Introduction

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice and welcome to Beyond the Guidelines, as tonight we obtain clinical investigator perspectives on key decision making in the management of lung cancer.

We have a great faculty today. We’re really looking forward to this program. The iPads in front of you have all the slides we’re going to be presenting here today. There’s also a survey you can take which we’re going to show you the results of as we go through the meeting. And if you have any questions or cases you’d like to run by the faculty, you can put them on the iPad as well and do your CME evaluation. To the many people who are on Zoom tonight, we know that this morning we had twice as many people online as we did in the meeting. First of all, welcome. We’ve been working with you all the last 2 years online and we’ll continue to do so. Also in the chat room there, you’ll see all the slides as well as the survey. And also if you have any questions, you can put it into the chat room as well. We’ll be video and audio recording this and putting it out in the next week or so for people who are not able to attend this evening.

This is the second of 9 programs we’re doing in this room. I know if it’s the first Friday in June, I’m going to be in this room talking about lung cancer with Heather probably. And she’ll be taking the red-eye in as she did last night. Anyhow. Really great to be here. Hi to the 2 people up there in the mezzanine. Those are great seats up there. Hey, good to see you all. Anyhow. We’re going to be back tomorrow morning talking about prostate cancer. And we have 40 investigators we’re working with this weekend. What a pleasure and honor to be working with them. Tomorrow night and Saturday night will be really special. Our work really focuses on the general medical oncologists in community-based practice. We know what a challenge it is to keep up-to-date with all the things that are going on. We’re just talking about some of that in these programs this weekend. But tomorrow and Saturday, you’ll see videos. This is something we’ve been doing since the pandemic started. We’ve recorded more than 2,000 actual real cases from a real-world library. We’ll be showing them this weekend. But also keeping them in mind tonight because that is our primary target. And although there’s a lot of lung cancer in general medical oncology, there’s also a lot going on in lung cancer to try to keep up-to-date with. And tonight, we’re going to take another attempt to try to make this information more relevant to docs in practice.

Here’s where we’re heading. We have 6 modules, one for each one of the faulty. They’ll be giving a talk at the end of each module. But we’re going to start out each module talking about taking care of patients and practical clinical decision making. And what we did, we know people turn to guidelines, they turn to UpToDate, et cetera, and they often see multiple evidence-based options. But one of our themes over the years has been to say to investigators we know you individualize treatment decisions. You can’t really characterize any specific situation without really seeing the patient. But, in general, what do you usually do in that situation? So we did a survey of these docs in the last couple weeks and as we go through this meeting tonight, we’re going to show you the results of the survey and really get the faculty’s input and also compare for many of these questions how you in the audience are taking care of patients with lung cancer.

Incorporation of immunotherapeutic strategies into the management of nonmetastatic non-small cell lung cancer (NSCLC) — Heather Wakelee, MD

DR LOVE: So let’s jump in and start out with probably the most interesting and controversial issue, immunotherapy in localized disease. We’ll talk about adjuvant therapy which, of course, exploded on the scene a year ago. Was it a year ago? I’m losing track in the pandemic. But I guess it was only a year ago. And then we’ll also talk a little bit, Heather will update us on Stage III as well.

But let’s start out with some of the questions that we asked to the faculty. And, of course, last year, we saw the neoadjuvant trial looking at chemo and nivolumab. So, Heather, we asked our faculty as well as the other investigators what kind of approach they would take to a patient who has got an adenocarcinoma of the lung and the surgeon says I’d like to see it shrink down before I take the patient to surgery. Most of the faculty is saying they’re on board with cis/pem/nivolumab. What are your thoughts about that, Heather?

DR WAKELEE: Well I think after the CheckMate 816 data, which we’ve seen updated recently with New England Journal publication, this is a very reasonable response. One thing I always say in Tumor Board though, if you’re hoping the tumor will shrink, it’s never going to shrink away from the mediastinum. It always shrinks into the mediastinum. So as you talk with the surgeon, it’s getting a sense of what kind of shrinkage do they need to feel like it’s resectable. Don’t expect it’s going to shrink away from the vital structures.

DR LOVE: We also asked the investigators how many times they’ve used neoadjuvant therapy whether chemo or with nivolumab or anti-PD-1. And you can see that in the past year, most of them have had some patients where they used this strategy.

Let’s jump into adjuvant therapy. And, Helena, I want to ask you about this question. First of all, we asked it to the audience. So we said you have a patient who has got a Stage IB nonsquamous that’s 4 cm, no targetable mutations and the TPS is 50%. So actually, a fair amount of the audience says they would not use any type of adjuvant therapy. And then some will say they will use chemo alone. But the most common answer is cis/pem, atezolizumab. Any thoughts, Helena?

DR YU: I think that, to me, the answer is with none versus #3 where people get chemotherapy and then atezolizumab adjuvant post-surgery. I think it really depends on the surgeons that you work for. I think neoadjuvant therapy kind of is surgeon dependent to some degree. What caused me to say chemo upfront was the 4 cm size. So I think our surgeons, if they’re slightly big or kind of in that 3 to 4 cm range, they do like to have us give neoadjuvant chemo first.

DR LOVE: So, Justin, actually, this is an adjuvant situation postop. We were talking about neoadjuvant initially. But this is postop and a controversial situation with a Stage IB. How do you approach these patients, Justin, with a high PD-1?

DR GAINOR: Yeah. And I think it’s really important to recognize that the staging system has changed too and that a lot of the studies we’re going to be talking about, IMpower010, they were conducted in this 7th edition where IB, 4 cm was more relevant. That’s now actually a Stage II in the 8th edition. So I think it’s really important when you’re talking at Tumor Board to remind people what staging system you’re using when you’re talking about these data because these adjuvant studies were done in the 7th edition, but now we’re in the 8th. So for this patient, 4 cm tumor, I would absolutely recommend chemotherapy there. How IMpower010 was done, it was that hierarchical design where it was focused really on Stage II, III, I would give atezolizumab particularly in the 50% because that was the subpopulation that really drove the benefit.

DR LOVE: So, Jared, here’s another question. I was curious, it seems like most of the benefit was in the high PD-1 and even though the approval is for PD-1 greater than 1%, I was curious what people are actually doing. We’re going to get into this tomorrow night when we talk about chemo/IO in upper GI cancer. Same situation. It’s approved for all PD-1. In any event, we’re saying the PD-L1 is only 1% and yet most of the audience is still saying that they would use cis/pem, atezolizumab. When we asked the investigators, now we’re starting to see some people say well maybe they’re going to hold back at least on — I’m going to ask Luis what his thoughts are about this in a second. But, Jared, what about a patient with a low PD-1 who technically could get it? Would you treat the patient? How would you treat the patient?

DR WEISS: I think patient values always play in here. When we look at immunotherapy, we like to pretend it doesn’t have risks and toxicities. It still can. And it certainly has 100% chance of medicalizing the life of that patient for a year. But for a fit motivated patient, yes, I actually would still offer it for PD-L1 of 1.

DR LOVE: So, Luis, how do you approach a situation like this?

DR PAZ-ARES: I would go for the same. I would do chemo followed by a PD-L1 or a PD-1 inhibitor. And that is totally fine to me.

DR LOVE: And it’s interesting. If you look down below, you see that some of these investigators are looking at PD-1 because they wouldn’t give it in the situation of PD-1 of 1% and a few of them flip back over for 50%. Corey, this is interesting, I think, very interesting. We asked these investigators how many people have you treated with consolidation durvalumab after chemoradiation in the last year? And then how many of those did not get through the full course of treatment? And it looks like most of these patients did get through the course of therapy. What’s your experience with giving durvalumab in the consolidation setting? I remember when the data first came out, there were a lot of concerns. I remember you verbalizing concerns. Is there going to be more pneumonitis? It doesn’t look like it’s playing out that way. What are you seeing in terms of getting people through the entire course, Corey?

DR LANGER: So the numbers here actually look more promising than the PACIFIC paper would suggest. 42% were able to complete the full year of treatment. If I’m reading the bar graphs correctly, it looks like a little more than 50% were able to do this. So I suspect there’s a learning curve on how to get folks through it. We’ve gone from q 2-week dosing to q 4-week which has made it easier, certainly more patient friendly. But I still encounter a fair amount of toxicity. And remember, not everybody completes it because still some patients have disease progression while they’re on it. So those are totally incapable of — or impossible to complete it. But these numbers probably match clinical reality. And it’s clearly become the standard, certainly in wild type nonmutated locally advanced non-small cell. EGFR, I’ve made the conversion. Heather, you’d be proud to hear that I’m no longer giving it to EGFR mutant positive patients.

DR LOVE: Your point about the recurrences, we didn’t think to ask them why they stopped. We probably ought to pull the recurrences. What we’re looking for is people who don’t get through it. It looks too like people who use it more maybe get people through it more successfully. So here’s the Heather situation that he’s referring to because Heather started talking about this a while back. What do you do with somebody in terms of locally advanced chemoradiation if they have an EGFR mutation? And initially, we were hearing from investigators, most of the investigators were “sticking with the data”, Heather, but you had some data that you were looking at also that made you think otherwise. You want to comment on that? And I guess your answer is osi?

DR WAKELEE: Well that’s a great question. I think what we have seen is that when we give consolidation immune therapy in patients whose tumor has an EGFR mutation or HER2 that we actually do not see improvement in efficacy. We had a lot of patients progress fairly quickly. We also had some increase in toxicity. Small numbers, so I don’t know if that’s necessarily true. But what you’ve done is the patient then has immune checkpoint inhibitor in their system, if they then progress and you need to start them on an EGFR/TKI, that does increase toxicity. We know that those combinations can be quite toxic with pneumonitis and hepatitis. I’m really surprised by this answer with so much osimertinib. There is an ongoing trial, that is the LAURA trial, where we don’t have the data yet. I think this implies that a lot of people assume that’s going to be positive and so the idea that you would stop with just chemo and radiation is enough I think makes people uncomfortable, so they start. I’m not necessarily doing that in practice, waiting for that data from the study, but I do expect it’s likely going to be positive.

DR LOVE: I’ve heard some people say well we have it in metastatic, we have it in adjuvant.

DR WAKELEE: Yeah. It makes sense to make that leap, but I do think it is important that we get the data to be sure about that. I actually answered other and I tend to give a bit more chemo to be safe. But do I know that that works? No. I don’t think that osimertinib is a wrong answer, but I do think that durvalumab probably is.

DR LOVE: Corey, you had a thought?

DR LANGER: Well I agree with Heather. I think a lot of us have extrapolated from ADAURA to this realm. Remember in the ADAURA trial, the greatest benefits were actually seen in Stage III, IIIA with astounding hazard ratio that was below 0.2. So it’s not a stretch then to apply it in this setting although as Heather has pointed out, we have no Stage specific locally advanced Phase III data yet. The LAURA trial will be the ultimate arbiter.

DR LOVE: And another question we — oh, Jared, did you have a thought?

DR WEISS: Well I would also comment that this is in the context of chemoradiotherapy which would give me some amount of pause after the SWOG experience. That’s different than postop.

DR LOVE: Which SWOG experience? With what?

DR WAKELEE: Okay. Are you talking about the 0023?

DR WEISS: Yeah. So I have equipoise for the potential for lack of benefit or even potentially harm until we see that data.

DR WAKELEE: Not everybody is going to remember that study. It was a few years back.

DR WEISS: I guess I’m getting older. You can see the loss of hair.

DR LOVE: In any event, we also asked this question here which is how would you approach a patient who has a RET fusion? Now you do see people talking about targeted therapy. Luis, any thoughts about that? Putting aside reimbursement issues, what would you do if you have a patient who had locally advanced, got chemoradiation, had a RET fusion?

DR PAZ-ARES: So if the patient is having localized disease amenable for chemoradiation treatment, this stage, the data we have is not supporting the use of a RET inhibitor straight after. On the other hand, we know that those tumors with RET fusions are not the most immunogenic, but those tumors were not excluded from the PACIFIC trial. So my first idea would be to do the PACIFIC trial, of course, being very vigilant and in case of disease progression, go for selpercatinib or pralsetinib. Of course, as he mentioned, that in those patients, you have started with immunotherapy, you’re having a higher risk of having some hypersensitivity reaction, some pneumonitis, rash, and so on. So you have to be careful and watch out.

DR LOVE: So, Justin, this idea of targeted therapy which started with osi right after an IO having more toxicity, people kind of now are applying it to all mutations. Does it apply to all mutations? A BRAF, smoker, Justin, for example?

DR PAZ-ARES: Well I feel it depends on the drugs rather than the mutation. Let’s say, for example, we know that with selpercatinib, you’re getting some 14% of the cases with hypersensitivity as compared to 2 to 3% if the patient didn’t receive immunotherapy first. But with pralsetinib, it looks like the data may be somehow lower. We still need some more data to be sure about that. And with other drugs, it’s quite the same. Let’s say, you may have issues particularly with drugs that are inducing transaminase with other drugs that are not inducing this is not an issue.

DR LOVE: So, Justin, any thoughts about that? Here are the responses of the investigators, incidentally. You can see, again, the most common — now, this is not the case, I think, even a year ago when we did these surveys. But now the majority are using osimertinib instead of durvalumab. And you also see a little bit of targeted therapy as well. Justin, you were on a webinar we did a few weeks ago and we asked the audience if you had a Stage III patient with a RET and you could give adjuvant RET therapy, would you do it? And more than half the audience said yes. I’m curious what your thoughts are about that, Justin.

DR GAINOR: Yeah. I think you made great points which is how many extrapolations are we comfortable with, right? We know that certainly in the metastatic setting, targeted therapy is superior to chemotherapy cross trial comparisons. But at the same time, we really don’t have any data for adjuvant TKI for RET fusions. It begs the question though, will we ever get that data, right? This is a population with only 1 to 2%. So at some point, I think we’re going to have to start extrapolating to these really, really rare populations. Right now though in my practice, if I had a Stage III RET positive patient getting definitive chemoradiation, I would probably pursue durvalumab in that setting.

DR LOVE: So, Helena, this will be first time this weekend, but not the last that I bring up circulating DNA as a possible arbiter of that. Any thoughts about that as a strategy in the adjuvant setting? Tomorrow night, we’ll talk about the SignateraTM assay that’s being used in colon cancer. What about circulating DNA in some of these difficult situations?

