Introduction: Risk of Autoimmune Toxicity with Checkpoint Inhibitors

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Year in Review, as today we talk about the management of lung cancer, specifically the use of immunotherapy and nontargeted approaches and key papers and presentations that have occurred in the past year. Today, we’re really fortunate to be working with Dr Matt Gubens from the University of California, San Francisco.

As always, if you have any questions or cases you’d like to run by us, just type them into the chat room, and we'll talk about as many of these as we have time.

As always, we have a 1-minute premeeting and postmeeting survey in the chat room. If you take that, you’ll get a lot more out of this meeting as well.

We know a lot of people end up listening to our webinars. If you’re into podcasts, check out our Oncology Today series, including a recent program with Drs Gainor and Reckamp that we put out there.

We do webinars all the time. Tomorrow, we’re going to be doing a post-ASCO program looking at renal cell carcinoma. See what’s up there, and particularly in terms of first-line therapy. On Thursday, we’ll be doing a program on triple-negative breast cancer. We’ve got a bunch of great cases we’re presenting by video to our faculty on Thursday. Next week, we’ll be back with gynecologic oncology, what’s been happening over the past year there. Particularly, a lot of stuff in endometrial cancer relevant to what we’re talking about today in terms of immunotherapy. On Tuesday, July 9^th, we’ll be doing Year in Review multiple myeloma. I was just thinking, we just did a melanoma program, Matt, recently. We were talking about the NADINA neoadjuvant trial the other day. I was making a note to ask you about that, so we’re going to bring that up. We’re going to do another breast cancer program, triple-negative disease, on July the 17^th. A program on ALK-targeted therapy in lung cancer on the 18^th.

But today, we’re here to talk about immunotherapy and other nontargeted approaches to lung cancer.

And we’ll be talking also about the use of nonapproved agents and regimens. So check the package inserts for more information.

There have been a ton of great papers and presentations, including at the ASCO meeting recently, that are relevant to the topics today. You can check out a lot of the specifics in the slide set that we have in the chat room. We’ll bring up a bunch of these papers as we go along here today. But there’s a lot to talk about and we want to make it as relevant as possible, as we always do, to docs in practice.

So here’s where we’re heading. We’re going to start out with a little bit of a warmup talking about checkpoint inhibitors. Not just year in review, but I’m going to call it 9 years in review. And then, we’re going to jump into a bunch of papers from this past year and talk about kind of what it means.

So Matt, I was reflecting back on this program we did. You may wonder why I’m bringing up a program on GU cancer that we did in February 2015. But at the end of that conference on the video, there’s a little 3-minute segment that’s been circulated around now for the last 9 years where I go to the audience, “I know we’re talking about GU cancer today but there was a press release this morning on nivo in non-small cell, and it looks like it maybe is going to get approved. And if it does, things are going to change like you never would believe and your infusion rooms are not going to be looking the same. Your life is not going to be the same.”

Here's a poll question we asked those people at the meeting. We said, if an IO like nivo is approved in lung cancer, what are you going to do? And of course, a quarter of the audience said I have no idea. The rest of the audience says well, maybe first-line, maybe second-line. They were not ready. We were not ready. And now, here we are 9 years later.

And this is from a talk you just gave at the ASCO meeting. Great presentation, Matt. And I wanted to put this out here in the beginning because in that talk, and I really recommend people to check out the talk because Matt goes through all the targeted therapies. But I just want to, you know, let’s just remember how many targeted therapies there are out there right now, 9 years, whatever, 20 years later, I guess. And as we go through today, we’re not just going to talk about people who don’t have any of these things, but we’re also going to talk about these people and what you do once you get through with targeted therapy. So we’re going to try to work that in as well. Again, just a reminder, now we’ve got HER2, mutation, overexpression, pan-tumor expression.

So just one other thing before we jump into it. I saw this paper in your CV, Matt, and I was just thinking, wow, 9 years ago, we didn’t know what we were doing. Now, we’re doing this. And this is, just as sort of a warmup, we had a video we used at the ASCO meeting recently where one of the oncologists said, I feel like half of these people come in with some kind of history of colitis and I’m not sure what are the types of colitis I ought to be worrying about, et cetera. And I saw your paper looking, I guess this is, maybe you can explain what you did here.

DR GUBENS: Yeah. This is something we wouldn’t have dreamed of 9 years ago. You’re right, a wild trip it’s been. But yeah, this is some really bright geneticists working with huge datasets and you develop a polygenic risk score based on a spit kit. What they do is they go back, look at —

DR LOVE: It’s germline.

DR GUBENS: Yeah, exactly. You look at 24,000 people who have Crohn’s disease or ulcerative colitis, figure out how their allelic expression differs from those who are normal controls, and then you apply that risk score to a set of lung cancer patients who have had immunotherapy. And what you find is the genetic factors that predict for ulcerative colitis also predict for colitis on therapy. And so what you see here is you can identify a group of people who are the 90^th percentile on this risk score who are very likely, kind of 15% to 20%, to have an honest to goodness serious colitis you have to manage. And so that’s something that is not high enough to deprive anyone based on that score. So this is more hypothesis generating. But again, this slide you’re showing tells us that even if these patients get colitis and you look at their survival curves compared to everyone else, it’s at least as good.

Now survivor bias is a big issue here. The more time you’re on immunotherapy, the more time you have to develop immune-related adverse events, but it’s reassuring. Just kind of this nuance of thinking about the host, their microbiome, their personal genetics, the tumor microenvironment, the tumor itself, again, it’s such a multiplex world to have to think about when we think about not just response, but even toxicity.

DR LOVE: Yeah. And this certainly is a practical issue in terms of managing patients and deciding maybe who to follow more carefully.

DR GUBENS: Yeah.

DR LOVE: I guess maybe at this point, it’s not exactly ready for primetime. But again, it also raises something that we’ve been talking about right from the beginning and I’m still not sure of the answer, which is what you kind of alluded to here, which is the relationship between autoimmune toxicity and treatment benefit. I’m not sure, 9 years later, whether you figured that out, but what’s your take?

DR GUBENS: Again, the data are hard to be rigorous about. There’s that hint though. And I remind patients of that and say, we will grapple with IRAEs as they come. But often, even if we stop treatment early, we may see some durable benefit, nonetheless. So it’s just kind of in the background of how we counsel patients anticipatorily and then reacting to adverse events that come up.

DR LOVE: Right.

Immunotherapy in the Neoadjuvant/Adjuvant Setting

DR LOVE: So that’s just kind of an intro to what we’re going to talk about. Now we’re going to sort of dive into a number of key clinical areas and find out what’s happened over the past year, anything that happened that really affected practice and maybe take a look at a few of the slides and think a little bit about what’s coming next, so to speak.

So we’re going to start out with localized disease. And I’m just going to start out with this list of papers because I think it really capsulizes maybe what’s happened over the past year. Maybe you can talk about sort of where you think we were about a year ago in terms of adjuvant/neoadjuvant IOs and where we are today, Matt.

