Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to “Implications of Recent Data Sets for the Current and Future Management of Lung Cancer.” We have a great faculty today: Dr Luis Paz-Ares from the Oncology Research Center at the Hospital Universitario 12 de Octubre in Madrid, Spain; Dr Zofia Piotrowska from the Massachusetts General Hospital in Boston; and Dr David Spigel from the Sarah Cannon Research Institute in Nashville, Tennessee.

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

As we do in all our webinars, there’s a 1-minute pre-meeting survey for you to take in the chat room, and a similar one at the end of the meeting. If you take that you’ll get a lot more out of this.

We do webinars all the time. On Thursday we’ll be finishing out a series on gastroesophageal cancers with Dr Piotrowska’s colleague at MGH, Dr Klempner. Then on November 29^th we’ll be doing a program on biliary tract cancers, a lot going on there, first-line therapy, targeted therapy. And then as we do every year we’ll be heading out to the San Antonio Breast Cancer Symposium. We’ll be doing 3 satellite meetings out there. These will also be broadcast online for you to check out starting on Tuesday, December 5^th, and then Wednesday night, and then Thursday night.

Then on Friday we’ll be moving over to San Diego, where we’ll be doing 4 CME satellite programs at the annual ASH meeting. Again, all these broadcast online starting out at 7:30 in morning, at least pacific time, 10:30 eastern time, with a program on lymphoma, going all the way until 7:30 — or 9:00 at night.

We’re also going to be reawakening our weekend-long general medical oncology summit meeting. We’re partnering again with the Florida Cancer Specialists, and we’ll be hosting a meeting in March at the Marriott in Miami, where we’re located here. We’ll be having a whole bunch of investigators come into Miami, and we hope you’ll come too, or join us online.

We know a lot of people end up listening to our webinars, so if you’re into podcasts check out our Oncology Today series, including a recent program with Dr Gubens reviewing some papers from the ASCO meeting.

But today we’re going to be talking about lung cancer, not just non-small cell lung cancer, but at the end of this webinar some super-exciting stuff on small cell. We’ve been waiting for new stuff on small cell.

As we do with this series, I met with 2 of our faculty, Dr Paz-Ares and Dr Piotrowska, to record a presentation, and we’re going to show some of the slides from that presentation. The other presentation that we recorded for this meeting was with Dr Aaron Lisberg from UCLA, who actually presented the second-line dato trial at ESMO. I was really curious to hear what he had to say about that, and he discusses that in the presentation. We’ll show you also a few slides from that as well.

Of course we will be talking about some unapproved use of agents, as is often the case when we talk about new research studies.

Here are the papers that were reviewed in these 3 presentations: a lot of data. Just a reminder, this webinar, unlike all our 1-hour webinars, is an extra half an hour, so we’re going to go for 90 minutes here today and try to put together these papers from a clinical, practical perspective, particularly for the general medical oncologists in community-based practice who’s got to keep up with a whole lot of interesting, fascinating and important data, but that is a huge challenge.

So I think just to kind of get warmed up, faculty, I thought I’d show you, speaking of general medical oncologists, an email that I received about a week ago from an oncologist, Dr Eric Fox, who practices outside of Philadelphia. He’s a medical oncologist. And he has a 74-year-old nonsmoking patient who presented to a nearby hospital with a large burden of metastatic disease, not previously diagnosed.

So she was found on initial workup to have widespread disease, was actually sent to hospice, so very ill, and the family arranged for a consultation with Dr Fox while she was still a hospice patient. He worked her up, found an exon 19 deletion, started her on osimertinib, had a tremendous response to osimertinib.

But Zofia, then she presented with shortness of breath, hypoxia, cough, new onset atrial fibrillation, and even though the tumor had dramatically improved she now had bilateral pneumonitis, got IV antibiotics and steroids, was thought to be a rare case of osimertinib pneumonitis. Of course we talk a lot about pneumonitis with T-DXd, et cetera. And of course this question is what to do. Hopefully she will recover, and maybe it’s something to say about the fact that she made it to hospice without getting worked up, which is obviously not a very good indication of people outside of our field on how they’re managing these kind of situations.

Zofia, any suggestions for Dr Fox?

DR PIOTROWSKA: Yeah, a really tough situation. These are the worst cases, a beautiful response but then these terrible toxicities, which are rare but can be really serious.

I think there’s really, in my mind, I think a couple of options here. And the first thing is to really allow her to recover, and sometimes this can take weeks to months, and you really need to make sure that the patient’s respiratory status is fully recovered back to baseline, off of any oxygen, really off of steroids. In that scenario, in my practice in these situations I think that it’s a bit of a conversation.

One option is to try rechallenge. I think the challenge with osimertinib is that the pneumonitis is often not dose dependent, so while we sometimes will try dose reduction I’m not sure that that really helps so much rather than just making us feel better that we’ve done something different. I think if you do rechallenge you have to watch incredibly closely because in my experience the likelihood of recurrence is extremely high, and so I think at the first hint of any respiratory symptoms or even with a short follow-up chest CT scan you often will pick up a recurrence of pneumonitis.

The alternative, which if the patient’s frail and had significant pneumonitis, I might truthfully lean towards just to try a different generation of EGFR inhibitor like a first-generation EGFR-TKI like erlotinib or gefitinib, which of course have their own toxicity concerns with a little bit more GI and dermatologic toxicities, but the rates of pneumonitis with those are a little bit lower. So I think it depends a little bit on the severity of the case, but in severe cases of pneumonitis I might lean towards a different drug.

DR LOVE: That’s an interesting thought. It’s been a while since we’ve talked about the first-generation TKIs. David, anything you want to add to this? Would you consider lazertinib or is that too close to osimertinib?

DR SPIGEL: I don’t think we know. I’d be a little concerned that it’s more like osimertinib than being different. I agree with Zofia. I think the big thing is let this patient kind of recover. Maybe the benefit she got will last long enough for her to recover from the symptoms. But it’s a tough situation. You don’t have a lot of options.

But I’d be most tempted to retry osi, perhaps at a lower dose, a lower schedule. I’ve done weird things like twice a week, 3 times a week, and ease people back into therapy. But you have to be kind of respectful of the severe symptoms she had, and of course it sounds like they’re planning to put her in hospice.

It is unfortunate that they didn’t think about or were able to test. Maybe they thought about it; weren’t able to test to kind of start this earlier.

DR PIOTROWSKA: And just to add to David’s point, I think it’s a good one, to wait until she has a need for another therapy, right? You might be able to spend some time watching her with scans before you have to reintroduce any therapy. I think one doesn’t have to immediately reintroduce a TKI the minute she’s recovered. You could wait and see if scans show some progression. I think that’s a great point.

DR PAZ-ARES: So I have a quite similar case, and there is a series, a Japanese series, where some 26 patients, something like that, had some prior pneumonitis due to osimertinib. They were rechallenged, but only cases that were Grade 1 or Grade 2; so let’s say mild cases. That seems to be a quite severe case. On those mild cases, osimertinib for most of the cases, it’s a good alternative. 80% of the patients do not have any issues at rechallenge. But having a severe case I would tend to be more conservative and maybe go to first generation and then have osimertinib for a later line, in rechallenge. That would be my choice.

DR LOVE: Yeah. I mean this lady also was a nonsmoker, and she got this degree of pneumonitis. It’s a real issue.

Localized Non-Small Cell Lung Cancer (NSCLC)

DR LOVE: All right. Well, let’s get into some of the new papers that came out, lots of them, many of them really having very important implications for practice. Here’s kind of where we’re heading. We’ll be talking about non-small cell until we get to the end, which is going to be one of the best parts of this whole thing because I think there’s really cool stuff going on in small cell right now.

But let’s get into localized non-small cell. And Luis, you covered this in your talk, and of course at the ASCO meeting we saw data from the ADAURA trial looking at adjuvant osimertinib. We saw some follow-up to that also at the ESMO meeting.

But also, Luis, we saw the ALINA trial. I think we’ve been looking for another adjuvant targeted study, and we got this with alectinib. And of course the hazard rate for DFS was similarly spectacular to the ADAURA trial, with you can see there a 0.24.

But I just want to kind of get your take on what all this means in terms of adjuvant targeted therapy in general. So David, I want to start out with the ALK finding. I imagine this is not a huge surprise to you. How do you see it being applied in your practice? And what kinds of issues do you think are going to come up in keeping people on adjuvant alectinib from a toxicity point of view?