DR YU: Yeah. I think it’s really exciting. I think that we’re seeing its use certainly in the locally advanced setting post-definitive therapy. I think it is a really good separator of likelihood of recurrence. So I envision, or there are already studies ongoing where they’re taking patients that are ctDNA positive post-resection in colorectal, lung and kind of escalating or making sure that their therapy is sort of stronger because of that. And I think we’re doing that in the metastatic setting too. As combinations come up for targeted therapy in the frontline setting, I think we are going to risk/adapt using ctDNA.

DR LOVE: So, Heather, we asked you — Luis, did you have a thought?

DR PAZ-ARES: I’d just like to — I fully agree with Helena. I could say this is a nice tool to be investigated. Today, I don’t think we use it. I don’t think you should decide the treatment of your patient in the adjuvant setting depending on the ctDNA being positive or negative because the data we have is that likely the technology today is not too sensitive. So maybe many of the ctDNA negative tumors are still positive and they could have benefit. I’m pretty sure that Dr Wakelee will comment on the tissue data which suggests even the ctDNA negative tumors would benefit from that.

DR LOVE: Maybe you can comment on that in your talk. We asked Heather to cover like the Bible in 10 minutes. So I’m really curious to see if she can. But go for it, Heather.

DR WAKELEE: Okay. So I’m going to talk about incorporation of immune therapy in nonmetastatic non-small cell. So just to remind everybody, we give adjuvant chemotherapy based on these meta-analyses of studies where the disease free survival hazard ratio was 0.84, overall survival hazard ratio of 0.89, 5% overall survival benefit. And that was enough for us to all say, yes, we should be giving chemotherapy. So I want to put that in context, some of those numbers as we go through this newer data.

All right. So first, talking about neoadjuvant. And that’s the CheckMate 816. There were a lot of nonrandomized studies. I think the one most of us know about is the NADIM which was chemo plus nivolumab, nonrandomized. Exciting results. CheckMate 816 randomized Phase III trial for patients who were felt to have resectable early-stage disease and they either got neoadjuvant chemo or chemo plus nivolumab. And it’s important to note that two-thirds had Stage IIIA disease, so mostly Stage IIIA. And about half of them had high PD-L1 or some PD-L1 expression.

And when we look at sort of some the main endpoints, it was this pathological complete response. No viable tumor. One-quarter of patients who got the combination had no viable tumor and 2% of those only getting chemo. And when we look at the major pathological response rate, and in lung that’s defined as only 10% viable tumor or less, that’s about 40%, close to 40%. Not as good as some of the earliest trials that we saw, but still good. So these were — this is what I look at as the definitive data.

And there are some subtleties to be aware of. I realize this is a little bit too busy of a slide to really see. The stage did not seem to matter. The histology did not seem to matter. The PD-L1 levels did matter. You still had benefit regardless of PD-L1 level, but the higher the PD-L1, the higher the benefit. So I think that is something we need to be mindful of. And it’s important when we think about the adjuvant data where we’re dealing with single agent immune therapy versus neoadjuvant when it’s chemotherapy plus immune therapy. If we think about metastatic disease, we know that when we’re giving single agent checkpoint inhibitors, the PD-L1 levels matter a lot. And when we’re looking at our combination of chemo and immune therapy, the PD-L1 levels matter, but less so. And I think it’s a similar story when you look, at least, at this data and you look at the IMpower data.

Okay. So what does this really mean? Well the event free survival hazard ratio was 0.63 compared to those high 0.8’s with chemo. So this is striking. Median event free survival is 31.6 months. So that’s good. It’s good. Is it absolutely fabulously fantastic? No. And so I think we still have some room for improvement. We do have FDA approval as of March. And a publication came out in New England Journal recently with more of this information. So that’s exciting.

It’s also important to note this is only the first of the neoadjuvant studies. There are many that will be reading out soon. This study was the only pure neoadjuvant study. All these others have adjuvant as well. And so that’s also going to be important for us as we try to figure out what’s really the best regimen when we’re going to have like 10 studies all Phase III reading out.

Okay. Now we move to adjuvant. So a year ago, I got to present this data to my computer as opposed to a group of people. But this was the first adjuvant trial to read out. And this is IMpower010, so this is with adjuvant atezolizumab given for up to a year after 4 cycles of chemo. You could have stopped after — usually 4 cycles of chemo. Normal stratification. And, again, this was IB to IIIA. We’ll talk about the breakdown on the next slide. And as was mentioned earlier, this study had — the statistics were a little bit complicated. So the first group we looked at were patients who had any PD-L1 expression and were Stage II to IIIA. And then we looked at anybody Stage II to IIIA. And then we looked at everybody. And then we looked at OS.

So some of the characteristics to keep in mind with this trial, the stage is different. When we look at the IIIA here, it’s 40% versus almost two-thirds in CheckMate 816. So you can't really do apples to apples. There’s also these are patients who have completed their surgery, have completed chemo and were well enough to get it and then go on. So, again, comparing that to a neoadjuvant population, you’ve got to be very careful. About only 12% of patients on this trial had Stage IB. And then when we look at PD-L1 expression using the SP263 assay. And for those of you who don't think a lot about PD-L1 testing, there are a couple of different assays. The SP142 is an outlier. That was used with some of the older atezolizumab studies. The 22C3 is the assay we use with pembrolizumab. The 263 is very, very similar to that assay. So when you’re think about how do you look for PD-L1, it matters which test you’re looking at.

Okay. And so this was the take-home. The disease free survival hazard ratio in the some PD-L1 expression, again, slightly more than half the patients had some PD-L1 expression, Stage II to IIIA, and that's 90% of the patients, hazard ratio is 0.66. That’s the on-label use. When you add in those who didn't have PD-L1 expression, that hazard ratio is 0.79. When you look at all-commers on the trial, the statistics weren’t finalized yet, but it's around 0.81.

Okay. And the PD-L1 really, really mattered a lot in this study. And more detail on this slide. If there was no PD-L1 expression, in this study, there was zero benefit, hazard ratio of 0.97. If there was any PD-L1 expression, it was 0.66 as we talked about before. But when we break it down more, you see that most of that is in the patients who had tumor with PD-L1 expression of at least 50% and then it was 0.43. Okay. So this study is really that high PD-L1 expression, but some in the 1 to 49%.

This is, again, the approval. Okay. A couple other subsets, EGFR, ALK. Small numbers. If there is ALK translocation, it didn't matter how high your PD-L1, no benefit. And we know this from metastatic. So please look for ALK. If you have high PD-L1, don't give immune therapy. EGFR though, it's more complicated. There seemed to be a signal even in patients with tumors with EGFR.

And this is prelim overall survival. Too early to see anything. And then safety. No surprises, but when you give a checkpoint inhibitor, you are going to get toxicity. We all know that from our use of this in multiple diseases, in metastatic disease. A lot of times, it's mild but it's not nothing. I give a lot more thyroid replacement now than I ever used to before, right? And there's rashes and other things. And sometimes it's serious. So you always need to the weigh the risk/benefit. If there’s only a little benefit, there’s still risk and you’ve got to really talk through that.

And this is the ctDNA analysis we talked about. The upper bar are patients where there was no ctDNA detected. Still some benefit with atezolizumab, probably because there was still some positive situations here, it just wasn't a good enough assay. Bigger benefit when we did find it. Sorry, I think I misspoke there. If you don’t see any ctDNA in this assay, there was still benefit. If you did, a bigger benefit. We’re needing better assays to feel really comfortable that it’s truly negative. And we are running assays like that at Stanford. We’ve got some trials ongoing. I’m sure many of the folks on this panel do too.

Okay. The other adjuvant trial is the PEARLS trial. This was presented at an ESMO plenary session a few months ago. It's a very similar study design, but it's with pembrolizumab. And when you look at the disease free survival for overall all stages regardless of PD-L1, hazard ratio of 0.76. Remember, it was about 0.81 for that similar all-comers patient population. But when we look at the greater than 50% population here, it's 0.82 verses 0.43. So in one trial with atezolizumab, all-comers hazard ratio DFS around 0.81. Here, it’s 0.76. Similar, but the PD-L1 results for high PD-L1, very disparate. That is confusing.

When we look at a few other subsets, smoking status. If you are still smoking, there seemed to be more benefit. We had a different result with the atezolizumab. The stage also here didn't matter in the study with atezolizumab, the IMpower study. The stage IB patients really did not seem to benefit. Here, it didn't matter. All stages, about the same. So this was a little bit confusing. And then the PD-L1, like I said, it kind of doesn't really follow all the patterns that we’ve seen before. And then one of the other striking things, if there was an EGFR mutation in the tumor, the patients seemed to benefit even more. Maybe it's small numbers. We don't know. There are a lot of questions that we haven't been able to figure out yet. And this is the prelim OS. Looks encouraging just like we saw in the IMpower study with atezo.

There are other studies to read out. So the ANVIL study with nivolumab. We also have durvalumab. So more data to come as we try to figure out the truth.

And then with locally advanced in the last 22 seconds. This is the PACIFIC overall survival, 5-year updated. It’s there. It really does benefit. But I don't think it's in all patients. If you have certain driver mutations, I don't think we're seeing that. These are some of the baseline characteristics including having the mutations where we're just not seeing that benefit. That's down at the bottom.

And then in 2 seconds, -2 seconds, the COAST study is looking at a few other novel agents. So monalizumab and oleclumab which you probably are not as familiar with. Some different mechanisms trying to get the immune system to work a little bit better. This is a randomized Phase II, but there was definitely some encouraging data with both compounds compared to durvalumab alone in the locally advanced setting. And so these are drugs to follow. And I will be done then. So I'm only a couple seconds over. Thanks.

DR LOVE: Awesome. So just kind of curious. Any situations where you might be tempted to use IO alone, atezolizumab alone? PD-1 90%, maybe a little bit frail patient, not looking too good after surgery, Heather? I can only imagine you get that question 5 times a day.

DR WAKELEE: Trying to get me in trouble, Dr Love. Personally, I do think that there is a benefit to chemotherapy in the adjuvant setting, but there are also patients where the harm from the chemotherapy outweighs the benefit. When we think about the checkpoint inhibitors, what's their harm? It’s different than the chemo harm, but there’s still real harm. And the patients I think I've seen the worst toxicity in are the patients where I would have assumed the worst toxicity had they gotten chemo when we deal with metastatic.

Would I be tempted to offer it to a relatively frail person or someone who said absolutely no way will you ever give me chemotherapy period, and the PD-L1 in their tumor was high and they didn't have a driver mutation? Yes, I would talk about it. I think that where we're heading is probably being able to give combinations of chemo and IO where I think there's even more benefit. Those trials are ongoing. Yes, I would think about it. I would be cautious about it. And I think one of the biggest challenges we still face is that the public perception tends to be if I get immune therapy, I'm not going to have any toxicity and if I have chemotherapy, it's going to be the worst thing ever. And I think that there's a lot in between there. I've seen patients horribly, horribly harmed with immune therapy and patients who sail through chemo. And so it’s trying to get people to really help in weighing those risks and benefits to be more accurate.

DR LOVE: I can see Corey. He’s ready to explode out of his seat. I was just thinking, Corey, I’ve been with you in this room for like 14 years. I remember when the original trials came out and we were all excited about chemo. I wondered whether it would even get approved with that kind of hazard rate. The hazard rate of atezo is way better than chemo.

DR LANGER: I’ll concede that. But remember, it's all event free of disease free survival. We don't have OS yet. The presumption, of course, is that it's going to translate into an OS advantage. It has certainly in metastatic disease.

DR WAKELEE: And in locally advanced.

DR LANGER: But if they’re not up to chemo postop, I’d have major qualms about giving them anything.

DR LOVE: So clearly, maybe there’s not a clear-cut answer to this situation. That is oncology. Okay. Final comment from Luis.

DR PAZ-ARES: We tried to answer that question on the PEARLS trial. Indeed, some patients that were not candidates for chemo or basically that refused chemo were included, 15% of the patients. Unfortunately, those patients were not benefiting from immunotherapy. So, of course, this is just a secondary analysis. There is not a robust answer. But I think it’s going to be important. Some of the other trials still ongoing do have patients without chemo. But today, I think the question is not answered. And I think actually, the question would be, you have a patient where you’re going to give chemo and then immunotherapy, would you give them together or would you start with chemo alone and then immunotherapy? We don’t have data, but likely I would do both together.

DR LOVE: So to be continued. And, you know, there’s a bunch of adjuvant IO trials in solid tumors that we were talking about this weekend. And I always refer them back to what you said to me after you presented these data and you were so excited. One of the main reasons you told me you were excited was the PACIFIC trial. And other tumor types were looking at the PACIFIC trial as well. And those, you know, looking good. Anyhow. To be continued. This is just a tasting menu to what happens every day in Tumor Boards around the world.

Contemporary treatment for localized and metastatic NSCLC with EGFR mutations — Helena Yu, MD

DR LOVE: Helena, let’s talk a little bit about another interesting area, EGFR and particularly, of course, in the adjuvant setting. So, again, we’re going to go back to the survey. We asked the audience, okay, you’ve got a patient, Stage IB, exon 19 deletion, high PD-L1. And most of the audience says, okay, they’re going with osimertinib. And actually, when we asked the faculty, interestingly, the most common answer was something I was getting a lot of bad feedback from when we were showing these kind of results from GMOs, so we weren’t giving chemo. And in this situation, you have the investigators giving osimertinib without chemotherapy previously although several of them are. When we go up to Stage IIA and IIIA, now we see much more of chemo/osimertinib from the investigators. Jared, any comments about what we’ve shown so far?

DR WEISS: Oh, gosh. I was hoping you weren’t going to call on me. These folks don’t have tomatoes, right? So I kind of stand in the minority in our community in having a lot of skepticism about adjuvant osimertinib. Sorry. Heather doesn’t have tomatoes.

DR WAKELEE: I’m good with you.

DR WEISS: All right. So I think we — and I’m not sure that our existing, that ADAURA is really going to ever properly answer it for me even once we get survival follow-up. It doesn’t address the population that we have in all of our clinics on this stage and probably all of you have where you can do aggressive surveillance and people rapidly cross over to TKI in the case of progression. Remember, that study was largely conducted in places in the world that might not have ready access to osimertinib. The crossover was a minority of progressors in the control arm. And so I worry that it’s never going to really answer what I should do in my practice.

