Part 4: Antibody-Drug Conjugates (ADCs): Overview and Treatment Sequence

After sharing their basic approaches to treating actionable mutations, our 4 panelists now share their perspectives on the place of ADCs in advanced/metastatic NSCLC and on the future prospects of ADCs as a component of combination regimens and/or as a frontline therapy.

This roundtable discussion is sponsored by Daiichi-Sankyo.

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Read the full Transcript:

Corey Langer, MD:

Aaron, I'm going to let you lead off on ADCs, because I have to confess, I'm not an expert on this.

Aaron Lisberg, MD:

So antibody drug conjugates are an emerging class of therapy in lung cancer. We don't have any current approvals, but there certainly are a number of agents that are very exciting with the early clinical data. And I think that looking forward a couple years, I could definitely see these agents coming into our clinical practice. So to kind of begin the discussion, I think it's important to understand exactly what an antibody drug conjugate is.

Aaron Lisberg, MD:

Most of them include a payload, which is delivered directly to the cancer cell. But the payload itself is oftentimes a chemotherapy that was administered several decades ago and was so toxic systemically that it was put on a shelf. But with a development of this new approach to administering the drug  in more of a targeted therapy approach, they are now actually tolerable. So when you think about an antibody drug conjugate, there's really three components that you need to consider. Each drug is designed a little differently and has different aspects. So, as the name would suggest, the antibody is essentially the first component to consider that is designed against a specific target

Aaron Lisberg, MD:

And the idea being that this antibody will bind to the specific target on the tumor cell surface. A number of targets that are being explored in lung cancer include CEACAM5, TROP2, HER2, as we talked about before, HER3, and there are a number of additional targets, and each of those antibodies is a little different. And the next component that you have to consider with an antibody drug conjugate is the conjugate. So we go to the end of the ADC acronym, and that's really called a linker, the idea being, as we'll talk about the mechanism action, that the antibody must be bound to the drug itself.

Aaron Lisberg, MD:

And so when the drug is administered through the IV and the vein of the patient, it doesn't become active immediately, because that would just leave us where the systemic chemotherapy left us with these agents, which essentially was too toxic. Rather, the antibody stays linked to the drug until target engagement. And then the last component that's important to understand is the drug. And essentially, another way of talking about that in terms of ADCs is the payload. And many of these have conventional chemotherapy approaches like topo isomerase 1 inhibition and such things. So that's kind of like the makeup of the ADC, and there are a number of steps that are needed to occur to allow effective therapeutic treatments. So taking kind of through the ADC journey, when it's injected into the vein, it goes in systemic circulation.

Aaron Lisberg, MD:

And then the antibody - again, we're talking about the best-case scenario - the antibody appropriately identifies the target on the tumor cell. It engages the target on the tumor cell surface. It is then internalized; the antibody drug cell conjugate as a whole is internalized into a lysosome and brought into the cell because of the enzymatic processes that occur in the lysosome that results in breakage of the antibody from the drug and essentially allows the drug to now be active since it's no longer linked to the antibody. That leads to cell killing of the tumor cell. And then there's other properties that are important in terms of permeability of that drug. Some payloads are permeable and allowed to essentially diffuse through the tumor cell membrane to adjacent cells.

Aaron Lisberg, MD:

This can be very effective. For instance, you can imagine a heterogeneous tumor cell population in which the target is only expressed on a subset of tumor cells. If that payload can go across the cell membrane, it can also kill tumor cells that are adjacent that maybe don't express the target, but still obviously would be of benefit to kill the neighboring cells. There are also potential negatives to that fact, and the permeability of the drug through the tumor cell membrane by way of potential toxicity that can occur. So that's kind of the makeup of these antibody drug conjugates themselves and the journey by which they lead to their effects. I guess I'd be interested in getting everyone's thought at this point in terms of how they're thinking of this class of therapies in non-small cell lung cancer.

Lyudmila Bazhenova, MD:

I think it's a great discovery, and I think we are now much better with ADCs that we have in development compared to the ADCs we've had, let's say, 5, 7 years ago. ADCs are not new to us. And I think what we learned, we learned about how to create the antibodies that are not immunogenisic. So the body does not, develop an allergic reaction to that. We also learned how to select the antigen better, right? Because we want to select the antigen that is expressed on tumor cells and not expressed on the normal cells, because if it does, then you're going to have more toxicity. And I think we learned, as you already mentioned, we are much better with our linkers because we want to have a linker that only releases the chemotherapy - not while it's circulating, but only when it gets into the tumor. And there is some science to that as well. And then a couple of other things like drug-to-antibody ratio, right? So do you need one molecule? Do you need two? You need 8, we don't know that yet. And I think based on our, let's say, prior experience with DL3 antibody, in a payload necessity that we have with that antibody, I think we got smarter in choosing our payload. I think they are going to be what we are going to be using in our patients going forward.