DR SPIGEL: Yeah, look, I think it’s different than ADAURA, right? It’s 2 years, and it’s not chemo plus/minus, it’s chemo versus, so it’s a different study. But the results are as dramatic to me. Just today a colleague from Florida reached out and wanted to know what he should test for for early-stage lung cancer, and I said EGFR and ALK. I think these are kind of ready for primetime. I personally, if it was my family member or me, I would act on these data. I think these are pretty solid.

And obviously we have the same arguments that we had for ADAURA. Is OS going to be positive. Is 2 years enough? What would be the case if you just got osi after chemo — I mean in this case alectinib after chemo? We don’t know those options. We just know what we have here, which is it delays the recurrence of disease, and it actually improves your chances of not having CNS kind of metastases, and I think that’s enough.

The last thing I’ll say on this is I think it’s probably a mistake to say this is exactly like ADAURA. They’re very different studies. It’s a different drug. It’s a different mechanism, different designs, different patient populations. But the results are very dramatic, and I think it’s good enough to act on.

I’ll say 1 more thing. I’m sorry because I found out today our colleagues, Dr Jack West and Dr Nate Pennell, who like debating this on social media, I heard today published kind of a joint statement in an article, I’ve got to find the journal, their views on ADAURA. So that’s kind of fun that 2 people on opposite ends have come together to publish something.

DR LOVE: Well, one thing, Luis, about ADAURA was before the survival data came out, and particularly when the data was first debated or presented, there were a lot of questions about whether there would even be a survival benefit, let alone a survival benefit with a hazard rate of around 0.5. And I just kind of wonder whether or not seeing this is going to change our view of adjuvant targeted therapy in general, Luis, and whether or not just the way the IPASS trial changed our thought about future targeted therapies and what kind of data we would need, are we going to need adjuvant RET trial, adjuvant MET exon trial, Luis? Or is there some other path to getting this done?

DR PAZ-ARES: Well, I think in the adjuvant setting it’s a bit different as compared to the metastatic, so I think you need to have some data saying how much disease are you preventing to relapse, and then ideally if you’re impacting or not the cure rate. This is very unlikely, and indeed ALINA so far didn’t show that. And then the third thing is about the impact on survival.

The impact on survival is also dependent on how many patients in the experimental arm are actually getting the TKI at the time of relapse, truly. So I think likely agencies are going to ask for a trial like that in every single patient with let’s say actionable genomic aberration, and I think somehow it’s normal to do so. That is my view.

DR LOVE: So Zofia, any thoughts? I can tell you that ever since ADAURA came out I’ve been doing polls of general medical oncologists saying would you use like adjuvant RET, and usually like half of the oncologists say yes, and the investigators all say no. What’s your take, Zofia? Any thoughts?

DR PIOTROWSKA: Yeah. I mean I think the more these studies come out showing similar results, admittedly with differences in trial design and differences in populations and differences in drugs, but overall still similar results, I think the more we are going to feel comfortable. I think also acknowledging the practical fact that it’s going to be really hard to do these same studies in all of these rare patient subgroups, and at some point it will become impractical.

I think at this point obviously it’s a discussion with patients. It’s a discussion to a certain extent with insurance because these are off-label uses, and so we won’t always get approval. But I think it’s a discussion that will be worth having.

One other point that I wanted to make about ALINA, and I’m curious to see what Luis and Dave think, is this issue of whether the ALINA trial supports the use of alectinib instead of chemotherapy. That’s to me a key difference in trial design between ADAURA, where patients could have adjuvant chemotherapy per the investigator’s choice and then were randomized to either adjuvant osimertinib or not, and so it really didn’t answer the question of whether we need the chemo.

And ALINA was different. These patients were randomized like some of the older Chinese studies of first-generation EGFR-TKIs, as well, to either chemotherapy, which has a small but real survival benefit, or alectinib. Personally I’m still a little bit wary of omitting chemo for these patients, and if I had a young, healthy ALK-positive patient I might be tempted to do both, extrapolating a little bit from both studies. But I’m just curious, on that practical note, what others think.

DR LOVE: So David — go ahead, Luis.

DR PAZ-ARES: Oh, sorry. Now let’s say most of these patients are pretty young or younger than the usual lung cancer patient, so they’re in good health. They are typically nonsmokers. So I would tend to extrapolate, as well, and maybe my patients are going to be recommended to have chemo and then alectinib for 2 years, even though I understand this is not the trial that has been done.

DR LOVE: So let’s move on —

DR SPIGEL: Yeah. Go ahead.

DR LOVE: I think otherwise we’ll be here for 3 hours. Let’s keep going here because really this is just a tasting menu. If you really want to get all the details you can go into these presentations, particularly for this next topic, perioperative immunotherapy. Again, I just want to talk like we’re on rounds here. I don’t want to pull out 50 slides. Luis’ talk is incredible in terms of going through all the papers.

But I want to just start with you, David. Can you just kind of capsulize right now how you and your center are looking at the issue of perioperative therapy?

DR SPIGEL: Yeah. It’s been a fun change. I mean I think many of us remember a time when preoperative or neoadjuvant therapy kind of fell out of favor, but it’s back. And so the way I describe it to patients and colleagues is you can kind of do a lot of things. You can give preoperative therapy alone with immunotherapy. You can give adjuvant chemo with immunotherapy. And you can do perioperative, so cycles before, cycles after. We just saw this too at ESMO with a trial called KEYNOTE-671.

And you have choices of IO agents. So we have dato with nivolumab and chemotherapy for 3 cycles before surgery. We have dato with pembro and chemotherapy alone before surgery; no adjuvant therapy. Now we have dato after, and we have dato after with durvalumab and atezo.

So what’s the take home? I think you need to use IO where you can. If you would like giving it only preoperatively and not adjuvantly I think it’s just kind of dealer’s choice at this point. We don’t have comparative studies to know which is best.

And so for me, I tend to still stick with 3 cycles of chemo/nivo in all comers, and then I like to see what happened at surgery to make decisions about whether I need any additional adjuvant therapy, a change in chemo, continued IO, or nothing. I let those results at surgery help me decide what do to next.

DR LOVE: Zofia, any comments? And what about choice of IO in the neoadjuvant setting? In the United States now we have 2.

DR PIOTROWSKA: Yeah. We have 2 options. We have the CheckMate 816 regimen with nivolumab and 3 cycles of chemotherapy, purely a neoadjuvant approach. And now we have the perioperative approach from KEYNOTE-671, which includes 4 cycles of chemo plus pembro before surgery, then surgery, then a completion of a year of adjuvant pembrolizumab. So both are reasonable options.

We did see at ESMO this year that KEYNOTE-671 was the first study to show a survival benefit with this approach. I think that that is compelling, and certainly we’ve had the discussion in our tumor boards about the fact that that does, I think, make that regimen appealing. At the same time, I totally agree with Dave that a lot depends on what happens to these patients at the time of surgery and whether or not they have a pathologic complete response.

I think 1 thing that’s been consistent across these studies is those patients who have a path CR do really well almost no matter what you do. You may argue that those patients are the ones who don’t need any additional therapy, they’re going to do really well.

On the flipside, the patients who don’t have a path CR, which is still the majority of these patients across these studies, up to 75% of them, I think the option of adding more immunotherapy, which you can also argue is the drug they just got preoperatively and really didn’t have the optimal response to, feels a little bit suboptimal. Now at the same time it’s the only thing we have right now, and I think it is reasonable, but what I’d like to see is more studies in that space to try to kind of augment that therapy.

So I think both are reasonable. I think with the patients who have a path CR I think likely are going to do well no matter what we do. The patients who don’t, I wish we had more. But still I think 671 would dictate that we continue on with immunotherapy for those patients in the absence of a better approach, maybe in the hopes that more will be better.

DR LOVE: So a final comment on this from Luis. There’s a question in the chat room, Luis, from Hassan. “Would ctDNA be helpful in this scenario, for example post neoadjuvant, to determine whether or not you need adjuvant?” And any other comments you have about perioperative immunotherapy.

DR PAZ-ARES: I pretty sure that into the future, not now, ctDNA is going to help. Today is not it’s not a very sensitive technology that we have, and therefore it is really difficult to make decisions based on that.

What is important to me today is that many patients are really good candidates for preoperative chemo/IO, neoadjuvantly. And importantly it’s very likely that immunotherapy works better before surgery as compared to after surgery. So I really like to recommend people to think about and also talk to the surgeon before going into surgery, even if it’s a patient with Stage II, resectable, particularly N1 disease. I mean it seems to me logical that those patients with the tumor and with the lymph nodes still there are more likely to respond to immunotherapy as compared to those where the tumor and the lymph nodes have been removed.

