Investigator perspectives on emerging findings with immunotherapy for resectable non-small cell lung cancer (NSCLC)

DR LOVE: Welcome to Oncology Today — a special edition focused on key presentations in lung cancer from the 2023 ASCO meeting. This is medical oncologist Dr Neil Love. For this program, I met with Dr Matthew Gubens from the University of California in San Francisco. In addition to this interview, there is also a video recording featuring Dr Gubens’ full slide presentation. To begin, I asked him to comment on one of the most important areas discussed at ASCO and recently in this field: the use of immunotherapy in the neoadjuvant and adjuvant setting.

DR GUBENS: It’s been an exciting time. We’re at the frontier and trying to grapple with these big data sets. I think the nivolumab/chemotherapy neoadjuvant study really has started to change practice and to do it pretty rapidly. Surgeons — to the credit of the investigators on these trials, they’ve done a really good job of capturing surgical outcomes, to understand that patients didn’t have to have more invasive surgery. Patients didn’t miss out on surgery. Patients didn’t have to get diverted to chemoradiation at high proportions. So surgeons have become more comfortable with the idea of saying ‘hey, medical oncology, take it away for a while and bring them back to me.’

So already it’s been good to see that evolution. But then the question has always been, it’s an easy question if you have a patient with a pathologic CR. It’s exciting when you get that result back. You congratulate the patient. And I often don’t give any further therapy because we already gave the neoadjuvant. But now that perioperative will be on the table without head-to-head data, we’re really going to struggle with this. And I have a healthy humility for a year of immunotherapy. It's tolerable for most but it’s not nontoxic. There is a cost to it that’s real. And as of yet, these data aren’t that mature.

Now if we start seeing, granted always with the caveats of cross-trial comparison, if we see those survival curves looking more robust when there’s the adjuvant component as well, I think that will move some hearts and minds. Right now they look almost superimposable. So I think that you’re kind of left with having to go your own way, if we get the FDA approval, which I assume is coming.

I think some of the discussion will be around what can we learn from the PCRs, and I think that might be an easier case — every PCR maybe you get to spare the patient the extra year. What if you have a major pathologic response? What if you have no response at all? Is it just a matter of 3 or 4 cycles wasn’t enough and maybe a year is the salvage? I have very little faith that patients who have no response after 3 cycles of chemo need any more chemo. But I think there’s better argument to be made for the postoperative immunotherapy, maybe.

But that’s where I think for now what I wonder is if there will be a move to say, well, let’s do belts and suspenders, I have the option. I don’t want to be faulted for undertreating, so as long as patient’s tolerating it, we’ll give the perioperative approach. I could imagine that being kind of the “set it and forget it” approach for some folks.

I can also see a lot of opportunity for shared decision making again to really say hey, here’s where the data fail us a bit. Here are the curves. There doesn’t seem to be much of a difference. If you got a good response up-front, maybe we’ll spare you the therapy on the backend.

We need to learn more about who it is that doesn’t have a path CR or an MPR. We learn a little more about how these patients do with longer survival follow-up.

It’s an exciting time. But we’re going to have data sets coming on both sides, perioperative and some more neoadjuvant. And so I think we’re going to have a transitional time for a few years where we’re not really sure which one’s superior.

DR LOVE: So I just sort of had an image that this was a webinar and I look up at the chat room and there are 5 people who say what about cell-free DNA? Because it’s all over oncology. And in colon cancer, they’re already ahead of you. But what about cell-free DNA in lung cancer in this kind of situation?

DR GUBENS: Right! I think that’s going to be a great opportunity. I know several of these trials have collected these data, so we’ll be seeing this refinement of how do the people with persistently positive ctDNA do versus those who don’t? And maybe that’s where the postoperative curves start to splay and maybe that will be informative in how we, in the absence of head-to-head data, choose to give more intensive or less intensive therapy? But I think for now, I would think of it more as an opportunity to de-intensify. If you have a PCR, you’re ctDNA-negative, what a nice opportunity to maybe not — kind of not have to bother with more therapy on the backend.

But again, if they’re ctDNA-positive, maybe we gave you the wrong stuff neoadjuvantly and we need to figure out how to change the therapy on the backend, to do a better job irradicating the micrometastatic disease.

So I think there’s a lot of potential there, but we are very far from the day where I know how to use the ctDNA in clinic, even though it’s available to me.

DR LOVE: So we’ll flip to the other side for another simple question which is how do you approach the use of adjuvant immunotherapy? When do you use it? And which agent do you use?