DR LOVE: So you ought to come tomorrow morning. We’re going to talk about prostate cancer because they used to say the same thing about PSA, just wait for the PSA to go up. You don’t need to use it earlier. Tomorrow morning, you’ll see it may be a little but different nowadays. Here’s getting back to the question we were asking before, adjuvant targeted therapy outside of EGFR. And in this survey, quite a few people have used some type of strategy. I can imagine having a medical oncologist as a patient who might want to be treated. So, again, an area of great controversy. So, Corey, I’ll let you take this one. We asked the faculty you have a patient with an exon 19, TPS that’s high, gets first line osimertinib, now has disease progression. So most people are going to get some kind of tissue, either liquid or tissue. What are some of the things that you’ve found that have been helpful? Have you actually treated people in that situation with what you find, MET, et cetera?

DR LANGER: We’re certainly amongst the 50% who would do both. More shots on goal. Sometimes you can't get the tissue or the specimen is inadequate to look for secondary resistance mutations. Liquid biopsy can be quite useful, particularly in patient who have a greater metastatic burden. So I find them complimentary. And we have now brought that to the frontline. And frankly, at the time of the diagnostic procedure, the faster we can get all the data together, the better off the patient is and the better off we are. Because we're often waiting 2, 3, 4 weeks turnaround time until we get the tissue back. So I definitely marched with the 50% who chose both.

DR LOVE: Helena?

DR YU: I would just say the one thing to add to what Corey said is we're seeing more histologic transformation with frontline osimertinib and that is something, of course, that you can only see on a tumor tissue biopsy. So I think for those patients where that is a suspicion, I would definitely get a tumor biopsy.

DR LOVE: Interesting. Corey?

DR LANGER: And I agree. I’d certainly do a biopsy on a patient who is having rapid progression because that’s the general scenario where the small cell transformation is frequently seen. But in the more common patient that has sort of a more gradual diffuse progression, I don't think I've seen small cell specifically in that. You certainly see a lot more EGFR. It’s typically somebody whose node went from 2 cm to 6 or 7 within 2 or 3 months or brand new liver mets.

DR LOVE: So I want to get over to this next question to Justin. I call this the ibrutinib question. Come on Sunday night. We'll talk about it in CLL, the controversy about keeping ibrutinib going on patients who are progressing. I was kind of surprised by the answer. I’ve kind of been hearing about this over the last couple years. Do you keep osimertinib going in patients who are progressing when you're switching to chemotherapy? Most people are saying yes. Justin, what are your thoughts?

DR GAINOR: Yeah. If we go back to when we were using first generation inhibitors, there was a randomized study looking at that. Do you continue erlotinib, gefitinib when you start chemotherapy? And that was a negative study. However, I think osimertinib is a different molecule. It’s got better CNS progression and is better tolerated. And for me, having CNS progression, CNS metastases are devastating for patients. And so I typically will continue the osimertinib, particularly in patients with brain metastases when I do switch to chemotherapy. I think for patients without brain metastases, there actually is an ongoing randomized Phase III study trying to answer that question specifically.

DR LOVE: So, Heather, why don’t you respond to this question? We asked the audience, you have a patient with an exon 20 insertion, that Helena is going to talk about in a second, and you’ve decided to use targeted therapy, which one are you going to use? And the audience, most of them say they don't have a preference. And those who do prefer amivantamab which is also true of the faculty. What are your thoughts about this, Heather? And how would you compare tolerability of the 2 approaches?

DR WAKELEE: Great question. There’s a few other things you can add to this list too. We had some nice data today with a new compound. This is still a hard one because these drugs do work, but they're toxic, but toxic in different ways. So mobocertinib has been rough with a lot of GI toxicity. And amivantamab is tricky because you do get a lot of — it's an infusion reaction, but it's a different one. There can be a lot of dyspnea. It can be pretty scary. And yet once you get to through that first day, it doesn't happen again. And so it's sort of plus, minus, but there’s also pneumonitis risk with these and rash. So it's difficult and yet they do work, not in the majority of patients, but in a reasonable minority. The duration of response, I think we're still trying to really wrap our heads around. There are other choices also. But short answer, I've used more of the amivantamab though we also have worked with mobocertinib in studies. So I’m split. I talked about both patients.

DR LOVE: Luis, I’d like your thoughts on this. And also, when we asked the investigators what are the common problems that you see with these 2 drugs, here are some of the comments that we saw most frequently. So I'm curious about your experience, but also this question, Luis, which we’ve been hearing some really interesting data on, amivantamab with lazertinib as a next generation agent. And a lot of the faculty say they’d like to use it if it were available. So, Luis, 2 questions. First, about this combination. It’s not available, lazertinib is not available. Amivantamab/lazertinib. And also, your preference between the 2 agents.

DR PAZ-ARES: Okay. So about the 2 agents, I could say that the safety profiles are totally different. Amivantamab, it’s very important to teach the patient and to teach particularly the nurses about how to deal with the infusion reactions. It’s not very severe, but it’s really the patient is having a bad time honestly. So we have to be prepared. But the good thing, as has been said, this typically happens once and that’s it. The other toxicity is mainly rash, diarrhea and with time, edema and so on. The TKI toxicity is typically rash, diarrhea, leukocytes, some nail toxicity, asthenia. The issue is that I could say none of the treatments are very friendly. In my experience, I could say the TKIs are somehow worse. I would prefer to go with amivantamab first. But you have to kind of see with the patient.

Concerning the second question, I think this is a treatment I’ve been using in trials and it’s a reasonable treatment. I couldn’t say today that it’s any better as compared to the drug osimertinib alone as first line treatment. We don’t know yet.

DR LOVE: What about the patient with progression on osi?

DR PAZ-ARES: Yeah. So we know that a good number of patients are responding like 1 out of 3 more or less. Still, we don’t know yet if that is any better as compared to amivantamab alone, to be honest.

DR LOVE: Good point. Okay, Helena, we gave you a big assignment as well, EGFR.

DR YU: Yeah. I say that mine is tougher than Heather’s.

DR LOVE: Yeah.

DR YU: But I will do my best to go fast. I put a lot of slides in for your guys’ information because there's a lot to go over. So here is my outline. So kind of going on the early-stage theme, Heather already showed this, the LACE meta-analysis that kind of started the trend for adjuvant therapy for cancer. And then that leads us to the ADAURA study which, of course, we've already talked about, 3 years of adjuvant osimertinib compared to placebo. Primary endpoint was DFS. And here, you can see that in the primary endpoint of Stage II and IIIA, marked benefit at 0.17. And the benefit deepened with higher stage, but remained across all stages, all subgroups and then with or without adjuvant chemotherapy.

In terms of patterns of recurrence, I thought this was really interesting. Most patients with osimertinib who received osimertinib, did not recur, but those that did actually had more local recurrences compared to patients on placebo where there was more distant metastatic recurrences. And then I think the CNS recurrence rate is striking where there was markedly less CNS metastases. And that speaks to what Justin was saying about the excellent CNS penetration.

So in regards to first line treatment, osimertinib, as all of you know, is a third generation irreversible mutant-specific EGFR TKI. It was the FLAURA study that established that as kind of best in class first line treatment when compared to erlotinib or gefitinib. Clear improvement in both PFS and OS and really has led to that being the standard of care, at least in the US.

I think that this is really important, the idea that osimertinib is better at treating and preventing CNS metastases. Of note, FLAURA did not have interval CNS imaging for all patients, but we know of the patients that started with brain mets, there was less CNS progression and then there was less symptomatic CNS progression in all-comers. And I think this is a really important point. I task studies moving forward, especially in the targeted therapy space, we need to have routine CNS imaging on all patients so that we can compare these different drugs.

And then what about osimertinib-based combinations? I think the 2 that are of most interest are combinations with VEGF and chemotherapy, so we'll talk about both. So there have been multiple Phase II, III studies that have looked at combinations of erlotinib with different VEGF inhibitors. They've all shown a clear PFS benefit, but no OS benefit. But this did lead to the approval of the combination in several countries including erlotinib and ramucirumab here in the US. We did, at MSK, a Phase I study combining osimertinib and bevacizumab and did demonstrate safety and feasibility and the desire, of course, to want to combine VEGF with the best in class TKI.

And so that leads us to this ECOG study, EA5182, that is currently ongoing. And it’s randomizing patients to osimertinib as first line treatment for metastatic disease compared to osimertinib plus bevacizumab. And we will have interval MRI imaging for all patients and so we hope to get some of that CNS efficacy data, thinking that perhaps VEGF inhibition also is known to have excellent CNS penetration. And there are other studies that are ongoing as well.

So what about chemotherapy? So I think what's different about chemo is that chemotherapy is active by itself in this population. And so when we think about combining 2 active therapies, there needs to be a clear improvement in progression free survival that’s more than the sum of sequencing or an improvement in overall survival. And the thought is that if we give EGFR TKIs and chemo upfront together, maybe we’ll further eradicate the subclones that would have survived with EGFR TKI monotherapy, so-called persister cells. And studies with earlier generation EGFR TKIs did show a survival benefit suggesting that by eradicating these persisters from which resistance ultimately emerges, we’re changing the natural history of the disease.

And so these are those studies. The studies were seminal studies out of Japan and India that really showed gefitinib plus chemotherapy had longer PFS as well as OS compared to gefitinib alone. And then based on that, the FLAURA study is ongoing — FLAURA2, excuse me, which is osimertinib versus osimertinib plus chemotherapy for all-comers. And so we await that data.

What about sequencing? I’ve heard this from people. But I think what’s important is thinking about earlier generation followed by osimertinib. I think what’s really important to remember, and we don’t always think this, but 35% of patients actually don’t get second line therapy. So our only shot on goal is that first line treatment. So we really have to put our best drugs forward. Remember, if we do erlotinib and then we have progression, only half of patients will have T790M and be eligible for osimertinib. And then finally, that excellent CNS penetration. And we know that CNS metastases cause significant morbidity and mortality for our patients.

Okay. Mechanisms of resistance. So this is our updated MSK data looking at mechanisms of resistance to osimertinib. The first thing that you'll notice is there’s a lot of colors on this pie. When we were thinking about erlotinib, two-thirds of the pie had T790M, but here it really does look to be quite diverse. There's on-target resistance which are EGFR mediated second site mutations, off-target which could be HER2 amplification, BRAF fusions, ALK fusions and then what we were mentioning before, that histologic transformation. We're actually seeing adenocarcinomas transform to squamous cell, large cell and small cell lung cancer. And, again, those are all seen on tumor biopsies. And so I think it's going to be a challenge to try to prevent these different mechanisms of resistance. And I think that medications that transcend specific mutations or resistance mechanisms will be important post-osimertinib.

This is just a table to show based on what mutation — mechanisms of resistance we find, there certainly are osimertinib-based combinations that we can try. I think the 2 — the one that has the most data is with MET amplification. We see that probably in 5% of patients post-osimertinib. But there is data to show that osimertinib plus savolitinib or a different MET inhibitor does have some modest efficacy. We're not seeing response rates at 70%. Overall response rate was 30%. Median PFS of 5.4 months. And there's multiple similar studies ongoing.

This is an interesting case of mine where a patient was on osimertinib, actually developed an ALK fusion and then got 18 months on osimertinib plus an ALK inhibitor combination. So I think we're going to see — rarely, there's truly targetable acquired mutations like this. And then this is just kind of examples of small cell and squamous cell transformation. I think that what’s really important is once transformation occurs, outcomes are poor for our patients. We have to treat this like a de novo small cell when it happens. And so really, the bulk of work should be at preventing transformation because it's hard to or not possible to reverse. And presence of EGFR, TP53 or RB alterations increase the risk of small cell transformation.

There are studies like this ORCHARD study which is ongoing where we’re biopsying people post-osimertinib. If we find something targetable in terms of mechanisms of resistance, they’re going into these different cohorts and then they’re also nonmatched arms for that two-thirds of patients where we don’t find acquired mechanism of resistance.

In terms of targeted therapies post-osimertinib, there really are 2 that have data. We haven’t talked about this one yet. Patritumab deruxtecan is a HER3-directed antibody drug conjugate. HER3 is expressed in the majority of EGFR mutant lung cancers. And so this study looked at patritumab deruxtecan post-osimertinib and post-chemotherapy. Response rate was 39%. I think what’s important to note is that you can’t see if because it’s too small, but patients had BRAF fusions, ALK fusions, KRAS mutations, different mechanisms of resistance to osimertinib and still responded to this. So it did appear to transcend the different mechanisms of resistance.

And then we talked about this a little bit already, amivantamab and lazertinib. Amivantamab is a MET EGFR bispecific antibody. Lazertinib is similar to osimertinib, third generation EGFR TKI. And this was looked at after osimertinib, but before chemotherapy. Response rates similar at 36%. So I’m looking at both of these agents with expectation and hope for approval in the near future.

And then finally to top it off, EGFR exon 20 insertions. So this is rare. It’s probably about 10% of EGFR mutations and ends up being about 2 to 3% of all non-small cell lung cancer. So small, but bigger than RET, ROS1, NTRK. So something that we should look for and is now treatable. So over the last year, there’s been 2 approvals. The first one is mobocertinib. And as we were just talking, this is an oral EGFR exon 20 inhibitor. The response rate at the highest dose level of 160 was 43%. Many patients do require dose reductions due to toxicity though. And then the other agent is amivantamab. Again, bispecific EGFR MET antibody, has both MET and EGFR toxicities. Overall response rate was 40%.

I think this is an important slide. So what outstanding questions are there for EGFR exon 20? I think can we move these drugs to the first line setting? I think that’s an important question. Can we sequence them? Remember, amivantamab is an antibody and mobocertinib is a TKI. So there might be less cross resistance there. We really need to know the CNS penetration of these drugs. Half of these patients will end up having brain mets. And then there are new EGFR inhibitors like the Cullinan drug that we spoke about today, Dizal, there’s several. So I think we look to those to see if they can improve upon that we have.

So in conclusion, early-stage EGFR mutant lung cancer, make sure you test. Do the molecular testing, use osimertinib when appropriate. For first line treatment, osimertinib monotherapy is the standard of care, but we're looking at combinations. And we mentioned this, but I think risk stratifying patients will be important to see who would really benefit from that escalation and who wound be happy just on osimertinib monotherapy. Mechanisms of resistance, there's no real dominant mechanism of resistance. And targeted therapies post-osimertinib, really focus on transcending specific resistance mechanisms. And then, again, amivantamab, mobocertinib for EFGR exon 20. But there are definitely new things to keep your eyes on as well.