DR GUBENS: Yeah, sure. A couple years ago, we first got this kind of understanding that neoadjuvant chemoimmunotherapy is safe, it yields better pathologic CRs. We don’t see path CRs with chemo in lung cancer. And we’re finally seeing some event-free survival or even overall survival benefit. So that was the first paradigm, let’s give 3 cycles of chemo/IO before surgery. The last year, what we’ve seen are some of the datasets looking at perioperative immunotherapy. So 4 cycles of chemoimmunotherapy, surgery, and then either an extra year or completion of a year total of immunotherapy on the back end. And Dr Wakelee’s paper along with Dr Spicer showed us the overall survival benefit of that approach in the perioperative pembrolizumab. And of course, we’re waiting for all the other players in this game to also have more mature results and replicate those results as well. But those are our 2 approvals in the US, neoadjuvant alone versus peri-adjuvant — perioperative, I should say.

DR LOVE: So I was mentioning we did a melanoma program the other day, and I promised the faculty I was going to ask you about the NADINA study that was a plenary presentation where, you know, we’ve been hearing about that from Georgina Long and a lot of investigators in melanoma the last few years. And finally, here it was. I’m not sure we’ve seen that with another solid tumor. I don’t know that we’ve seen that with lung cancer, but you tell me. The thing there was these people did better if they got immunotherapy neoadjuvantly, a lot better. Any thoughts about that as you look at the current landscape? And some of the papers we just talked about, the CheckMate 816 study, which has really driven practice to a great extent. And then, of course, the perioperative approach with pembro that you mentioned as well. Any thoughts about where that’s heading?

DR GUBENS: Well, again, before these studies came out in lung cancer, we had the adjuvant data, adjuvant atezolizumab, adjuvant pembrolizumab. And I think there’s this realization that treating a tumor in situ may be advantageous. It gives us a readout, we get a pathologic response, maybe a pCR, a partial CR — partial response, rather. But I think that that melanoma data is very galvanizing, but it comes with some caveats, right? Melanoma, though it's also very immune responsive, it’s also easier to give nivo/ipi before a skin surgery than it is for an intrathoracic surgery. There are some data we’re awaiting for CTLA4 and PD1 inhibition, but I think that the balance of risks and benefits, for now, for the data we have still favors more of immunotherapy with just PD1/PD-L1 inhibition with chemo initially.

But again, this field is wide open and it’s changing hearts and minds. I think there was a reluctance among some surgeons to entertain the idea of a tumor treated by immunotherapy, worried about fibrosis, worried about a patient who might develop pneumonitis that keeps them from the OR. That’s our biggest fear, right? But I think there’s, with these data and with really rigorous surgical data that come out too from Dr Spicer and a lot of other surgical colleagues, I think there’s a lot more comfort with this approach. So I think there has been a paradigm shift in that pendulum from, do chemoRADs and consolidate with immunotherapy for a broader swath of our Stage IIIs. Now, some of them we’re pulling back into the resectable territory. Maybe too far, some argue. What’s resectable? Do you decide that a priori? You should. I think sometimes, there’s a hoped-for resectability that sometimes we overestimate in our optimism. So it’s the pendulum swinging.

DR LOVE: So Rubing in the chat room brings up the issue of PD-L1 assays and its relevance to the use of perioperative therapy. And also, I want to raise the issue, again, I know melanoma is not the same as lung cancer. It was amazing. They had 59% path CR or whatever.

DR GUBENS: Yeah, right.

DR LOVE: With 2 doses of ipi/nivo. It’s amazing.

DR GUBENS: Right.

DR LOVE: Okay. I know that melanoma is not the same but even so, pretty — and it also brings up the issue of durva/treme, which we’ll talk more about with metastatic disease. But also, I wonder whether, do you think anti-CTLA4 is going to be part of our neoadjuvant strategy in the future?

DR GUBENS: Well, we haven’t seen those data from 816, so I’ll be curious if those pan out. I don’t know kind of what we’ll see, again, both efficacy-wise but also safety-wise. Because remember, even in the metastatic setting, we haven’t seen a wildly better message for the CTLA4/PD1 inhibitors over a PD-1 single agent. We’ll see those data in a few minutes, of course.

DR LOVE: So the other thing —

DR GUBENS: But to the question about PD1, I think that’s —

DR LOVE: Yeah.

DR GUBENS: In all these forest plots, none of the FDA labels depend on PD-L1 expression.

DR LOVE: Right.

DR GUBENS: But I think in each of the forest plots for pCR and for EFS, you see some signal where there’s a gradient for PD-L1. But I always think of that with a little bit of a caveat because keep in mind that the specimen you’re doing that off of is that little FNA or maybe a tiny core if you have good operators. That may be not the only representation of what’s happening intratumorally. So that’s why it hasn’t quite risen to the level of being a selection factor, but it’s among the maybe more relative factors you might say to, you might use to decide pro and con, along with stage and histology and all that.

DR LOVE: Yeah. And particularly, patients where you’re sort of on the fence. And speaking about people on the fence, of course, it’s not going to be too long before somebody in the chat room is going to say, what about ctDNA?

DR GUBENS: Right.

DR LOVE: But I’m going to sort of ask, I’ll bring it up before they can even bring it up here.

DR GUBENS: Preemptively, right. Yeah, yeah.

DR LOVE: But colon, obviously, it’s very much part of the algorithm. And then oncologists are using it in colon, doing it in breast and everything else, and asking why not. And all the investigators are going, we need more data. And there was more presented at ASCO. Any thoughts about ctDNA assisting in this perioperative situation? Are we getting close to that, Matt?

DR GUBENS: I think so. And all these Phase III trials are collecting some ctDNA. Sometimes, it’s how present is it before surgery after the neoadjuvant therapy? How much is present after surgery? So we’re going to see some data parsed out about that. I think the other kind of important situation is intensification versus deintensification for people who don’t get neoadjuvant therapy. There’s still going to be a large swath of the patients who see a surgeon first. Maybe they just decide they really, in their heart of hearts, they want to get to surgery despite our discussion of the benefits potentially of neoadjuvant. Well after you see that resection, how do we decide in whom we give adjuvant chemo and adjuvant immunotherapy? And I think, again, the data aren’t ready for primetime, but you’re seeing these decent efforts to try to determine that and integrate those data into the trials.

DR LOVE: Yeah, I find it —

DR GUBENS: This is also interesting to look at. These are Stage I patients.

DR LOVE: Right.

DR GUBENS: To kind of say in our current structure, you’re not going to give adjuvant anything to a Stage I patient. But we also know not an insignificant proportion of those are destined to recur. And if you can identify them, maybe 4 cycles of chemo or a year of immunotherapy is a relatively tolerable thing to offer to improve that risk. So I think this is really important risk stratification.

DR LOVE: I always found it frustrating. The lung people would go, you know, it’s only a 25% recurrence rate. You say that in breast cancer and you’re going to get adjuvant therapy.

DR GUBENS: Right, exactly. Exactly.

DR LOVE: And if you go from 20% to 17% and it’s not a very toxic therapy, at least the patient can decide whether to do it or not. But anyhow. Maybe that’s going to change with ctDNA.