DR LOVE: So I want to talk about locally advanced unresectable disease, including a press release that just came out. But Zofia, Venu in the chat room has a 78-year-old woman with Stage IB adenocarcinoma, 3.7 cm, ALK positive. She says the trial restricted to greater than 4 cm. So what would you think about, again putting reimbursement aside, in this situation, Zofia? What would you think about for this patient, including your issue about chemo?

DR PIOTROWSKA: Yeah. So I think extrapolating this is similar to what I would do with an EGFR-positive patient in this situation. I think I’d make a decision about chemo separate from a decision about TKI. So a 3.7 cm tumor, node negative, to me probably wouldn’t rise to the threshold of giving adjuvant chemotherapy, so I think I’d probably pass on that.

I would, however, have a discussion about the TKI. And here is, I think, a situation where I would (1) kind of extrapolate from the EGFR space, but (2) really have a discussion with the patient about what they want to do, what they’re kind of willing to tolerate in terms of the additional burden of the oral therapy, which although it’s well tolerated with alectinib it does add toxicities. I think this is right on the cusp of where we would consider a TKI, and so I would offer it. But I think if a patient said I’m good, I just want to have surgery and monitor and save this for recurrence, I would also feel okay with that.

DR LOVE: So David, we bring the perspective of the general medical oncologist to our work, and there’s been a lot of work done in the adjuvant setting in breast cancer, kind of thinking through this, getting patient input, et cetera, because adjuvant therapy in breast has been out there a long time ago, and maybe trying to put some of the difficult decisions in their hands. But for therapies that have low toxicity, and I would consider targeted therapy in lung cancer relatively low, certainly compared to chemotherapy, maybe not that different than say endocrine therapy in breast cancer, I mean I’m not saying they’re the same, but maybe in the same ballpark, but there, once they get the hazard rate the apply it all the way down, and then they think about a risk/benefit. So if this trial didn’t include the stage they would say okay, well what’s the risk of recurrence, you apply this thing to it, you come up with the absolute benefit, and you sit with the patient and say would you be willing to try this drug for a while to get this kind of a benefit. Do you think that is a reasonable approach in lung cancer?

DR SPIGEL: Yeah. I think it’s very reasonable. It’s funny how we learn a lot from them, our colleagues who take care of patients with breast cancer. I’m thinking specifically about neoadjuvant therapy in triple-negative breast cancer, where often providers change care based on the results. We’re just now trying to understand how to do that in lung cancer.

But I think your point about adjuvant aromatase inhibitor therapy or tamoxifen is very apt for this kind of conversation with patients, and I do think we’re probably moving in that direction where we’re looking at probably more than 2 years and 3 years of these agents down the road. I mean I think patients may end up staying on these drugs for a while. If you’ve made it to 2 years and 3 years you’re probably going to make it to 5 or 10. It’s hard to believe we’d be talking about that. But that’s what happened in breast cancer.

And I think you’re correct. Breast cancer adjuvant therapy can have its own set of challenges in terms of taking a daily therapy and dealing with side effects that seem like they’re not as bad as chemotherapy but can be hard, and so too can an ALK inhibitor and an EGFR-TKI. It can be manageable, but it can be bad, and so you have to learn how to manage that over an extended period of time. But I think very similar to breast cancer.

DR LOVE: Who knows? Maybe cell-free DNA will make this more straightforward. They’re excited about that in breast cancer as well.

DR SPIGEL: Yeah. I do think, and maybe we’ll talk about that later, I do think that’s going to be a strategy we’re all hopeful will be a more common way to manage patients really across malignancies, but especially in lung cancer.

DR LOVE: So Luis, you discussed this trial, the PACIFIC-6 trial that was reported at ESMO in your talk, durvalumab followed by sequential CT/RT. Can you talk a little bit about what types of patients, if any, that you used this strategy in, Luis, and what you thought about the study?

DR PAZ-ARES: So these are for patients not particularly fit, so they are not good candidates for concurrent chemoradiation, so they are typically given chemo and then radiation. The good thing here in these nonrandomized trials is that the outcomes of the patients, let’s say survival data, are very similar to those in the PACIFIC trial with chemoradiation and then durvalumab. So indeed the 3-year, for example, survival is similar to the PACIFIC trial. So I think are very relevant data.

DR LOVE: You also commented on the issue that’s been heavily debated about locally advanced non-resectable EGFR tumors and whether they should be getting durvalumab — osimertinib. Any comments on that, Luis?

DR PAZ-ARES: So collectively the data we have today I would say the data are more in favor of using let’s say osimertinib as compared to durvalumab. I would say you see here this PACIFIC real-world data where patients treated with durvalumab after chemoradiation, they have worse PFS if they have EGFR mutations. Even the survival is very much the same, likely because they do have later osimertinib. And there are some other data already presented at the World Lung Cancer meeting somehow backing these data. So I’m not really sure about the efficacy of durvalumab in this very setting.

DR LOVE: So Zofia, Carlos in the chat room says that he encountered a thoracic surgeon who was concerned about neoadjuvant IO making surgery more difficult. Actually, Luis presented a bunch of data suggesting maybe it’s easier after neoadjuvant IO. I don’t know if you’ve heard this from your surgeons, Zofia, but what are the facts?

DR PIOTROWSKA: Yeah. I think that this is getting to be overall, I think, disproven as a theory, and this is something that surgeons were overall I think concerned about initially, but this has not borne out, either in the trials, nor would I say in my clinical experience. Of course I’m not a surgeon, but when we’ve discussed it at our tumor boards it really seems like these cases are not significantly different than patients who have not gotten neoadjuvant therapy. And as you alluded to, I think this has borne out across the studies in terms of operating room time, the risks of complications, all of those factors which don’t seem to be increased.

So I think the adoption of neoadjuvant therapy has required tremendous collaboration between medical oncologists and surgeons. And for those of us who practice at academic institutions, where our surgeons are right next door, and we share tumor boards, and see patients together, I think that that is something that’s come easily. But I know that for some community centers where those surgeons are maybe not directly next door, they’re seen separately, I think it requires really close collaboration and communication and open lines of discussion. But it’s so important for patients.

DR LOVE: So David, our crack chat room has already asked about the PACIFIC-2 press release. They’re all over it. I think this came out was it today or yesterday? But in any event, I initially didn’t quite follow. I had to go look up what this trial actually was, which it’s kind of surprising in that it was kind of giving durvalumab with neoadjuvant — with chemoradiation therapy and then continue it a la PACIFIC versus no durvalumab. And by doing that they were including people who wouldn’t have gotten into the PACIFIC-1 trial because they either progressed or were in bad shape, et cetera. Can you kind of explain what this trial means or what this trial might mean when it’s actually presented?

DR SPIGEL: Yeah. Well, so remember the original PACIFIC study was to give chemoRT, in what Luis just commented on in PACIFIC-6, the same kind of design, to give concurrent chemoRT kind of through the institutional standard and then give durvalumab, actually originally for a year in that study he just showed, for 24 cycles. I think this study, PACIFIC-2 though, if I’m not mistaken, because many of the later PACIFIC versions have indefinite durvalumab, so I do want to clarify it’s a little bit different than PACIFIC.

But the main difference between PACIFIC and PACIFIC-2 is the use of IO with chemoRT. So this has been something that a lot of other disease settings have started to incorporate IO with RT. I think in practice I’m sure Luis and Zofia also, and a lot of our participants, have wrestled with giving concurrent RT at times for palliation or maybe in a definitive way. But this trial was designed to prove the safety of that strategy, as well as efficacy.

And so yeah, I think we just saw a press release that this regimen, we’re going to be hearing more I’m presuming at ASCO, but I don’t think we know. And maybe Luis and Zofia involved in this, where they know more. But we know that safety has been achieved and that we presume efficacy also has been achieved.

DR LOVE: So although it says that it didn’t meet its endpoint, I guess, the primary endpoint of progression-free survival. But Zofia, again, you were kind of explaining to me before we got started it’s kind of like this is 2 different populations and doesn’t really relate to what we’ve been doing for many years now, which using the PACIFIC strategy. Can you kind of just explain that a little bit better?

DR PIOTROWSKA: Yeah. Luis and I were chatting a little bit before we came on. I think a key difference about the study from the original PACIFIC trial is that if you recall on PACIFIC the patients got chemoRT and then if they were nonprogressors were then randomized to durvalumab versus no durvalumab. And I think there you’re really selecting the best of the best patients. And in PACIFIC-2 these patients got durvalumab up front, and there was no selection for the patients who really had the best possible outcome after chemoRT in the sense that they were well enough to continue on treatment and they didn’t have progression.

