotherapy in individuals who are on low-dose steroids, 5 or 10 mg of prednisone a day. We’ll resume the IOs after they’ve had toxicity management with steroids at those dose levels. I don’t know what the full dose was, Ticiana, but I think that might have been a situation where I would have bent the rules.

And needless to say this individual would not have qualified for a clinical trial that allowed immunotherapy, but I think in the real world in actual clinical practice many of us have started bending the rules. We’ve developed at least some comfort level with milder disorders.

The 60% is awful compelling, and whether it was pembro or pem combination with platinum and carbo it would have been a debate. With the liver mets I think I might have done the triplet.

I’m intrigued when Ticiana mentions that the patient responded to the tumor treating fields, and that included the liver lesions, but the tumor treating fields are not necessarily in continuity. They’re over the chest lesion. Isn’t that correct, Ticiana?

DR LEAL: Yeah. The tumor treating fields does reach the upper abdomen. And again, we’ll talk about this in our discussion, but the thought that perhaps tumor treating fields with IO can lead to immunogenic cell death and have systemic effects versus local effects or the combination I think is still being investigated.

DR LANGER: I think that many of us would call than an abscopal effect or perhaps some combination thereof, and that makes the whole notion of adding this device to standard treatment, particularly to immunotherapy, where it’s shown the greatest benefit, as Ticiana will expand upon, quite attractive.

DR LOVE: Just to be clear, though, Ticiana —

DR LEAL: I will say this case was like — this case was a long time ago, so remember we didn’t have PD-L1 testing in 2015.

DR LOVE: Interesting.

One thing I wanted to clarify, Ticiana, the way the device is set up does it actually cover the liver? Or how much of the liver does it cover if it does?

DR LEAL: So the arrays are — they are placed on the patient’s chest, and it covers the upper abdomen. The way the treatment plan is created is based on the patient’s CT scans. So there is some coverage of the upper abdomen, which will include the liver, the upper part of the liver. It doesn’t include the entire liver.

DR LOVE: So I meant to ask you before we got started maybe just a show of hands other than Ticiana, the 3 of you, how many of you actually had a patient who got tumor treating fields?

Okay. So I guess Ticiana’s the only person.

So I’m kind of curious. We get a lot of questions, Ticiana, and we’ll talk about this later, too, but just since you brought up this woman, what her quality of life was like and how much was it impacted by the therapy. Also what you’ve seen and how her skin reaction or irritation compares to others. We heard the same story, it’s being used in ovarian cancer, so I heard a couple cases there. But I’m just kind of curious what it was like for her to use the device.

DR LEAL: Yeah. At the time it was kind of a — and I think even for now it’s a very novel way of thinking about treating lung cancer. So this patient was randomized to tumor treating fields therapy. We had a lot of education, and for us it was all novel as well. We had a lot of support from the device company, who really did troubleshoot a lot of the device-related issues at the patient’s home.

The rash itself was kind of like a folliculitis kind of rash, and it was localized to the area but certainly got to the point where we felt we needed to hold to make sure that it got better, and then we were able to reintroduce it with these measures.

In terms of the quality of life, the main thing was just coping or dealing with having the device on for 18 hours a day or as close to 18 hours a day as possible. That part was a bit of a challenge for her, to make sure that she had it for 75% of her day. She wore it as a little backpack and took it to places. People didn’t know she had the device, so there wasn’t a social concern about it. It was more just being aware. And I think for her it was a little bit about like it reminded her that she had to wear a device because she had lung cancer. And so she kind of had to cope with that idea, and I think she did as best as possible, and we gave her all the support that she needed.

One thing that we had at the University of Wisconsin is we had palliative care in clinic with us. So I’m a big believer of early palliative care just for that support, and I always tell my patients this is an extra layer of support, and they were also very helpful in providing additional recommendations even outside of the trial to help her cope with this new idea of having a device.

DR LOVE: Yeah. It’s very interesting. I never thought to ask. I kind of assumed that it would be obvious to people that the patients were wearing a device. It’s very interesting that you’re saying in fact that it is not.

I’m just kind of curious, Jacob. We’ll talk more about this later after we take a look at the data, but just thinking about this type of therapy I was just reflecting, we did a webinar on pancreatic cancer, where they’re also studying tumor treating fields, so we were talking about it. And pancreatic cancer, chemotherapy really doesn’t work very well, immunotherapy doesn’t work, targeted therapy doesn’t work, and I was like well at least it’s another strategy, a different type of look, or a different type of approach.

Any thoughts about this, Jacob? People — I remember at the Society of Neuro-Oncology 10 years ago when this first got introduced, and everybody is like what is this? Any thoughts in general about if it does turn out that we have convincing data how people are going to react to the actual pragmatics of this, Jacob?

DR SANDS: Yeah. That’s such an important point that Ticiana brings up, is wearing that around reminded the patient that they have cancer. And I was kind of getting at that aspect earlier, I think, with hair loss. That’s another one of those things where yes there is a look to it in such, but for patients they’re now looking like what they picture as someone with cancer. And first line getting carboplatin, pemetrexed, and pembro, for example, although patients are getting chemo, they walk through the store, and nobody knows that they have it. This one is kind of a blend of those because walking around with a backpack nobody knows, but the patient is reminded constantly of that and can’t mentally escape it.

And it brings up that aspect of care that I was kind of alluding to at the initial case in that so much of the work is deciphering where patients are psychologically and mentally and emotionally and then tailoring our discussion to really where they’re coming from.

Many patients — or I’d say everybody experiences life in an emotional way, and we tend to discuss cases in these intellectual ways. And for patients I think that’s where the real disconnect, where patients feel like you’re not talking with each other but kind of past, is that they’re discussing things emotionally, and we’re coming at them in these very intellectual ways. And so recognizing that, like Ticiana did, with this patient, and then being able to kind of find ways to help them process that or picture it in a different way.

And in some cases a common way with chemotherapy, for example, is people will kind of picture it as being this terribly toxic thing, and so there’s a lot of fear around that. And so I’ll try to discuss it more as this army going in to attack the cancer, and just the way that they’re mentally holding the imagery around some of these things. And for some people that works, and for some people it doesn’t, and frankly I also — it’s hard to even imagine, even though I’m seeing these patients all the time, where they really are and where that internal challenge really is. But it is an aspect of oncology that I think is really important in optimal management.

DR LOVE: Yeah. These are such great comments, really interesting. All of our work — we go to the Oncology Nursing Society Congress every year, we usually — this year we did 10 symposia, but the umbrella under that is called “What I Tell My Patients.” And I think people value so much, particularly new to oncology, like what do you really — what do you say? These pearls that come out, and hopefully we’ll get a lot more as we go through this program.

Current Management of NSCLC After Disease Progression on Anti-PD-1/PD-L1-Containing Regimens — Dr Langer

DR LOVE: We’re going to shift now and get into the presentation part and Corey is going to provide some perspective on second-line treatment, the main topic that we’re talking about today, since in general that’s where people post IO are getting treated. Corey, could you please go through your slides?

DR LANGER: Thank you, Neil. This has been a great discussion so far. So I’m really going to set the stage for what I think is the current standard of care and hopefully my colleagues will show how that’s going to change. This is my current paradigm for front-line treatment, at least as of this month. I think it could change at any moment. But certainly 50% or higher of PD-L1 we treat with — generally with pembro either alone or combined with histology-appropriate chemo if patients are highly symptomatic or have large tumor burden. For less than 50% generally it’s histology-appropriate chemo plus pembro. There is an indication for pembro alone with any degree of PD-L1 expression, but by and large that is not favored.

For no PD-L1, high TMB, perhaps squamous histology, you can make an argument for ipi/nivo or 9LA. For those who are TKI refractory, and Karen talked about these individuals, probably about 30-40% of our population these days, the role of IO is less well settled. So pem/carbo with or without bevacizumab would be a standard in nonsquamous, or as she mentioned the IMpower150 regimen, pac/carbo/bev/atezo, but again after the patient’s established progression on the appropriate TKIs. And I think when it’s QNS, and we’re reasonably assured that the patient probably doesn’t have a molecular marker, we default to either 189 or 407. Of course the POSEIDON approach, which is essentially 9LA on steroids with the chemo continued beyond 2 cycles but continually, is also an option.

This is the INSIGNA trial, I included it as 1 of the choices in my case, taking patients with PD-L1-positive nonsquamous and randomly assigning them to either pembro alone or pembro combined with chemotherapy, so a direct comparison of 024 to 189, but with progression — at the time of progression testing whether continuation of the checkpoint inhibitor beyond progression actually adds to outcome. So there are actually 3 arms. So Arm A, at the time of progression they go on to chemo alone. Arm B, chemo combined with pembro, and that theme is carried on, as well, with the S1800 and ongoing Pragmatica trial; does continuation of IOs beyond progression confer any benefit?

In this era of checkpoint inhibitors we are seeing 5-year survival rates now 30%, sometimes higher, with high PD-L1, but the majority of these individuals still will experience disease progression after checkpoint inhibitors with or without chemo, most within a year of treatment initiation. And once progression manifests, death, unfortunately, with rare exception, is inevitable.