Immunotherapy for Locally Advanced Non-Small Cell Lung Cancer (NSCLC)

DR LOVE: Alright. Let’s talk a little bit. I was confessing to you, I get confused between FLAURA, LAURA and et cetera. But I think it was LAURA that was one of — this was a huge year for ASCO. We had 3 lung plenaries. Incredible.

DR GUBENS: ASCO Lung. That’s right. That’s what we call it.

DR LOVE: ASCO Lung. That’s what this is. Right. So obviously, the first one, of course, is something that I guess was not a big surprise because everybody’s already doing it, which is EGFR patients. And we can show the data, but it was everything everybody expected. It looks great. I’m curious whether people are going to do neoadjuvant, you know, pre-chemoradiation therapy. I don’t know. But meanwhile, the one question everybody is asking and I want to ask you is, what about, getting back to your talk you just gave with the 18 different mutations, which one of those, if any, are you going to apply the LAURA thing? I hear people saying well, maybe ALK. You’ve got 12, 13 choices. Are you going to use durva for everything except EGFR?

DR GUBENS: Right. So I’ll be honest with you. At that ASCO talk, I think it was the second question from the audience was exactly what you just asked. So that’s on the tips of everyone’s tongue. I think I always go back to the point there’s probably more similarities among the EGFR/ALK/ROS1 group of mutations in terms of what we know about their response to immunotherapies. In the metastatic setting, granted. But even in some of the small numbers we have in PACIFIC and other trials that suggest that it’s not helpful. And then to kind of know that they have active TKIs that could do a better job in that setting. Now obviously, we’re talking about years of therapy with a TKI. We’re not just talking about toxicity, which is real, even if it’s more modest than chemos or immunotherapies. We’re also talking about a financial toxicity. But I think for now, I’m more comfortable extending the analogy of LAURA to the ALK situation. Acknowledging, just as in the adjuvant setting, ADAURA was positive and then ALINA was even more positive, I think it’s not implausible to say that an ALK inhibitor would be pretty appropriate at that point if I could get my hands on it.

But when we look at some of the other mutations, even though we have targeted therapies for MET exon 14 or RET or HER2, these are also mutations that happen in a different demographic set of patients. MET exon 14 is famous for having a higher representation of people with tobacco history, for example, and patients who we know in the Stage IV setting have actually pretty reasonable immunotherapy outcomes. And so in my personal practice, even before LAURA, I would not give adjuvant — consolidation immunotherapy to EGFR, ALK and ROS1. I would pretty much offer it to everybody else.

Now in terms of actually using a TKI, I’ll now give osimertinib as a consolidative TKI per LAURA. I’d probably try to sneak it for ALK inhibitor, and that’s probably where I’d stop as of today.

DR LOVE: And also, I just want to point out here the top paper there, part of a consensus really for radiation oncologists. But I thought it was a really cool paper where they went through a bunch of scenarios. Here’s the paper right here. Particularly, again, it had some specifics about the type of radiation, et cetera. I think for medical oncology, it didn’t seem like too much different there, Matt, other than durva was pretty standard, I guess. The other thing too I should have mentioned is this DUART study because people have been asking, what about patients who we can get radiation but you don’t want to give them chemo? Again, I think people have been doing this already, but I guess we have data now?

DR GUBENS: Right. Both of those, those last 2 bullet points, PACIFIC-R is a real-world experience. It actually also included some patients who got sequential chemo and radiation. So these are patients, we’re kind of waiting for registration, in, I think, mostly a European setting. And we saw that even those patients got benefit. And then DUART, I think, is important because we do have a subset of patients where we can give them palliative radiation, maybe not 60 Gy and 30 fractions, but 40, 35 Gy, something like that. And we can get them immunotherapy, but chemo is just not going to be in the cards. Well DUART showed that that set of patients actually did okay and had a better outcome than you would have normally expected.

I want to take one step back, if you don’t mind, to LAURA. I think one of the other insights of LAURA that I neglected to mention and was really nicely pointed out by the discussant, Dr Sequist, who RTP knows and loves, is to kind of point out that the control curve on that study is not as good as the control curve on the PACIFIC study. Our patients who have Stage III unresectable EGFR-driven tumors have a very high likelihood of having micro metastatic disease, higher even than the PACIFIC population. So just kind of it’s good news on the trial, but keep in mind that that’s probably because the control arm doesn’t do very well. And secondly, notice that that’s an indefinite use of osimertinib. It’s not a 3-year term like we do for FLAURA — I’m sorry, for ADAURA. It’s indefinite, reflecting that a large number of these patients really have metastatic disease that we’re trying to suppress. Anyway, sorry to interrupt there.

DR LOVE: No, no. So actually, I was just looking at a case that came into the chat room. This is typical of what oncologists are dealing with. Very simple except I don’t know the answer. A 54-year-old woman, this is from Rubing, Stage IIB non-small cell adenocarcinoma, postop, referred for adjuvant evaluation. Planning for adjuvant chemo. You can tell me how much benefit you think that’s going to provide. PD1 is 0. No actionable mutations. Would you give chemo followed by IO? Adjuvant chemo? Does IO play a role here? Would you give this patient an IO and how?

DR GUBENS: First of all, the chemo question. And I think I’ve maybe talked about this with you years ago. We’re not much further in the chemo world. We have this, I hold up my hand, we say there’s about a 5% absolute benefit. And as you know, there are patients who say, 1%, I’ll take it. Other people will say 5%, what the heck are you talking about 3 months of chemo for? But I would offer it to any Stage B patient and talk about the pros and cons.

As you might remember, not this year, this was a couple years ago, but there’s kind of a funny disparate result between the atezolizumab immunotherapy adjuvant trial and the pembrolizumab adjuvant trial.

DR LOVE: Right.

DR GUBENS: The atezolizumab, clearly beneficial for PD1 50% or higher. Kind of middling at 1 to 49. And didn’t assess, less than 1. Whereas pembro, they went for the whole kit and caboodle. They got approval because they were positive 0 to 100%. But there was kind of a wonkiness to their data where the 50% and higher didn’t do as well as the 1 to 49. So it was kind of not the gradient that you expect. So I think a lot of us scratched our heads about those data. Is it just a fluke? Is it something about the assay, the patients? Who knows. But that has led to my personal practice, if they didn’t do neoadjuvant and I see them postop, if they have PD-L1 50% or higher, I strongly recommend it. Obviously, as long as there are no actionable genomic alterations. And 1 to 49, I have a pretty careful conversation with them and say, here’s kind of where the data aren’t totally clear but I would offer it and here’s maybe the toxicity profile we would have to think about. I will mention it to less than 1% because it’s an FDA approved indication, but I would say that based on the preponderance of not just adjuvant, but metastatic data, that I really am hard put to suggest it strongly to those patients.

DR LOVE: One of the themes —

DR GUBENS: Even though it’s on label in the US.

DR LOVE: To me, one of the relevant themes here that has always been an important issue in oncology, and I just feel like we’re talking more and more about it, we just did the ONS meeting, it was the whole theme, which is patient advocacy.