DR GUBENS: Sure. So we have 2 approvals right now. We’ve got atezolizumab in the PD-L1-positive population. And then we have pembrolizumab in the unselected PD-L1 population. What an interesting pair of studies. The PEARL study that led to the pembro approval, that it was positive for its primary endpoint. But it’s 1 of the very few trials in the whole lung immunotherapy space where there wasn’t a nice gradient, where the high PD-L1 patients did better than the 1 to 49s did better than the nonexpressors. It was kind of a weird, wonky difference there. And you have to kind of scratch your head and think about was it something about the assay? Was it just freak chance?

So in my practice I tend to talk about that issue with patients. If a patient has over 50%, then it’s kind of a no-brainer. And these are patients usually who had early-stage enough disease or chose not to do — for other reasons chose not to do neoadjuvant therapy. So is their first immunotherapy exposure. I offer, without reservation, patients PD-L1 50% or higher either therapy. We happen to have the order set built for atezolizumab just because it was first passed the post. But I would have no reservation about either of them. One to 49, I have a discussion and I admit that the data are weaker, but I also admit — and always keep in the back of my head how imperfect the PD-L1 biomarker is — and adjuvant therapy is a chance for cure. I tend to be on the side of offering those patients the access to the year of immunotherapy with all those caveats.

But for the nonexpressors, I tend to recommend against even the approved pembrolizumab. It’s hard for me to understand the logic of why that’s the 1 case where the PD-L1 nonexpressors do well. I’ll talk about it and my savvy patients will push me on it and we’ll have a discussion. But for the most part, if they’re asking my advice, I’d probably withhold it for PD-L1 nonexpressing patients. Especially if their clinical phenotype is also kind of of that group.

If I have a heavy smoker who has low PD-L1, then I actually might reach for TMB. Even though the data aren’t as convincing there. I’ll say with that phenotype? Okay, I’ll take the opportunity to give you pembro for 0% PD-L1. But if I have a young, nonsmoking patient with PD-L1 0%, I’d say, let’s just do surveillance. That’s been my approach to date.

Immunotherapy for early-stage unresectable disease

DR LOVE: Let’s move on to Stage III unresectable. In your presentation you went through a number of new concepts that are being tested in clinical trials. But again, the data just keeps maturing. People are using that as a standard therapy. Anything different about how you’re approaching that compared to in the past, particularly the issue of what you do with people with some type of genomic abnormality, everything from EGFR-ALK to HER2? Anything new about how you think through that issue?

DR GUBENS: Well, first of all we’re definitely getting genomics in a broader swath of the population because even in the patients that it’s a neoadjuvant therapy, the presence of an activating EGFR mutation, or an ALK fusion, does kind of color how I think about neoadjuvant therapy. I want the data to inform adjuvant therapy. If they have EGFR mutations, I want to be prepared to give them osimertinib. So we actually have this data on more patients than we used to.

In PACIFIC, you didn’t have to have the data. If they happen to have it, they reported EGFR and ALK, they were allowed the trial. I admit, when PACIFIC came out and the initial PFS suggested a hint of benefit for VEGR, I said: curative setting. I know that immunotherapy doesn’t work for EGFR patients in the Stage IV second-line setting very well, but maybe this is 1 chance with radiation on-board that it might work better. I’ve gone the other way, kind of as the data have emerged and the survival benefit hasn’t really been shown. And the increasing realization that if I have to put a patient on osimertinib, and they’ve just had immunotherapy, I’m putting them at risk of pneumonitis.

So I really have leaned against EGFR and ALK in favor of either surveillance or trying to finagle a 3-year adjuvant — kind of quasi-adjuvant or a consolidative course of TKI.

So I think in those patient populations, I’m avoiding the durvalumab.

For patients more in the RET, the MET exon 14, the KRAS space, I think those data, first of all, are more sparse. And these are patients, even phenotypically are the patients I think are more likely to benefit. So those have not led me to advise against the use of the consolidative durvalumab. But, again, this is really an area we need to learn more about over time. But MET exon 14 patients often have a tobacco history. These are patients where, absent data, and we haven’t really seen data in that unresectable setting, they don’t get benefit, I’m going to give that patient a year of durvalumab.