The mechanisms of checkpoint inhibition really have to do with the immune cascade, inability of T cells to traffic into tumors, failure to actually infiltrate within the tumor itself, the failure of T cells to recognize the tumor even if they are at the tumor site, inadequate cell kill or inadequate release of antigens that can stimulate the T cells, whether it’s in the nodes or elsewhere. And at each point there are additional checkpoints or regulatory processes that can be manipulated, and this is really — underscores how we are trying to combat this, at least in trials.

Vaccines, of course, are being added to checkpoint inhibitors. These are generic or personalized. There is a role for potentially adding chemoradiation, for that matter microwave ablation or other ablative approaches, in the hope of triggering tumor antigen release and immune stimulation. Adoptive T-cell therapy is being looked at, including CAR T, and then of course an array of monoclonal antibodies targeting either costimulatory signals or removing coinhibitory signals. And again, there are scores of trials evaluating these approaches in this setting.

So we set the stage. The standard of care, I would argue, is still docetaxel with or without ramucirumab. Whether other cytotoxics have a role is debatable. Ticiana’s going to talk about tumor treating fields, Jacob about ADCs in depth, and Karen will talk about the continuation of checkpoint inhibitor combined with angiogenesis inhibitor, in this case pembro/ramu.

There is another approach. We haven’t really talked about that, and that is local ablative therapies for oligoprogression, and I would say about 30% of my patients are experiencing oligoprogression. In that situation it may be completely feasible to continue the checkpoint inhibitor along with local radiation.

The REVEL trial is — actually predates the IO ERA, second line, included both squamous and nonsquamous, docetaxel the standard of care plus or minus ramucirumab, with the primary endpoint of overall survival. And you can see it hit the primary endpoint, a p-value of 0.0236 with a hazard ratio of 0.85. You also see a month and a half improvement in progression-free survival and an improvement in response rate from 14% to 23%, and the p-values in this very large study were highly positive.

So this was the first study in second-line non-small cell to show a survival benefit versus docetaxel alone. It took us nearly 20 years to get to that point. It was only another year when the checkpoint inhibitors emerged on the scene, and this was the first study I’m aware of to show a benefit for an angiogenesis inhibitor in squamous cell. You can see the curves, statistically significant, clinically modest improvements in both progression-free and overall survival, but it’s still my standard of care outside of a clinical trial.

When it comes to toxicity there is a slight increase in pulmonary hemorrhage, from 2.4% to 3.8%, but I would argue 5% or less is probably acceptable, and I think even though there is increased toxicity, including febrile neutropenia, this combination is doable. I tend to adopt the Japanese dose, 60 per m², as opposed to 75 per m². You do see increased incidence of hypertension, leukopenia, but these are by and large manageable.

The big question is what are the data for this combination post IO era. So this is a retrospective analysis from Japan looking at 152 patients who had been treated with nivo, many in the second-line setting, who then went on to salvage cytotoxics, 40 of whom — about half received combination ramucirumab and docetaxel. And the response, you can see the demographics on the left. The duration of prior nivo is pretty short. It was only about 2 months. Response rate here was 60%. So again, a small series, but pretty impressive. The disease control rate was essentially 90%. There were no surprises when it came to toxicity.

Another trial from Europe looking at docetaxel and ramu, again as palliative second line following first-line chemo plus checkpoint inhibitors, more modern era, published just 2 years ago in Treatment of Lung Cancer Review. 77 patients. Response rate of 33%. Disease control rate of 62%. Median PFS just under 4 months. A somewhat less salutary median survival, 7 1/2 months, with KRAS mutations harboring poor outcomes and lower PFS.

Then finally, probably one of the biggest real-world experiences is combination ramucirumab and docetaxel in the REACTIVE study. This was from Japan. It looked at 280 individuals.

Virtually all got the 60 per m² dose, which I typically use. They received a median of 4 cycles of therapy. The response rate here about 28%, disease control rate about 60%. You see a PFS of 4.6 months, a median survival of 11.6 months. In multivariate analysis nonadenocarcinoma histology and poor performance status, no surprise, were associated with poorer progression-free and overall survival.

Finally, in the last minute or so, other second-line strategies. Is there a role for bevacizumab beyond progression? What about the afatinib approach that Karen had alluded to? This is a trial I was associated with, the AvaALL trial, which is a randomized Phase III of standard of care, at that time pemetrexed/docetaxel/erlotinib, with or without continuation of bevacizumab beyond progression. This is the study schema, and the bev could actually continue beyond second meaning third progression.

Overall survival is the primary endpoint. The secondary endpoints included PFS2 and PFS3, and that’s progression — time from randomization to second and third progression. Primary endpoint was not met. The hazard ratio here is 0.84. You see a numerical 1 1/2-month advantage with a p-value of 0.1. But PFS3 actually was met. You see a statistically significant improvement in — or delay in progression if you continue bev beyond even the second-line approaches, a hazard ratio of 0.63 and a p-value of 0.045.

So a potential approach, but I think the conclusion, the last bullet, really applies to our modern era, can we apply angiogenesis inhibitors to immunotherapy combinations.

And final the LUX-Lung 8 trial that led to afatinib’s approval specifically in squamous in second line, again predating the IO era, a direct comparison to erlotinib. Remember, before the era of targeted therapy erlotinib had a blanket second and third-line approval regardless of histology, so it was, you could argue, at least a standard at that time. A big trial, nearly 800 patients, half of whom had responded to prior chemotherapy. Virtually all has squamous histology.

And in fact, the study was positive. You see a 1.2-month improvement in median survival, hazard ratio of 0.83, and a p-value, and this is the update just from 2 years ago in Clinical Medicine, p-value of 0.0193. But as Karen implied we don’t tend to use it very much. PFS was significantly improved. Response rates were really low, 5.5% compared to 2.8%, disease control rate of 50% versus 39%.

Finally, this is an ongoing trial at our institution. I alluded to this combination carbo with nab-pac or solvent-based paclitaxel 80 per m² days 1 and 8 combined with ramucirumab. And this is specifically designed for individuals who’ve had disease progression on pem/pembro in the KEYNOTE-189 regimen. We’re accrued about 12 patients to date.

DR LOVE: So just a few follow-up thoughts. Maybe I’ll start with Ticiana. Any thoughts about why we see progression on checkpoint inhibitors, mechanisms of resistance, predictors of benefits? And any personal hopes you have about any particular strategy to try to improve benefit? I guess the addition of antiangiogenics certainly would fall into that category, but I’m just kind of curious, Ticiana, what are your thoughts about how we can improve activity of checkpoint inhibitors?

DR LEAL: Yeah. One thing that I think is increasingly important is to identify not only predictors of benefit but predictors of potential risk of lack of benefit, so talking a little bit about NGS and looking at those negative NGS bad actors like KEAP1 and STK11, and do we need to treat those patients in a different way given the concern of lack of benefit in patients with these mutations. So that’s one thing.

Continue to work on biomarkers of benefit is another one. We know PD-L1 is a marker of benefit. We saw the patient in our case with high PD-L1 that had less benefit than we thought they would with Dr Langer’s case, realizing that PD-L1 is a good biomarker but not perfect. So I definitely think we might need a combination of biomarkers to look at benefit from immunotherapy.

In terms of second line and beyond, I think the 4 cases we discussed really outlined how this is a population of high unmet need. Every single one of us actually recommended a different therapy than the standard of care for our patients, and I think that says a lot, and I think that really means that doing clinical trials and getting the answers in a prospective fashion.

I’m not really impressed with the activity of docetaxel/ram post IO on its own. I think there’s a lot of retrospective data. But the overall survival there is still like 8 to 9 months, and that is not better than the retrospective studies that we’ve seen with post progression use of IO.

I definitely think the strategy of the Pragmatica study looks very promising, hoping to see there the combination of IO plus ramucirumab panning out. And then I think we need to think beyond the platinum rechallenge setting, which is really hard for patients. There may be a role, but the toxicities are really high, and can we develop better therapies with better duration of response for our patients. Thinking about novel checkpoints, I think, is going to be key, and then also of course the ADC story.

DR LOVE: So Jacob, I’m curious about your thoughts about how we can get more out of immunotherapy. I’m curious whether you think — obviously anti-CTLA4 is being pursued. I’m curious whether you think that has much future. Also other checkpoints. We just did a webinar last night on melanoma. We were talking about relatlimab, the anti-LAG3 agent, whether other checkpoints might be helpful in the future, Jacob. Any thoughts?

DR SANDS: Well, I’ll admit I’ve never been a big proponent for CTLA4 inhibition. It just seems that overall the majority of patients there tends to be a bit more toxicity than benefit. That being said, there is a compelling tail to the curve that identifies that there might be a subset of individuals that truly are benefiting. I don’t think we’ve yet really been able to identify who those specific patients are.

There are kind of some generation CTLA4 inhibition that I think we’ll see if that helps improve some of the efficacy versus toxicity. And so there’s certainly more to the story, and I don’t mean that as a closing of the door entirely, but just that I don’t think we’ve yet really identified them.