DR GUBENS: Yeah.

DR LOVE: And patient involvement if they want to be involved. If they’re a patient that doesn’t want to be, that’s fine. But for people who want to be involved, and particularly if they have education or the background to understand some of the subtleties, let them participate. I love working with you because you don’t mind just saying what you do, understanding that there are a lot of other evidence-based options. But this is really what oncologists want to hear.

DR GUBENS: Sure.

First-Line Immunotherapy for Metastatic NSCLC

DR LOVE: So let’s go to another thing that we’ve been talking about. And you can tell me what we’ve learned, if anything, over this past year. But a decision that oncologists make every day, which is first-line therapy and the use of immunotherapy. And the issue, thinking back to that initial poll question we were asking, whether you use it first-line or second-line in terms of where we are. At this point, to me, it seems like mostly what we’re looking at is follow-up of the older studies. And we’re still, I guess, still with the same question of really, first of all, who should get chemo? And I’m thinking differently about this now actually since I saw the FLAURA data. Right now, we’re giving chemo and osimertinib.

DR GUBENS: That’s right.

DR LOVE: Well, maybe we ought to be thinking about chemo and IO for the same idea, you know, early progression or whatever. And then the other thing you see down there at the bottom, durva/treme, which is the role of anti-CTLA4.

DR GUBENS: Right.

DR LOVE: Particularly, with people with low PD1. So I guess first of all, my question is —

DR GUBENS: To your point though, osi is a great drug and I haven’t, this isn’t a targeted talk, I haven’t moved to osi plus chemo.

DR LOVE: Right.

DR GUBENS: There’s a lot of interesting chat about that you’ll have with the other team over there. But I think this is so different because you have those patients who have PD-L1 greater than 50%, especially the higher the PD-L1, the better.

DR LOVE: Right.

DR GUBENS: They are destined to enjoy such long duration of benefit without the need for chemo. And always with the caveats, they don’t have a high burden of disease. I have a lot of confidence, though none of us are soothsayers, that I’m going to get them to second-line therapy if they need that second-line therapy. But I’m still a big proponent of immunotherapy alone for the high PD-L1 expressors, even though we have the data available to us to really give any therapy we want, any combination thereof.

But I think you’re right, there hasn’t been any kind of rip-roaring new indications or data, but kind of some reassurance in some of these 5-year outcomes and beyond knowing that that plateau on the curve is real and that some 20%, 25%-ish of patients really are going to enjoy long-term survival. Some nuances about rechallenging if they stopped after 2 years. But I think the other kind of maybe the things to pick out in the recent updates have been a little more reassurance that the CTLA4/PD-L1 signal of benefit, interestingly, for the PD-L1 nonexpressors. Remember, for whom nivo/ipi is not technically approved though it’s on the NCCN. There was that signal that they kind of do better than you’d expect. And that was replicated in the POSEIDON study when you have durva and treme with chemo as well. So I think it’s, for those who are inclined toward double immunotherapy with or without chemo and intrigued by that less than PD-L1 — PD-L1 less than 1% subpopulation, I think now we have 2 sets of data that kind of replicate that long-term benefit.

DR LOVE: Here’s the POSEIDON study that you were talking about. Again, another CTLA4/PD1 strategy that kind of looks encouraging. What are you doing nowadays when you have PD1 0 patients first-line metastatic disease?

DR GUBENS: I talk about some of these data. I work in the Bay Area. I have a lot of people averse to chemo. And so if there’s any plausible approach that’s chemo-free, they’re often kind of more all-ears about it. And so the patients in whom I’ve used the double immunotherapy have tended to be either PD-L1 less than 1% or people who really can’t get chemo or just say I am not going to get chemo in shared decision making. But yeah, you’re showing these data. The less than 1%, that forest plot still is showing that we’re seeing that the CTLA4/PD-L1 combination seems to have some benefit. And here, you have this, this is the overall survival data. It’s kind of intriguing here that the hazard ratio, 0.76, is favorable to the durvalumab alone arm. So those numbers, the absolute levels of the hazard ratio, I’d say that 0.84 seems to underperform a little bit compared to other PD1/PD-L1 with chemo studies that were on the other slide. So I’m not sure, that might be the underperformer rather than the other one being the overperformer. But it’s definitely intriguing. And I think at least, again, it’s a Wild West. We don’t have head-to-head data. I’m not sure we will in the next few years. You kind of have support for the approach you want to take.

DR LOVE: What about the patient where you’re kind of reluctant to use chemo, kind of on the fence about whether or not they might be able to tolerate chemo? And a strategy actually that I see used in prostate cancer where you start out with a treatment and then you intensify if the patient doesn’t do well. So prostate, they add in more hormones.

DR GUBENS: I’ve absolutely done that.

DR LOVE: But what about starting out with PD1 and then adding — yeah?

DR GUBENS: Absolutely. In fact, I’ve had several patients where I start with the PD-L1 alone because of the high — with PD-L1 inhibition alone because of the high PD-L1. And if they have, you know, they don’t have a good response, I will then kick in the chemo with cycle 3. I always do a first image after 2 cycles, 6 weeks. It’s a little early, but on almost all the immunotherapy trials, at least in lung, on the spaghetti plots, you’re seeing your lack of benefit or benefit by that first timepoint. So it’s not unusual for me to kind of talk to patients about an early intensification if there’s a hint of progression early on.

DR LOVE: Any flavor to the autoimmune toxicity that you think you’re seeing in lung cancer patients with combination immunotherapy that maybe you wouldn’t see in a younger melanoma patient or other situations where, for example, like in HCC, you have durva/treme but a lower dose, et cetera? What do you see when you bring in CTLA4 in a lung cancer patient? Anything in terms of toxicity that’s characteristic? I hear a lot about colitis.

DR GUBENS: Yeah, that’s what I was going to say. Colitis has, in my experience, been pretty, pretty rare for PD1 or PD-L1 single inhibition. Whereas we’ve seen several cases with dual inhibition. That’s probably the most prominent. I personally haven’t seen a huge bump in terms of pneumonitis rates, which is another big concern in our clinics, but I don’t think it’s a marked difference, at least in our experience.

DR LOVE: I was thinking again about how lung cancer so often kind of leads the way because there’s just so many patients. And then when something happens, it’s really — and I was just thinking that where we’re heading here today, the last thing we’re going to talk about is kind of PD1 all over again because you guys are the first one with a CD3 bispecific, tarlatamab. So you led the way with IOs. And it looks like if we’re going to see CD3 bispecific, which is, of course, a whole huge area of tolerability that oncologists are dealing with now in myeloma and lymphoma, maybe we’re going to see that also in lung cancer coming up in the near future.

Novel Agents and Strategies

DR LOVE: Alright. Let’s talk about some new agents. And one in particular, datopotamab deruxtecan, which has been presented both for breast and, we were just talking about breast the other day, but also in non-small cell lung cancer as well. A lot of people think this drug may get approved. But we’ve been seeing more and more data alone, with IO, also in people with targetable lesions, I think is very interesting. The side-effect profile is interesting. So if this does get approved, I’m not exactly sure whether we’re ready in terms of when to use it, how to use it and particularly, the tolerability issues.