DR LOVE: So we’re getting a lot of questions from the audience, Helena. One, patritumab deruxtecan. Monday night, of course, we're going to be talking, and actually tomorrow night too, of trastuzumab deruxtecan which, of course, is approved in both upper GI, of course, as well as breast cancer. What do you see tolerability-wise? Of course, we’ve seen interstitial lung disease with the other agent. What about this one?

DR YU: Yeah. I think this is a new hybrid that we’re going to see more and more of. So antibody drug conjugates are like part targeted therapy, part chemotherapy. So we’re seeing a little bit of each type of side effect. So you definitely get some cytopenias. You can see alopecia, so chemo side effects. For HER3, we’re seeing much less pneumonitis in terms of patritumab deruxtecan. I think it was less than 5%. Remember, trastuzumab deruxtecan, pat deruxtecan and then the TROP2 inhibitor, they all actually have the same chemotherapy backbone too. So there’s going to be some overlapping toxicity.

DR LOVE: And, of course, we’re going to talk about this agent, trastuzumab deruxtecan, here, particularly in HER2 mutant lung cancer, later on, where it seems to be very active. So, Corey, a couple other questions from the audience. Helena mentioned the issue of TKI plus antiangiogenic, what about erlotinib and ramucirumab for some of the weird mutations?

DR LANGER: In some of the unusual mutations.

DR LOVE: Yes, unusual.

DR LANGER: I haven’t seen much data. Afatinib has the official approval there. We tend to use osimertinib in the same setting. When I do use afatinib, I tend to use it at a lower dose. In fact, 50% dose and escalate when I can as the patient tolerates. I don’t think I’ve seen specific data combining angiogenesis inhibition with either erlotinib, or for that matter, osimertinib in the unusual mutations. If it’s happening anywhere, it’s happening in your shop, Helena.

DR LOVE: Yeah, Justin, can you comment on that? Also, Justin, I’m curious. I really wasn’t aware that you see transformation to squamous. If they have high PD-1, will you give them PD-1 if they’re squamous? Anyhow. Both questions. First of all, erlotinib plus ramucirumab in unusual mutations. Any role for that, Justin?

DR GAINOR: My sense is that that’s an approval more based on convenience, looking for where there’s an unmet — where there’s not data. But I tend to extrapolate for the atypical EGFR mutations and still use osimertinib in this setting acknowledging that it’s not included in the big, randomized studies. But there are now retrospective studies looking at it. So typically, I’ll still use osimertinib in that setting rather than a first generation or second generation inhibitor. Your second question was —

DR LOVE: It was about squamous.

DR GAINOR: Squam. Yeah, I think the squam question, we too have seen that. I think the question is always is this reflecting heterogeneity? Because it’s a different timepoint. Sometimes, a different site. Was this an underlying adenosquam to begin with? How much is truly transformation versus outgrowth of the squam component? We don’t know. I still think that that’s likely not going to be a PD-1 responsive tumor. Our experience has been even when these tumors transform to small cell, they’re not very responsive to PD-1 pathway blockage either. It’s a big question for us. We certainly will give chemotherapy for those patients. But whether we add PD-1 or not, we constantly talk about it. It’s uncommon and there’s really no data to guide us.

Research advances shaping the current and future treatment of metastatic NSCLC with ALK rearrangements, ROS1 rearrangements or RET fusions — Justin F Gainor, MD

DR LOVE: So we’re going to move on now and talk about targeted therapy. And we asked a few questions to the audience. Jared, if you can respond to this first one. Basically, we said what’s your first line therapy nowadays for people with ALK rearrangements? Most of the audience is saying alectinib. When we ask — let’s go to the next question. And most of the faculty also say alectinib with one exception. So. Jared, how do you approach first line therapy of ALK? And what do you think about, I don’t know, maybe you’re the one who said lorlatinib. I’m not sure.

DR WEISS: I was not. I was actually going to say, this time I guess you owed me an easy one after that last one. I’m with the majority on this.

DR LOVE: The other one was easy, actually.

DR WEISS: It’s great taste and less filling. You have a great PFS. It’s an extremely tolerable agent. It’s very patient friendly. It’s not clear that giving a later generation agent first will improve your PFS too. So I’m with the majority on this. This fits my human goals of care nicely.

DR LOVE: So we asked this other question which has been a real issue. We were talking already about the issue of checkpoint inhibitors in people with targetable mutations. And we asked the audience where would a checkpoint inhibitor fit in in a patient with ALK? And interestingly, you even see some people saying first line, some second line. Very different from what we see in the investigators who generally either don’t use it at all or beyond third line and generally don’t look at PD-1. Heather, is that the group you’re in?

DR WAKELEE: Absolutely. I’ve really — I think when you look at the data that exists in the world, there’s like one patient with an ALK translocation who responded on a checkpoint inhibitor study once and he or she ended up grouped into a couple different analyses that showed up, but they always included the same institution, so I think it was the same one patient. Otherwise, I have a lot of patients who have ALK translocations. We noticed very early that they frequently have high PD-L1. I have never seen any of them respond. And I really think it’s important for this audience to be hearing that. If there’s an ALK translocation, ignore the PD-L1. Don’t give them a checkpoint inhibitor. It’s not going to work and you do end up increasing the toxicity. It looks like Corey is going to contradict me.

DR LOVE: I’m not going to give Corey that chance yet. But anyhow. Second line therapy, you think people are on board for lorlatinib. And Justin is going to go through the data. What about ROS1? We said you’ve got a patient with brain mets and ROS1. The audience is sort of split between crizotinib and entrectinib, but the faculty is much more oriented because of this CNS disease. Above, they’re already thinking about it, in general, over crizotinib, but particularly in a patient who has brain mets. Luis, any comments in terms of entrectinib and CNS penetration?

DR PAZ-ARES: Well I think crizotinib is an effective ALK inhibitor, but with bad penetration to CNS as compared to other agents. In that sense, entrectinib is having — sorry, ROS inhibitor, entrectinib is a much better drug in that direction in terms of having CNS penetration. And indeed, the initial data suggests that maybe responses are there. So for that reason, I may choose entrectinib in that setting.

DR LOVE: I’m not going to go through every one of these slides. You can check them out afterwards. You’ll see patterns in terms of how people respond in terms of checkpoint inhibitors based on what the lesion is. We asked about first line therapy, Justin, and the audience seems to be more oriented around selpercatinib. And actually, the investigators are as well. Justin, what do you think that's from? Do you think it's from the difference of the drugs or why do you think people are choosing selpercatinib?

DR GAINOR: I think partly, it’s the first-mover bias.

DR LOVE: Right.

DR GAINOR: Essentially, first agent to market, first one published in a high-profile paper. I think it gets used more. When we look at the data, things look pretty comparable in terms of response rate. They do have slightly different toxicity profiles, but I think it is simply that. People start getting used to using a drug.

DR LOVE: Right. And Monday, we’ll be talking about CDK inhibitors in breast cancer. We used to say that about palbo. First CDK inhibitor, everybody was using it and then abemaciclib came out with a positive adjuvant trial and people are using abemaciclib. So I think they follow the data. Here’s some more of these slides related to where they use checkpoint inhibitors in general. Obviously, they're not using it first line. These are some of the types of tolerability issues. Helena, how does this sync up with your experience in using these 2 drugs? And is the tolerability profile different, Helena?

DR YU: We had this study of selpercatinib. So, again, it’s comfort in use. But I do think that these capture it nicely. And I think part of these questions about targeted therapy and immunotherapy is that we actually have a couple lines of targeted therapy available for use. So just by that, I think the investigators are saying we're going to use the IO treatments later, if ever.

DR LOVE: Right. Here’s a really interesting question, Corey. This concern that people have had about giving an IO in the first line setting and then finding out the patient as a targetable lesion and being worried that they're going to have toxicity has led a lot of people not to give an IO until they have their NGS back which also can be a problem because it's not back right away. So we came up with a couple of questions related to that. And one of them has pretty surprising answers. So I'd like you to respond to that. So first, we presented a patient, both of these are cases with high PD-1, of a patient who presents with highly symptomatic metastatic non-small cell, nonsquamous non-small cell lung cancer with a high TPS value. So you're thinking, yeah, in general, you're maybe thinking about a checkpoint, particularly in somebody who is really sick. But we asked the faculty, would you add a PD-1? And the answer is no. But then we said supposed the patient had a long smoking history. And all of a sudden, a bunch of people — I was surprised at that. But it makes sense, but I was just surprised. I’ve heard that before PD-1, people actually looked at smoking status to predict benefit. Any thoughts, Corey? Do you do that?

DR LANGER: I’ve converted. I think we are all in agreement if they're never smokers, we’re banking on the presence of an actionable marker, an oncogenic driver. And in this day and age, we’re probably right now about 40 or 50% of the time. And, again, it's both tissue and blood that I would obtain on this individual. The long smoking history, again, they're playing the odds. More likely than not they won't have an oncogenic driver. I was amongst the 7 or 35% who said let's still wait. 15, 20, 25% of these folks may have a driver and it would be inappropriate, I feel, as long as the patient can wait, to start off with a checkpoint inhibitor and then have to segue to a TKI, particularly if it’s an EGFR mutation or ALK. So in that situation where they absolutely need treatment and we don’t have the molecular back, I will give them pem/carbo with or without bevacizumab. I will not give them a checkpoint inhibitor.

DR LOVE: So, Justin, we gave you the challenge of talking about ALK, ROS1 and RET. Go for it.

DR GAINOR: Okay. So I’m going to cover the fusions. So ALK rearrangements, we’ve known since 2007. We have a lot of drugs, right? And common nomenclature you’re going to hear us talking about is first generation, second generation, third generation agents. I think in my mind what distinguishes these is thinking about it as you go from first to second to third, you see increasing potency, you see increased CNS penetrance and you see increased coverage of ALK resistance mutations. That’s pretty much across the board.

Okay. And I consider this the beating up on crizotinib slide which is essentially, so 4 of these studies were randomized studies, all comparing a second generation inhibitor versus crizotinib. One thing to keep in mind is that for many of these studies, they’re reporting both investigator assessed PFS as well as centrally assessed PFS. And sometimes within the same study, the numbers can be quite different. So it is important when you're looking at them. I’ve tried to denote it here that you're comparing apples to apples, acknowledging that these are all cross-trial comparisons. But essentially, we have 3 randomized studies comparing alectinib versus crizotinib, all of which showed very, very similar results as well as a randomized Phase III with brigatinib against crizotinib also showing significant improvement in progression free survival. Naturally over the last couple of years, we’ve made comparisons between alectinib versus brigatinib. You saw that in the survey. From a hazard ratio perspective, they were quite comparable. It comes down to alectinib was the first study, the Global ALEX study, and produced a median progression free survival by investigator of close to 3 years.

One important point about ALK positive lung cancer is it does have this particular tropism for the CNS. So these patients have high rates of CNS metastases, higher than, say, ROS1, in our experience, higher than EGFR mutant lung cancer. And this is not simply that when we were first doing these studies, we had a poorly CNS penetrant drug, crizotinib. It does look like there's some biological basis to this. It’s also important to note that how the CNS activity of agents, particularly the second generation inhibitors, how that has been presented has been slightly different from study to study. So we don't have a clear comparison. Nonetheless, we see across the board that second generation drugs are clearly superior to crizotinib when it comes to CNS penetration. On the left, this is from the Global ALEX study. This is looking now at cumulative incidence of brain metastases. So in red is crizotinib. In blue is alectinib. So a profound difference. In the middle we have the ALTA-1L study. This was, again, with brigatinib. And here, we’re looking at survival without intracranial disease progression, so intracranial PFS. Again, marked difference with brigatinib have compared to crizotinib. For the sake of completeness, I’m also including the eXalt data. This was using another second generation inhibitor, ensartinib, which I would say also showed CNS activity. But given the number of already approved agents in the ALK space, I think this is an agent that's looking for a home and I don't really see a place for it.

It is important, I put this slide in because it really, in my mind, highlights the effects of crossover. And we tend to think of overall survival as our gold standard, but the fact that we have so many different randomized studies of alectinib versus crizotinib, Global ALEX, obviously a global study, J-ALEX was conducted in Japan. The main difference between these studies though is J-ALEX allowed crossover, no difference in overall survival, Global ALEX did not allow crossover and we see a separation there. So I think this really just shows the effects of crossover. I think clearly, the second generation inhibitors have become our standard. As we saw with EGFR though, resistance emerges. And it is important to note that the way resistance emerges is quite different with ALK. So when we use the second generation ALK inhibitors, we see a lot more on-target alterations. About 50% of patients will develop an on-target ALK resistance mutation when we do tissue-based biopsies. And interestingly, they’re smattered throughout the kinase domain. So there's no — and each inhibitor is a little bit different. But there is this common vulnerability, this ALK G1202R mutation which is in the solvent front which is a common vulnerability of the second generation inhibitors. We also see this with ctDNA where you can see lots of these ALK resistance mutations.

And this has now led to the third generation ALK inhibitor, lorlatinib, which in preclinical models was able to overcome all of these ALK resistance mutations. And we see this in the clinical data. So this was the initial Phase I, II study. And what was interesting is the investigators broke down responses to lorlatinib based upon whether there was an ALK resistance mutation there or not. So these were patients who had already received a second generation inhibitor, then came into the study and received lorlatinib. And there actually was a significant difference in response rate, 60-something% versus 30% if you have an ALK resistance mutation and a separation in PFS. Nonetheless, compared to chemotherapy, most investigators will use lorlatinib post a second generation ALK inhibitor. And most notably, this agent does have activity against that G1202R mutation that I highlighted.

Now this leads us to the CROWN study. And I should also add that in preclinical modeling studies, that preclinical studies would suggest that actually if you start with lorlatinib, you actually may not see those ALK resistance mutations. It's really that only if you start with a second generation drug that kind of forms a scaffold of ALK resistance mutations to then acquire additional compound mutations. So what if we take this agent and move it to the first line setting? This is the CROWN study, a randomized Phase III, enrolled close to 300 patients. These data were updated at AACR and so many people probably missed this update. But in my view, this is profound. Here, we’re talking about a hazard ratio of 0.2. I recognize it’s hard to see. And now if you’re looking at the 3-year landmark, the 3-year landmark for progression free survival is still 63%. And if we compare that versus alectinib, it’s only around 40%. So in my view, this is game-changing data because I do think that if you start with a third generation inhibitor upfront, you can lead to pretty significant PFS. The challenge though is with toxicity and specifically, this agent does have more mood and cognitive effects as well as peripheral edema. In my experience, those do, at least the mood and cognitive effects, improve with dose reductions. This is also to show that this agent is quite active whether you have brain metastases or without brain metastases.