As far as other immunotherapy drugs, like LAG3, there’s a lot of enthusiasm about that. I haven’t really seen results to celebrate in the same way as what we’ve really hoped for. Actually, the thing I’m most excited about really is something that Dave Barbie’s lab, a colleague of mine, looking at EZH2 inhibition and how that might help impact some of the outcomes. This is still preclinical data, and some of this is now hoping to bring into the clinic. There are some clinical trials now happening with EZH2 inhibition.

And so we’ll see what some of that shows, but as far as what’s being used in the clinic right now there isn’t — there isn’t something that’s really the PD-1/PD-L1 inhibitor level, like that changed the paradigm.

DR LOVE: So EZH2, like tazemetostat?

DR SANDS: That’s right.

DR LOVE: Interesting. So the idea, you combine that with an IO?

DR SANDS: Yeah. That is one of the trials that’s out there. How exactly these alter the immune environment there’s still a lot to learn from that.

Now this is something particularly within small cell that I’m very interested in, and some of his work has really been around small cell. How these might translate into other settings there’s still a lot to know.

I think what I’m highlighting is really that I think it’ll take some years to develop some of what I find the most compelling concepts. LAG3 is something that, gosh, I think like 8 years ago I was really looking forward to that coming into the clinics and such, and unfortunately that hasn’t really panned out, at least thus far, in the way that we had hoped. So I guess I still think we’re kind of some years before we see a next-level paradigm shift.

DR LOVE: So a final comment from Karen, anything you want to add to this discussion? Any new research approaches that have you excited or interested, particularly something that might add onto immunotherapy, but even beyond that?

DR RECKAMP: So I think that the first comment is that as we’ve seen here this is a very heterogeneous field. There is no 1 kind of second-line, subsequent line, so we have patients who have received single-agent immunotherapy, PD-1/PD-L1. We have patients who have received immunotherapy with chemotherapy, potentially patients who have received combined immunotherapies with CTLA4. And the — some of these are primary resistance, some of these are acquired resistance, and then the multitude of possibilities, as Corey pointed out, of acquired resistance are many.

And so to treat them as 1 group, I think that’s where we do a disservice. And as Ticiana mentioned, we make these decisions that are very subtle based on how long they were on prior therapy, what toxicities they had, whether they responded to single-agent immunotherapy. We’re thinking about all of these things, and it’s a very complicated algorithm that we’re looking at. And then we decide in a trial that we’re going to lump all these patients together and treat them together, and then we get a multitude of negative trials. And so I think we have to think more strategically about how we’re doing this, and I think that ultimately selection is going to be beneficial in this subsequent-line therapy if we can find those selection markers. But that’s been elusive to this date, and I don’t have a marker that is the magic marker right now. But I think that’s where we need to go, and we need to understand why patients are having tumor progression post IO and start to be more — have more rational designs for our trials.

Potential Role of Novel Immunotherapy-Based Combination Strategies in Progressive Advanced NSCLC — Dr Reckamp

DR LOVE: Okay, so we’re going to continue now with our presentation, and Karen is going to talk about the potential role of novel immunotherapy-based combination strategies. Karen, could you please go through your talk?

DR RECKAMP: Thank you. So this will focus mainly on immunotherapy-based combinations with antiangiogenics since there’s a lot of data in that area. This is just the background that we saw from Corey that we have approved options. The nintedanib is a European option, but what we see here is that the progression-free and overall survival still leaves a lot of room for drug development in the second-line and subsequent treatment setting.

So thinking about angiogenesis, we do know that angiogenesis can modulate the immune system and that VEGF can induce PD-L1 expression, especially on dendritic cells, and suppress the maturation of T cells and impede T-cell extravasation. It can inhibit proliferation and cytotoxicity of the CTLs and stimulate proliferation of regulatory T cells in the immune microenvironment and also can mediate the effects of myeloid-derived suppressor cells so causing an immunosuppressive environment overall. Inhibition of VEGF can restore many of these phenotypes. VEGF receptor 2 specifically may decrease the infiltration of suppressive immune cells while increasing mature dendritic cells.

So combining the blockade of PD-1, specifically pembrolizumab, and VEGF receptor 2 with ramucirumab may overcome resistance by reducing neovascularization, upregulating proinflammatory cytokines, and modulating the tumor microenvironment.

So we know that VEGF and VEGF receptor inhibition has been combined with immune checkpoint inhibition successfully in the clinic. Most of the FDA approvals that we have are based on front-line therapy and immunotherapy-naïve patients rather than pretreated: renal cell, endometrial, hepatocellular. Many of these are with TKIs, and again, most of these are where TKIs have been approved as single agents, and then have shown benefit with the combination, and then the bevacizumab/atezolizumab for hepatocellular carcinoma.

And again, we know that pembrolizumab is an anti-PD-1 monoclonal antibody, ramucirumab is a VEGF receptor 2 monoclonal antibody, and there was preliminary data showing safety and efficacy with the combination of pembrolizumab and ramucirumab in a Phase I trial across multiple tumor types, including non-small cell lung cancer.

So based on this we performed a randomized Phase II trial, which was the S1800A, done in the LUNG-MAP platform. And these were patients who had had prior immunotherapy and had at least benefitted at least 84 days and had had platinum-based doublet chemotherapy and had progression, with ECOG performance status 0 or 1, and they received either standard of care therapy or ramucirumab and pembrolizumab on the experimental arm. And the standard of care were specified in this trial as docetaxel/ramucirumab, docetaxel, gemcitabine, or pemetrexed for nonsquamous non-small cell lung cancer. And the planned accrual was 130 patients.

In this study the bottom line showed that we saw an improvement in overall survival for ramucirumab and pembrolizumab with a hazard ratio of 0.69, and the median overall survival for the combination of ramucirumab and pembrolizumab was 14.5 months versus 11.6 months. So a significant benefit, and I think importantly the majority of patients in this study had received docetaxel and ramucirumab as the combination with the highest response rate and survival in this setting.

And when we look at these subgroups we found that all subgroups had hazard ratios of less than 1. PD-L1 status did not appear to alter the outcome. There were more patients that had overall survival benefit that had squamous cell histology, and those who had received chemo followed by IO potentially higher benefit. This is also in part just due to the timing of where patients were enrolled, that there were less patients getting front-line immunotherapy in the beginning of this study. And then like STK11 and KEAP1, we looked at — these are very small numbers, but also seem to benefit.

So what about other — what about the receptor tyrosine kinase inhibitors? And we have to remember that when we think about the TKIs for VEGF and VEGF 2 that they are actually multitargeted and have — also blocked things like AXL and MET and FGFR, and we know that we’re getting a multitude of potential immune modulators in addition to the VEGF modulation.

So some of the data that is out there is cabozantinib and atezolizumab, the COSMIC-021 study, again showing responses, about a little less than 30% response rate and progression-free survival about 4 months with that combination. And based on this there have been multiple evaluations in multiple patient populations, but this was presented at ASCO in 2020 and showed in patients who had refractory — highly refractory disease and highly pretreated disease that there were patients who had responses here in the — all patients we had a disease control rate of about 65% and progression-free survival of 4.5 months. And this did not differ also by PD-L1 status.

And then the studies, the Phase III studies that are ongoing, the CONTACT-01 study, which is cabozantinib/atezolizumab versus docetaxel. We got a press release in December with 366 patients enrolled. The overall survival endpoint was not met. There was a Phase II study randomized that is still recruiting and is more specific to the MET, RET, and ROS1 populations, so more selected use of cabozantinib in combination.

And pembrolizumab and lenvatinib, highly anticipated results for this study. This combination is being used in the front-line setting and in subsequent-line settings. The LEAP-008 study is in the refractory setting. Again, a Phase III study looking at about 400 patients, and we do not have data for this study yet.

So the sitravatinib and nivolumab study, this was actually published and presented by Dr Leal here. But again, responses seen with the combination in early Phase II data, and some patients with prolonged progression-free time. Here it shows sitravatinib and tislelizumab, another PD-1 inhibitor, again with modest response rates but overall survival in the 10-month range.

So the SAPPHIRE trial, a Phase III trial looking at sitravatinib and nivolumab versus docetaxel again. Again about 500 patients enrolled, so in May of 2023 we had another press release showing that the primary outcome of overall survival was not met for the study, and we await that presentation of the results.

So the HUDSON trial that looked at multiple combinations with ICI in the pretreated population looking at olaparib, ceralasertib, and the results showing here, looking specifically at the ceralasertib combination, which showed the highest progression-free and overall survival in patients. And this is moving on now to the Phase III LATIFY trial, which is ongoing. And again, the combination with a progression-free survival of 5 months and overall survival with an impressive 17 months. But again, these are single arms in multiple — in multiply treated patients post IO.

And so then moving forward, just discussing our S2302 Pragmatica-Lung trial. So this was, again, a study that grew out of the S1800A trial. And again, what we wanted to do was look at the 1 question of overall survival.

So this did receive breakthrough approval by the FDA for the ramucirumab and pembrolizumab, but due to the smaller Phase II study most want additional data to move it forward into something that they would use as standard of care. In order to bring these 2 drugs together we really needed a partnership with the FDA and CTEP that helped us to think more pragmatically about how to answer this question and hopefully answer this question quickly while it is still relevant.