Corey Langer, MD:

I think that has influenced some of my, shall I call it skepticism? The Rova-T initiative rovalpituzumab tesirine initially looked quite promising in small-cell, identified the target was an antigen that was relatively unique to small-cell, but the toxicity was horrendous. And every time more patients were accrued to the study, the response rates kept decaying, they kept going down. So I understand, and I believe that certainly the newer ADCs I think will conquer some of the toxicity that we've witnessed in the past. But I worry that perhaps we're starting to use them, or many of the studies are using them indiscriminately without necessarily having biomarker enrichment. And the toxicity still looks very similar to chemotherapy.

Corey Langer, MD:

The notion of potentially combining them with other active agents and earlier lines of therapy, I think that's going to be a formidable challenge. The incremental, or perhaps synergistic, toxicities that we observe may be very difficult to manage.

Misako Nagasaka, MD:

Sure. So Lyudmila and I have experience with trastuzumab deruxtecan  or T-DXd in the clinical study setting and I also have experience using trastuzumab deruxtecan, but that’s a TROP2 ADC in non-small cell lung cancer. And I completely agree with Corey, it is basically chemo, it’s just chemo given in a better way. So you really have to be careful about chemo-related toxicities. As a physician, I would like to see a biomarker that’s predictive of response, and maybe this isn’t a biomarker, but maybe something like patient characteristics to tell me that, hey, this is the patient that you’re at a higher risk for developing ILD on T-DXd. So you maybe, probably, shouldn’t use that kind of thing. So, I think there's much more to be studied just in the single-agent setting and I agree with Corey, we have to be really careful about combining these agents, because although they are, in a way, targeted, it is chemotherapy and it has additional toxicities.

Corey Langer, MD:

Aaron, convince us why this is going to be the next wave of the future.

Aaron Lisberg, MD:

Well, ultimately, data does the talking, right? So we'll see what the data shows, that's the answer. That will tell us. But in terms of placement, in terms of treatment algorithm, as with any agent, these are initially being explored in the relapse refractory setting. And I think that's very appropriate. And a lot of the randomized trials at this point are randomized against our current standard of care in patients without actionable genomic alterations after chemo and immunotherapy, docetaxel. And I think we can all agree that docetaxel is not a drug that we enjoy giving for the same reasons that the panel has identified. We like to do more good than harm whenever possible.

Aaron Lisberg, MD:

And that often times turns out not to be the case when we go to docetaxel. So we don't have a lot of options where these drugs are initially being explored. And my bias is that the data has looked better, that there is less bone marrow suppression with a lot of these drugs, that the tolerability has been better. We've had a lot of experience with the Dato-DXd, which is the Trop2 ADC from Daiichi. And we have a number of patients that have really had their lives changed and have been on the therapy for years. And I can tell you, seeing them every week, they're doing very well, and they look very different than a patient that I have given docetaxel to, so there are differences there, but I share the concerns of the panel about moving these agents into the frontline setting.

Corey Langer, MD:

Is it your impression that these drugs are going to probably combine better with immunotherapy than chemo?

Aaron Lisberg, MD:

Well, I don't have the answer. And so, for instance, there's the TLO 08 study right now looking at the Dato-DXd in combination of pembrolizumab versus pembro alone in patients with high PDL1 status, and then there's a forthcoming study evaluating all the potentials combining only with immunotherapy or potentially subbing this drug in for some of the chemotherapy components.

Aaron Lisberg, MD:

Another thing that's been discussed that I'd like to touch on is the biomarker-driven nature of this. It'd be wonderful to have a strong biomarker to select, and certainly with the HER2-targeted ADCs, we have that. And with patritumab, which is the HER3-directed ADC, in some ways we’re selecting, at least in terms of development right now, it’s for the EGFR population. But interestingly, in the HER3 data, as well as the TROP2 ADC data, the pretest hypothesis would be that the expression of the target would be the biomarker that the higher expression of HER3, or the higher expression of TROP2, would correlate with response.

Aaron Lisberg, MD:

And if you look at a-scores from presentations a couple years ago at ASCO, you'll see that there's no clear correlation between the target and efficacy of either drug, which is very interesting and obviously head-scratching. I think that there is a dearth of understanding at this point, so identifying potential other biomarkers, and any time we can enrich for patients, more likely to benefit and less likely to have harm, I think is very important, but it's going to take time and more experience with these drugs.