So I think 1 potential conclusion from this is that perhaps you’re adding immunotherapy with their initial chemoRT is not going to be enough to kind of rescue those patients who are going to have the poorer outcomes, and so by not eliminating those patients from the study population you’re washing out the benefit of the immunotherapy.

EGFR-Mutated Metastatic NSCLC

DR LOVE: So let’s move on now and talk about metastatic disease, and we’re going to talk about targeted therapy, particularly things that are new. We could talk a long, long time about this topic, but we’re going to focus on particularly some of the new data sets that came out.

And interestingly we’re starting to see some interesting data on first-line treatment. I thought we were past that, but first-line treatment of EGFR activating mutations, Zofia. Pretty interesting. I think when you and I sat down it took us almost an hour just to get through the EGFR stuff from ESMO. But anyhow, we’ll see if we can do it a little quicker here. This is a great slide that summarizes some of the data that was just presented, and maybe we can just go off of this.

Can you kind of summarize some of these trials, I guess starting out with FLAURA2?

DR PIOTROWSKA: Yes. So I think that the top-level summary here is that for patients with classic EGFR mutations there’s been a few different approaches to try to improve outcomes with first-line osimertinib and to do better, but the way that’s been attempted is by adding things to the TKI. And one of the challenges here is that osimertinib sets a very high bar in terms of patient quality of life and how patients feel on it. It’s an oral regimen. It’s well tolerated. It has a decent median progression-free survival. And what we learned from both FLAURA2 and MARIPOSA is that adding something to osimertinib can improve progression-free survival but also adds complexity and toxicity.

So FLAURA2 looked at the combination of carboplatin/pemetrexed/chemotherapy first line added to osimertinib, so newly diagnosed patients were randomized to either osimertinib alone or osi plus chemo. And we saw an almost 9-month improvement in progression-free survival with that combination. But we also saw, as you might expect, that it adds an IV therapy to a purely oral regimen. It adds the toxicities of chemotherapy to these patients’ first-line treatment which otherwise is a purely oral one.

And I think the conclusion overall for many of us who looked at this data was that this is great, but it may not be right for every patient. And so there may be some patients where adding chemotherapy up front is going to really improve outcomes and be worthwhile, but for many patients keeping with osimertinib monotherapy and saving chemo for a subsequent line of therapy may be okay.

You have here the slides about CNS outcomes, and I think just to highlight the greatest magnitude of benefit looking post hoc at these patients, was in the patients with baseline CNS metastases, where we saw a PFS hazard ratio of 0.47. I think somewhat surprisingly we saw that the addition of chemotherapy here deepened the responses and led to more complete responses compared to osimertinib, which is a pretty CNS active drug.

So in my practice I think this will be 1 population where I might think particularly about adding chemotherapy first line. Again, for patients where I think that they’re young and well enough where they’re able to tolerate that regimen.

DR LOVE: Before you continue, I’m curious, Luis, how you’re going to think through this. Zofia brought up the issue of brain mets. What about the patient who’s very symptomatic, a lot of disease, needs a response?

DR PAZ-ARES: Very much the same. So I mean looking at the subanalysis the CNS metastases group of patients is the more obvious ones. but of course if I have a patient which is fit, young patient, and is having very symptomatic disease, requires a fast response, high burden of disease, that would be a good candidate.

I’m also still looking forward to having some biomarker analysis that has not been shown. Let’s say what happened with those that do have co-mutations in p53? Maybe those patients are benefiting the most. Looking forward to seeing those type of biomarker analyses as well.

DR LOVE: David, any thoughts? I’ve got to say I was kind of surprised by the CNS thing. I don’t know. Maybe it could be numbers. Is there any biology that would explain it?

DR SPIGEL: Look, I think we’ve always kind of quoted chemotherapy’s effect in controlling brain metastases may be 20%. I’ve never believed that number in practice. But maybe you’re just seeing the additive, maybe not synergistic benefit. But who knows? I mean the numbers are small here, but there appears to be some benefit.

DR LOVE: All right. Let’s talk a little bit about MARIPOSA, Zofia.

DR PIOTROWSKA: Yeah. So another combination approach. So here you’re taking a TKI, and in this case there were actually 2 TKI monotherapy arms, there was osimertinib control arm, as well as a lazertinib control arm, and this was really for contribution of components. Just to say lazertinib is Janssen’s third-generation EGFR inhibitor, and there was some data that showed that really the outcomes were very similar, so I think we can consider these 2 drugs comparable. And then the experimental arm here really was the combination of lazertinib with the bispecific antibody against EGFR and MET, amivantamab, which may sound familiar from patients with EGFR exon 20 insertions, where we have amivantamab approved as monotherapy.

So here amivantamab and lazertinib together again improved progression-free survival, in this case by about 7 months. Hazard ratio was 0.70. But once again, I think that it adds — IV therapy, ami, is given once every 2 weeks, actually weekly for the first 4 weeks and then once every 2 weeks thereafter. It does add, I think, a fair bit of toxicities and ones that can impact patient quality of life, including dermatologic toxicities, infusion reactions. And then 37% of these patients had venous thromboemboli on the combination of ami/lazertinib, and so actually for these patients treated with the combination they’re recommending prophylactic anticoagulation for the first 4 months of treatment.

So to me I think this data is compelling, although it’s not a slam dunk. Similar to what we talked about with FLAURA, I think it would be great to see biomarkers. We’ve seen in later-line settings patients treated with ami/lazertinib, there was a small data set presented at ASCO last year, suggesting that MET immunohistochemistry could potentially be a predictor of response to this combination. And so I’m hoping that they’ll do those types of analyses on these baseline samples to see if that’s something that is seen in a subset of patients, and if so maybe if that might enrich for patients particularly likely to benefit.

DR LOVE: David, any comments? Any situations that you could envision where you’d like to use this strategy?

DR SPIGEL: I mean I don’t know. I think we all have patients who say what can I do that’s more aggressive than just osimertinib. And so I’d probably lean more towards chemo plus than a lazer/ami approach just given some of the side effects.

Now one thing I would say, Zofia, I’m curious your thoughts. That was with IV ami, and so there’s a subQ formulation that we’re expecting to come into play that side effects could be quite reduced. And that could change things, but that’s not how this study was conducted.

DR PIOTROWSKA: Yeah. I suspect that there will be more data on that and follow-up studies. I think that the biggest advantage that I’m aware of with the subcutaneous formulation is the decreased infusion reactions.

DR PAZ-ARES: Yes.

DR PIOTROWSKA: I think to me —

DR SPIGEL: Which is a big deal.

DR PIOTROWSKA: It is a big deal, but at the same time if you think about 2 years of treatment the infusion reactions happen with the first infusion and then most patients get through it.

DR SPIGEL: Yeah, sure.

DR PIOTROWSKA: So it is a big deal. It requires careful monitoring. It takes up more chair time. It can be really scary for patients and sometimes serious. So not to say that it’s not a big deal, but if you can get those patients, even with the IV formulation, through that initial infusion that is less of a concern. But I don’t know how much the subQ formulation will mitigate things like the dermatologic toxicities, the cumulative edema that can be seen in some patients, the VTs. And so I think that’ll be important to see.

DR LOVE: Can you comment a little bit on — go ahead, Luis. Sorry. Go ahead.

DR PAZ-ARES: Yeah. So there is a paper, actually it’s a Nature paper last year, showing that looking at genomic aberrations there is a signature that is predicting for copy number variations, and they are able to predict which patients with EGFR mutations do develop MET amplification at some point. So that should be something we should study here and look at if those patients are the ones that are truly benefitting from amivantamab to prevent resistance to happen, right? So that would be a nice thing to maybe try to study here in this data set.

DR LOVE: So Zofia, can you comment on some of the new data sets that have come out on people progressing on EGFR-TKI for metastatic disease, usually osimertinib. We’re seeing some new data here, MARIPOSA-2, the HERTHENA-Lung01 trial. Can you comment?

DR PIOTROWSKA: Yes. So MARIPOSA-2 took the same combination of amivantamab and lazertinib and basically added it to chemotherapy post osimertinib. And I think we saw fairly compelling data. We saw improvements in progression-free survival. We saw actually almost a doubling of response rate with both chemo/ami/lazer and chemo/amivantamab. And interestingly we saw improved intracranial progression-free survival whether amivantamab or ami/lazer were added to chemotherapy.