And so this is a large trial looking at 700 patients and does not pre-prescribe the standard of care arm, and it is really what you would do in your standard practice. We’re trying to impower investigators to do what they would normally do, but we do lead them to the NCCN Guidelines. And then Arm B is the ramucirumab/pembrolizumab, and we are simply looking at overall survival. So this helps us to ask this in a very pragmatic way and reduce the burden of data collection, so I think that’s one of the most important parts of this study.

And the secondary objectives are to look at high-grade unexpected adverse events, and so we expect that probably about 10% of unusual adverse event reporting will be required for this study. And so this study is mostly to just answer the overall survival question for ramucirumab and pembrolizumab to potentially make this an option for patients in the standard of care setting.

So again, we want to impower investigators to treat patients as they would in the real world, decrease barriers to enrollment, there are very few eligibility criteria for this study, and minimize the data collection.

And just an example, for the Pragmatica study we were focusing on stage, prior therapy, performance status, and safety for our eligibility. We enroll and treat patients as they would in the real world with institutional guidelines and investigator discretion, and minimal items are collected. We don’t collect labs. We don’t collect imaging or RECIST. These are all done as standard of care.

And again, the data capture, we have reduced the timepoints for data submission, and reduced the number of forms. There are no CT imaging or assessment forms, no lab forms that need to be filled out, no specimen collection. And again, the AEs, only high-grade AEs that are related and unexpected, and all Grade 5 AEs.

So this is significantly reduced data, and so there’s less data to monitor and audit in this study.

So we’re hoping that this will allow sites to open trial and again utilize their resources to enroll patients and not worry about some of the details that probably never even get looked at in the submissions and really focus on the idea of survival and high-grade toxicities in these drugs that we know a lot about their safety and efficacy.

DR LOVE: So I’ve got to say wow. I did not know all that stuff about the Pragmatica study. That is super interesting. I want to hear a lot more about that. That is really cool.

I want to start with you, Jacob. So 2 issues, at least from my point of view that I’m curious to hear about is — one is just what do you think about this strategy of basically continuing pembro and adding in ramucirumab, where you think it’s heading, but also this really fascinating approach, the Pragmatica study. Any thoughts?

DR SANDS: Yeah. So to me it was surprising, the data was surprising. I would have anticipated if I had to guess more of a progression-free survival than overall survival benefit, and it was obviously the reverse, which I found intriguing.

The Pragmatica trial is an exciting one in really revolutionizing the way that we’re doing clinical trials, hopefully. I think a lot of times our trials end up being held back by being so rigorous about enrollment criteria and all of this that we end up enrolling really a different population than the average lung cancer patient. This is more relevant particularly in small cell lung cancer, where it’s a more rapidly progressing disease, and then we require all these biopsies and these various other testings to be done prior to enrollment, which means that we’re not enrolling patients with faster-growing disease. To have a trial that really allows for a more pragmatic approach is exciting, and it’ll be really interesting to see what the experience is with that.

DR LOVE: So Karen, I’d like to hear a little bit more about who’s been involved in addition to you and where this idea came from. Is this all coming out of the cooperative groups? Is industry involved? And who’s — did the pandemic have anything to do with this? Can you kind of tell us a little bit more? I don’t know whether I’m the last person to hear about this or not, but I just think it’s really interesting and would love to hear more about why it’s happening.

DR RECKAMP: Yes. Thank you. I think that this was — this grew out of, again, the S1800A. We had a combination of pembrolizumab and ramucirumab, that’s 2 different industry partners in that combination, and drugs that are approved for many indications with well-known toxicities.

And the LUNG-MAP platform has been highly integrated with the FDA and CTEP and Friends of Cancer Research and FNIH to run it, and so part of the mechanism has allowed some of our industry partners to potentially interact with the FDA about study design a little more fluidly. So it did come after the S1800A study. This came from a discussion with our industry partners and with the FDA and with CTEP saying we want to do that Phase III trial, but we understand that potentially the industry partners are not engaged enough to put what they would normally do into a Phase III trial because these are 2 different companies with drugs that are approved in multiple areas.

So then it became a creative discussion, and it was — a lot of that was led by Rick Pazdur at the FDA saying how do we do this in a pragmatic way. And this was on the — just on the edge of when both the FDA and the NCI were starting to talk about pragmatic designs and what that meant. And so it really got these conversations going, and I think the timing of it was really impeccable. I’m not sure that it had to do with post COVID, but I think also interestingly we’ve all suffered from the great resignation and restructuring with hybrid work for our research staff, and it's been a little bit of a struggle.

And the pure amount of data that needs to go into a database for a Phase III registration trial and the amount of monitoring and auditing and all those things, and the burden on our staff, is huge. And so to run a trial like that is not a small thing. So to take away all of those layers and say we know that there’s a survival benefit in this Phase II trial. We’re only going to answer that 1 question, we know the safety of these drugs, they’ve been used in thousands and thousands of patients across multiple diseases, and we’re going to cut back all of the excess, and we’re going to just get to those questions. And that was the basis of it, and the support kind of started to grow around that idea.

DR LOVE: So interesting. Corey, I’m curious about your thoughts on that, also LUNG-MAP. I was flashing on the old BATTLE study that started at I think it was MD Anderson, where they — to me that was the first example. Now you see it throughout oncology. Any comments, again, on how they’ve been approaching it with this Pragmatica? And also, Corey, I always view you as the eternal skeptic. What do you think about this strategy? Do you think in a couple years that’s what we’re going to be doing or even before then?

DR LANGER: I hope it’s what we’re going to be doing, at least a new standard of care. So LUNG-MAP was actually spawned in part by the BATTLE study from MD Anderson, and as best I can determine it’s going to be immortal. It started out as a study looking at biomarker and biomarker nonspecific agents in second-line squamous cell and now has morphed into basically second-line all comers regardless of histology. We have separate molecular components of the study. It’s multiple studies under 1 rubric, so a single IRB approval without having to get separate trials approved.

For the wild-type population that do not have molecular markers a number of studies have been done under that rubric, and Karen’s, frankly, has been the most successful to date. It’s the only one that generated positive data. But it was a joint partnership, as she’s pointed out, between industry, CTEP, cooperative groups, and community oncologists, and also by the FDA, ultimately, generating Pragmatica.

Pragmatica is high risk but high reward. Both Jacob and Karen have pointed out all of the benefits of doing this, the cutting down on expense, cutting down on the sheer volume of paperwork, on the headaches that are involved with this, on all the audits and other problems that go into clinical trials.

My biggest concern is the inclusion of PS2 and PS3 patients who will no doubt go on, and I worry that while we will see a benefit, I hope we’ll see a benefit, in 0 and 1, I have yet to see drugs approved, at least in non-small cell lung cancer, on the basis of data in PS2 and PS3, and they may otherwise dilute an otherwise positive trial. And I’ve spoken to Mary Redmond, actually, about this to make sure hopefully that doesn’t happen, that it’s properly powered for the 0 and 1s.

Finally, this is revolutionary. It’s setting the stage. We have trials now in locally advanced looking at stereotactic radiation plus concurrent media chemoradiation for mediastinal disease versus our standard approach adopting the same rules, eliminating unnecessary blood draws, tissue biopsies, getting rid of all the timeline rules that exist, the 60-day rule for prior scans, and then addressing the point of combining immunotherapy with angiogenesis inhibitors. That’ll go back to the OAK trial, atezo, when it was done beyond progression versus docetaxel, actually in a retrospective analysis did show a survival advantage versus other agents, and IMpower150 when we see a separation of the curves for the combination of bev/atezo and chemo, that separation actually increases over time once the chemo’s stopped. I am convinced there is at least some potential synergy here between monoclonals targeting angiogenesis and checkpoint inhibitors.

DR LOVE: Really interesting. Final comment from Ticiana. The reason I brought up COVID is I remember in the beginning of COVID, the pre-vaccine year, people were wondering whether you actually were going to be able to do clinical research. How are you going to bring telemedicine in, will clinical research actually be able to continue, and of course that was actually achieved. But I think, to me, it also was kind of taking a look at how we take care of patients, where does telemedicine fit in, and how we do clinical research, and I’m thrilled to hear about this effort with Pragmatica. Any comments, Ticiana?

DR LEAL: Yeah. I mean I think COVID changed our lives forever, right? We took a big hit, lots of centers shut down, lots of people changed fields, and then we had to kind of come back and innovate and strategize and think about how we can be creative so that we can foresee challenges that we never thought we would have to deal with before.

So I do think that if anything good came out of COVID is that we weathered the storm, we made it through, and we became more creative. And the telemedicine thing I think was something that a lot of us weren’t accustomed to doing, but now we know that that can be a strategy that can bring care to patients. We can reach more people. We can meet people where they’re at. And if we can integrate that with clinical trials in a way that’s safe for patients, and it brings therapies to patients, I think that is a win. And now we’re doing virtual consults globally.

So I think telemedicine is a big win. I think these creative efforts and being more pragmatic and being more real world, to really include patients and include diverse patient populations, that’s another big thing that I think trials like Pragmatica are going to allow. If we create strategies in eligibility criteria that is more open to real-world patients we’re going to have a more diverse population, and that I think is also going to be a big win.