And this is looking at the data in a different way but basically, the lower right is the most important. This is patients without brain metastases going into the study and basically only one patient developed CNS metastases on lorlatinib. And this is just to highlight the toxicity. I mentioned the mood and cognitive effects are really the big differences. And really, that's the argument for some people doing a sequencing strategy of a second followed by a third generation inhibitor.

Moving on to ROS1. This is very homologous to ALK. They share 77 % homology in the kinase ATP binding domain. Crizotinib, this agent is very active in ROS1 rearranged lung cancer. 72% response rate and a 19-month progression free survival. It is important to remember, one take-home here is that while many ALK inhibitors are ROS1 inhibitors, not all of them are. Okay? So alectinib does not target ROS1. That is the wrong answer. It has no ROS activity. Okay. But you'll hear there are other agents, other ALK inhibitors that do have ROS activity. But you really need to remember that point.

One of the vulnerabilities of crizotinib is that it has poor CNS penetrance. And you saw this in the questions, then entrectinib was favored by many investigators, particularly in patients with brain metastases. So what is the data for entrectinib? We see in the upper left, a high response rate of 67%, median progression free survival of close to 16 months. In the lower left, this is best response by CNS status. You can see both patients with and without brain metastases respond. And a very impressive intracranial objective response rate of close to 80%. One comment is that CNS activity can be a double-edged sword. By the name entrectinib, this does have TRK activity and so TRK within the CNS can cause dizziness which can be a significant side effect for these patients. So that, in my view, is one reason why patients without brain metastases, you might not favor this drug because of those CNS effects.

There are other ROS1 inhibitors currently in development. So repotrectinib, this is an agent that’s shown activity in patients both TKI naïve and previously treated including those with ROS1 resistance mutations. Lorlatinib, this is one of those where they're ALK and ROS1 dual inhibitors. This agent has shown activity in the TKI naïve and in the crizotinib treated setting, but it is not approved for ROS1 and it is, so far, not being developed further in the ROS1 space despite the signal.

Finally, RET fusions. Found in 1 to 2% of lung cancers. We already commented on selpercatinib. This agent is very active in the patients previously treated with platinum, response rate 64 to 70%. High response rates in the treatment naïve, 85 to 90%. These data were updated at various meetings including ASCO last year and ELCC. And more or less, the data have held up. The latest update for the median PFS platinum treated patients has been 25 months. Main side effects, dry mouth, diarrhea and elevated transaminases.

Pralsetinib, this agent also one of the selective RET inhibitors in the treatment naïve setting. In the initial publication that we put together, response rate was 70%. Prior platinum doublet patients, 61%. This is now combining all of those datasets together. The median PFS among post-platinum patients was 17 months. Interestingly, in the treatment naïve patients, in that initial publication it was only 9 months. However, the protocol actually excluded patients unless they were not candidates for platinum doublet chemotherapy. So with a subsequent amendment, which is in the lower box there, essentially now 25 patients or the more typical treatment naïve patients who would have been eligible for platinum doublet chemotherapy, now we see an 88% response rate and the PFS hadn't been reach. So I view both of these agents as very active. Both have CNS activity. And we now have, just like with the other stories, resistance emerges and we now have multiple next generation RET inhibitors that are currently in development. And with that, I’m going to leave it there.

DR LOVE: Awesome. A couple follow-up questions. What’s your first line therapy for ALK, Justin?

DR GAINOR: So maybe I was the one person there.

DR LOVE: I figured that.

DR GAINOR: But I would say pre-AACR, it was alectinib. Post-AACR, I would say it’s lorlatinib.

DR LOVE: And the dizziness with the TRK inhibitors. What do patients tell you? And what's the pathophysiology of the dizziness?

DR GAINOR: Yeah. It’s TRK expression within the CNS. And it's an on-target effect of TRK within the CNS.

DR LOVE: So they lose their balance?

DR GAINOR: Yeah. It can be unsteadiness. It can be dizziness. It can be very disruptive because it's patients experiencing this every single day.

DR LOVE: Interesting.

Targeting alterations in MET, HER2, KRAS and other oncogenes in NSCLC — Jared Weiss, MD

DR LOVE: All right. We’re going to move on now and talk about MET, HER2 and KRAS and a couple other really interesting findings from this survey. So first of all, starting out with MET exon 14 skipping mutations. We asked people what’s their first line therapy? And right now, we're hearing capmatinib. Luis, any comment? When we asked the faculty, also we saw capmatinib more than tepotinib. Any thoughts?

DR PAZ-ARES: Well honestly, I think both drugs could be my first choice. I'm not sure one versus the other. I think they are quite similar in terms of safety profile. And they have not been compared one to each other. And the data looks to me pretty similar. So for sure, these second generation MET inhibitors are the way to go.

DR LOVE: But from your point of view, it's actually a coin flip?

DR PAZ-ARES: Yeah.

DR LOVE: Okay. And, again, you see maybe a little earlier use of PD-1 in MET patients. We also asked, here's where we saw a really interesting finding. I'm curious, Corey, what your thoughts are. Thinking back to the sort of history of using first line targeted therapy which, of course, started out with EGFR, then ALK and eventually, we kind of got to a point where we weren't doing randomized trials against chemo like we did in the beginning. But in any event, we asked the audience what's your first line therapy in a patient who has a HER2 mutation? Interestingly, some people say trastuzumab/pertuzumab, but quite a few people said T-DXd. Most people say chemotherapy or PD-1 in this patient with a high PD-1. This is what I found interesting, Corey. A fair number of investigators are saying T-DXd first line which kind of makes sense, but you tell me. What are you thinking?

DR LANGER: I’m torn. The data that we have for the most part in the second and third line are quite impressive, response rate of over 50%. PFS is not in the category that we're seeing for ALK or EGFR or RET. So I'm amongst those who would probably do it second line although 45% of my peers chose it first line. And I have equipoise whether it's carbo/pem with either bev or pembro. I’ve gone both ways. It’s an example though of an antibody conjugate finally that's making its way into the clinical setting in metastatic non-small cell which is not true yet of any of the other oncogenic drivers though EGFR is probably right behind. So I think we'll see studies coming up looking at it in the first line setting. And I dare say the PFS will probably rise as it seems to in just about every other oncogenic driver.

DR LOVE: Heather, there’s sort of a generic lesson here too or issues here too, when does the targeted therapy come in? What kind of data? Do you need a randomized study? In the past, again, you saw more than 50% response rate. People are bringing it first line. T-DXd, as Jared is going to talk about, has another issue which is interstitial lung disease. Makes it a little more complicated. Any thoughts, Heather?

DR WAKELEE: So I’m one of those chemo people still in the first line for some of these targets. I’ll confess to that. And I think that the T-DXd data, to me, has been much more impressive than I've seen with some of the other targets. And so I'm actually willing to consider it in first line. And I'm actually in discussion with a patient who was just diagnosed with HER2 mutant lung cancer. So there, I'm willing to. And I look at 2 things. I’m going to look at the response rate, but that duration of response has to be good. And with some of the targets, chemo works really, really well, especially pemetrexed in things like RET and ROS. And so I haven’t given up on first line chemo with pemetrexed even in some of those. But I realize that makes me an outlier here, but that's the way I think about things. It’s got to work for at least as long as the chemo is going to.

DR LOVE: Luis?

DR PAZ-ARES: I’d just like to come back here to a different issue which is the fact that patients on TKIs maybe live longer, but typically disease will relapse always. Here, we had an occasion where the genomic aberration is not predicting for not response to immunotherapy. And the patient had a high PD-L1 expression, more than 50% where you may expect a 35% survivorship at 5 years. So it's kind of —

DR LOVE: That’s sort of reflected in what the — a lot of investigators were saying first line IO. So are there data with HER2 mutant in terms of IOs?

DR PAZ-ARES: No. So that was MET mutant.

DR LOVE: Oh, I’m sorry. This is HER2 here.

DR PAZ-ARES: Okay, sorry.

DR LOVE: Go ahead, back to her.

DR WAKELEE: I was just going to say, I think for MET, I have seen data that goes in both directions.

DR PAZ-ARES: Absolutely, absolutely.

DR WAKELEE: So I’m confused about it. But with HER2, I think of it like EGFR and I don't think the IO works as well.

DR LOVE: What about in terms of IOs, Justin, in HER2? Do we know anything whether or not patients with HER2 mutations respond to IOs?

DR GAINOR: Yeah, to Heather’s point, I would characterize the HER2 more aligned with the EGFR and other drivers. The piece of data that I would like to see that may help us with this decision making is, you mentioned the ILD. And I think the ILD rate there is 25, close to 25%. Does the fact of prior PD-1 on board, does that modulate that risk? Because I think that would, if it is that patients with prior PD-1 on board have a much higher risk of pneumonitis, that would influence me to then use T-DXd first line to mitigate that.

DR LOVE: Of course, you see ILD in breast cancer where they don't use IOs very much.

DR GAINOR: Sure. But this is much higher, right? This is 25%. So it could be a dose effect.

DR LOVE: What grade is that? What grade? Because you can see grade — one thing — what grade do you see?

DR GAINOR: So it’s a range.

DR WAKELEE: It can be really bad.

DR PAZ-ARES: I don’t think it’s more than 10%.

DR LANGER: Grade 3 is much lower than that. I think it’s 10% or lower than that.

DR PAZ-ARES: It’s 10% or lower than 10%, I would say.

DR LANGER: Yeah. But it’s still significant.

DR PAZ-ARES: Yeah.

DR LOVE: So, Corey, what about, and we, again, talk about this in breast cancer, GI cancer, do you do anything differently in terms of following patients on T-DXd to look for ILD? Most of the investigators say no imaging other than imaging and clinical evaluation. You can look at the CAT scan, et cetera. What do you do?

DR LANGER: Our patients have disease in the chest, so it's not hard to find the ILD. And obviously, if they're symptomatic in between, you get the appropriate imaging and that will virtually always entail a CAT scan and pulse ox. So I think the important point, and you showed it about 5 slides ago, the drugs that are used in breast typically are not necessarily active here. Trastuzumab alone, trastuzumab/pertuzumab. There have been small Phase II retrospective —

DR LOVE: A lot of the audience said —

DR LANGER: — response rates, 20, 30%. Some activity, but not on the level of trastuzumab deruxtecan. You saw that the entire faculty here chose that.

DR LOVE: Yeah. And, again, you saw the same thing in upper GI cancers. Initially, before T-DXd came along, people were trying trastuzumab, pertuzumab. T-DXd came along and they sort of forgot about that. Helena was talking about the chemo side effects that you can see with this conjugate which we hear are, and we'll talk on Monday night in breast cancer, much less than IV chemo. A little bit of — what I hear, Helena, I don't know in lung cancer, a little bit of alopecia, maybe some GI effects, but not like IV chemo, maybe somewhere in between. Is that your take?

DR YU: Yeah, that’s right. And I think what’s interesting about the cytopenias in the ADCs is that actually they’re more common in cycle 1 and then they actually sort of resolve versus with chemotherapy like carboplatin, obviously, the myelosuppression gets worse as you get more.

DR LOVE: That’s interesting.

DR YU: So that’s a distinct —

DR LOVE: That is interesting. Okay. KRAS G12C, Jared, 30% of the audience say they want to use sotorasib first line, but when we asked the investigators, they don't say that at all. When we say where would you consider it? Most people say second line, sotorasib, adagrasib, of course, not approved but we're seeing some data here. Any thoughts about your first and second line approach to KRAS G12C, Jared?

DR WEISS: So I think starting with the general case, I think the first question is the relative efficacy which, of course, is multi-dimensional between your 2 choices. We don't have a lot of data with sotorasib or adagrasib in frontline, but it looks like we'll probably wind up with a PFS somewhere around 11 months. And we have a dataset at ASCO that shows us that in KRAS patients not further selected, when we give them triplet, we get a PFS of around 11 months. So that doesn't help us that much. Beyond being small data, it’s not terribly different.

The next question is are they differentially toxic? Certainly, the toxicity profiles are different. Is one clearly superior? Maybe the TKO a little bit so. And then finally, I come to whether sequence matters. And here, I think mostly about toxicity. In general, we've discussed a few times on the stage here tonight the idea that perhaps TKIs are a little more toxic given after immunotherapy. With the 2 drugs we have data on, most of the patients are after immunotherapy. It’s left unanswered whether that profile might get better in the absence thereof. So, to me, this comes down to shared decision making with the patient and an individual patient situation. In a patient with low-bulk disease, not terribly symptomatic, I like the demedicalization that the TKI offers. But for my generic patient who is more heavily symptomatic in need of response, I'm probably going with triplet more often.

DR LOVE: And, Luis, what about IOs in KRAS G12C? The faculty says they're thinking about it first line. Do you agree?

DR PAZ-ARES: Yeah. Typically, today for a KRAS positive — I mean, mutant tumor, the way I would go would be like chemo/IO or IO alone if he is very high PD-L1 expressive.

DR LOVE: Have you seen responses to IO alone with KRAS G12C, Luis?

DR PAZ-ARES: Oh, yeah. Absolutely, absolutely. It’s a good predictive factor, not a negative predictive factor, G12C.

DR LOVE: I don’t know. I personally find this a little bit confusing. We have a series right now, a webinar that Justin was on, as part of that and we talk about this constantly. Docs in practice are trying to figure out what to do with these less — where there’s much less data. And they see this, you’re all using it first line.

DR PAZ-ARES: So the issue is that, of course, you start to kind of dissect out more what is apart G12C. If they’re having like an LKB1 mutation or so, then things start to be a bit more grey, right? So maybe the benefit is not as clear, but you have to realize that those tumors with LKB1 or KEAP1 mutations, they do badly always regardless of the treatment. So it’s more a prognostic rather than a predictive factor anyway.

DR LOVE: I don’t know if you saw the paper that came out in New England Journal of sort of T-cell, it seemed like CAR T in pancreatic cancer, KRAS G12D. I can’t wait to ask the GI people tomorrow night about that. They had a patient with a 75% response to — it sounds kind of like CAR T. Is anything like that being done in lung, incidentally?