But I think we all acknowledge as groundbreaking as PACIFIC was to change the paradigm and real standard of care, I think we all acknowledge those survival curves still fall off. We cure a subset. We cure more than we did before. But there’s still a long way to go. So is there a chance in that post-radiation period, so many neoantigens floating about, I really think it’s a ripe area, and I appreciate the COAST Phase IIs, now PACIFIC X studies that are really taking the Phase III approach and trying to prove that enhancing the immunotherapy effect might be beneficial here, and especially in a curative setting. So I really respect that kind of clinical development.

There’s a kind of tweaking around the edges. Do we add the immunotherapy during radiation? Which is being asked by other companies. I’m open to that idea. I’ll be curious to see how those data pan out. Do we use it even earlier in the course? I think these are some more subtle questions to be sussed out as well. But I think it’s an important area to be looking at these novel combinations but also to learn more about how the genomic alterations may play into this situation.

DR LOVE: What about other alterations in terms of whether you go with the durvalumab, for example RET?

DR GUBENS: RET, I tend to give the durvalumab. I think EGFR and ALK, we have enough of the Stage IV data that suggests single-agent activity isn’t that good. The preliminary data from PACIFIC, not that good. But for the other alterations which really weren’t measured or there were no patients on PACIFIC, I’m still going to give the benefit of the doubt in the curative setting.

As much as we’ve gotten nervous about osimertinib with immunotherapy, that’s not true across all the TKIs, right? Our colleagues in GU give their TKIs with immunotherapy all the time. So I’m less worried about that safety implication that I have to worry about for EGFR patients in particular.

DR LOVE: Although, their TKIs are usually VEGF. I don’t know if that makes a difference or not.

DR GUBENS: Fair enough. That’s fair. It may well be an osimertinib-specific issue too. So I’m not as shy about it, I’d say. But I think it’s also important as we do more genomics, again how did those patients do in the neoadjuvant setting? Again, there’s neo-ADAURA. We’re going to give those patients osimertinib. But for the METs, for the RETs, for some of the KRAS patients who have STK co-alterations, are we going to see differential benefit from the neoadjuvant immunotherapy combinations? These are really going to be data that these great Phase III trials need to show us the subgroups and help us understand better.

DR LOVE: Well, also the idea of neoadjuvant targeted therapy. I know there was a trial where they were going to give neoadjuvant targeted therapy, I think it was mainly EGFR and ALK, to people with local-advanced disease before they got chemoradiation to decrease the tumor bulk. And that trial sort of happened. But it always seemed like kind of a cool idea.

You mentioned that you would consider a TKI rather than durvalumab. So, for example, osimertinib? What about ALK?

DR GUBENS: I haven’t been lucky as yet. That hasn’t come up that often in my practice. But the couple of times, one time the patient opted for surveillance anyway. One patient we tried for adjuvant — excuse me, consolidative ALK inhibitor and we got turned down by insurance and we just decided to ride it out. That patient’s actually 3 years out on surveillance. So maybe in the end he was cured by the initial chemoradiation. So, whew!

The LAURA data will come out soon. LAURA, of course, being the consolidative osimertinib after chemoradiation. But that one I don’t feel back asking insurance for. Again, when you think about it logically, we give 3 years of adjuvant osimertinib, Stage I through IIIA resectable. I give infinite osimertinib to Stage IV, or even Stage IIIC that’s not radiate-able and beyond. Why would I avoid that little sliver in the middle? They’re at very high risk of recurrence. So I’m willing to offer it if I can get my hands on it. But I’ll look forward to LAURA to flesh that out.

But kind of the same idea, I posed this at one of our conferences, with the robustness of the adjuvant osimertinib data, we know that, for example, alectinib is a better ALK-TKI than osimertinib is an EGFR-TKI, why wouldn’t you make that logical jump? It’s a devil’s advocate question. But hopefully the data emerge soon that let us do that with some data behind us. But I think as these come fast and furious, these drugs come out that are better, later generation, better CNS penetration, better tolerability, are we going to hold ourselves to the same standard of every 5- to 8-year trial to actually get it to patients. And I wrestle with that, obviously from a policy point of view, too.

DR LOVE: That was actually my next question. I’ve been asking you and a lot of other people that for a long time. I actually spoke with Tom Lynch when the ADAURA data first came out, he was — you’ve been asking this for — since 2005.

DR GUBENS: You have been!

DR LOVE: But anyhow, I was just kind of curious, because now you’ve got the survival data — I mean I wonder if there were people who thought maybe survival data wasn’t even going to be there, let alone hazard rate close to .5, which is really interesting, let’s just say. And I would imagine that would make people think even more about the idea of are we going to wait 7 years for everything else to catch up. I was kind of surprised by that hazard rate. What did you think?