DR LOVE: So 1 more other outcome of COVID is it certainly had a big effect on continuing medical education. I mean think about what we’re doing here today. It’s amazing that we can just sit down, do this, pop it out, and people are going to start using it in a couple days. I mean amazing, and it goes even beyond that.

TROP2 and Novel Antibody Drug Conjugates Under Evaluation in NSCLC — Dr Sands

DR LOVE: All right. Well let’s continue. We were talking about how ADCs are really changing the face of oncology, and Jacob’s going to talk about TROP2 and other novel antibody-drug conjugates in non-small cell.

DR SANDS: So we’re going to focus a lot on TROP2 because really particularly for the nonactionable alterations that really is the up and coming. I’ll just point out, though, we do have patritumab deruxtecan in HER3. This is post EGFR progression. There’s also of course, as mentioned earlier, trastuzumab deruxtecan for HER2 mutations. I’m not really going to touch on those so much, and so I call them out at the beginning. As I said, we’re going to focus a bit more on TROP2.

So first of all, what is TROP2? Frankly, there’s still a lot for us to learn about this. This is something that generally seems to be on tumor cells, not really in normal tissue. So these are obviously important factors when thinking of targeting something for cancer treatment, the fact that it is on the tumors and not in the normal tissue. It is thought to be a poor prognostic indicator. There are different data sets on this, but more of them point to poor prognosis from it. And it is thought to be an oncogene that leads to initiating signaling mechanisms that increase tumorigenicity, aggressiveness, metastasis, so essentially being a driver that — a poor prognosis. This all fits together.

Now antibody-drug conjugates in general have 3 components. There’s the antibody. There is the linker that then binds to the payload, which is generally some form of chemotherapy.

First of all, sacituzumab govitecan was really the first for TROP2 antibody-drug conjugate. You can see this was published in 2017 in JCO. And then in lung cancer the demonstrated a response rate of 19%, median response of about 6 months. Now clinical benefit being incorporating stable disease as well. I know Corey had, in some of the data he reported out, also showed a disease control rate. We increasingly see this.

And I’ll admit, in non-small cell lung cancer I’m not always sure what to make of a disease control rate, stable disease itself. There may be some patients that truly benefit, but generally it’s not going to be all of them certainly. In small cell lung cancer, which is so rapidly progressive, I give a little more stock to stable disease, but that did show 43% clinical benefit rate.

Now specifically about datopotamab deruxtecan. So this is another TROP2 antibody-drug conjugate that really has a lot of ongoing studies and one that we’ll mention that is awaiting reporting out. This drug, TROP2 is how it binds to the cell, and you can see there on the left side is where it binds. It’s pulled in, and then in the lysosome is where the payload is then cleaved from the ADC, and that’s where it then has its effect.

Now datopotamab deruxtecan has deruxtecan as its payload. This is a topoisomerase I inhibitor. It leads to cell death, which then releases all this payload into the surrounding tissues. And it does have what’s called a bystander effect, meaning that its membrane permeable and therefore crosses into surrounding cells and then can lead to cell death within the surrounding cells as well.

On the right there you see the initial dosing from the Phase I, so started at 0.27 mg/kg, up to 10, which was a bit toxic because of mucositis and skin in particular. So we’re going to look at 4, 6, and 8 mg/kg dosing, and this was initially reported at World Lung in 2021, and you can see here the different dosing cohorts.

And here’s the baseline characteristics. This was enrolled in the United States and Japan in squamous and nonsquamous.

You can see there in the previous lines of therapy it has different lines, and you’ll notice in there is TKIs and that a percentage of patients had EGFR mutations. EGFR was not the only actionable alteration. These patients had previously been treated in all cases, so whether they had actionable alterations or not all patients had previously been treated, and this is later progression. But it did include across all cohorts.

And this has just recently reported out. This was in the JCO this year looking at these different dose levels. You can see the 4, 6, and 8 mg/kg cohorts, the waterfall plot really showing the majority of patients having some degree of tumor shrinkage. And there in the spider plot you can see that there’s really some durability to many of these responses.

Now the overall response rate is around 30% across the cohorts, and then the duration of response you can see is really, I’d say, a surprising 10 to 12-month duration of responses, and so there really is an indicator of durability to those. The progression-free and overall survival are also listed there. This of course was a single-arm trial so we don’t have a comparator, but these are quite compelling results.

Now on the left side there is from that same publication this year looking at the toxicity profile. And on the right there this is from when it was previously reported out at World Lung, and the final publication has similar numbers, and I just like that figure as far as a way of being able to visualize the toxicity profile.

Some of the things to point out on here. Well first of all, notice that it’s the notched portion of those bars on the right graph that are really the Grade 3 and beyond, and so there was fairly minimal, as far as the Grade 3 and beyond toxicities. But something to point out, there is the stomatitis there, the second bar from the top. This is something that, although the majority are Grade 1/2, if that’s ongoing it’s a problem. I think stomatitis is one that really can be a big hit to ones quality of life even when it’s lower grade if it’s ongoing.

Alopecia we discussed before in the other case, and not everybody really seems to get this, but some patients do really get pretty — they get full alopecia.

The other thing, dry eye, as mentioned in the case, is on there as well. This is not usually a severe problem, but it also is something that really requires ophthalmology involvement, and so that’s something to be aware of. Mucosal inflammation, as I mentioned on there, kind of goes along with the stomatitis.

Now this has also been looked at in combination with pembrolizumab. This is the TROPION-Lung02, and you can see there there were 6 cohorts, the first 2 being just with pembro, and then Cohort 3 to 6 also involving platinum therapy.

Initially this was enrolling in second line and then in kind of midway through Cohort 2 started enrolling in the first-line setting. Cohort 3 to 6, also some of those were later lines.

On the top right there is the preclinical work that really shows that the combination of dato-DXd along with an anti-PD-1 or PD-L1 inhibitor looks to perform better than either of those individually.

So in the TROPION-Lung02 data, here we see it included adenocarcinoma, as well as squamous. On the bottom there you see that the majority really were first-line therapy, but there were some that were second line and beyond. And that data was reported out at ASCO this year, and these are from those slides in the presentation. You can see the waterfall plots look particularly good.

Again, on the right side there, that’s the first-line setting. On the left there all patients, so many of those were also first line, but we do see really the vast majority of patients having some degree of tumor shrinkage.

And here are the spider plots really showing the durability of many of these as well. And this is the data set that is still maturing, but there’s really a very strong indication here of efficacy from those results.

The toxicity profile. Again, this is from the slides presented at ASCO and generally pretty well tolerated. I will focus on a couple of them. Again, you see the stomatitis there at the top, and so that really is an ongoing area for just being aware of when treating patients with dato-DXd. And that has, in some cases, really improved with dose reduction. I’ve found that in patients where I couldn’t control it with things like a steroid rinse or even ice chips during infusion, just keeping the mouth cold kind of like there are those caps to really help prevent alopecia, for example, using that similar concept with ice chips at the time of infusion. And there is ongoing study really looking at better controlling stomatitis while on dato-DXd.

Of course the other thing is ILD, and so we’ll talk a bit more about this one. You can see across both trials, on the left there is from the presentation at ASCO, and on the right there is from the publication from the TROPION-Lung01 study, so left being including pembro or pembro and chemo, on the right is just the dato-DXd by itself.

ILD, there is an adjudication committee. Of course they’re getting all the data from the cases as well. It’s a challenging thing to define in these patients because in — I’m not sure that there are any cases really where there is pathologically confirmed ILD, and so we’re seeing scans that show some inflammatory-looking findings, which of course we call ILD, and in patients with lung cancer having some shortness of breath, as well, then that all of a sudden becomes a Grade 2 if there’s any suspicion of that being drug related.

Certainly we are seeing more of that in these trials across the board than what we would expect. I worry a bit that as we become increasingly aware and attentive to the potential for ILD that we may then start calling everything ILD. And of course we see patients where they have some incidental inflammatory-looking findings. Someone who’s on docetaxel, for example, can have these inflammatory-looking findings that we say well, we’ll just follow and see what that shows, and with time sometimes these kind of wax and wane.

So I think there’s still a lot of work to do, not just in better defining the potential etiology around the ILD in this case, but actually even a more detailed description of the actual incidence.

There are multiple trials ongoing. The first, dato-DXd versus docetaxel is the one that has reported out progression-free survival benefit. The overall survival data is still maturing. I put a little graphic there for Lung07 because that’s a 3-arm, and so to be able to look at that more quickly. But just to say that there are multiple studies still ongoing in actionable and wild type, as Corey had described it.

Now CEACAM5 is another — there’s an antibody-drug conjugate targeting this. This is about 20% of lung adenocarcinoma. Tusamitamab ravtansine binds to this. The data for this looked at moderate as well as high expressors, and really it’s just the high expressors that have about a 20% response rate. You can see in moderate expressors it was only about 7%.

Certainly some durability. You see in the swimmers’ plot there many who kind of fall in that moderate range, and this is where, again, that disease control rate you see is 64 and 60% across. But I think in this case we’re really looking more at the overall response rate with some portion of those really having some durability. There are multiple trials further with this tusamitamab ravtansine in combination with chemoimmunotherapy and in other disease settings.