DR GUBENS: Yes.

DR LOVE: But let’s take a jump into this and maybe you can help prepare us for it. So first, I want to talk a little bit about —

DR GUBENS: My sense is —

DR LOVE: Go for it.

DR GUBENS: It’s kind of amazing how quickly these ADC trials, the drugs have been developed and the trial programs have been developed. We’re talking so many trials in parallel enrolling so many patients. I feel like it’s the immunotherapy experience, but maybe over half the timeframe. It’s really remarkable. As you’d imagine, any —

DR LOVE: I’ll just mention —

DR GUBENS: Go ahead.

DR LOVE: I was just going to say just to mention another thing I’d like you to kind of bring in is, (A), I mentioned before people with targetable mutations who get beyond targeted therapy.

DR GUBENS: Yeah.

DR LOVE: But another thing that we saw some data on that, again, everybody asks about with everything including ADCs, is CNS. And we saw some data there of dato in CNS disease at ASCO. So we picked out a bunch of slides, but I just really wanted you to just talk about it in terms of what you think about the data and, if the drug is approved, how you think you might use it.

DR GUBENS: Well, keep in mind, kind of the TROP2 is, I think, the first set of molecules that are kind of first to get their studies accrued and get some data out there. And I kind of think of Dato-DXd and sacituzumab govitecan kind of neck and neck in there.

DR LOVE: Right.

DR GUBENS: And it was really in this last year where we got the dato-DXd data, the TROPION-Lung01 here. This is randomized against docetaxel, our eternal foe for second-line. Docetaxel beats almost everything. And yet here, the overall study showed that the dato-DXd beat docetaxel. But when you looked at the subgroups, there was this marked difference. So even though the overall, you know, the primary endpoint was PFS in all-comers, when you looked at nonsquam versus squam, there’s this very disparate signal where nonsquamous folks including patients who have these actionable genomic alterations who did even better than average, actually did quite well. Whereas on the squamous side, there was maybe even a deleterious effect. So I think this is a really fascinating thing and I’m not sure was predicted a priori and actually wasn’t replicated, for example, in the sacituzumab govitecan similar study, the EVOKE study that was presented at ASCO. Now then, you start wondering, is this something about the patient population? Is this something about the molecule? You always have to think about these molecules because you’ve got the target, you’ve got the payload, you’ve got the linker. There’s a lot of kind of variables there. And one wonders if, is it an irinotecan-based difference versus topoisomerase 1 difference? The payload? Is it something about the design elsewhere? It’s just fascinating, right?

But anyway. So I think you’re right. I have no inside line. This was a positive study though it was a subgroup that really was the primary driver of that positivity. Are we going to see broad approval, at least for nonsquamous, of this new drug? And with it, all the toxicities and logistics we need to know to really use it when it’s a better drug than the docetaxel we’ve been using for a decade and more.

DR LOVE: So we’ll talk a little bit about the tolerability issues that have to be considered. But just sort of sticking a little bit with in terms of where or if to place this drug. And you mentioned the negative sacituzumab study also which is important to consider. You would think if it’s going to get approved, maybe it’s going to get approved in nonsquamous. And I guess the question, first of all, in terms of efficacy, any questions about it? And I guess is this, whether it’s a post-hoc analysis, I don’t know if that colors the way you look at it. But certainly, if the study had only had nonsquamous in there, we wouldn’t be having much question about it.

DR GUBENS: Right, right, right.

DR LOVE: But I guess we’ll see what the FDA says.

DR GUBENS: Right. There’s no love loss for docetaxel, right? It’s been our second-line for a long time and no one loves a taxane. It’s what we have when we don’t have much else. So I think there’ll be some gentle interest in something that beats docetaxel somewhat. You saw some kind of early OS data that might be trending in the right direction. But I think that one of, we’ll talk a bit about toxicities as you were showing on the slides, but I think the other thing that really both the sponsors and all of us are asking the question of, well if it beats docetaxel a little bit in the second line, is there any advantage to having it as part of a first-line regimen? No one’s going to not do immunotherapy. But the Phase III trial designs have all the permutations of one of these ADCs plus immunotherapy, ADC plus platinum plus immunotherapy. So kind of those data, which are very much accruing and I think maturing quickly, we’re going to see some Phase III first-line readouts in PD-L1 less than 50%, greater than 50% in both of these TROP2 agents and others in the next year or 2. So I think this might be the first kind of foot in the door, but I think we’re going to have to reckon with these drugs and the logistics and their toxicities because they’re going to be a part of the process, even as we refine the technology. And hopefully eventually, figure out how to design our ADCs better and have the right payloads and the right targets.

DR LOVE: My head is still ringing because I did a recording earlier today with Sara Tolaney on ADCs in breast cancer.

DR GUBENS: Yeah.

DR LOVE: And all the trials she was talking about was ADC plus IO.

DR GUBENS: Right, right.

DR LOVE: And, of course, bladder cancer, that’s first-line therapy. Enfortumab plus pembro beat cisplatin-based chemotherapy. I’m wondering whether that might be the direction.

DR GUBENS: That next slide I think you were about to show.

DR LOVE: Go ahead. Right.

DR GUBENS: And again, I think whenever we incorporate these ADCs, and that includes trastuzumab deruxtecan for our HER2 patients, eventually some HER3 ADCs, you’ve got to really pay attention to these toxicity profiles. They’re not unmanageable, they’re just, you have to recognize them prophylactically, anticipate them, have your staff including APPs and RNs kind of be on the lookout for them. And then the 2 things — the 3 things that stick out here, as you see. Mucositis is real. It can be kind of proactively dealt with. And I think they’ve done some nice studies about using a steroid mouthwash from day 1 to kind of head some of this off at the pass. Secondly, ocular events. I think that strikes fear in the heart of a lot of us oncologists. And these days, I don’t know about other people’s facilities, it’s really hard to get in the door of an optometrist or ophthalmologist. They are, I think they’re busier than we are. And so if you have a patient who has a legitimate eye issue, I think all of us, our hackles are raised a bit. And then ILD, which I tend to think, obviously, I defer to my breast colleagues, I think we have to worry about that a little more than they do just because, A, I think our patients are at higher risk of it but also, B, we have more of a diagnostic dilemma. Because what if it’s a recurrence? What’s if it’s edema? What if it’s radiation pneumonitis? So all those questions don’t mean this drug is not going to be used and shouldn’t be used. It just means we have to kind of be ready for these issues as they arise in a way that I don’t think we’ve had to for some of the other drugs in our armamentarium.

DR LOVE: Yeah. And Sara was claiming, as you just said, that they are able to prevent the mucositis very effectively, according to her. Of course, they developed that strategy with the steroids for breast cancer. And in terms of ophthalmic eye, we’re all over it. We’re ready.

DR GUBENS: Yeah.

DR LOVE: We’re already ready. We’ve already done a CME program just on ophthalmic issues with ADCs.

DR GUBENS: Great. I’ll watch that.

DR LOVE: We’re ready.