DR GUBENS: I was also surprised and gratified. Again, there was a lot of debate in our world about what patients saw on progression. And that is a fair criticism to level. We don’t want to let a sponsor, if you will, get away with getting patients inferior treatment at progression. But it’s just the nature of the field advanced in the course of the conduction of this trial. So there’s a there even – if maybe everyone was 100% cross over to osimertinib, it was still going to be a robust hazard ratio, one would think.

So yeah, I was very pleased about that. And again, you’ve been asking Tom Lynch for over a decade. He was also playing with the earlier goals. These were earlier generation drugs and more toxic, not CNS active. I think when we only had the PFS data for ADAURA, not yet the OS data, we were grappling with, well, do we want to give it if you’re not curing, all I had to do was show a patient the CNS curves, and to even delay CNS progression or prevent it!

DR LOVE: Absolutely!

DR GUBENS: They’re sold! And I was sold, to be honest. That, I think, clinched it for me. And when you talk to patient advocates, that really is important to them. And, again, as you point out, Dr Love, the ALK inhibitor is better in the brain, has a better PFS and arguably might even be a little bit less tolerable – or more tolerable in some folks.

So, again, I’m not pretending we should be doing things absent data, but are there ways to kind of accelerate the development and get patients enrolled, or have really nice, robust, board trials to get them access to these drugs? I would want an ALK-TKI after resection. But I know in California I’m not going to be able to get that from my insurer. And that’s fair. But what’s the middle path?

First-line therapy for patients with metastatic NSCLC with and without targetable mutations

DR LOVE: So I want to pick up on a few things that you got into in your talk and just expand a little bit. One thing, in terms of first-line therapy for metastatic disease in patients without targetable mutations, because we were talking about the trial looking at performance status-2 patients, for example, with durvalumab, et cetera. And I’m just kind of curious where you are in terms of PD-0 patients nowadays?

I hear more and more people talking about anti-CTLA4 and PD-1 in that situation. Is that something you’re thinking about more?

DR GUBENS: I have been thinking about that more. The data have been interesting. And now have been replicated. So we’ve seen them both in the nivo/ipi trials, but also the durva/treme, this pattern where the nonexpressors seem to have a robust benefit. So I have been increasingly tempted to either do just double immunotherapy or double immunotherapy with a couple of cycles of chemo, or some kind of abbreviated course.

And again, it’s more anecdotal in my case, but for the right patient that feels like a good approach — especially if we can get a good, robust benefit. But also it helps us conserve a next line of therapy too. If we get a robust response with nivo/ipi, I still have a platinum/pemetrexed in my back pocket. So there’s always been some intuitive appeal. Now that the data are maturing and showing us some benefit there, I have been using that from time to time.

More recently of course, with the cisplatin/carboplatin national debacle, it’s been kind of interesting to say, well, here’s a really provocative reason to use nivolumab/ipilimumab even in the patients — in the providers who hadn’t been using it as frequently before. So there’s a there. And I think it’s important to keep in the toolbox.

DR LOVE: How do you decide between ipi/nivo and durva/treme? We just had a webinar last week on HCC, durva/treme, there’s all hot between that and atezo/bev. Of course, I think a lot of people have more experience with ipi/nivo. How do you decide which one you’re going to use if you’re going to do it?

DR GUBENS: Like with many things, until and unless there’s much stronger data for a follow-up regimen, we often kind of get stuck, because the builds in our computer system, in our nurses’ facility with teaching, and our own comfort level tends to rest with the first agent. I have no compunction about the durva/treme approaches, though we literally haven’t built the Epic build for it at our center. There’s been no kind of pressure from insurance just to change it.

But it’s good to have some other players in the field too. But generally our approach has been to use nivo/ipi or nivo/ipi with chemo.

Nivo/ipi with chemo is what I would tend to give someone who has big burden of disease. I think I have 1 shot at goal. I’m going to give them the kitchen sink, if they can take it. I can pull the chemo back off. I can use it again in the future. But that’s also where I’ve used it aside from the PD-L1 0% patients.

What will also be an interesting, crowded field is as these Phase IIIs of ADCs, like the TROPION studies, come to fruition, assuming they’re positive – I don’t want to make that assumption, but let’s say they’re positive, how are we going to choose from those options? Chemo/IO versus ADC/IO versus chemo-platinum plus IO. And I think that’s where we’re going to have to delve into the unique toxicities.