The 1 toxicity to point out to this is the keratitis, and this is something that does tend to improve with holding the drug, so it does look like it’s easier to control.

DR LOVE: So really a lot to talk about there. I’m kind of curious, Karen, what are you thinking you’re going to be using for second-line therapy assuming dato looks as promising as it sounds like? And also I’m kind of curious about — I don’t know how often you get to third-line therapy, I imagine not too infrequently, how it might affect third-line therapy. What are you thinking at this point, Karen?

DR RECKAMP: Yeah. So I think of it more as subsequent therapy versus lines because there also are those patients who might get, like Corey’s patient who got pembro and then carbo/pem/pembro, and so it’s different to think about lines versus what they’ve received before and what makes most sense in their course of their disease. So it is a little bit more like a chronic disease than it used to be, even for patients who don’t have actionable mutations.

But I think ADCs are going to be part of this. I think the challenge to move it up to front line with the toxicities I think that might take a little longer. But I think we will be utilizing this in second line and beyond for our patients, and it may not be instead of, it may be in addition to, and so I think it provides — these drugs provide more options for our patients, and it really is understanding the toxicities and these kind of off-target toxicities that may be related to where the drug is being released, maybe early or things like that, like the ILD, and trying to make sure that we have as safe of molecules as we possibly can have. So I think that’s kind of where the field is going to continue to move, is try to make these safer and safer and more — get the efficacy to the target.

DR LOVE: I guess the thing I was wondering about is I’m kind of curious if you kind of start out with carbo/pem/pembro, and let’s say you decide you’re going to use dato second line after you see the data, do you think you can use docetaxel or docetaxel/ramucirumab third line?

DR RECKAMP: I definitely would if the patient was somebody who could still tolerate that type of therapy I definitely would continue to use the tools in our toolbox and just move it to the subsequent line.

DR LOVE: Corey, any comments on this fascinating agent and also the idea of using it first line? I mean the idea of chemo plus IO, obviously you all really established the beachhead for that, but it’s being used in so many other cancers, but also IO plus ADC is a very common regimen, first-line therapy diffuse large B-cell, Hodgkin lymphoma. I mean there are a bunch — bladder cancer I was just talking about. Any thoughts about this agent in the second line and maybe in the future first line, Corey?

DR LANGER: So going to the first-line question I think that’s a much higher bar. We already have established regimens there. The results with 10% — up to 30% 5-year survival now with various — with IO-based strategies is going to be hard to exceed. And then the toxicity issues of combining this, particularly with chemo. I think the IO/ADC combination’s probably a bit better tolerated.

This is very much like chemo. The side effect profiles of the ADCs are essentially chemo with added side effects such as ILD or the ocular toxicities. Toxicities that we typically have not dealt with so much in the past, so the challenges there are great.

But as Karen pointed out, we use the term second line. It’s really subsequent line. There are separate second-line trials, presumably the approval if it meets its OS benefit, and I think it’ll probably meet that. We’ve already seen the PFS benefit.

It’s quite tantalizing. You look at the data that Jacob showed, the median survival for the Phase I/Phase II is about 11 months. The PFS was about 5 months. That looks very similar to docetaxel/ramu, but you’ve got to remember in that trial the median number of prior regimens was 3. 50% had received 3 prior regimens. So this was really fourth or fifth-line treatment for a number of individuals, and it was still generating data that good. So once we see the numbers from PFS and hopefully OS I think skeptics will be convinced.

I’m still very worried about the ILD. Any grade is 20%. Granted grade 3 was about 3 or 4%, but our comfort level dealing with unusual side effects is marginal.

DR LOVE: Speaking of skeptics, I’ve got to ask you, it’s off topic, but I’m kind of curious, Corey. Were you surprised with the survival benefit with ADAURA? We were wondering whether it was even going to be — I think people were even wondering whether it was going to even be there let alone what it was. I’m curious. What do you think?

DR LANGER: I’m not surprised there was a survival benefit, but I am surprised by the magnitude of the benefit.

DR LOVE: Yes, exactly.

DR LANGER: I think survival curves showing benefit is either banana shaped, where you see a bulge in the median, and then they join over time, or fishtail shaped, where it separates and then it separates more. And in fact at least so far, and we don’t have longer-term follow-up, but at 5 years it looks like a fishtail curve, so raising the question of whether these drugs are really sidle and not just static.

So remember by and large people on ADAURA were off treatment at that point. This was 2 years beyond the conclusion of treatment we’re still seeing a survival benefit. So I think any skeptics have been convinced at this point.

DR LOVE: Yeah. I was telling Professor Long in a melanoma program about the ADAURA data because they have the same kind of question with adjuvant BRAF therapy.

A final comment from Ticiana. I’m curious about — Jacob was so eloquent in really verbalizing the issue of ILD in lung cancer, when we talk, for example, about T-DXd in breast cancer, GI cancer, these people don’t have prior lung disease, and they’re only discussion is how often they need to do screening for ILD, which they do do pretty aggressively, particularly in breast cancer. But of course lung cancer is a completely different story in terms of ILD.

Any thoughts about how much of an issue this is going to be with dato, and for that matter even T-DXd, Ticiana?

DR LEAL: I think it’s really important to work in a multidisciplinary team. I think increasingly we need to understand what’s really going on and getting more bronchoscopies and getting more specialized opinions from pulmonology and interventional pulmonology and radiology about a differential diagnosis. There are things that can mimic ILD and not be ILD. I definitely agree with Jacob that we need more detailed workups. We need more integration of our specialists in the multi-D team to get us a better understanding of what’s really going on.

I think we are accustomed to treating immune-mediated pneumonitis. Obviously we’ve done this for a long time. These are a little bit different. I think it does generate concern, but I think with more experience and integration of a multi-D approach to managing and diagnosing is this really ILD is going to be key to move forward.

DR LOVE: Jacob, any final thoughts about these trials in the first line, and how do you think that’s going to play out over time? How much of an issue do you think ILD’s going to end up being for dato?

DR SANDS: Well, to Corey’s point that these antibody-drug conjugates really are like chemotherapy, I’d say I agree halfway, where there is certainly overlap of what we see within chemotherapy. I think as far as fatigue that’s generally quite a bit better. So it’s not quite like platinum chemo, but it’s also not quite like pemetrexed, which is really quite easy on people, or maybe somewhere in between.

There are some people that just do exceptionally well, like that case that I had of a patient, 21 months, continuing his career, continuing doing all of his normal daily life while on the therapy. That’s not typical of something like platinum-based chemo. But it also — this is not immunotherapy, where most patients end up having no toxicity. So it is somewhere in between them, but certainly to the point that there is a unique toxicity profile that one needs to kind of become more accustomed to; the eye toxicity, the mucositis, and the ILD.

The ILD, it’s such a tough thing because it’s important for everyone to be aware of it, yet it’s also really important for people to not just immediately conclude that that in fact is what is going on. And so to Ticiana’s point, doing these workups are really important. And there’s a window there, where if someone’s not really having any symptoms you don’t want to put them through a bronchoscopy. When they get to the point where symptoms are severe you can no longer do it. So where is that sweet spot where you might actually get some kind of diagnostic workup that can help. And I think it’s really important for clinicians to be very focused on making sure they’re getting workup instead of just coming to a conclusion that it’s from the drug.

DR LOVE: So just to clarify in terms of “not being able to do it,” and I’ve noticed a little bit of a disparity between, for example, the breast investigators and, for example, the pulmonary investigators, even GI investigators. The breast investigators, if you get symptoms — any symptoms of ILD you’re not getting T-DXd again, and probably I would say the same thing for other similar ADCs.

But in lung, Jacob, I don’t quite find that — maybe you all are so used to dealing with the compromised pulmonary function that you’re willing to maybe take risks that the breast people won’t. But if you have somebody who has symptomatic ILD will you restart therapy after they resolve?

DR SANDS: Well, the tough thing is who’s having symptomatic ILD. Our patients tend to have respiratory symptoms that can kind of come and go to some extent. I think if you have somebody who has very clear signs within their lungs, inflammatory findings throughout their lungs, and very clear symptoms, that’s one thing. And that’s what I think people tend to picture when talking about somebody with symptomatic ILD.

But there is a much more subtle potential there, as well, where we see these kind of waxing and waning inflammatory findings in patients, and many of our patients kind of have baseline respiratory symptoms or sometimes have a bit more cough. Is that from ILD? Is that actually real? Is this from the drug? There’s a real question about a lot of these cases, and that’s the space where I think we have to be particularly attentive to just not come to some conclusion.

At the same time, as our radiologists become more aware of this, and so they see that this patient is on this drug, they see something in the lungs that maybe historically they would say, “Oh, there’s a subtle inflammatory finding to follow up later.” Now we’re going to see in reports a drug-related ILD, and that’s not necessarily a radiology call in some of those cases. And so being attentive to the possibility of this while also being attentive to not just coming to the conclusion that all of these are drug-related ILD. I think that’s going to be that challenging space to kind of work with 2 potential truths.