DR LANGER: CAR T?

DR LOVE: CAR T in lung or T-cell. I’m not even sure what they did there.

DR LANGER: It’s starting to be looked at, but it’s not ready for primetime.

DR WEISS: We’re working on IMD for GD2-CAR for pan lung cancer, squamous, nonsquamous and small cell.

DR LOVE: Awesome. All right. Well let’s talk about MET, HER2 and KRAS, Jared.

DR WEISS: Okay. So a number of years ago, my friend and mentor, Corey Langer here, gave a talk that he called thoracic potpourri at ASCO. That’s kind of what I’m doing here and having a lot of targets as listed here. I’m a recovering New Yorker, so I’m going to have to talk a little bit quickly here. But I find MET a really interesting story. So as we dissect the CITYSCAPE data at ASCO, it’s interesting to look back on MET and other stories of subgroup analyses on randomized Phase IIs that we all assumed would transform forward into Phase III and that repeatedly failed to do so. And in MET, we have 2 such stories here. The first with onartuzumab. You’re looking at the Phase III data of the subgroup that looked good in randomized Phase II. So this was erlotinib plus or minus here in the MET high population. The same thing happened with tivantinib. Again, you’re looking at the negative Phase III data here. Here, if you subgroup yet again, so the subgroup that was positive in the randomized Phase II was the nonsquams. That’s a negative study here. If you subgroup further to the nonsquams that were IHC high, you start to get a hint. Of course, that was not approvable.

But moving forward a little bit in history, crizotinib, I’ll remind you, was actually not originally labeled as an ALK or ROS1 inhibitor. It was originally on the shelf at Pfizer labeled as a MET inhibitor and later came back off the shelf in what may still be the largest Phase I study ever done. Certainly, one of the largest and another interesting example because that’s been copied repeatedly, the use of large Phase I expansion cohorts for rapid approval. At any rate, here, you’re looking not at IHC, not at FISH copy number, but at the ratio of FISH copy number to Centromere 7. In other words, duplication within the chromosome. And we get our first hint of a real aha shown by the waterfalls at left or the PFS in the middle. But really, the capmatinib story really shows that progression even more nicely where, granted with small numbers, in the IHC, we have a bit of a separation by expression. The MET to CEP7 ratio here, a different cut point, but starting to get more towards an aha moment, even more discrimination. And at least in academia, we’re pretty much all getting our molecular, not a la carte, but in next generation sequencing typically with an RNA fusion panel as well. And so what we’re getting back is MET copy gain number where clearly, there’s a nice separation here. And in a copy gain number of at least 6, we’re getting to numbers that are approaching what gefitinib set years ago for true targeted therapy. I would note parenthetically that you can’t rely just on high copy gain number because the different lab companies define that differently. Some will give you the gain number. But to my knowledge, if you query any of them, will give it to you. And capmatinib has at least compendia listing for that.

But the biggest aha is a slightly different way of looking at this. The MET del 14 really shows true targeted therapy type outcomes. I guess I’m beating up on crizotinib a little bit too here. Although with the next generation agents, capmatinib and tepotinib, we’re getting to nice response rates as outlined here, PFS north of 10 months and good survival and that is on-label and FDA approved for both of those agents.

Amivantamab is an agent we’ve seen in several contexts here. At ASCO I’ll remind you, it’s an EGFR MET bispecific. You’re looking here at World Lung data from late last year, 9 evaluable patients, all of whom had evidence of response. The updated data at ASCO showed 3 out of 6 response in treatment naive patients, 5 out of 11 in patients without prior MET inhibitor exposure, and 4 out of 19 pretreated with a MET inhibitor. And I have a reminder to tell you about that data. The people on the web are laughing much more than you guys are.

So I’ll just try again, telisotuzumab vedotin, beyond being a mouth full that I can’t say, is an anti- c-MET antibody conjugated with a tubulin inhibitor. Ross Camidge is updating this data at ASCO at this conference but the theme really is fairly unchanged. It’s just greater N with perhaps greater confidence. The clearest signal here is in the EGFR wild-type, nonsquamous, MET high, where more than half of the patients are responding. I would also highlight for you an upcoming abstract on the combination with osimertinib in patients who’ve progressed on osimertinib with a 58% response rate in 19 patients.

We’ve already talked a little bit about the KRAS data. Sotorasib is FDA approved for KRAS G12C non-small cell lung cancer. The waterfall plot here shows a 37% response rate and we have a PFS of 6.5 months.

Adagrasib is not approved. You’re looking at the data available to me when these slides were CME approved. In brown we have 16 patients with non-small cell treated at the recommended Phase II dose, 53% response rate, median PFS of 11 months. This agent has a PDUFA date in December and we saw today the potentially registration enabling data in 116 patients, 98% of whom were pretreated with chemo and immunotherapy. The response rate there was 43%. PFS again 6.5 months. Grade 3 treatment related adverse events in 46% with GI effects predominating. We have not yet seen publicly the data on adagrasib in patients with active and untreated CNS mets but we do know that it made an oral.

Trastuzumab deruxtecan is an antibody drug conjugate that we’ve already discussed here a bit in the discussion section. It’s 3 parts, notably linking the trastuzumab sequence via a tetrapeptide-based cleavable linker to a topo I payload. And here is the data on that agent. We have a response rate of 55%. Here the adverse events, notably 25% of patients discontinued due to adverse events. I consider that a relatively high number. We were talking about ILD. It is indeed about a quarter of the patients, 6 out of the 24 had this at Grade 3 or higher.

So I’m going to breeze past this because I think we’ve already had this discussion along exactly these lines earlier, and I’m going to end on I think 2 final topics. Dapo — gee, I put it down, the spelling here, datopotamab deruxtecan, another agent I trip over. This is a TROP-2 antibody drug conjugate. Our Phase I data gave us a dose, 6 mg/kg, response rate of 28%, and a duration of response of 10.5 months. Toxicity as shown at right. Multiple studies being embarked upon on the basis of this data, a Phase III as well as additional Phase I and Phase IIs. Here is that data in graphic form. I forgot this slide was inserted, but it’s exactly what I just spoke to you a moment ago so I’ll breeze forward.

Here's the safety data on this agent and it fits the theme that I think we’re seeing with antibody drug conjugates which is that qualitatively we’re seeing a chemo-like toxicity profile plus some ILD but less toxic than chemo along those same lines. I think of it as slightly targeted chemotherapy for the most part.

And the final agent I believe I’m talking about is seribantumab. Here, being evaluated for NRG1 — why are all the new drugs hard to pronounce — here being studied for NRG1 gene fusions. The drug is a HER3 monoclonal antibody amongst 10 evaluable patients. At ASCO we see 3 having 3 of 10 or 30% having a response, 90% disease control rate in the first cohort there.

DR LOVE: So.

DR WEISS: And I guess the New York speed got me done with a minute to spare.

DR LOVE: Yeah. Excellent. So yeah, I’m a recovering Baltimorean. I don’t know if you know that as well. But yeah, I noticed the Hopkins people always call their trial the Oriole, Oriole trials because of the Baltimore Orioles.

Anyhow, Corey, any thoughts about, at this point, differences between adagrasib and sotorasib, either efficacy, tolerability, indirect comparison, if both are coming available. It seems like not impossible. How are you going to choose?

DR LANGER: I am impressed by how similar the results are. I mean the response rates are within 5% of each other and the PFS I think was virtually identical. The presentation today during the lung session did imply a bit more toxicity, perhaps a higher rate of Grade 3 and higher. It may have been due to better due diligence though, in tracking that. Certainly the treatment discontinuation rates were identical. So at the end of the day, I think it’s very similar to the capmatinib and tepotinib story in MET mutations. You take your pick. The advantage, sotorasib, and the reason most of us have chosen it is because it’s already approved and we have an experience with it.

DR LOVE: So Helena, of course in breast and upper GI you’re talking about HER2 amplified. Here we’re talking about HER2 mutant. But you do see HER2 overexpressed lung cancer. How does T-DXd work there and is it something that you want to use or have used?

DR YU: Yeah, I think that there are sort of different levels of driver. I would think of HER2 mutant as a true driver. HER2 amplified can kind of be seen with a different driver and I think that it looks positive, but everything looks a little bit less in terms of response rate, PFS. So I think for people without options, I certainly think it’s going to be something in our armamentarium.

DR LOVE: Jared?

DR WEISS: Just a quick comment. You brought up cellular therapy interest in solid tumors. There is a CAR macrophage being developed for overexpressing HER2.

DR LOVE: Has it been used in patients?

DR WEISS: It has been used in patients. I’m not aware of publicly available data at this time.

DR LOVE: Any responses?

DR WEISS: I can’t answer to nonpublic data.

DR LOVE: All I need to see is one good response to get excited.

DR WEISS: I’m going be like — you can’t get me in trouble.

DR LANGER: Before we embrace this. This is very labor intensive therapy. It’s incredibly expensive. And solid tumors so far at least have really defied applicability or application here. It is, at least for now, in the realm of leukemia and lymphoma. Like everyone else, I want to see these succeed in solid tumors, particularly lung cancer. I have a lot of skepticism.

DR WEISS: We do have a GI CAR study just published in Nature Medicine with rather impressive data, hopefully starting off a story that will bloom. Otherwise Penn and UNC are in trouble with all the manufacturing capacity we’ve invested in.

Current and future management of metastatic NSCLC without a targetable tumor mutation — Corey J Langer, MD

DR LOVE: All right. So we’re going to move on now and let, in a second, have Corey review the issue of first line therapy and beyond in patients without targetable mutations and the role of checkpoint inhibitors. But let’s first see what the audience and the faculty think about some of the common situations.

So Heather, I’m going to let you tackle this one. We asked the audience. We have 3 agents now approved as monotherapy in patients with high PD-1 and we asked the audience suppose one of them were priced 50% below, because we already surveyed people. They all think they’re the same activity. And most of the audience says yes. We actually put this out at a conference. We had a bunch of people say that they wouldn’t. And when we asked the faculty, first of all most people felt there wasn’t a difference in pembro, atezo, and cemiplimab in this setting, and that they would use it if it were less expensive. But interestingly, several people feel that pembro for some reason has greater activity. Any thoughts Heather?

DR WAKELEE: Well I think for the pembro I think we’ve seen a few examples today of if you’re the first, you’re the one people think about. And there have been a few studies where some of the numbers looked better versus some of the other agents and the numbers but that’s cross trial comparison. So I don’t think there’s clearly a difference there.

As far as the cost, that’s a very complicated question. In the past year one of my roles has been to be the medical director of our cancer service line. So I’m working much more closely with the hospital administrators. So I think a little differently now, which — then I have to get away from that job. But I think that — I’ve spent a lot of time also very vocally talking about in the world of biosimilars, what’s the point if we’re only reducing 10 to 15%, then it’s just about who’s going to get the drug purchase, which I get from Pharma. You know, that’s for your company but are we really doing a greater good? Are we helping more people? Are we helping health economics know? We need to have much more substantial drops. And so from that perspective I think from a more altruistic, what do we really need to be doing societally? Yes, I think we should be looking to how can we lower costs. But it’s going to require a lot of changes in how we do healthcare in the US if we do that.

DR LOVE: So I’m flashing back on a day long Think Tank we did on Quality in Oncology. That was really an interesting experience. But we’re not going to get off into that. We’ll get back into some of the clinical research questions.

So here’s one we’ve been talking about for a while, Luis. The patient who’s got a high TPS, we say 50% in this situation, modest disease burden. And most of the audience says that they’re going to go with single agent pembro, but coming up in a pretty high second is chemo/pembro. The faculty, a little bit more oriented towards monotherapy with pembrolizumab, certainly in an 80-year-old but even when we present a 65-year-old. Is that generally your approach Luis?

DR PAZ-ARES: I would say like I, for high PD-L1 expressors I tend to use, in 3 out of 4 patients, IO alone. In 1/4 of the patients I may use chemo/IO. Typically those patients are those that are having more aggressive disease, more higher burden, more symptomatic disease, and maybe low TMB, if I have the data, may be of interest. Particularly for women, women seem not to benefit as much from immunotherapy as single agent as compared to male. That is quite consistent across trials.

DR LOVE: Heather is giving you a, really, look. What’s the data? Women don’t benefit as much from IOs?

DR PAZ-ARES: Yeah.

DR LOVE: Really? Where’s that from?

DR PAZ-ARES: So, well you know there is a strong difference between, not only in humans but in any species, about the way we handle immune, let’s say the immunobiology. Let’s say, women, let’s say females tend to be more responsive to immunotherapy, to have better immune native and acquired immune system. They do respond better to vaccines as compared to males.

DR LOVE: Hmm.

DR PAZ-ARES: You look at the number of let’s say HIV infected patients. The count number of virals is much higher in males as compared to females.

DR LOVE: You think it’s a hormonal thing?

DR PAZ-ARES: It’s all, that is very consistent. The response to immunotherapy, to vaccines, to flu let’s say, is much better in females. On the other hand, autoimmune disease are more frequent in females as compared to males.

DR LOVE: Right.

DR PAZ-ARES: So there are a number of reasons for that to be true and this is pretty consistent at least in lung cancer.

DR LOVE: Wow, interesting. Okay, so a couple other questions. And Justin, I’m curious what your thoughts are. I’ve heard different points of view over the years on this. Is there a correlation between autoimmune toxicity and treatment benefit? Two thirds of the audience says yes. What do you say Justin?

DR GAINOR: I think the challenge is how to disentangle the fact that patients who are responding are receiving more doses of therapy, right? So, and if you receive more doses of therapy you’re more likely to get toxicity. So people have tried looking at this by taking early landmark analyses, looking at 6, 12 weeks into therapy. It does look like there is even a little signal there, that if you have autoimmune toxicity, even at those early landmarks you have better response rates. So, but to me I think it’s largely driven by just more exposure to therapy.

DR LOVE: That’s a really great point, although you can see in this middle graphic that actually most of the investigators think there is a correlation although maybe it’s there but that’s the reason. Corey?

DR LANGER: So Mark Socinski last year at ASCO actually did a presentation on IMpower150, showing the point of at least an association between autoimmune toxicity on that trial, at multiple points, at 1 month, 3 months, 6 months, 12. Not severe toxicity. This was typically Grade 1, Grade 2, Grade 3 manageable toxicity. And I think that’s, retrospective analysis certainly bore it out. Again, that’s a very aggressive regimen. It’s the kitchen sink with bev, paclitaxel, carbo, and atezo, something that most of us don’t use clinically except maybe in EGFR TKI refractory patients.