Again, I think of these ADCs as — they’re not targeted the way an amivantamab bispecific, or even the way trastuzumab deruxtecan. I know when it hits a HER2 mutation I know how it works. TROPION is not biomarker-specific, right? So it really is just maybe a more elegant, or a different way of delivering chemo. How are we going to choose from among these? And I think, again, the toxicity profiles will matter. The shape of the curves will matter. And that’s where I appreciate some of those TROPION trials do include kind of standard chemo/IO, IO with the ADC and then chemo/IO with the ADC. So we’ll kind of see some splay in those curves and the toxicity profiles. But I think the field’s about to get pretty crowded when you look at these ADCs come to the first line.

Current and potential roles of antibody-drug conjugates in the treatment of NSCLC

DR LOVE: That actually was the last thing I was going to ask you about was ADCs starting out with Dato-DXd. So, the first-line trial that you talked about in the presentation that you were just alluding to was really fascinating. Like you say, god knows we’re going to deal with that one since it reported with all these arms. But I’m just curious what do you see in the immediate future? I know there’s a second-line trial that I guess is going to be presented very soon.

In any event, I guess a lot of people are thinking that Dato-DXd might be second-line therapy in the near future. Any thoughts about how that’s going to play out, particularly in terms of tolerability? I would think it’s going to be better tolerated than docetaxel. But you tell me.

DR GUBENS: Again, differently tolerated. I think that’s where we have to see what mucositis looks like. As lung cancer doctors, we’ve kind of been spared some of the bad mucositis that our colleagues deal with in other tumor types. Ocular stuff always gives us a little pause. I can manage dry eye with maybe some educational materials, but if you get anything deeper than that — and we actually struggle with ophthalmology availability at our institution. I could imagine that if I have choices and that winds up being a high percentage thing, it might slow down our excitement about it. But again, I’m open-minded to see how the data play out. But I know that’s some of the anticipatory stuff with, not just that ADC, but the other ADCs coming down the pike as well.

DR LOVE: Absolutely. We actually did a program, I guess an onco-ophthalmologist recently on ophthalmic issues in oncology.

DR GUBENS: New specialty.

DR LOVE: There’s so many ADCs and other things, not just ADCs — erdafitinib that caused ophthalmic issues — now oncologists have to deal with that.

So final question about an ADC, T-DXd. Of course, we talk about it a lot, not just breast cancer, GI cancers, biliary tract cancers. Can you talk a little bit about right now what your take is on it in non-small cell?

DR GUBENS: Yeah. This has been an important, newer emerging genotype, right, the HER2 exon 20 mutation. And I really had some great success in the second-line. And we have the first-line trial open, but I think that there’s been enough enthusiasm, I’ve seen a lot of my colleagues just reach for it first-line if they can get it.

I think a couple of things that we’ve learned over the course of using this drug is, you know the very first New England Journal paper was at a dose of 6.5 mg/kg. And we kind of realized that in our lung population, that’s going to really increase the risk of pneumonitis. Which I think our breast cancer colleagues are aware of and handle but I think they’re heightened for us. And so we kind of settled at the 5.4 approved dose. Kind of proactively looking for pneumonitis, even as we do our q3-month echocardiography. But this is a drug that’s really been fun to see develop and be very effective.

I’ll be curious to see what the first-line data show. As you know, very often when we use our targeted therapies up-front we get a much more robust first-line duration of benefit. But I think again, as we get more facile with the ADCs, I’ve learned that I have to tell patients, I’m excited about how this targets your mutation but there’s still chemo in that linker. And so we’re looking out for — we’re looking for stomatitis. We’re looking for neutropenia. I think actually more than half of my patients on trastuzumab deruxtecan do have to get growth factor to stay on their dosing. So these are good drugs but again, come with a suite of toxicities that we have to get more used to.

And I think the other space in lung cancer we’re looking forward to understand, not just the HER2-mutated patients, but there’s a whole set of patients who have HER2-amplification. And Bob Lee has done a lot to kind of figure out that difference. And is it this generation of HER2-targeted therapies, or the next TKIs or other designed ADCs that’ll be more effective against those HER2-amplified or overexpressed patients. Kind of the way that the breast cancer world is seeing a broader swath of patients become eligible over time. We’re not quite there yet.

DR LOVE: Yeah, and that also brings up the issue that first came out with breast cancer. I’m starting to see it in others, which is so-called HER2-low. So 1 or 2+ without FISH amplification where they see really good responses. I’m assuming they’re going to look at that in lung, in GI cancers, in everything else. But I haven’t seen anything on that yet, at least in lung cancer. Have you?