Other Promising Therapeutic Strategies for Patients with Progressive Metastatic NSCLC — Dr Leal

DR LOVE: So we’re going to move on now, and Ticiana’s going to present other promising therapeutic strategies, but particularly what she just presented at ASCO. I think it was one of the most anticipated presentations. Certainly I was really curious to see it when I saw the press release. I think everybody else was similarly curious, and also to see where this is heading. So Ticiana, can you review the data?

DR LEAL: Definitely. Thanks. And thanks for that callout for ASCO presentation.

So here are the learning objectives. I’ll briefly talk to you about mechanism of action of TTFields and why this is a strategy that we decided to investigate in the LUNAR trial for patients with non-small cell lung cancer, some practical considerations, future directions, and then briefly touch upon other strategies, and I’ll talk about subsequent lines of therapy, as we’ve discussed in all the prior presentations.

So tumor treating fields, this is a new way of thinking about treating cancers in general. Tumor treating fields have been investigated in other tumor types. And really what tumor treating fields does is these are alternating electric fields that are tuned to a specific frequency, and I’ll show you preclinical data on how this was developed in non-small cell lung cancer, that basically disrupt mitosis. And within that, this leads to aneuploidy endoplasmic reticulum stress, and downstream effects of that also include immunogenic cell death, so a multimodal mechanism of action of how this can be an anticancer strategy.

So tumor treating fields, as it affects mitosis. Let’s think about the basics of the physics of electric fields. So just to kind of go back to the basics, an electric field is a field of electric forces that surround any charged source, so whether that source is positive, negative, or dipole. And basically what we can see is that in a constant field these charged particles will move in the direction of the opposite polarity. With the use of alternating electric fields what we’re seeing is the charges will move back and forth, and these dipoles will rotate, and this disrupts mitosis, not only in metaphase, but also in telophase.

And so here’s where we’re at. Here’s tumor treating fields. This has actually been already approved in 2 other disease types, FDA approved for newly diagnosed glioblastoma, as well as recurrent glioblastoma. This has now been FDA approved since 2011 based on randomized Phase III trials demonstrating an improved overall survival. And then we also saw the approval of this with the device exemption approval by the FDA in a single-arm Phase II study in malignant pleural mesothelioma.

So preclinical data has shown that these frequencies are actually based on cancer cell histologies and specifically for non-small cell lung cancer the optimal frequency has been established at 150 kHz.

And here’s the preclinical data to show that. Basically what they’ve done is frequency-dependent effects of these TTFields in preclinical models demonstrating decreased cell viability is most effective at this 150 kHz.

We’ve also demonstrated preclinically the use of tumor treating fields with chemotherapy, specifically taxanes in non-small cell lung cancer cell lines, showing that the addition of tumor treating fields to paclitaxel led to a decrease in the number of viable cells. And we’ve also shown that the addition of tumor treating fields has actually led to immunogenic cell death in non-small cell lung cancer cell lines, and this is shown in this graph, including showing some markers of apoptosis and immunogenic cell death, in the middle and on the right.

With the use of tumor treating fields and anti-PD-1 immunotherapy we’ve also seen in preclinical models that when you add tumor treating fields to anti-PD-1/immunotherapy you see, again, decreased tumor viability in the combination of tumor treating fields plus anti-PD-1/PD-L1 versus each modality alone or control.

So prior studies have also shown the feasibility of using tumor treating fields in patients with non-small cell lung cancer. This is EF-15, which was a Phase I/II trial that investigated the use of tumor treating fields in combination with pemetrexed in patients with previously treated non-small cell lung cancer.

And here the primary endpoint of this study was device-related toxicity, as well as time to in-field progression. This was a single-country study. This was all conducted in Switzerland. There were 4 sites that were involved in the study.

And what it showed was that the application of tumor treating fields plus pemetrexed in patients with pretreated non-small cell lung cancer, after prior platinum-based chemotherapy, was feasible. It was safe. The median overall survival here with the addition of tumor treating fields plus pemetrexed was 13.8 months, which compared favorably in this population of patients in the second line who received pemetrexed at that time. The median time to in-field tumor progression was 6.5 months, and the median time to systemic progression, rPFS, was 5.2 months.

And this is an important distinction here on the left, is the time to tumor progression. A little bit of what we were talking about in terms of is this a local effect or is this a systemic effect. And what you’re seeing on the left is the time to progression in-field versus systemic. And as you can see there, there really isn’t a significant difference in this study between time to progression both in-field, as well as systemic progression.

So again, this was all the basis and the rationale for the next study, which was the LUNAR Phase III study, which was a pivotal study, randomized Phase III, to evaluate the safety and efficacy of tumor treating fields therapy with standard of care, compared to standard of care alone in patients with metastatic non-small cell lung cancer who had progression on prior platinum-based chemotherapy.

So here you see 276 patients who got randomized 1:1 to tumor treating fields therapy, which then was combined with the systemic therapy of choice of the investigator, which could be immunotherapy versus standard docetaxel versus the standard of care alone.

This study was conducted prior to approval of immunotherapy in front line. And what our studies showed, and this was the primary endpoint, was that the addition of tumor treating fields to standard of care systemic therapy in this patient population in the second line and beyond after platinum-based chemotherapy led to improvement in overall survival in the ITT population. You see here the median overall survival of 9.9 months versus 13.2 months, with a hazard ratio of 0.4.

Secondary endpoints included the overall survival in the ICI-treated patients, and as you can see here there was a striking difference that was meaningful in this subgroup of patients, with the median overall survival of 10.8 months versus 18.5 months with a hazard ratio of 0.63.

In the population treated with docetaxel you see here there was a numerical improvement in overall survival that did not meet statistical significance, with a hazard ratio of 0.81.

In terms of safety and tolerability overall in terms of all grades what we saw was, there was more dermatitis in the treatment fields plus standard of care. We’re seeing here all grades 42% versus 2%. However, the majority of these were Grade 1 and 2 in nature, and the high-grade toxicities were actually quite low at 2%.

So again, no difference in systemic toxicities, no differences in pneumonitis or other immune-related AEs. And there were quality-of-life measures that were evaluated in this study, and the detailed analysis is ongoing, but the data that we have so far is that there were no notable differences in health-related quality of life when you added tumor treating fields to standard of care.

And so here is the breakdown for the tumor treating fields adverse device effects. The median usage of the device was 15 weeks with immune checkpoint inhibitor and 13 weeks with docetaxel. And again, as stated, the majority of these device-related effects were actually low-grade in nature, 1 and 2. Again, most notably dermatitis. The majority of the cases resolved, in 87% of the cases.

And as I stated in our case discussion the management of this is really actually quite simple, and obviously there are things that you can do to pre-emptively identify patients who might be higher risk and be proactive about managing patients and advising them on when to call the clinic if they are having dermatitis or other skin-related concerns. The majority of the dermatitis cases resolved, with the median duration of 3 weeks. There were no Grade 4 toxicities and no Grade 5 toxicities that were attributable to tumor treating fields therapy.

And so here is the basic outline of what we used and what we can use in clinical practice if this does get approved by the FDA, really being proactive in assessing for risk factors for any skin-related conditions and whether they are using other therapies that may impact skin-related conditions. Ensure that the skin is clean and dry, well shaved, prior to using the array application. And then you do have to replace these arrays every 3 to 4 days and reposition them about 2 cm to an alternate layout. And this really does reduce the chances of developing dermatitis, in my experience.

Importantly, though, if patients do develop dermatitis you can monitor, use topical steroids, use topical antibiotics if there are signs of folliculitis or infection. And then certainly, if needed, hold the tumor treating fields, remove the adhesive bandages, give a break of 2 to 7 days, and then when things improve you can certainly apply the arrays back on using the principles in the prevent and minimizing precautions.

So this is a slide. The pictures are not mine, and these are not my patients. This was actually provided to me by the company. But we were talking about the clinical applications of how we rolled this out and what our experience was on trial.

Of course that was experience that was on a clinical trial population, but really the way that this goes is if there is a patient that is identified as a good candidate for tumor treating fields therapy by the clinician the clinician will then prescribe tumor treating fields therapy. And then what happens is the company actually troubleshoots and delivers and supports the patient and their family, including education of the patient and the caregiver about how to use the device, when to call, and they’re available 24/7 for support.

So the arrays are actually changed at home by the patient and their caregiver. Again, we talked about that time interval of 3 to 4 days. And then patients continue to come to clinic, they get their systemic therapy with their treating oncologist, and continue to work with clinic in managing any side effects from the systemic therapy and certainly if they have any side effects from the tumor treating fields.

And as we talked about here, like how does it work? This is a portable medical device. The treatment is locoregional. You’ve got adhesive bandages on the chest, and then patients are connected to this portable device that has a battery pack. And you see there’s a little cord there. Patients have to carry a backpack, a purse, to kind of take the device with them. And as the technology has evolved, even in the study, the actual battery pack and the device actually was smaller, which I think is more comfortable for patients.

But shifting gears about what other strategies I think may be relevant as we talk about what we do in clinic is thinking about in patients who had prior immunotherapy, who benefitted from prior immunotherapy, is there any evidence or data about using immunotherapy post progression. And we talked about this in our prior talks.