DR LOVE: You hear a lot of cases though, of people who have explosive autoimmune problems and then they’re NED for a couple of years. Heather?

DR WAKELEE: I was just going to mention, I think anecdotally I can certainly think of at least 5 or 6 patients off the top of my head in my own practice like that and so, you know, there’s something there but that’s sort of the extreme because they’re not — they don’t have cancer anymore but they have a lot of other problems they’re dealing with so.

DR LOVE: So Helena, what about this top question, ipi/nivo either by itself or with chemo? I’ve heard people talk about that particularly related to PD-1 low patients as being encouraging. Is there a role in your practice for ipi/nivo in lung cancer right now, Helena?

DR YU: Yeah, I was one of the no answers there, despite a lot of the data coming from MSK. Yeah, I don’t really see — obviously there’s cross trial comparisons but I don’t really see a clear use for that in my practice.

DR LOVE: So Justin, any thoughts about that question, about ipi/nivo?

DR GAINOR: Yeah, I mean, likewise I tend to give chemo plus PD-1 for my low expressors and high expressors with fulminant disease. I have — I actually saw a patient last Friday who was like, under no circumstances will I ever, ever have chemotherapy. And so we talked about nivo/ipi. And she was a squam with low PD-L1 expression. It was actually, like that setting made sense. Technically on label, the label is 1% or above, although many of us are tempted in that 0 population.

DR LOVE: Right.

DR GAINOR: You know, the label was just because that was what was prespecified as the analysis, not that there wasn’t benefit in the low group. But that would be a situation where I would think about it.

DR LOVE: Corey?

DR LANGER: I’m pretty much like Helena, I’ve not used it typically off study. And although I will very shortly show you the one situation, as Justin has implied, where it may be potentially, may be better than chemo with pembro. But we have no Phase III data comparing the 9LA regimen 2 cycles of chemo with ipi/nivo versus histology-specific chemo and pembro.

DR LOVE: So come back tomorrow night. You’ll hear about another anti-CTLA-4, not currently available, tremelimumab, positive trial in HCC with durvalumab. People are saying it’s probably going to get approved. So there’s going to be another CTLA-4 maybe available.

Luis?

DR PAZ-ARES: Well I think that it’s important to look at 1 dimension that sometimes what we used not to discuss with patients, which is like the probability of being a long-term survivor. For example, let’s say you look at the number of patients being progression free at 3 years, you are PD-L1 negative. Of course this is a comparison across trials. But ipi/nivo may be a good opportunity there. Always we felt reserved because those are across trial comparisons. But this is consistent with the fact that the CTLA-4 inhibition may somehow help the immune memory in the long-term and so on. So you know, I think this is an alternative that may be worthy to discuss with some patients that like to bet for the long-term, even they know that the costs in terms of toxicity may be there.

DR LOVE: So Heather, of course people are concerned about the toxicity. In this HCC study they use a lower dose. They only use one dose. So maybe, you know, it’s a non-chemo regimen. I want to ask you about this other graphic we have here. I keep hearing about dermatologic issues.

DR WAKELEE: Uh huh.

DR LOVE: They’re not certainly as concerning as colitis or pneumonitis et cetera. But more and more cases are getting presented and we have all kinds of dermatologic problems. What do you see in your practice? The investigators median estimate 20% of their patients have significant dermatologic problems. What’s the spectrum of what you see, Heather?

DR WAKELEE: So I think it might even be higher than that. Before checkpoint inhibitors existed I talked to the dermatologists once in a while. And now we have like 6 people who do supportive dermatology and their whole job is to work with the oncologists for all of the patients who have dermatological complications of all the treatments that we give them.

DR LOVE: And ophthalmology’s coming too incidentally.

DR WAKELEE: Yeah, well yeah.

DR LOVE: We’re doing a program on ophthalmologic toxicity.

DR WAKELEE: We’re working with the rheumatologists, the nephrologists, everybody, right? But with dermatology it’s really a significant issue and it’s a huge range of different rashes. So in the era of targeted therapy only, and we’ve gotten used to dealing with the pustular rashes that we got with the EGFR drugs, and you sometimes see that. But you get just dermatomyositis, I mean, you can just, every — I can’t even describe all the different rashes that we see. And they’re having to do biopsies a lot just to even understand what it is, though it’s usually immune mediated in some way.

DR LOVE: You would think so. All right, Corey, we gave you the challenge of talking about managing patients with targetable mutations, particularly as it relates to IOs.

DR LANGER: Thank you, Neil. It’s a pleasure to be here. I call this the wild-type group, those without oncogenic drivers. And if we think about it, this is probably, if not the majority, the plurality of patients that we encounter. Far more common than HER2 or RET or any of the others.

So this very complicated slide’s going to walk us through what I consider to be frontline treatment landscape in practice, at least in North America. Certainly regardless of histology, PD-L1 positive at 50% or greater, pembro has become our standard. We have data now for cemiplimab in the EMPOWER-Lung 1 trial, which likewise has shown PFS and OS benefit and for TC3/IC3, the Genentech assay for atezolizumab in the same setting. If we look at PD-L1 1% or higher, this benefit, or at least the approval extends for pembrolizumab. It should be noted in the KEYNOTE-042 trial, the positivity of that trial was generated by the 50% or higher group. When we look at 1 to 49%, pembro wasn’t any better than chemo. They had de facto therapeutic equivalence. In contrast, when nivo was looked in this setting it was negative. And we have CheckMate data which I’ll show you shortly, where we see both the PFS and OS benefit compared to chemo alone. And this applies equally to both squamous and nonsquamous.

If we look at any PD-L1 status or those who are untreated, and we’ll look at squamous first, KEYNOTE-407, pembro plus platinum plus taxane, again both OS and PFS benefit. For the 9LA regimen, combining 2 cycles of chemo with ipi/nivo, again a tandem OS and PFS benefit. No such benefit for durva with or without treme in this setting. And for atezo with carbo/nab-pac, a PFS benefit but not an overall survival benefit.

The array of choices expands further for nonsquamous. So KEYNOTE-189 trial, certainly for 50% or lower, but some cases if clinically necessary, we have one shot on goal, patient quite sick, we’ll preferentially use that regimen. 9LA likewise has benefit. IMpower150 which we talked about briefly, the retrospective analysis for toxicity, combining atezo and bev with carbo paclitaxel showing a clear across the board benefit. And then a somewhat more obscure trial, IMpower130 with atezo, carbo, and nab pac. Remember, not everybody is a candidate for pemetrexed. If you have renal insufficiency and a creatinine clearance below 40 or 35, taxane becomes the more attractive drug and we have the Phase III study actually showing a benefit.

I think my — just fell off.

DR LOVE: We’ll get it.

DR LANGER: Everybody hear me? So the standard of care, at least as far as I’m concerned, in North America, defined by 3 studies. KEYNOTE-024 which now has 5-year survival. 33% 5-year survival. This is single agent non-chemo non-platinum data. I hesitate to use the C word for cure but I am certain, at least a portion of those folks have been cured. And you can see that those curves are nicely plateauing. And certainly the progression free survival is about 17% at 5 years.

For KEYNOTE-189, a major improvement in response rate, PFS and OS which has stood the test of time. Remember, this was only just published 3.5 years ago in New England Journal. And then for the squamous — actually for this study, the benefits are seen across the board regardless of PD-L1 status, although arguably a bit more pronounced in the 50% or higher where you see about a 17-month difference in median survival.

And then finally, for squamous cell, 407 showing amazing response rate past 60%, and again, commiserate improvements in PFS and OS for a taxane combination, be it paclitaxel or nab-pac combined with carbo and pembro compared to chemo.

So is there any role for other checkpoint inhibitors? Cost might be the issue. But if we just look at the regular data, the actual randomized data, it’s really hard to distinguish these results from what we’ve already established. So EMPOWER-Lung 3 is essentially a combination of KEYNOTE-407 and 189, allcomers regardless of histology, any PD-L1 expression, no EGFR, ALK, or ROS aberrations, and good performance status. So cemiplimab combined with investigator's choice or platinum doublet chemo versus chemo alone. Big trial, 2:1 randomization, 466 patients. Still fairly early data but the OS curves here look very similar to KEYNOTE-189 and, in fact, the median survivals are virtually identical at 22 months versus 13 months. So continued reproducibility amongst all these Phase II and Phase III trials.

Is there is a niche for dual checkpoint inhibition with an anti-CTLA-4? And here we have 3 trials that have informed the conversation. You can see the vast majority of us are not necessarily using this combination upfront but there may be some subgroups where the benefits are more pronounced.

The 227 was an incredibly complicated trial, originally reported PFS in the high TMB group. That fell by the wayside. It’s really 2 trials rolled into 1. Those with any degree of PD-L1 expression comparing chemo to either nivo alone or ipi/nivo, and those without PD-L1 expression, chemo to ipi/nivo or chemo combined with nivo. So 2 trials for the price of 1.

If we looked specifically at those with PD-L1 expression, we see a clearcut benefit. And these are mature data now at 4 years. 29% alive in the ipi/nivo group compared to 18% in the control group and chemo alone with the nice hazard ratio of 0.76. The benefits are seen regardless of histology and if anything are more pronounced in the squamous group where the hazard ratio is 0.68, for nonsquamous 0.81. But we even, and Justin mentioned this earlier, we see benefit in the group that it’s not formally approved. Less than 1%. Again, 24% versus 10% 4 year survival, And, if anything, the benefits are more striking in squamous with a hazard ratio of 0.53, for nonsquamous 0.69.

CheckMate 9LA combining 2 cycles of chemo with ipi/nivo versus chemo alone. Again, trying to eradicate this early drop-off for toxicity or rapid disease progression, stratified by PD-L1 status, sex, and histology. And once more we see a clearcut benefit. The more mature data from last year’s ASCO shown on the right with a hazard ratio of 0.71 and about a 4.5, 5 month improvement in median survival.

When we look at 9LA the benefits are seen across the board, regardless of PD-L1 status, so whether it’s 0, 1 to 49%, 50% or higher, the hazard ratios are incredibly consistent. But the group that seems to benefit the most, and this is seen both with ipi/nivo alone and also 9LA, is squamous, particularly less than 1% with a hazard ratio of 0.48. I would have total equipoise comparing KEYNOTE-407 to 9LA in that population, certainly in squamous and certainly in those with less than 1%.

POSEIDON. Unlike the movie adventure, this ship did not capsize but it remains to be seen whether it’s really going to add. This was a complicated study comparing durva with chemo, durva/treme with chemo versus standard chemotherapy. A fairly large effort, over 1,000 patients, with a 1:1:1 randomization. At least in the durva/treme group, once more we see a PFS and OS benefit. But I’m hard pressed, at least looking at the raw data here, to believe that this is going to be superior to 9LA. And remember, the chemo here was not just 2 cycles. It was continued for at least 4 cycles with maintenance therapy.

What are the options in those with higher than 50% PD-L1 expression? Well CITYSCAPE has been very interesting. These were data that were literally published in the last 2 weeks in Lancet, looking at both 50% or higher on the top and those with 1 to 49%. On the left we have PFS, on the right overall survival. And you see a striking punitive advantage in the high group, the hazard ratio at 0.23, a 4 fold difference in median survival. And that certainly launched the Phase III in this sphere. And all we know is the press release from 3 weeks ago. SKYSCRAPER-1 trial does not meet the endpoint of PFS despite the striking difference with tiragolumab plus atezolizumab. So again, this is the TIGIT antibody, looked really promising in Phase II or randomized Phase II. But stay tuned. The press release also said there was a numerical advantage? And the other coprimary endpoint, overall survival is way premature.

In North America we have the INSIGNA trial which is directly comparing pembro to pac — to carbo/pemetrexed and pembro in 50% or higher but also 1 to 49%. And this trial is unique. At the time of progression, the pembro group, if you will, some would argue that’s the control, can cross over to continuation of pembro beyond progression with chemotherapy.

Finally, we’ve already covered this other promising strategy, the antibody drug conjugates, I think are the wave of the future, at least I hope they are. Dr Weiss talked about — also can’t pronounce it, datopotamab deruxtecan —

DR LOVE: Dato-DX.

DR LANGER:   — which targets TROP2. Go through this quickly. Again, different dose levels, 4, 6, and 8 mg/kg. The higher dose level is associated with more toxicity, particularly ILD which we talked about. But overall, allcomers a 28% response rate, fairly impressive, with the duration of response exceeding 10 months. So they’re going forward with the 6 mg/kg dose.

And Helena’s talked about patritumab deruxtecan and, again, primarily in EGFR mutated disease, this targets HER and HER3. And we see response rates, including those who have gotten prior osimertinib and platinum-based chemo, 39% with a PFS of 8 months.

So I’ll end here. Are there biomarkers beyond PD-L1 to aid patient selection? Unanswered question. How do we choose between monotherapy and combination? Again, the INSIGNA trial answered that question. The role of checkpoint inhibitor combinations versus pembro and histology specific chemo. We need that trial. It’s not happening. Maybe it’ll happen in Europe. What is the role of ADCs? I think we’re going to see that in the second line and maybe migrate into the first line. And then a number of other unanswered questions. The optimal number of chemo cycles? The optimal duration of checkpoint inhibition? Can we ditch pemetrexed in those who have high PD-L1 expression? And mechanisms of resistance, as we talked about earlier.

DR LOVE: So we’re going to move on and talk about small cell in a second, but just one follow-up question, Corey. I’m curious if you see a patient with metastatic non-small cell, has a high PD-1, and you’re about to start single agent IO, what you tell them if they ask you what the likelihood is they’ll be alive in 5 years? And I’m curious how it feels to answer that question nowadays?

DR LANGER: Oh, that’s a tough one. We actually now have data. I never answer that question quite as directly as patients would probably like. They tend to fixate on those numbers.

DR LOVE: How do you answer it in your head?

DR LANGER: So I answer it this way. Best case scenario, you’re going to be in that group that’s going to really benefit and you could be alive at 5 years and beyond and may be cured. I finally am using that word in the metastatic setting. Worst case scenario, it doesn’t work, we’ll know that pretty quickly, we have other options.

DR LOVE: And for this audience, what would you say the likelihood is, that they’re going to be alive and well in 5 years?

DR LANGER: We have the data. 33%.