And I think that that’s certainly compelling, and what it tells me is I think amivantamab, possibly amivantamab/lazertinib, does benefit these patients, and they probably should have access to this therapy at some point in their treatment course, if they don’t get it first line perhaps in combination with chemotherapy. I think the fact that we saw similar outcomes with ami as with ami/lazer, but we saw more toxicities when the 4-drug combination was used, tells me that probably for most patients chemotherapy plus amivantamab will end up being where the sweet spot is if we’re adding amivantamab here. So if approved I think is a regimen that many of us will probably reach for for our patients who progress on TKIs.

Patritumab deruxtecan I think is another drug to really keep an eye on. This is an antibody-drug conjugate, a class of drugs that we’ve had lot of interest in as a field. This in particular is a HER3-directed antibody-drug conjugate with a TOPO1 isomerase payload. And you can see the data set here. 225 patients, so I think a fairly sizeable data set here. All of these patients had had prior TKI and prior chemo, and the response rate was 30%, just a hair lower than what had been previously reported with this drug in the Phase I study. PFS was 5.5 months. Response is seen across a diverse spectrum of resistance mechanisms suggesting that this is a drug that we can reach for really no matter what our post-osimertinib biopsy shows.

And in think really intriguingly we saw that this drug can have CNS activity. Relatively small number of patients, so I think we have to interpret these data with some caution, but about a third of patients with intracranial disease having an intracranial response. So a little bit of a paradigm shift in thinking about ADCs. Historically not something we’ve thought of as something very CNS penetrant, but I think one of the themes that has emerged from ESMO this year is that perhaps ADCs can have CNS activity.

So patritumab deruxtecan I hope will get approval as monotherapy, and if so it’s certainly a drug that I will reach for in my practice.

DR LOVE: So David, any thoughts about these 2 strategies and if they were both available to you which one you might want to use first?

DR SPIGEL: Post osi I mean I’d lean towards an ADC, kind of a MARIPOSA-2 strategy just with all the same issues that Zofia brought up with MARIPOSA-1.

Zofia, I was going to say, and Neil knows more than us, of course, there are some data of CNS control in breast cancer care with, I’m going to say it wrong, with —

DR LOVE: T-DXd.

DR SPIGEL: T-DXd. There we go.

DR LOVE: T-DXd.

DR SPIGEL: And so yeah, I’ve been kind of surprised by that, that how could these molecules actually affect CNS disease. But I’ve seen in breast that they have data. So this is also encouraging now in lung cancer, but it is hard to understand, isn’t it? I think everything we’ve been told and we tell patients about the blood-brain barrier may not be true.

DR LOVE: We’ll talk about — no, go ahead, Zofia.

DR PIOTROWSKA: I was just going to say there was a nice session at ESMO really lumping all of these CNS kind of abstracts together, and it was a really interesting session. And I think that was one of the take-homes, is whether you’re looking at trastuzumab deruxtecan or patritumab deruxtecan, these drugs can have CNS activity.

DR LOVE: Yeah. I was mentioning on Thursday we’re doing another one of our programs on gastrointestinal tumors. In the last webinar we did we actually had a patient who had HER2-positive esophageal cancer with brain mets who had a complete response in the brain to T-DXd. Of course T-DXd is being used now in many cancers beyond breast cancer.

Luis, what’s your take, again, on these 2 options and your experience with patritumab in terms of tolerability? Any issues there? It does have deruxtecan. Do you see ILD?

DR PAZ-ARES: Well, I think the ILD right now as compared to 3 years ago, that we were not that used to diagnose that early, to monitor that, this is not such a big issue, particularly using the right dose. We tend to use the reduced dose based on this HERTHENA trial as well. So this is not a big issue as of today. I would say that having 2 opportunities here I would tend to use likely for my patients first the ADC and maybe amivantamab would be something I would use later on.

DR LOVE: So Zofia, you also talked about the issue of maybe treatable mutations in these patients. We’ve heard a lot about that in the past, but there was a paper at World Lung looking at tepotinib in people who had MET overexpression. So this is not MET exon 14 mutation but overexpression. It looked like they benefited. What’s your thought on this, and is this a strategy you’re using, Zofia?

DR PIOTROWSKA: Yeah. So this is patients with MET, acquired MET amplification after mechanism of resistance to first-line osimertinib, so just to clarify because I think it’s an important point. These are all patients with EGFR-mutant lung cancer who received first-line TKI, in this case osimertinib. And we know from a series of biopsies done in these patients that up to about 20% or so of patients can have MET amplification detected by either FISH or NGS. Interestingly we see this by tissue. We can also see it by liquid biopsy, although the sensitivity of ctDNA-based liquid biopsies is a little bit lower for the detection of MET amplification, but whichever method you see it by this data set would tell us that these patients can respond.

So here patients got continued osimertinib, and tepotinib, the oral MET inhibitor, was added. And it was I think a nice data set. 98 patients. The response rate to this combination, and all in patients with acquired MET amplification, was 50%. PFS was 5.6 months. There was some intracranial responses, which is not surprising because we know both of these drugs have CNS activity.

I think this really tells us that it’s important to look for MET amplification. And so really just a plug here for patients who progress on first-line osimertinib to do tissue biopsies I think remains our gold standard, to look for MET amplification, to look for histologic transformation. This combination is not yet approved in the US, but we can sometimes access off-label combinations of MET inhibitors with osimertinib combined with capmatinib, tepotinib. Again, that requires off-label approval, but there are also ongoing studies of these combinations, whether with savolitinib, the MET inhibitor from AstraZeneca, with tepotinib and with capmatinib, actually some randomizing patients versus chemo. So there are treatment opportunities for these patients if you find MET amplification.

DR LOVE: So maybe we can quickly hear about your case, your 68-year-old woman who presented with metastatic disease, EGFR L858R, gets osimertinib, good systemic and CNS response, but then she had disease progression after 14 months, although the brain MRI remained stable. What happened with this patient, Zofia?

DR PIOTROWSKA: Yeah. So I just told you that tissue biopsies are the gold standard, but unfortunately this patient had largely progression within the pericardial space, pericardial nodularity that we were not able to biopsy, so we sent a repeat liquid biopsy. And this patient had a somewhat rare resistance mechanism in the sense that she had acquired EGFR resistance mutations L718Q and L718V. This is not something that at the time was clinically targetable. I think if I were treating her now I might see if any of the fourth-generation EGFR inhibitors on clinical trials would have activity against these mutations, although they’re largely developed for C797S.

But she, like many of my patients, then went on to receive chemotherapy, carboplatin/pemetrexed. In this patient’s case actually we continued the osimertinib because of her disease stability in the brain. Unfortunately she then progressed after chemotherapy, and so this is a situation where I think many of these agents that we were just discussing are potential options we might think about.

So this is a situation that’s challenging because many of the options we’d like to use don’t have approval yet. I think this would be a case that would be great for patritumab deruxtecan if we had it. There is also nice data to say that amivantamab/lazertinib may have particular benefit in patients with EGFR-mediated resistance mutations. Unfortunately for my patient she did not have access to either of these options because the clinical trials were not available, and she developed pretty rapid disease progression. But I think all of these options are on the table.

DR LOVE: So yeah. Go ahead, David.

DR SPIGEL: So you continued osi and added chemo? Is that what you did there or no?

DR PIOTROWSKA: We did. We do, for patients like her, where they have CNS disease that is controlled on osimertinib, and their disease progression is systemic but not intracranial. I’d be curious to hear what both you and Luis do, and maybe we don’t have time to go into this in detail, but it is something we consider, and there are prospective studies looking at that combination — at that question to try to answer this.

DR SPIGEL: Yeah.

DR LOVE: Actually, I had just written down that question to ask you all, David. It’s just mind meld there. So Luis, just in general, in what situation do you continue osimertinib with disease progression in the metastatic setting?

DR PAZ-ARES: We only use that when you’re having let’s say oligoprogression, so then you do a local treatment and go on osimertinib, let’s say to irradiate or to even remove by surgery a new lesion, if the rest of the disease is controlled and just go on osi. We are not by the label able to really continue osimertinib if the patient is having systemic progression, and let’s say add chemotherapy. That is not feasible. And truly based on the MARIPOSA-2 data I’m not sure this is a strategy I would do even if I was able to do it, to be honest.

I understand this trial was not designed for that, but I’m not sure the data are robust to go on osimertinib after progression.

DR PIOTROWSKA: I agree with you. I can’t disagree with that conclusion.

Other Targeted Treatment for Metastatic NSCLC

DR LOVE: Let’s try to get through a few more targeted treatments because I really want to make sure we have enough time to talk about antibody-drug conjugates. So exon 20 insertions, Zofia. Can you comment on the paper presented?