DR GUBENS: No. I think they really just looked at the really highly overexpressed patients. I think these agents aren’t going to be effective against more of the low HER2, but again, maybe future agents or combinations might be a way to exploit that.

Emerging biomarkers in small cell lung cancer research 

DR LOVE: So one other thing I was curious about, particularly as it relates to small cell and new research, is the role of SLFN11 and other emerging biomarkers.

DR GUBENS: Yeah, to be honest this is all really early work. I think there’s been a lot of news lately, especially out of MD Anderson and MSK, looking at subtypes of small cell lung cancer driven by the genomics. And I think what’s interesting is 1 of these 4 subtypes is the subtype of small cell lung cancer that tends to have the most robust benefit to immunotherapy.

Now, it’s not strong enough to not give immunotherapy to the other 3 subtypes, but again, we need to get to the bottom, get to the biology of why these small cell variants respond differently, and if we have to use different strategies: PARP inhibitors in some maybe, and SLFN11 is 1 of these biomarkers of the subtype that may benefit more.

But I think we’ve always — even as we’ve added immunotherapy to the initial chemotherapy, even there the response rates and the duration of benefit, the tails on the curve, haven’t been as robust as you might expect for such a hypermutated tumor, right? So I think that this work to try to get the preclinical side of things understood to eventually lead to more precision-based approaches is important. But very, very nascent.

DR LOVE: It’s really amazing. Like you said, you would expect, based on what we think about it, that they would respond so well, and yet it kind of doesn’t really seem to be the case.

You also mentioned this other study that I thought was really interesting, putting in radiation therapy to select sites in addition to chemoimmunotherapy, chemo/durvalumab. What’s the thinking behind that? Is it just reducing the bulk of tumor? Or the thought that maybe it’s going to put out some type of abscopal effect?

DR GUBENS: Well, I think part of it, especially in small cell, it’s so important to get local control. These are patients who progressed and progressed badly. So already that’s some benefit. And that’s where the old Slotman data, I still do that even with the chemoimmunotherapy. I do work in consolidated radiation after the first 4 cycles as I’m starting maintenance. But I think the question of that more targeted SBRT, doing it early, it does beg that question, can we get a more systemic abscopal effect? I know the running joke is you see more papers published on abscopal effect than patients who we are clear benefit from it. But we’re hoping there’s a there. And I think earlier controlled disease can’t help to be better. And maybe if there is that kind of abscopal effect, maybe it’s better to be doing it early in the course of the chemoimmunotherapy too.

DR LOVE: I feel like we haven’t talked that much lately about small cell since the initial 2 first-line Phase III trials came out. From your perspective, are you still approaching first-line therapy the same way you did a couple of years ago? Have we learned anything more? It’s always been like kind of a coin-flip about which IO you use. Are we still in that basic boat, or anything different?

DR GUBENS: Really nothing’s emerged to change our practice as yet. There is this Cooperative Group trial that’s asking this consolidative radiation question. So that will be important. But I think an important question to answer as something some of us are doing just kind of on principle anyway.

I think we’re still left with these same data sets. And beyond progression on these initial chemoimmunotherapy approaches, still we have lurbinectedin, great to have something on the table. It’s, again, a modest duration of response. And then we’re reaching for taxanes and the not so beloved topotecan. So, still crying out for options.

I think the most exciting data that we’re seeing emerge is the DLL3 story. Remember a few years ago we were seeing the first of these agents look very exciting, but really, unfortunately, fell by the wayside because of undue toxicity. But now as they incorporate DLL3 as 1 of the targets of constructed BiTE therapy, these are looking (a) more tolerable, but (b) potentially with really robust response rates and durations activity. DLL3 is a great target. I think we just weren’t mature enough in our design of ADCs back in the day to hit it with the right leverage.

So I’m really looking forward to some of the data in these kind of — and we saw some of the DLL3 data in Phase I presented at ASCO this year. So hoping to see those mature. And I think that’s really, aside from the subtypes of some small cell lung cancer and kind of splitting in a lumping fashion, if we have DLL3 positivity, I think this is a great opportunity for a specific marker.

DR LOVE: But again, this is a bispecific or ADC?

DR GUBENS: It’s a BiTE, actually.

DR LOVE: A BiTE.

DR GUBENS: The last 1 had been an ADC. But this is a BiTE, yeah. But other companies are looking at other DLL3 constructs. But the one that reported out this year was a BiTE.