DR LOVE: 33%. Interesting.

Current treatment paradigm for small cell lung cancer — Luis Paz-Ares, MD, PhD

DR LOVE: Okay. We’re going to finish out talking about small cell. And again, we’re going to start out with some management questions. First line therapy. This is another one of these what comes first thing, I think. So carbo/etoposide/atezo more than durva but interestingly a quarter of the audience would add trilaciclib, which we’re going to talk about, to these agents. When we asked the faculty, actually there’s only one person who says they would add trilaciclib. But again, more people using atezo. Helena, is this first come in first order or it’s a better regimen?

DR YU: Totally. I think we’re creatures of comfort and familiarity and I think, again, first out of the gate so that’s why we use that.

DR LOVE: You know, we were talking about toxicity and the atezo study they had a placebo arm that I thought was really interesting. And we were talking about dermatologic problems, et cetera, Luis. But 25% of the placebo patients had autoimmune toxicity which kind of tells you how hard it is to figure out what’s going on. Any thoughts?

DR PAZ-ARES: I fully agree with that. I mean, in fact we have seen that in many trials. Interestingly, you look at the quality of life data, they looked better into the durva trial as compared to the atezo trial likely because of the placebo control as well. If you know you are on the right treatment, you feel you’re doing better, likely. Because all the other, let’s say efficacy endpoints, were similarly, right?

DR LOVE: So, and the investigators agree. It’s a coin flip. We’ve had a bunch of these already and kind of a similar approach.

Justin, what about this issue of antibiotics? There are people who say they think that patients who are on antibiotics get less benefit from anti-PD-1 antibodies. Do you agree? Do you advise? Do you try to limit antibiotics?

DR GAINOR: I think the challenge here is that, so some make the argument that it’s going to alter the microbiome and that in turn is going to alter sensitivity to checkpoint inhibitor. On the flip side, if you’re receiving antibiotics before you start, generally you’re sicker, right? And I think it’s hard to disentangle that. My sense is it’s more — you’re just sicker. And so you’re that — your performance status is likely to be worse, you may have more comorbidities, or more disease burden, and that’s what’s maybe translating into less activity.

DR LOVE: So, Jared, we asked the audience how many of them have used trilaciclib and about 21% say yes. We also asked them this question, whether they agree or not. The addition of trilaciclib to chemo regimen improves the quality of life of patients with extensive stage disease. Most people say they don’t know. Jared, any comments?

DR WEISS: There’s published literature on this and it does. The agent does improve patient-reported quality of life with most of the improvement centered around fatigue, an adverse event that I think we’re least equipped to deal with in our practices.

DR LOVE: And I take it that you’re the person who’s used it in the survey. Can you talk a little bit about your experience and why you use it and other people at least currently aren’t?

DR WEISS: So you know, when I give my 3-year-old, if I were to give my 3-year-old ice cream when I get home, she would look up at me and say daddy where are my sprinkles? And I think that’s a little bit of our reaction to trilaciclib and its lack of PFS or OS advantage. Sure it’d be sexier, it’d be far more exciting if it gave us a PFS or OS advantage. But if you give me ice cream or even frozen yogurt I’m still going to eat it. This is an agent that I think we should all be prescribing with a yawn. Yes it’s not improving survival. Yes it’s not improving PFS. But it is decreasing myelosuppression. It’s decreasing adverse events. For those who care, it happens to decrease alopecia. And patients feel better for energy. So I view this like the dexamethasone and Zofran in my chemo orders. I prescribe it with a yawn. It’s sort of standard and I don’t think about it that much.

DR LOVE: Heather?

DR WAKELEE: I really haven’t used it. I think that Jared’s arguments are good ones. I mean this is — again, it’s all — I do this a lot, right? Weighing things. So yes, it reduces myelosuppression. It has a few other things it might, it has minimal benefit. It doesn’t have that many side effects. But it does cost more and does that cost outweigh — well it costs something. It’s not free.

DR WEISS: So there is cost efficacy analysis which is why I was shaking my head.

DR WAKELEE: Okay.

DR WEISS: Granted put out by company, and granted I know nothing about cost analysis so I won’t speak authoritatively on this, but that does suggest that it’s cost savings because of how incredibly expensive myelosuppressive events are.

DR WAKELEE: Well, and that’s the thing. It’s sort of trying to weigh all of those things, right? So if it’s truly a prevention that then helps prevent admission to the hospital and whatnot I’m not opposed to it. I just, I haven’t had much experience with it. I don’t see that many small cell patients. I’ve looked through the data. You know, it’s just that extra hump of, okay, one more thing to add. But, it’s reasonable. And I think we do need to be thinking about what are the things we can add that are going to help our patients’ quality of life, are going to help reduce toxicity? I’m also always a little wary when we reduce toxicity, about reducing efficacy, though I know the data doesn’t show that.

DR LOVE: Before I ask Corey, just to get back to you, Jared, you know one of the issues here is when I first heard about it and I thought about, okay, just as, you know whatever, they’re going to have less neutropenic fever et cetera, okay that’s one thing. But when we talked a couple of months ago and you were talking about quality of life. Do you think you see that in your patients? Do you think you can see a difference?

DR WEISS: So, because I was involved in the trials and because I’ve drunk the Kool-Aid and continued to use it post, I have treated a lot of patients with it. And I think it does. And I had some patients who got drug on trial and in the interim between trial and approval got retreated, and had a very different experience. This is anecdotal. It’s a more beaten up patient, more beat up bone marrow. But yes, my experience has been favorable.

If I could comment on the efficacy. There’s no hypothesis for harm just because small cell is obligate RB null, like. It shouldn’t right? And it didn’t.

DR LOVE: I think I can read Corey’s facial expression.

DR WEISS: We don’t disagree that often. Go for it.

DR LOVE: Go for it guy.

DR LANGER: It’s not that I really disagree, it’s just I can’t remember the last patient with small cell I hospitalized for neutropenic fever.

DR LOVE: Yeah, but he’s saying it’s more than that. That’s what I’m saying.

DR WEISS: I’m saying fatigue matters.

DR LANGER: It certainly hasn’t disseminated. And somebody has done some cost analyses with other people who are far more knowledgeable in this, I’d really want to look at that data a little bit more closely, particularly in the absence of admissions for neutropenic fever. We’re constantly looking for the drug that’s going to improve PFS and more importantly OS. We’ve not seen it with this so —

DR WEISS: You like sprinkles.

DR LOVE: I like quality of life though if it’s for real.

DR YU: Yeah.

DR LOVE: All right. Let’s go on to second line therapy and maybe this is another quality of life issue where people now have flipped over to lurbinectedin, at least in the audience and also the faculty. And in fact, on average, the faculty has used it in, for patients with small cell. And I think, Luis, you’re going to talk about this. The main perception is that it’s better tolerated. You’re going to talk about the data, Luis, but I’m curious about your actual clinical experience with the drug in terms of tolerance?

DR PAZ-ARES: I mean in the second line setting we have a drug, let’s say the standard which is topotecan, which is really a terrible drug. It’s really not easy to tolerate. It’s not really too beneficial. I mean, that is my personal opinion. And it’s a really toxic drug. So although lurbinectedin is not overwhelming in terms of activity. It's an active drug but not overwhelming, but it's much better in terms of tolerance. That is the true, I mean, yeah.

DR LOVE: And the faculty’s seen responses. Most of the people in the survey have actually seen responses with lurbinectedin.

Helena, you say you don’t take care of many patients with small cell. Of course you have your interest with targetable mutations. Any perceptions in terms of this agent as a second line agent in small cell?

DR YU: Yeah, I mean I see probably more transformation than I do de novo small cell but I have used lurbinectedin. I think I was the one that might have said paclitaxel or temozolomide. I think oral options are good, as we don’t have those in small cell, but I think reasonable and I think, I just haven’t seen much responses for anything and kind of beyond platinum/etoposide.

DR LOVE: Interesting. So Luis, we asked you to review where things are with small cell nowadays.

DR PAZ-ARES: Okay, so let’s go for it. I mean just to start I feel it’s important to remember what happened with chemo alone. This is an extensive stage disease. What we expect is like 6 to 7% of the patients being alive at 2 years, even in those patients with limited stage, I mean the survivorship is not actually exceeding 30%. So we learn a lot about what is behind the biology of small cell lung cancer which are the genomic abnormalities, epigenetic dysregulation which highway the cell cycle and other developmental pathways that are typically dysregulated here. And also we know something about the immune biology and those are typical targets here.

Likely, because of the data we have in non-small cell lung cancer, we have been trying for a number of years, novel immunotherapy in the disease. We learned that specifically chemo plus IO, chemo plus PD-L1 inhibitors do improve survival. Here you have the 2 trials with durvalumab and atezolizumab showing very consistent results. Hazard ratio in the range of 0.75, increasing median survival of about 3 months. And here you see the meta-analysis of all the trial, hazard ratio of 0.75 for OS and for PFS. More importantly, you look at the data in survival at 2 years regardless the agent you use with chemotherapy, is always 22%. So remember, we were talking about chemo alone, 6 to 7%. So it looks like there is some — it’s not overwhelming but there are some patients that do have benefit and it seems to last.

Now you see here the data of the CASPIAN trial. This is 3-year follow-up. You see at 3 years survival is increasing from 6% with chemo to 18% with chemo/IO. So 3 times as high, 6 versus 18%. So I think the number of patients benefitting truly are not very high, some 20% of the cases. But actually, for those patients, the benefit is there.

Unfortunately, we don’t know which patients are going to benefit. Like we know PD-L1 expression is not helping here. Only 5% of the tumors are having expression in tumor cells. 20% of the tumors are having expression in immune cells, but no expression in tumor or in immune cells are of help.

If you look at TMB, same here. You see that is not helping to predict which patients are benefitting. So we are not going to, let’s say, know when we are starting the treatment which patient is going to benefit or not. That is a pity.

Some of the more recent data looking at the transcriptomic subgroup of small cell lung cancer suggests that the so-called inflamed subtype may be the one benefitting the most. This is data only coming from a subanalysis of a subset of patients in the IMpower trial so we don’t have validated data and therefore we have not used in yet the transcriptomic subgroups to somehow see which patient has benefitted or not. On the other hand, those data suggest that the other subgroups also benefitting, maybe the magnitude of the benefit is not as high as in the inflamed group but anyway. Let’s say the bottom line is, as yet, this biomarker is not ready for primetime tomorrow in the clinic.

Well what happened after the incorporation of atezo or durva into the first line treatment? There are some other options. There are some other improvements. It’s been mentioned the trilaciclib data that is clearly decreasing the number of patients developing severe neutropenia or the lasting time for severe neutropenia. All the other data are maybe not as important I could say. But what is true is that you’re somehow reducing important events particularly with neutropenia. Febrile neutropenia is reduced not on a, let’s say, in absolute numbers, not such a, let’s say, high magnitude of reduction still. It depends if you’re not using DCSF regularly maybe that is going to be more important I would say.

And of course there is a benefit in terms of quality of life. I’ll agree that quality of life is important. The other thing is that if we have the right tools to measure quality of life which is a different issue here.

There are some other agents that we are testing. For example, some epigenetic regulation. We know that there is some strong dysregulation of transcription on epigenomics here in small cell lung cancer. This is one of the agents that’s being tested, actually now in Phase III trial, LSD1 inhibitor. At least in a trial, the initial cohort of a Phase I trial suggested that in combination with platinum etoposide looks pretty good in responses.

There are some other alternatives being also tested, including a STING pathway agonist and modulation with chemotherapy, radiation therapy, and so on. We know that PARP inhibitors do have a clear effect on inducing the expression of PD-L1 inhibitor, and we have data, preclinical data, less clinical data suggesting that there is some synergism. A number of trials are actually interrogating this question, if it is worth it or not to combine PD-L1 inhibitors in this setting, first line or later with PD-L1 inhibitor.

There is another agent we have commented, lurbinectedin. This is clearly transcriptional inhibitor in small cell lung cancer with an effect clearly on tumor cell but also able to somehow regulate a microenvironment inducing a more immunogenic microenvironment including a clear diminishing of tumor-induced macrophages and so on.

On a single agent trial in the second line setting, responses are about 35%, being 44% on patients with sensitive relapse. Duration and survival being of course better in patients with sensitive relapse and not overwhelming in RECIST and relapse I would say.

In terms of tolerability, as you see here, it’s pretty good. Febrile neutropenia less than 4% altogether and no major toxicity issues. I would say it’s pretty favorable.

The drug was combined with doxorubicin, maybe not the right decision to do, in a Phase III trial as compared to topotecan or CAP, resulting in a negative trial. No improvement in OS. There was, however, some improvement in the toxicity profile, even doxorubicin was added here. A lot less toxicity. Importantly, a subanalysis suggests that those patients treated with monotherapy after the cumulative dose of doxorubicin was achieved, they did a lot better particularly when the high dose was used.

There are a number of other trials combining lurbinectedin with irinotecan or atezolizumab with nice results on early data. You see here results, response rates 62%, particularly relevant on those patients with sensitive relapse, 77%. More importantly, look at the PFS. Median PFS 6.2 months, being close to 8 months on those patients with sensitive relapse. So those data, I think, are pretty relevant. The drug actually is being now studied on a Phase III trial as compared to topotecan in the second line setting.

Another Phase I/II trial have combined atezo plus lurbinectedin. Nice data. Responses in some 50% of the cases. Toxicity, as you expect, typical of adding the toxicity of lurbinectedin plus the toxicity of atezolizumab. So really well tolerated and this is also being studied on a Phase III trial on the maintenance setting as compared to atezolizumab alone.

The final word for this compound, tarlatamab,a BiTE, binding CD3 on the T-cell and DLL3 on the tumor cell, and by that engaging the response in this tumor setting. The drug is pretty well tolerated, taking into account it’s a BiTE, so there are some cytokine release syndromes but typically mild in some 40% of the patients. Responses are happening in some 20% of the tumor.

So overall I would so immunotherapy is here. It’s part of the first line treatment, in combination with chemo and a number of other agents are being explored including lurbin in the second line setting and tarlatamab particularly in terms of the novel immunotherapies.

DR LOVE: So I want to thank the faculty. Thank you all for attending. Come on back tomorrow morning. We’ll answer the question, are PARP inhibitors now a part of first line therapy of metastatic prostate cancer regardless of genomic status? We’ll talk about that tomorrow morning. Thank you so much.