DR PIOTROWSKA: Sure. I’ll try to be brief with this one. So for patients with EGFR exon 20 insertions as of today chemotherapy has been our standard first-line therapy, and we’ve had amivantamab monotherapy in the US approved as a post-chemo option. And the PAPILLON study looked at adding amivantamab to first-line chemotherapy.

The control arm here was chemo alone, and we saw nice outcomes. We saw an improvement in progression-free survival, I think a fairly impressive PFS hazard ratio of 0.4. We saw an improvement in objective response rate, 47 versus 73%. We saw maybe a hint, although the data is immature, of an overall survival benefit. I think that it’s hard to make too much of this because it’s still early days, and the number at risk are quite small if you look at those later time points.

But I think this is meaningful. I think all of the issues that I raised earlier about the challenges of adding amivantamab are still present. We see more dermatologic toxicities. We can see cumulative edema. We see infusion-related reactions, and then here of course all of the chemo side effects.

I think the difference between MARIPOSA is that here patients are already getting chemo, so it’s really just adding another IV therapy. So I think that if this is approved this will likely change our practice. It may not be right for everyone. There may be patients who are older where we worry about the toxicity, but for many patients I think this will change our standard of care.

DR LOVE: So T-DXd. I feel like I talk about that every day. And incidentally, Luis, you were talking about the PACIFIC paradigm. We just did a program on post-GYN ESMO. There was a big presentation adding IO to chemoradiation with cervical cancer that was very positive. So yeah, another tumor type taking the PACIFIC model.

How about HER2-mutations and T-DXd, Zofia?

DR PIOTROWSKA: I think the topline results here are that these were final results from the DESTINY-Lung02 study which really helped us to understand this question of the right dosing of T-DXd for patients with HER2-mutant lung cancer. Remember, this actually was already approved in the United States I think last year based on the results of DESTINY-Lung01. But in that study T-DXd was used at a higher dose, 6.4 mg/kg, and we saw a 26% rate of ILD, so in DESTINY-Lung02 they randomized patients to 6.4 versus 5.4 mg/kg.

And the bottom line is that we saw comparable efficacy outcomes but lower rates of ILD. We still saw ILD, 13% of patients having ILD, so it’s something we still have to watch for very closely. But overall the 5.4 mg/kg dose seems to be the safer one and the one that the FDA has approved and the one that we’re using for HER2-mutant lung cancer.

DR LOVE: So we talked a little bit about CNS outcomes with T-DXd, and of course we’re talking about HER2-mutant disease. David, what about the use of T-DXd in HER2 overexpressing, which of course is where it’s primarily used with breast cancer. What do we know about that? It looks like it has some activity, maybe not as much as with HER2-mutant.

DR SPIGEL: Yeah. It’s been a little frustrating, right, because we know the activity in not just breast cancer, but even gastroesophageal disease in overexpressed patients, and there are data in lung cancer, as well, but it has not led to an expansion in the label in lung cancer. It’s limited to some of these rare mutations in HER2.

But if you had it available it gets asked all the time, should we be giving it to patients off-study. If you can get it in high-expressing patients I think there’s activity there, so I think it would be an option.

DR LOVE: So Zofia, can you comment on LIBRETTO-431? To me, I think it may be not too surprising, but I think maybe an important study conceptually. Can you talk about what they looked at?

DR PIOTROWSKA: Yes. So LIBRETTO-431 was a first-line randomized study for patients with RET fusion-positive lung cancers, and this is a population where we’ve seen a lot of progress in recent years. We saw that the selective RET inhibitors, including selpercatinib, which is the drug that’s used here, as well as pralsetinib, had previously been demonstrated in single-arm studies to have really impressive activity, high rates of response, high rates of intracranial activity, and overall fairly good safety profiles. And so that had actually led to accelerated approval.

But this was a confirmatory study comparing selpercatinib to standard of care chemotherapy, interestingly in this population plus or minus immunotherapy with crossover to selpercatinib in the control arm. And what we saw was not at all surprising, which is that selpercatinib clearly won this race. It was better in terms of all efficacy endpoints, and the safety was expected, no surprises. I think this really confirms the practice that I think all of us were already using, which is that if you find a RET-positive patient it makes more sense to start that patient on a selective RET inhibitor like selpercatinib or pralsetinib than it does to start them on chemo.

But one interesting side note of the study was that if you looked at the control arm the outcomes are actually very similar regardless of whether patients got chemo alone or whether they got chemo plus pembrolizumab. And I think this also reaffirms what we would have predicted, which is that these patients with RET-positive disease, many of them who are never smokers, don’t benefit as much from the addition of immunotherapy to chemo. And so I think another important lesion from this study is when you’re moving a patient with RET-positive disease, say from a drug like selpercatinib to maybe chemotherapy in the later-line setting, may be less of a role here for a drug like pembrolizumab than we might in other non-small cell lung cancer subtypes.

DR LOVE: So Luis, one of the things I really liked about this study is one of the things that I’ve kind of been observing over the years is the issue of how much data do we need in order to take action, and we talked about it as related to adjuvant therapy. But we know a lot of our audience if fairly new to oncology and maybe doesn’t know the history of targeted therapy, that there was originally a randomized trial, I think it was called the IPASS study, chemo versus I think it was gefitinib or erlotinib, and I think there was 1 in ALK like that, and then there have been very few studies like this since we assumed the principle would apply.

I was going to ask you, Luis, if you could, would you use T-DXd first line or do you need a study to prove it? And any thoughts about this study here and kind of what it means in general?

DR PAZ-ARES: So I think when you’re having an oncogene-addicted disease, and you have a specific drug such as the case for non-small cell lung cancer driven by RET fusions, I don’t think today we need a randomized trial if the data of single-cohort trials shows enough magnitude of benefit as compared to historical controls.

The reason for randomized trials is because diseases are not homogeneous, are pretty heterogeneous, so you have to be sure that patients are distributed in the 2 arms. But your disease is defined genetically, such is the case on RET-driven tumors, I don’t think randomization is that important and indeed the results were as expected. So I think we shouldn’t do trials in diseases like that in the metastatic setting anymore, to be honest.

DR LOVE: David, just out of curiosity, in what line therapy do you use T-DXd in HER2-mutant disease?

DR SPIGEL: I think it’s something you could use up front, but we didn’t talk a lot about safety. I mean there are some issues there that you’ll have to reconcile when you think about what you’re replacing. So if you’re replacing carbo/pemetrexed with an IO we kind of find it to be a very efficacious and safe regimen. And so somebody who does well on T-DXd, that’s great, but if they develop ILD or other toxicity you start to say well was that the great choice, the best choice. But I would still discuss that as a first-line option, no question.

DR LOVE: Go ahead, Luis.

DR PAZ-ARES: No, no. I was thinking that now we have Phase III data with chemo plus so maybe in that setting that would be a place where I would think about it. At least my label in my region is going to be quite strict at this stage, having obviously data in that setting.

Updates on Immunotherapy in Metastatic NSCLC

DR LOVE: So I want to go through a few other papers, kind of moving away from targeted therapy. First to just get your thoughts in terms of where we are in immunotherapy in metastatic disease. But first, Zofia, Ruby in the chat room wants to know what’s the difference between a RET rearrangement, RET fusion, mutation, point mutation? Do RET inhibitors like selpercatinib work on all of these?

DR PIOTROWSKA: A really important question. So for RET in lung cancer you’re really looking for the fusions or rearrangements. So common ones are CCDC6-RET or KIF5B-RET. These are the oncogenic drivers. So there are other partners, but you’re really looking for the fusion events. Occasionally we see RET mutations, which I would say on their own in the absence of a RET fusion, are not something that we target.

The one caveat here is RET mutations can arise in the context of a RET fusion-positive cancer treated with a selective RET inhibitor and can be resistance mutations. And that’s important because in some cases we have some next-generation RET inhibitor clinical trials that we might consider. But for a newly diagnosed patient really I only get excited about RET if it’s a fusion event and not a point mutation. Really important point to clarify.

DR LOVE: So Luis, we talked about neoadjuvant IO, now we’re going to talk about metastatic disease. We saw some data from the EMPOWER-Lung 1 and 3 trials looking at cemiplimab both in terms of patient-reported functioning, but interestingly a paper looking specifically at cemiplimab in these 2 studies, so either cemiplimab alone or with chemo, specifically in squamous cancer. I was mentioning our GYN symposium. Cemiplimab has great activity in cervical cancer and is used a lot there. And this was data presented in the squamous patients.

Luis, at this point, when you think about IOs, either as monotherapy with chemotherapy, obviously we have 3 where we have data and they’re available. First of all, from your point of view can you distinguish the 3?