DR GUBENS: I’m going to download that tonight.

DR LOVE: You guys aren’t ready.

DR GUBENS: We’re not ready, but you are.

DR LOVE: You’re not ready, but everybody else is. And who knows? I don’t even understand half of the stuff there. But at least we know what to do or at least who to talk to.

DR GUBENS: Right.

DR LOVE: And the other issues, I guess, will get ironed out as we move forward. What about the issue, there are 2 other things I was curious about and we saw data looking at this. One was the issue of — so first of all, you’re seeing in the TROPION study looking at first-line therapy. And we’re starting to see some data there, again, looking at it with IO. I’m curious about your thoughts on that. Also, in terms of biomarkers that predict benefit in this situation. We saw some data at ASCO looking at that. Audience, you can check out these slides later on, but I just want Matt to talk about it. This very important dataset that we saw last fall at ESMO looking, again, this population of people with targetable lesions but after they get through targeted therapy, which I thought was great that they looked at that. Particularly, because it seems to work better with nonsquamous and it looks like it works well in those patients. And then finally, at ASCO, we saw data on CNS activity. So any thoughts about CNS activity?

DR GUBENS: Who’d a thunk it, right?

DR LOVE: Yeah. So how about all this stuff with dato?

DR GUBENS: Yeah. Well, I think this has just been neat not just with dato, but even with trastuzumab deruxtecan.

DR LOVE: Right, right.

DR GUBENS: Who knew 5 years ago that these huge bulky molecules are going to have a CNS benefit.

DR LOVE: Right, right.

DR GUBENS: But we’re seeing it across these programs, and it’s very encouraging. Now do you hang your hat on it? You’re still going to call the radiation oncologist. But to know that in a disease where brain metastases play a pretty big role in morbidity and mortality, it’s just good to know we have some activity up there, right?

I think the French group study that you kind of flashed through, Dr Planchard’s study, it’s kind of interesting. For HER2, it’s so important to either, in lung cancer, have the mutation or have high expression. We don’t have this kind of minimal HER2 expression where we can give a HER2 ADC. It’s so fascinating, not for lack of trying, that it just hasn’t seen that TROP2 expression plays a significant role in the benefit for these drugs. And so that’s going to really differ by target. You mentioned the BiTE that we’ll talk about in a minute in small cell. DLL3 expression is important in a small cell lung cancer, but it’s not actually part of the FDA label. So, again, it’s going to differ by ADC, it’s going to differ by mechanism. But, again, just all these, we’re going to have this table in our head that keeps growing and growing. Not just of the parameters of the drugs, but what kind of factors to look out for. But pretty neat core of the science going on there.

Immunotherapy for NSCLC with a Targetable Mutation

DR LOVE: So I’m trying to wade through all this stuff and find the things that people need to know to take care of patients right now. And it’s a challenge because there’s so much stuff to look at. Let’s talk about this population out there who does have a targetable mutation. What do we do once they get beyond that? And particularly, where immunotherapy fits in. Also, new agents. There’s a TKI I’m curious about. I’m not sure how to pronounce it, ceralasertib, that’s been combined with an IO, durvalumab. But first, can you talk a little bit about the issue of this sort of classic — well, now, it’s a classic conundrum of people who respond to targeted therapy, i.e., for example, EGFR, and then progress?

DR GUBENS: Yeah. So from the early days immunotherapy, maybe not quite 9 years ago, but 7 to 8 years ago, there were EGFR and ALK patients who were getting these later-line single agent immunotherapies. And just every study showed a response rate that was in the low-single-digits, if any. So we just know that even if those patients express high PD-L1, the biology of these tumors don’t favor that particular checkpoint being part of the pathogenesis. And so this study happens to be kind of a retrospective paper that we did looking across our University of California campuses and just kind of looking at patients who got these. We’re doing it practically because, what else do we have at nth line? And we just really didn’t see a PFS or OS benefit, even in our retrospective data kind of replicating what had been seen before and maybe even a deleterious effect for EGFR patients after a TKI. Again, this whole question about overlapping toxicity.

But I would draw to your attention, we didn’t pull the slides, there was a neat paper presented that we’re going to have to see how it pans out, the HARMONi-A trial. This was the ivonescimab. This is the bispecific against PD1 and VEGF, so kind of, you know, we’ve known for a long time, and this is in EGFR patients after osimertinib progression. It’s a Chinese Phase III trial now enrolling rest-of-world patients because of how provocative the results are. This is a patient population we don’t think of PD-L1 as having a lot of benefit. VEGF has always kind of had this nebulous role where maybe it’s good added to TKI, never with OS benefit, maybe good in subsequent lines. But this bispecific, there’s a marked PFS benefit in that post-TKI line of therapy. So I’ll be very curious. I know it’s actively enrolling rest-of-world partly for the FDA’s sake to get some data to replicate outside of China. But that was one of the more provocative lung papers at ASCO. And I’m sorry we didn’t pull those. That’s my fault for neglecting that. But especially as we talk about targeted — people with genomic alterations who need nontargeted therapy eventually, that was a very provocative paper.

DR LOVE: But you’re talking about a bispecific that attaches to VEGF and PD-1?

DR GUBENS: Exactly. Yeah, yeah. Ivonescimab.

DR LOVE: That sounds like a good idea.

DR GUBENS: Yeah, exactly. Yeah, yeah.

DR LOVE: That sounds like a good idea.

DR GUBENS: Oh yeah. Sign on.

DR LOVE: Never heard of it, but it’s —

DR GUBENS: Yeah. A Phase III trial, really well done, kind of post-TKI, EGFR patients. So kind of interesting. So we’ll pull that and keep an eye on it. There is, again, like I say, there’s another part of that study that will enroll enough X-China patients that the FDA will at least look at the data if it looks as positive. Pretty nifty.

DR LOVE: But do they see single-agent responses?

DR GUBENS: I’m sorry, it was this bispecific plus chemo versus chemo plus ivo.

DR LOVE: Oh, plus chemo.

DR GUBENS: Yeah, yeah.

DR LOVE: Okay, alright.

DR GUBENS: So it’s kind of like we’re looking in the EGFR space of chemo with TKI, chemo with EGFR MET bispecific.

DR LOVE: Yeah, sure, sure.

DR GUBENS: So it’s kind of the next step. So kind of interesting. Anyway. Be that as it may, I think your point is well taken. Both for the immunotherapies and for the ADCs, we have to think about these patients differently and kind of, even if they’re included in the trial, stratify by them or at least have really good subgroup analyses of them. Because you had pointed out before, the ADC benefit, here’s this trial that has some benefit with VEGF. We just have to pay attention to that over time, I think.

DR LOVE: Yeah. I guess this is sort of the same kind of strategy except with 2 different drugs rather than a bispecific. But any comments? I don’t know if there’s a nickname for cera. But the TKI plus durva, any thoughts about it?