This is the OAK study, which is a randomized Phase III study that established the role of atezolizumab versus docetaxel in patients previously treated. And here what they did was patients who were on the study, who had progression of their disease, this is a nonrandomized study, they could continue on immunotherapy with atezolizumab beyond progression.

And then the other cohort that you see here is the docetaxel arm. And what we’re seeing here is that the treatment with PD-1/PD-L1 — PD-1/PD-L1 blockade post progression actually led to improved outcomes in this nonrandomized cohort of patients using the OAK trial data.

And it was actually quite meaningful when you looked at the study. The overall survival for the population post progression in the atezo arm was 12.7 months, in the docetaxel arm it was 8.7 months, and then when you look to the patients that actually got no treatment the overall survival was 2.2 months. And you can see the curves here in this nonrandomized retrospective analysis really does demonstrate that perhaps post progression there is a subset of patients who benefit from continuing on immunotherapy.

In addition, they also demonstrated that about half of the patients actually had stable disease post progression on atezo, and about 7% of patients actually went on to have a response post progression on atezolizumab post progression. So I think while this is not an approved strategy I think a lot of clinicians do perhaps use this strategy, and I think we need to better understand who are the patients who will continue to benefit post progression on single-agent immunotherapy to prevent toxicities and perhaps have continued benefit.

And I think Corey also outlined very well potential pathways and ways that we can overcome resistance to PD-1/PD-L1 inhibitors. This is an outline of all the different efforts, including use of other novel immune checkpoints, other novel strategies including the VEGF. And I think as we develop new strategies thinking about biomarkers, not only of benefit, but also of resistance, are going to be key.

And then lastly just commenting on early integration of palliative care. We talked about how are patients have so many needs beyond tumor control. There are so many other needs in terms of symptom control, managing not only their emotional well-being, their physical well-being, and how they continue to lead their lives as best as possible. As we improve strategies that hopefully can continue to lead to longer survival.

So this was a study that we’ve mentioned before, the Temel study that was published in The New England Journal of Medicine. This is now in 2010, and I think this was a really well-designed, impressive study that demonstrated the benefits of this early integration of palliative care services, so in patients with advanced non-small cell lung cancer early integration of palliative care, in addition to the usual oncology care was actually significantly superior to not only improving quality of life, mood, but also importantly patients having less aggressive therapies at the end of their life, but importantly with improved survival. So I think integrating palliative care in the clinics with oncology is definitely another really important strategy that may be a very meaningful thing to improve outcomes for our patients.

So in conclusion, immunotherapy resistance in the setting of recurrent or metastatic non-small cell lung cancer is heterogeneous. Better therapies are needed. We demonstrated in our study that tumor treating fields therapy with standard of care led to improved survival with no added systemic toxicities. We are investigating the use of tumor treating fields now with current standard of care, specifically immunotherapy, in the front line, as well as in patients with locally advanced non-small cell lung cancer following chemoradiation, and early palliative care leads to longer survival and should be integrated early.

DR LOVE: So thanks so much. I love that slide with the mechanisms. That’s one of my favorite slides that you put up there from your paper.

So I’d like to give Corey, Karen and Jacob a chance to comment or ask any questions, but first let me start with my question, which is the obvious one, why do you see such a difference in the IO arm versus the docetaxel arm, and who are those patients in the IO arm who didn’t get it first line? How many of them were people with relative contraindications? Was it people who couldn’t access it because of where they live? Any thoughts about that?

DR LEAL: Yeah. That’s a great question. One of the things that I think, this study really was designed prior to the use of IO in front line, and literally midstudy the standard of care changed where immunotherapy then was used in the front line. So I think that’s the main reason of what you’re seeing.

With the data that we have, the baseline demographics and the PD-L1 data that was available, was not different between the subgroups, including the subgroups that received tumor treating fields. But 58% of the patients in the tumor treating fields plus docetaxel group received a prior ICI versus 2% in the tumor treating fields plus ICI group. So the majority of these patients really were patients that were IO naïve, and that was in part, I think, because of the shifting paradigm of moving IO in the front line.

And this was a global study where still, as that shift happened in the US, around the world people still didn’t have access to IO in the front line. And so this is the way that the study went, and the data, I think, does show that the combination is more striking in the IO plus TTFields.

However, as you look at the subset the numbers are smaller, and so it’s hard to make any meaningful conclusions of would a patient with docetaxel not benefit with the addition of TTFields. We saw a numerical improvement in survival. We saw preclinical data showing benefits with the taxanes. It met the primary endpoint in the ITT population. So I think further studies are needed, but I don’t conclude that you can’t use it with docetaxel, but you definitely can see that the benefit seems greater in the TTFields plus IO.

DR LOVE: So Jacob, thoughts or questions?

DR SANDS: Well, I guess the question, Ticiana, is this something that you’d consider incorporating? Where would you incorporate it? How convinced are you from the results from this 1 study?

DR LEAL: Yeah. I mean I definitely think the front-line studies and the chemorads — post chemorads studies are much needed and much awaiting. They’re actually already ongoing.

If this gets approved by the FDA in clinical practice where I would see myself considering the use would be in those patients that received prior IO that were IO sensitive that I’m now thinking about do I rechallenge with IO. Do I go to docetaxel? Do I think of another strategy?

I think in the IO rechallenge sensitive population I definitely would consider using tumor treating fields plus IO because I think there’s a lot less toxicities; obviously cross-trial comparisons of other studies.

And I would consider it with docetaxel. When we look at the overall survival results here with TTFields plus docetaxel I think it compares favorably with docetaxel plus ram, and the toxicities are much less. So I would consider in those 2 settings. I think we need more data, and I think the data will come, and hopefully we’ll see that this will pan out in the front line as well.

DR LOVE: Karen, any thoughts or questions? I was just flashing on maybe we’ll be doing pembro/ramucirumab/tumor treating fields someday, but any thoughts or questions?

DR RECKAMP: Yeah. I think that’s an interesting concept and may be possible. I think tumor treating fields is possibly something you could add to multiple types of therapies. I think from this study, as Ticiana has given us the details, many of these patients were never pretreated with ICI. So this is really not a subsequent therapy but an initial ICI therapy.

The other issue is that many of the patients that she mentioned didn’t have PD-L1 testing. So we don’t know how many of these on each arm were high, and I think that’s actually incredibly important when you’re talking about untreated patients, patients who have never received prior ICI. So I think there is some questions into what’s driving this efficacy, and so I’m not quite sure it’s ready for primetime for everyone, but I think it’s an interesting modality, and it may be a good adjuvant to lots of the types of therapies that we do.

DR LEAL: I’d just like to add — to our presentation at WCLC we do have some data on the PD-L1 subgroups.

DR LOVE: Right.

DR LEAL: The data that we have available. So we’ll be in Singapore presenting some of that data.

DR RECKAMP: Great.

DR LOVE: Right. I saw that. So final questions from Corey, or comments. I was talking about the incredible change in the oncology waiting rooms that happened about 7 or 8 years ago when checkpoint inhibitors come in. I kind of wonder 10 years from now do you think we’re going to look out in our waiting rooms and see a bunch of people with these devices? Any questions or thoughts, Corey?

DR LANGER: I think technology’s going to hopefully help us out here, that the devices will be less obtrusive, less labor-intensive, less bulky. Folks at least at the company that manufactures this I know are working on that.

This is unprecedented. I’ve never seen a device of this sort, of any sort really, alter outcomes in the metastatic setting. Certainly in the locally advanced setting our radiation oncologists have been playing with all sorts of devices, but not in this setting.

The criticism that it only appears to be working with ICIs I think we have to take seriously. The data with docetaxel alone obviously are a bit weaker. But remember, that’s just a subset analysis. These are relatively small numbers in that group.

So the implications really are for front-line and for locally advanced, where it may make the most sense; patients completing chemoradiation, then going on to durva plus or minus TTF. The disease is within the chest, presumably still within the chest, and hasn’t metastasized. So I wouldn’t be surprised if we realize even greater benefits in that setting. And there will be studies. I think, Ticiana, you’ll be reporting on the patterns of recurrence in-field versus out-field versus looking at bone or extrathoracic metastases, whether there are major differences.

And then also the duration of the treatment. In GBM 75% time with these treatment arrays seems to be the sweet spot. If you can hit that or higher you have greater relative survival benefit. If you fall below 55% or 65% that survival benefit has been reduced. So that analysis I believe, correct me if I’m wrong, Ticiana, will also be taking place.

DR LEAL: Yeah. And in GBM specifically they used a threshold value of 50% or greater average monthly usage, and we’ll be able to capture that because that’s all in the device, so hopefully we’ll have that data. And at this time we saw the median device usage, but I guess we’ll have to see what the data shows, if there is like in GBM that association between the monthly usage and outcomes. In GBM it correlated with overall survival and PFS.

DR LOVE: So Corey, Karen, Ticiana and Jacob, thank you so much for spending this time with us today. It was really exciting. There’s so many interesting things going on right now. I’m really looking forward to see where this leads in the future. So this concludes our program.

This has really been a great afternoon. Thank you so much.