DR PAZ-ARES: Well, to be honest, if I’m using in high expressors I tend to use pembrolizumab or cemiplimab. Those are the ones I’ve been using for quite some time. If I’m using chemo/IO I think we have data now with cemiplimab. For some reason I’ve been using pembrolizumab for ages, and I think at least in squamous, I mean it is clear. Still, on the other hand I don’t see any clear reason to change on the other hand, so I suppose that I would understand any choice. There are now some 8 or 9 agents with very similar results, and I wouldn’t say that if you choose any other than you’re wrong. I tend to use the ones I’ve been using for ages, right? I don’t know whether you do, guys.

DR LOVE: And also I want to ask David, this is something we ask a lot in our different meetings, which is if you also agree that you can’t really distinguish these agents, if one were priced significantly less than the other would that change the way you approach it?

DR SPIGEL: Yeah. Luis, I completely agree with you. I think the EMPOWER data from 1 with monotherapy and 3 with chemo looked very much like the pembro study. I mean I think the data looked pretty compelling, and I think cemiplimab for me is very much something I’d feel good in a blinded taste test to be okay with. And so I’m not sure I agree the same with atezo based on the data, and we were part of that study.

But the ultimate question I think you’re asking are there differences in these drugs. I mean we haven’t been able to compare them head-to-head, and so we have no data to say that pembro or cemiplimab are better or worse than each other. I just think we have 4 great randomized trials that show that they’re better than chemo alone, so…

DR LOVE: So to be continued.

DR PAZ-ARES: Actually, at ESMO there was another trial, the PERLA trial. That was a Phase II trial —

DR SPIGEL: Yeah, yeah. That’s right, with dostarlimab.

DR PAZ-ARES: Yeah. And they compared chemo plus pembro versus chemo plus dostarlimab. The good thing about this trial is that they used a direct compactor, right? They used chemo/pembro so you don’t have to do cross-trial comparisons. And that is something that maybe agencies should ask for any new agent, right?

DR SPIGEL: Yeah. Luis, that’s a great point. A little bit under the radar. That’s the only data set I’m aware of.

DR LOVE: Yeah. I was surprised when I saw that.

What about CTLA4/IO, Zofia? Of course ipi/nivo has been out there. We saw more data from the POSEIDON trial at the World Lung meeting looking at durvalumab/tremelimumab, a combination that actually we were talking about in the webinar in biliary cancer. That’s now approved first line in biliary.

Any comments about IO or PD-1 plus CTLA4, Zofia? One area I hear people talking about it was PD 0 patients.

DR PIOTROWSKA: Yeah. I think this is still an area where we need to do a little bit more work to really understand which patients are most likely to benefit. I think we’re, to be honest, still guessing a little bit at this point.

The place where I have found this combination to be potentially useful in the clinic are 1) you’re right. PD-L1 negative patients, where we worry that their benefit from a PD-L1 inhibitor alone won’t be as much, but also patients with comutations, so STK11 and KEAP1 comutations, where again we worry that their response to PD-1 inhibitor or PD-L1 inhibitor alone won’t be good enough. So especially younger patients, where we really want to kind of throw everything that we can at those patients, I think a regimen like POSEIDON with chemo plus PD-1 and CTLA4. You could say the same about CheckMate 9LA also as another option. I think that the comutation patients are the place where I’ve tended to use this most.

But I think we truthfully need better biomarkers to tell us which patients really need this combination because there is a little bit more toxicity with the CTLA4 addition.

DR LOVE: David?

DR SPIGEL: I mean there was a suggestion, Zofia, too, that maybe squamous zeros would be the place, but I just haven’t found that to be true. I have tried it a handful of times, and I just don’t see that it’s any better.

DR PIOTROWSKA: ...so much better, yeah.

DR SPIGEL: Yeah.

DR PIOTROWSKA: Agreed.

Emerging Antibody-Drug Conjugates for Metastatic NSCLC

DR LOVE: All right. Well, let’s talk a little bit more about antibody-drug conjugates. Actually, believe it or not we did a similar program last week on breast cancer. I felt like that’s all we were talking about there all of a sudden in breast cancer too, as well. Of course this was the ESMO ADC maybe. In any event, 1 ADC that was presented in both breast cancer and lung cancer was datopotamab deruxtecan. (Oops. Wrong way.)

So Luis, I’m curious what your thoughts were about this Phase III TROPION-Lung01 study that compared dato-DXd to docetaxel and found a benefit in terms of the intention-to-treat population with a hazard rate of 0.75. And in terms of overall survival at this point not significant. And we’ll talk about the tolerability issues that were discussed.

But first, in terms of the efficacy, Luis, what was your thoughts about it, and does it get you interested in potentially wanting to use this agent?

DR PAZ-ARES: The interesting thing here was that the benefit in terms of PFS was restricted to nonsquamous tumors. Hazard ratio being 0.66. And actually patients with squamous were doing worse as compared to the docetaxel. Truly we knew that a subset of patients with nonsquamous are benefitting the most. Those are patients with genomic aberrations, EGFR mutations, ALK translocations and so on.

In a different trial we have seen the TROPION-Lung05 responses in some 35% of the patients with genomic aberrations, and those data are actually consistent here.

So the question then is what happened to those patients with adenocarcinomas with nonsquamous and wild-type patients, let’s say without genomic aberrations. Well, the data suggests that the hazard ratio is still in favor for those patients. Maybe the benefit is not as high. The second thing is what is going to happen when the data are mature enough for survival. At this stage we haven’t seen survival benefit, but the data are still quite immature.

In terms of safety profile, I would say we have seen relevant toxicities such as ocular events and stomatitis. That is very important, in part because as a lung cancer doctor we are not very used to those toxicities. So I’m pretty sure that we will learn to better treat and to better manage like this stomatitis and ocular toxicity. For example, when I give to my patients the dexamethasone rinses they do have problems even at the local pharmacies to get the preparations done. So anyway, I think we have to improve a bit on that, do some education to patients and to doctors.

DR LOVE: So David, I’m curious about your thoughts. Interesting, we had Sara Tolaney on our breast ESMO meeting last week, and they really pioneered the use of mouthwashes for mucositis from everolimus. When they started doing the dato trials as soon as they started to see the mucositis they pulled out the mouthwash. And she told me last week it works, but they have a lot of experience with that.

So David, what’s your take on this? What’s your thoughts about the histology difference there and about how much of an issue the side effects are going to be?

DR SPIGEL: I’m going to agree with Luis. I mean I think it’s a positive study for PFS. It looks like the weight of that is carried by the nonsquamous. The overall survival is not there, but it wasn’t intended to be at this point. And so is this good enough to replace docetaxel in a refractory patient population in at least adenocarcinoma? It looks like it met that bar. Whether that’s okay for the FDA or they’re going to wait on OS to give an approval I think we’ll have to wait to see.

The side effects. I think you guys did a nice job describing them. I mean it’s not without side effects. ILD’s a real problem in these patients, but fortunately it is relatively low. The steroid rinse, that’s new to me in terms of trying to figure out how to make that work. I’ve been using it for a while and don’t see it the same that Sara does, but it’s probably because I’m just not as smart as her in figuring out how to get patients to get better on it. But I certainly try it.

DR LOVE: So yeah, and I have to find out what the secret sauce is there. Zofia, what’s your take on this, and also I mean if the drug were available would you prefer or use it only in nonsquamous? And any comments in terms of the side effect profile?

DR PIOTROWSKA: Yeah. I think overall I was somewhat underwhelmed by these data. I think it’s always good to have more options, but having seen the press release saying this was a positive study I think we were all hoping for more. I think in the overall population it sounds like we can all agree that a 3-week, essentially, improvement in PFS is not clinically meaningful. So I think if we’re going to use it it’s the nonsquamous patients. We have to keep in mind that that’s a post hoc subset analysis, but it does seem to be closer to a 2-month improvement in PFS, so not a slam dunk but some improvement.

So I think it’s another option. Is it going to be an option that replaces docetaxel or is it going to be another option that we might use in sequence after docetaxel? I think that probably both will be used. To me the worry, if this improved PFS by close to 2 months and was better tolerated than docetaxel that would be great, but I think the mucositis is a tough one, and I think having to try to get patients to find these oral steroid rinses — I’ve heard that eating ice chips or sucking on ice chips during the infusions might help. The kind of things that can be a little bit tricky. I think that that’s going to be a limitation.

So again, always good to have options. I think I will use it. The question is going to be where in the sequence and where does the FDA approve it if it does approve it.