DR GUBENS: Well, it’s an ATR inhibitor. I think if you scroll to the next page, it’s all these studies looking at a postimmunotherapy failure kind of situation, right? And all we have brewing in lung cancer right now in kind of that Phase III setting really is TIGIT and then kind of VEGF, right? So we’re looking at those 2 Phase III studies actively accruing and soon to report out. But I think this study design, you can tell how small the print is. How can we think about precision oncology and think about what we can add to immunotherapy? So as you see, KRAS versus nonactionable mutations, both getting the durva plus ATR inhibitor. And there’s a there there. It’s modest, 13% versus 4.5%. This is, mind you, compared to docetaxel with a kind of high-single-digit response rate. So is there enough of a there there for this to kind of get to later phases? Maybe. But it’s among the many efforts to kind of throw something plus immunotherapy in that postimmunotherapy failure line.

Small Cell Lung Cancer

DR LOVE: So we may circle back. We’re getting some cool questions in the chat room, but I want to make sure we get through to small cell.

DR GUBENS: Oh yeah.

DR LOVE: And then maybe we can loop back for some of these other issues.

DR GUBENS: Sure.

DR LOVE: Because it’s kind of interesting stuff going on here with small cell, beginning with the plenary session here, the ADRIATIC.

DR GUBENS: Yes.

DR LOVE: Again, not a big surprise.

DR GUBENS: No.

DR LOVE: I kind of wonder, do we really need to wait? We waited, like, 5 years for this.

DR GUBENS: But keep in mind, we don’t see that many of these patients. I think the only reason we’re seeing more limited-stage small cell is because of screening efforts being a little more ambitious and widespread. They’re not widespread enough in the US. But this isn’t that frequent in our clinics to actually find a patient who has limited-stage disease. But like you said, I don’t think this surprised anyone, but it’s very good to have the data in hand to say that just as we anticipated, immunotherapy ongoing in the metastatic or extensive-stage setting, here, 2 years of durvalumab clearly made a difference.

DR LOVE: And again, I think everybody saw these data.

DR GUBENS: Yeah.

DR LOVE: And not too unexpected. Anything, you know, you want to say in general about the use of IOs in people with small cell? Obviously, we’ve been using it now for a few years in combination with chemotherapy. Any observations? Have you seen any long-term responders? Anything different in terms of the kind of autoimmune problems they develop? They’re often sick people with a lot of tumor-related symptoms. Anything you want to say in general about your experience with IOs in small cell?

DR GUBENS: I think it still feels like even though there are some of those longer-term survivors, and I have a handful of them, that tail on the curve is a little lower than it is in non-small cell lung cancer, despite all our hopes and prayers. These are often tobacco exposed, very highly immunogenic, but not quite as many. Dr Liu, of course, presented a nice long-term outcomes paper on the atezolizumab folks. And there is a subset of patients at 2 and 3 and 5 years, but it’s a smaller proportion.

I think how that fits into ADRIATIC is the question, do you give these people 2 years of immunotherapy? Just as we ask after atezo or durva failure in the extensive-stage setting, what’s next? Are these patients we have to go straight to the BiTE for? Do we rechallenge if it’s been a spell? That’s probably what I would do initially. But I think that those are some of the questions that remain to be answered. And I think a lot of the interesting data that’s not ready for primetime, but the subtyping of small cell to say maybe there’s a subtype of small cell where immunotherapy is particularly likely to be helpful from the get-go. And others where maybe you need to bring in a PARP inhibitor or bring in other mechanisms of action, if not in the first line, in rapid access second line. I think that’s some of the more provocative work happening.

DR LOVE: So I guess another thing would be —

DR GUBENS: Yeah, Dr Liu’s study. Yeah, exactly. Yeah.

DR LOVE: Right. Anyhow. Anything you want to say about this, more further follow-up from the CASPIAN study?

DR GUBENS: To this day, my couple of longest-term survivors were the people who got nivo/ipi as, not even second line, but, like, nth line. For whatever reason, and a couple other investigators have mentioned that too. And obviously, that approval kind of fell by the wayside, but one wonders. And that data set was kind of interesting in seeing that there were some folks, it wasn’t predictive by PD-L1, but who had some nice, long, chemo plus dual blockade of PD1 and CTLA4.

And again, here’s the ATR inhibitor rearing its head again. Here’s another.

DR LOVE: Right, exactly.

DR GUBENS: Again, I think here, is there one of these subgroups, one of these 4 subgroups identified by the MD Anderson and other teams that maybe this is the right approach from the beginning or, again, in early relapsed/refractory disease? I think this is early, but certainly provocative for a tumor that still needs our help.

But this is where the exciting stuff is happening, this BiTE. And, again, we’ve kind of joked that maybe it’s good that the first BiTE or cellular therapy in lung is in a small cell population because at least, we have time to prepare a smaller patient population. These are logistics that my hospital is literally working on this week. I have a meeting on Friday about, how are we going to operationalize this drug that requires a couple of hospitalizations and a different kind of CRS monitoring than we’ve ever had to do in solid tumors? Pretty exciting to have this dataset come out and the approval very recently. I think we’re a month into this approval. And, again, 40% response rate in the heavily pretreated population. A real significant overall survival. This is a very exciting development. But logistically, it’s a bit of a handful.

DR LOVE: Well, the good news is the oncology community is going to be ready for you because they’ve been working on this the last 2 years in myeloma and lymphoma.

DR GUBENS: That’s true. Yeah.

DR LOVE: So you just need to talk to the lymphoma and myeloma people.

DR GUBENS: Yeah.

DR LOVE: I’m not sure that the tolerability issues, they sound like pretty similar to what we’ve been hearing with CRS.

DR GUBENS: Very similar.

DR LOVE: Cytokine release syndrome.

DR GUBENS: Yeah.

DR LOVE: Of course, one of the issues is, how is cytokine release syndrome going to go down in a patient with COPD and heart disease compared to a young patient with lymphoma?

DR GUBENS: That’s what I worry about.

DR LOVE: Any thoughts about that?

DR GUBENS: I don’t think we have data on that, but one always wonders as we start extrapolating this randomized control trial to — I’m sorry, this registrational trial, excuse me, to the real world where I have patients on a list waiting to get on this. But they’re the patients who’ve been waiting and they’ve been through multiple lines and they’re a little beaten up by some past therapies, so one wonders. I think we’re too early on to really know how much different the CRS, for example, experience is going to be, but we have to be ready.

DR LOVE: When you were talking about what are the new trials in up-front therapy, I thought the next thing out of your mouth was going to be adding this thing in.

DR GUBENS: Not quite, but it’s coming. It’s coming, right? I think we need to get our sea legs on a drug like this, but I think that’s the next step. And remember, DLL3, that’s been a provocative target for a long time. I think, you know, rova-T.

DR LOVE: Right.

DR GUBENS: I think probably in this setting, you talked to a bunch of us how excited we were. It didn’t pan out, speaking of ADCs, where we didn’t quite have the biology right.

DR LOVE: Right.

DR GUBENS: But this is kind of that first commercial application of DLL3, and we’re very excited about it.

