Experts Discuss the Latest Studies on ADCs for Lung Cancer at ASCO 2024

In a comprehensive discussion on the role of antibody-drug conjugates (ADCs) in the treatment of lung cancer at the American Society of Clinical Oncology (ASCO) annual meeting, a number of significant advancements were highlighted, including TROP2-targeting therapies.

MedPage Today brought together three expert leaders in the field for a roundtable discussion: Moderator Roy Herbst, MD, PhD, is joined by Anne Chiang, MD, PhD, and Sarah Goldberg, MD, MPH, all of Yale Cancer Center in New Haven, Connecticut. This final of four exclusive episodes delves into the latest developments in ADCs — including their potential to revolutionize chemotherapy for small cell lung cancer and their role in non-small cell lung cancer — and the future of lung cancer research.

Click here to watch the other videos from this ASCO roundtable series.

Following is a transcript of their remarks:

Herbst: OK. One last topic. Know your ADCs. OK, so what do you think, ADCs at this meeting? TROP2 comes right to mind.

Chiang: TROP2, exciting. I’m going to talk about ADCs in small cell because that’s I think going to be the future of chemo for small cell. It’s not going to be [topotecan]-irinotecan, it’s going to be chemo in the form of ADCs delivered. And we have several different targets, SEZ6 ADC that was presented at ASCO looks very promising. I-DXd [ifinatamab deruxtecan], which is directed towards B7-H3, small cohort, about 20 patients, but overall response rate about 52% and the duration of response around 5 1/2 months.

So I think that I would definitely look at this space. I think the other part of it is that we’re moving up ADCs, combining them with immunotherapy and perhaps we can replace etoposide. Maybe we can even think about getting rid of that platinum doublet in the first line. Wouldn’t that be exciting?

Herbst: Assuming it works. And I always worry that with some of these ADCs we’re using, it’s a way to deliver chemo, but it’s chemos that might not be that active traditionally in lung cancer. So maybe the reason for some of the variability we’re seeing. But Sarah, in the non-small space, there are plenty of these too, right?

Goldberg: Yes. So we saw a couple of important studies at ASCO this year and you mentioned TROP2. I think that’s really where we’re starting to see some, I think really important data emerge in some of the phase III studies.

So one of the studies that was presented was sacituzumab govitecan [Trodelvy] versus docetaxel in the second-line setting. That was a negative study. So that didn’t show — there were maybe some trends — but it didn’t show an overall survival benefit compared to docetaxel, which is really disappointing.

We did see data now a couple months ago for Dato-DXd [datopotamab deruxtecan], looking at that versus docetaxel. And overall that also didn’t seem to improve survival, although in the subset of patients with non-squamous, non-small cell lung cancer, there was a benefit. So I think we’re definitely seeing signals that there’s activity. I think we know that in some patients there’s great response and some durability, but I don’t know that we’ve figured out exactly how to use it yet.

Which of the subsets are most likely to benefit? Is it the non-[squamous] versus the [squamous]? I didn’t mention, but in the sacituzumab trial, the one subset that looked like maybe they did seem to benefit were those who didn’t do well with immune therapy. So maybe those are the patients. I think we’re still searching. And then there’s combinations. So do we combine that with immune therapy? Is it with a platinum in the first line?

There’s a lot going on right now, so we’re starting to see some of the second-line data. We’re starting to see some new targets, some new payloads, and trying to figure out how to optimize this for lung cancer, and then combination. So there’s definitely a signal. I hope this becomes part of our standard practice, but I don’t think we’re quite there yet.

Herbst: No, I agree.

Chiang: There’s some toxicities too.

Goldberg: Yes.

Herbst: Toxicities, lack of really compelling efficacy — to be continued. I think moving them up and maybe if they’re truly more effective, less toxic, but otherwise we already have chemo-IO [immunotherapy] regimens that are pretty good. It’d be hard to beat. But more on that.

Goldberg: There’s lots of trials that are ongoing like that. Looking at it in the first line.

Herbst: And I’m impressed there’s so much now on the biology, the linker, the pharmacology. We have to think about pharmacology for all these drugs.

Goldberg: The other thing that we started to see a little bit this year at ASCO, but we need to see much more of, is biomarkers. So looking at the TROP2 level and a lot of different…

Herbst: Well, we saw some abstracts on that, looking at patients with poor biomarkers, meaning broader disease burden. I guess the drugs seem to work as well there as the amivantamab [Rybrevant]-lazertinib [Leclaza], things like that. But exciting that we have all these things coming down the pike.

OK. So we’re pretty much at the end of the time, but I’d like to just do one final question to each of you, and I’ll answer myself. Five years from now, we’re sitting here in Chicago, what will be in lung cancer, your prediction to be the highlight of the ASCO lung program? Where are we going, Anne?

Chiang: Well, I’m going to talk about small cell. We’ve got a big trial coming out with SWOG. We’re going to have 900 patients. We’re going to get their tissue during induction and subtype it, look at biomarkers, and based on which biomarker we’re going to give them that biomarker-directed therapy plus IO versus IO. So I think being able to really understand the heterogeneity of small cell and target the selective vulnerabilities, I think we’re going to make a lot of progress in that.

Herbst: I love it. So personalizing things.

Chiang: It’s called PRISM.

Herbst: OK. PRISM it is. We’ll wait to hear more. Sarah?

Goldberg: There’s so many directions this could go, but maybe one thing I’ll mention that we haven’t really talked about is resectable early-stage disease. The last couple of years, really, we’ve seen very, very exciting data where we’re seeing prolonged relapse-free survival in patients with resectable lung cancer when you add immune therapy, particularly in the neoadjuvant or perioperative space. But we still don’t know the right patients to select for that. When do you give it neoadjuvant? When do you give it perioperative? When do you not need it at all? How long do you need it for? So there’s so much more there.

And so I think in the next few years we’re going to start to see who really is having this long-term survival, who are we curing, and then how can we optimize it? I don’t know if it’s going to be looking at ctDNA [circulating tumor DNA], MRD [minimal residual disease], AI [artificial intelligence]. I mean there’s so many different ways we could think about selecting the right patients and the right strategy, but I think that that’s going to be a really big area that we’re starting to see so much already and I hope we’ll be able to refine it better in the future.

Herbst: Great. And for me, there’s so much, but I do think refinements are going to occur, but I think we’re going to personalize our therapy. One, we have to personalize the modality of therapy, chemoradiation versus neoadjuvant therapy versus adjuvant therapy. Those are all decisions that will be made in the tumor board. It’s important that patients go to a tumor board, they be seen early by a multimodality team. They also have their tissue profiled, and all that’s occurring as we speak.

And then I think we’re going to use those information, and we’re going to say this patient has a tumor that’s being driven by this type of carburetor, so we’re going to treat it with this drug, and this other tumor is driven by the other pistons, and we’re going to treat there and target the pistons. This is something we need to figure out, what’s driving these different tumors. But science to medicine, and then of course, access for all. And something we didn’t talk much about, but looking at some of these trials, they didn’t always get to the broadest swaths of the population. So we have to think about diversity in our trials. Innovation, diversity, completion. It’s what we do. It’s why we’re here at ASCO. And we’ll all be back in our Yale clinics probably on Wednesday, seeing those patients.

And I really appreciate, Anne and Sarah, you taking the time to join me on this panel.

Goldberg: Absolutely.

Chiang: Thank you, it’s great.

Herbst: I hope you have a good rest of ASCO and we’ll see you back at home.

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