DR LOVE: And in terms of the ophthalmic issues, David, I was telling Dr Lisberg I feel like we talk about ophthalmic things every day, but we haven’t talked about it much with you all, but almost everybody else, ADC, even other things besides ADCs. We did an entire CME program on just ophthalmic issues in oncology. But I have not seen any ophthalmic issues with agents when the drug delivery was DXd until this. It kind of sounds like similar to what we’re hearing for mirvetuximab, like a dry eye.

DR SPIGEL: Yeah.

DR LOVE: And seemingly like more of a nuisance than like a serious problem. A nuisance kind of problem. Is that your take, David?

DR SPIGEL: Yeah. Well, I mean it’s beyond a nuisance in some patients. I mean it could be kind of chronic dry, red eyes. It looks like just a bad conjunctivitis. I haven’t really seen visual acuity changes, but I’ve seen folks who just are constantly — it looks like they have constant allergies and try all these eyedrops. It’s not an easy thing to dismiss, and it is something you see across ADCs, not all, but it’s common.

DR PAZ-ARES: Neil, I think it’s going to be very important that we have our ophthalmological clinics really open to our patients every day, as we did with our dermatologists. So right now we’re really a lot better in managing skin side effects, so that is going to be important, as well, to those ophthalmic issues. And today, to me, it’s not easy to have ophthalmologists see my patients on the very date I’m having a clinic, so that is going to be something we have to work out really.

DR SPIGEL: Luis, even if they see them and send you a note you can’t understand what the note says.

DR PAZ-ARES: Yeah.

DR SPIGEL: I mean you have to —

DR PAZ-ARES: We’ll have to learn about that. That is the full issue. I mean it’s ask, first of all.

DR SPIGEL: Yeah. Yeah.

DR LOVE: Anyhow, as we’ve been talking about, these novel agents tend to move up, and we also saw some data at the World Lung, Zofia, bringing dato up into the first-line setting, the TROPION-Lung04 study combining it with durvalumab. I think we were mentioning the idea of IO plus ADC is getting a lot of attention, first-line therapy in bladder cancer nowadays. Any thoughts, Zofia, about where this strategy might be heading?

DR PIOTROWSKA: Yeah. It’s interesting I think. Of course always a drug may have some activity in later lines. Many companies try to move to the first line, and I think we’ve seen this type of approach with a number of different ADCs, kind of trying to create novel platinum doublets, where one of the chemo partners is replaced by an ADC. I think, to me, obviously we’ll have to see what it looks like, but the toxicities in particular, I think, are going to be a concern that we’re going to have to keep an eye on, again particularly in first-line therapy.

For the nonsquamous patients I think carboplatin/pemetrexed/pembrolizumab overall is a fairly well-tolerated regimen, so I think we’re going to have to really see how these patients feel on these therapies. I’m frankly a little bit cautious about whether this is going to be a viable first-line strategy. But I’ll reserve judgment until we see more data. What we’ve seen so far has been extremely limited single-arm small cohorts.

Small Cell Lung Cancer

DR LOVE: All right. Well let’s finish out talking about small cell. Again, we’ve been looking for interesting, exciting things in small cell for the last couple years, ever since the IOs came out. I’m starting to think that maybe we’re getting close.

So first of all, there was some data presented at ASCO from the CASPIAN study, some patient-reported outcomes data that was just kind of a reminder of this strategy with durvalumab and atezolizumab plus chemotherapy that came into the first-line setting. Dr Lisberg was pointing out that in these data that actually the 3-year survival was increased in these patients.

And he was commenting in general, David, on kind of what he’s seen in his practice in terms of benefit of adding IO to chemo as first-line therapy. And when the data first came out, and we were looking at the data and comparing the 2 trials, and then it settled into practice, I always kind of wondered how much it really meant in terms of quality of life to these patients. It’s hard to pull that out of trials, even a study like this looking at patient-reported outcomes. What’s been your observation in the pre-IO and post-IO era, David? Does that give you a sense of encouragement that we’re moving forward or maybe not really?

DR SPIGEL: Well, look, I mean we all use it, and I think we use durva or atezo at times. Look, I think it’s been a modest, it’s a real but modest improvement. If you’re asking about quality of life for patients who are on prolonged IO with small cell, for the few patients I have that are on prolonged IO therapy in small cell I don’t really see it to be any different than prolonged IO in non-small cell.

So I think it was a major advance, certainly, in the care of patients with first-line disease, but I think we all feel that it was a small step, and we’ve got to make more substantial steps for patients.

DR LOVE: So I want to talk about some of the new agents that are starting to come out in small cell, Zofia, beginning with this one, I-DXd, in refractory small cell, an antibody-drug conjugate targeting B7-H3. Any comments? It looks like it maybe has some activity.

DR PIOTROWSKA: Yeah. I’ll certainly let my co-panelists weigh in, as well, if they have more experience. I personally have not used this drug. I think that I would say that, taking a big step back, I think that where we see the most excitement right now is with kind of a slightly different approach with the BiTE therapies, and so I think that’s probably this kind of flew a little bit under the radar just because I think we are all quite excited about the bispecific T-cell engagers.

But I think that there’s a number of these different approaches being tested, and so we’ll have to really keep an eye on these to see. I think a key question with all of these therapies is going to be, are there biomarkers that tell us what’s going on with these patients, or is this an all-comers approach. But I’ll let Dr Paz-Ares, who presented this data, comment on tarlatamab. I think this is really the standout for me in this group.

DR LOVE: And also I guess I’ll point out, Luis, as far as I know this is the first CD3 bispecific that’s been reported to have positive results with a solid tumor. Does that sound right?

DR PAZ-ARES: Well, I think so. This is kind of the first BiTE that is shown to be active on solid tumors, but particularly on very poorly immunogenic tumors such as small cell lung cancer. We’ve known for a number of years that those tumors that have downregulation of class I, so antigen presentation is not happening in many of those tumors. That is the reason why there are poorly immunogenic.

So the good thing of the BiTE is able to activate these cells on a noncanonical mechanism, and the proof of that has been this trial showing that 10 mg of tarlatamab is really showing responses in 40% of the patients, a bit better than 100 mg in this trial that was part of optimizing study. And the better thing was that PFS and OS seems to be pretty reasonable. Let’s say 45% of the patients — sorry, 60% of the patients would still be responding at 6 months, PFS being about 75% for those patients at 6 months in terms of survival.

And the other thing is that safety profile is pretty reasonable. I can say 50% of the patients are having CRS, typically Grade 1, and for most of the cases have been only in cycle 1 and some patients in cycle 2. But the more important thing is only 1 patient — 1%, having Grade 3 cytokine release syndrome.

The same is to be true with ICANS. With 10 mg we have seen only ICANS in some patients in the first or second cycle, and only Grade 1 or 2. Not a single patient had Grade 3. Still, even if you look at the table the toxicity is not very severe, but we have to admit that when your patient is having fever that is Grade 1 CRS, but you don’t know what is going to happen 2 hours later. So you have to monitor the patient. You have to be sure that the patient is not getting into worse CRS because that maybe requires some urgent measurements, right?

So the main issue is that we have to learn how to monitor those patients, which patients should be in hospital, which patients can be treated from the beginning at home, and this is something we will learn in the near future. But the more important thing is that it looks like we got a new study here.

DR LOVE: So David, the good news is I think the general medical oncologists are going to be ready for you because I was mentioning we’re doing all these meetings at ASH, probably half the stuff we’re going to talk about is, between myeloma and lymphoma, bispecifics, the hottest thing in oncology. General oncologists are learning about CRS, and they know it’s coming to their clinic soon.

David, just curious, if you could, would you want to use this drug, based on what you’re seeing on this slide, second line?

DR SPIGEL: Let me tell you, it’s not just this drug. There’s a number of DLL3-targeting drugs in development, and absolutely. This is something I’m very excited about, and I think if you were going to gamble you would say this is going to be another major breakthrough in small cell. Early days, we need more data, but absolutely exciting. And Neil, remember an older drug, an ADC that used to go by the name of rova-T, was trying to target the same antigen.

DR LOVE: Right.

DR SPIGEL: This is just targeting CD3 at the same time. So yeah, very exciting. I think Luis nicely summarized these data which just were published in The New England Journal.

DR LOVE: All right. Well, I think we’ve come to the end of our time. And Luis and Zofia and David, thank you so much for sharing your knowledge and experience with us. Audience, thank you for attending. Come on back on Thursday night. We’ll hear what Dr Klempner has to say about T-DXd and many other things in gastroesophageal cancers. Be safe, stay well, and have a great night. Thanks so much, faculty. Thanks, Luis. Thanks, Zofia. Take care, David.

DR PAZ-ARES: Thank you.

DR PIOTROWSKA: Thank you.