DR LOVE: Yeah. We had John Heymach on a video at ASCO and he was talking about work they had done where, I guess, they showed, I want to quote him correctly, that they could detect DLL3 in, I think it was, people who had EGFR and then progressed on osimertinib. Maybe I’m thinking — no, no, no, that would have been small cell. Sorry, I’m thinking about small cell here. But in any event, I guess they found DLL3 and think that it should work, I guess, maybe outside of small cell potentially. Have you seen any trials looking at that?

DR GUBENS: Well, keep in mind that small cell transformation is one of our more aggressive, not that common, but not uncommon modes of resistance.

DR LOVE: Yeah, that’s what he was talking about.

DR GUBENS: So I think there’s been this interest. Obviously, the biggest place for developing these drugs has been in small cell, but there’s a whole range of high-grade neuroendocrines including in prostate resistance, EGFR-driven and other targetable alterations resistance that I think that’s a logical next step. Some of those patients were on the Rova-T studies back in the day, some of the other DLL3 compounds. So one wonders if that’s kind of the next step for one of these drugs. Yeah.

DR LOVE: Yeah. Actually, that was what he was looking at. It was people who had EGFR who transformed to small cell. And they saw DLL3 —

DR GUBENS: Because those patients are very hard to treat.

DR LOVE: Right.

DR GUBENS: They have terrible prognosis. Really, we kind of throw some platinum/etoposide at them. We debate whether to leave on the osimertinib. And they do okay, but not for long. So one wonders if, especially in that fitter population, maybe this is the perfect next-line therapy when someone like John, Dr Heymach, can show us, hey, there’s actually some plausible biomarker here that might suggest its benefit. So we would be all-ears for that kind of approach.

DR LOVE: So oncologists are getting a lot of experience, or at least they’re hearing a lot about cytokine release syndrome. Actually, I’m not sure how many people, their patients have actually gotten treated yet, but they certainly are hearing about cytokine release syndrome. But the other thing they’re hearing about, again, you hear this with CAR T too, is neurologic issues. Do you know whether or not they’ve seen that with this tarlatamab?

DR GUBENS: They have, but not at some of the high rates of some of the approved CAR T-cell products, thankfully. And I think, again, for this patient population where we worry, as you mentioned, about some of the neurologic, paraneoplastic syndromes that are already on board, one was kind of maybe concerned about that. But really, the CRS has been relatively manageable to the point where I know they’re looking at not — right now, you admit the patient for the first 2 doses. But there’s even kind of some logistic work to be done to maybe make those just long outpatient stays. So to do that this early in the development for this patient population is suggestive that at least this particular BiTE is not going to be the worst of the BiTEs that we’ve all seen in the heme side.

DR LOVE: Well, there’s also well-tolerated BiTEs on the heme side though. You have mosunetuzumab where I hear people using outpatient corticosteroids for low-grade CRS.

DR GUBENS: That’s true. Yeah.

DR LOVE: So I don’t know if that is going to happen with lung cancer as well. Question from the chat room. And we did a program about this recently, B7-H3 ADCs. What’s B7-H3? And do you see any future for those? Also, patritumab deruxtecan is another ADC we’ve heard about. There, I’ve heard about that with, again, EGFR progression. What about some of these other ADCs? Do you see those coming into lung cancer?

DR GUBENS: Definitely. And the results have been fairly mixed. And you have to look at, again, how much of it is the target of choice, how much of it is the payload of choice?

So with your second question, patritumab deruxtecan. I think we’re all eagerly awaiting. That’s enroute probably to some approval. Again, really gratifyingly in the EGFR later-line population. There’s this kind of HER3, kind of makes some sense there might be some homology enough where that would be of use. And we’ve seen some good data. Again, we love our osimertinib. But when we get past the TKI benefit, we start running out of tools pretty quickly. So I think there’s a lot of enthusiasm for that one in particular.

B7-H3 and others on the list. CEACAM is also one of them that has been looked at in lung cancer, that are overexpressed in lung along with a bunch of others.

DR LOVE: Right.

DR GUBENS: Mesothelin has been kind of looked at in lung and, of course, in mesothelioma including in CAR T-cells. So the field is vast. The question is, how do you signal find quickly to not have to run a whole lot of Phase III trials for a negative result, but to really hone in on the signals that actually work? But those are all in play.

DR LOVE: So one final ADC I’d like to ask you about. Technically, it doesn’t fit, I never know where to put this, whether into targeted or nontargeted, but that’s T-DXd.

DR GUBENS: Right.

DR LOVE: And, of course —

DR GUBENS: I struggled with that even in my ASCO talk. Is it an actionable genomic alteration? Now the approval includes lung with 3+ expression too. So yeah, is that targeted? It’s not an AGA quite, but it’s in the same vein. But I always make that differential point that unlike breast where minimal, you know, trace HER2 might be enough to give that drug, we really need high levels of expression to anticipate some benefit. And then, of course, in our use of that drug, we’re very enthusiastic about it, especially in the mutated patients, in the HER2 mutation-driven tumors. Really good outcomes, but always with the back of our head mindful about the pneumonitis risk because that’s a real, I worry more about that than cardiotoxicity. I’ve seen more of that, at least in my experience. So something that’s maybe a little differentially needing attention in the lung population getting T-DXd versus the breast population or the gastric population.

DR LOVE: I think anybody getting T-DXd is going to get a lot of people looking at their lungs, for sure, very carefully.

DR GUBENS: Yeah.

DR LOVE: But also, it’s used a lot. And you see patient after patient who really has palpable clinical benefit. And so my —

DR GUBENS: Yeah, I have a patient 2 years out with brain mets.

DR LOVE: Yeah.

DR GUBENS: This was her second-line therapy. And it’s just very gratifying to see. She has tremendous quality of life and, knock on wood, her Echos and her scans continue to look good. So this is a really important tool in our armamentarium. And the addition of the pan-tumor HER3 amplification indication, I think, is really useful. And the lung data are robust there. Not as robust as the mutation, interestingly, but robust enough to say I want that second-line before I try with docetaxel and some of the less specific ADCs.

DR LOVE: We could have spent the whole hour just on T-DXd. And on Thursday, when we do triple-negative, we also are going to get into this because one of the cases there where the patient has a HER2 mutation. They don’t have any data in breast cancer with HER2. But they say, what about lung cancer? Because you guys are already using it.

DR GUBENS: Yeah.

DR LOVE: Then, this pan-tumor approval comes in. And now, we’re looking for IHC 3+ in lung cancer patients. So, again, a lot to talk about there, but a really important option that now is available to a lot of patients including a lot of patients with lung cancer.

Anyhow, Matt, I knew it was going to be a crazy, wild hour, and it was.

DR GUBENS: Wild, as always. Lung ASCO is always exciting.

DR LOVE: I hope you all got something out of this, but I think there are a lot of things that are very positive that came out of this. It’s always a challenge to sort of sort through it. Hopefully, it was helpful to you today. Come on back tomorrow. We’re going to try the same thing with renal cell cancer with Dr McKay and Professor Powles. Matt, thanks so much for working with us today. Audience, come on back tomorrow night. We’ll see what’s going on with renal cell cancer. Be safe, stay well and have a great evening. Thanks so much, Matt.

DR GUBENS: Take care. Thank you.