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口袋女优 brought together three expert leaders for a virtual roundtable discussion on lung cancer: Moderator , was joined by , and , all from the Yale Cancer Center in New Haven, Connecticut.

This final of four exclusive episodes looks at the exciting ongoing development of antibody-drug conjugates (ADCs) in non-small cell lung cancer (NSCLC). You can see other videos in this series here.

The following is a transcript of their remarks:

Herbst: Okay, final topic, ADCs. Who would've thought we're delivering chemotherapy now as a warhead with an antibody and a linker. There's so many of these, hardly a day goes by I don't hear about a new one. A lot of them -- but I guess the one at the top of the list, we'll talk about a few -- but , I hear about Trop-2 [trophoblast cell surface antigen 2]. What is Trop-2, Dr. Kim?

Kim: Yes. So Trop-2, it's a protein that's expressed on lung cancer and it's expressed both in the adenocarcinomas and squamous cell cancers as well. It's being looked at as a potential target in drugs called ADCs. So the ADC would be targeting Trop-2 and would be releasing its cytotoxics in that tumor vicinity.

Herbst: Okay. And, Anne, have you worked with any of the Trop-2s in clinical trials? We've gotten them in our lung group through the gynecologic cancer group, but there are two or three of these Trop-2s now and there's a that's about to report. What's your thoughts?

Chiang: So at the world lung congress [World Conference on Lung Cancer; WCLC] that just happened, there was a really exciting Trop-2 antibody, sacituzumab govitecan reported for small-cell [SCLC] patients. And Trop-2 is on about 80% of small-cell tumors. This trial, which we had several patients on, actually ultimately reported an overall response rate of almost 40% in these pretreated patients. So I had patients who were on it for months, 6 to 8 months, doing really well. And that, for that patient population, is pretty amazing.

Sacituzumab govitecan has done well in the breast cancer arena. It certainly is an option there and I think we're learning how to use it and other tumor types including non-small cell. I think there was an interesting that looked at the Trop-2 ADC with IO [immunotherapy] and saw some benefit, and I think we're just looking at overall at the TROPION. There is definitely activity in non-small cell settings, so stay tuned. I tell my patients, they're [ADCs] like targeted missiles because the antibody recognizes the tumor cell, and then it's tethered to the chemotherapy molecule, that's then released as the drug is endocytosed. And sometimes you can have a bystander effect. We still have to learn about the potency of antibody-to-drug ratio and [we're] still learning how to use these drugs. But I think they could be very effective, especially for those tumor types where you don't have great penetration into the tumor.

And again, I'll go back to small cell. Small cell does not have a lot of tumor infiltrating lymphocytes and so we haven't seen the benefit necessarily of IO in the same way as we have for non-small cell, and so something that targets the drug-chemotherapy directly to the tumor microenvironment I think can be very helpful.

Herbst: Thanks, Anne. Extra-credit question gang, what does Trop-2 stand for? Anyone know?

Chiang: Trophoblastic growth factor? I don't know...

Herbst: I know, because I looked it up. I wouldn't have asked you the question if I didn't know. Trophoblast cell-surface antigen 2. So I just bring that up as a segue because these are targets. So this is a target. Why are we not measuring a Trop-2 level when we use the drug? Why is it being used in all patients, So Yeon?

Kim: Yes, I think it speaks to the difficulties of trying to find great biomarker assays. PDL-1 is one biomarker assay, but of course, it's not perfect even though it's predictive of immunotherapy. But if we look at even the earlier lung cancer immunotherapy trials, it's really just that one-third of patients who have a very good response to immunotherapy in general with PDL-1 positivity. So looking for better biomarkers to measure Trop-2 expression, that certainly attacks that, we should also be working towards. There's ways that I think we could improve biomarker as the analysis instead of measuring with IHC [immunohistochemistry]. We could think about quantitative ways using flow or mass spec [spectrometry] that could possibly better predict patients who may do better with Trop-2 ADCs.

Herbst: Excellent. Okay, let's have a little lightning round here. I'm going to go through a target; you tell me what's in play, what's hot, what's not. HER3, tell us about HER3 ADCs.

Chiang: I think there's a that came out recently at the world lung [WCLC] that's with the, I can't ever say it, patritumab deruxtecan, and I think that's really super exciting. That's for EGFR-mutated patients after they've progressed on other EGFR TKIs [tyrosine kinase inhibitors] and platinum therapy and there definitely is some activity there. So stay tuned for that.

Herbst: So Yeon, HER2 ADCs, there's a drug called Enhertu [trastuzumab deruxtecan] in HER2, I'm not sure if I'm allowed to say this in this program, but it has other names. Tell us about HER2 ADCs and there are a couple of them out there. And then toxicity concerns for those, of course.

Kim: Yeah. So one of the HER2 ADCs that's demonstrated a benefit in HER2-mutant NSCLC was trastuzumab deruxtecan. And interestingly, what was most interesting I think, was that there was actually a benefit regardless of, really, expression. Which speaks to possibly HER2 expression, not really behaving the same way that HER2 expression is observed in other pathologies and tumors such as breast cancers where the amplification really equates to expression. So I think there's definitely much more research that needs to be done with HER2-mutant or HER2-express[ing] lung cancers.

As far as demonstrating toxicity, ILD [interstitial lung disease] has been one concern for toxicity with trastuzumab deruxtecan, and I think that can be reduced with the dosing. So they looked at different dosings for trastuzumab deruxtecan, it was really the lower dose, the 5.4 [mg/kg] that demonstrated a lower ILD. Part of an explanation for that might be that HER2 is actually also expressed in bronchial or lung cells as well, so that could potentially explain the ILD that we see with trastuzumab deruxtecan. But I think we can minimize that with dose reductions or a lower dose.

Herbst: What other ADCs, and I guess ADCs are finding a unique target, getting an antibody, putting a little linker on there and then attaching a warhead. And the idea is to get to the site and penetrate. I know a big idea, a big concern of all these is do they get into the brain? Do they have a bystander effect and get cells that might not have the target? What's in the future? I know it's hard to predict the future there, Anne, but give us a few thoughts.

Chiang: Again, in small cell there are the ADCs. We talked about Trop-2, but they're another class, or they're another group of , which is a protein that's on the surface of the small-cell cancer cells and those look pretty good as well. So I do think this is a good approach that has been demonstrated in other cancer types, and as a way to really target and be precise in targeting either small-cell or non-small cell cancer cells.

The toxicities that you already mentioned are really important to monitor. And I think the other path to the future is thinking about the bispecifics [bispecific antibodies], which target the tumor cell on one side and then bring the immune system to the tumor with the other head.

Herbst: Excellent. Well, we've had a good discussion here. Anything else anyone wants to bring up?

Chiang: Yeah, Roy, I'd love to talk a little bit about two topics. One is with all the trials we've been talking about, I think cost is something that we will have to think about as a healthcare system when we're talking about perioperative therapies that are extending [survival] 1 to 3 years after surgery. There's a lot of costs related to that.

And then finally, as you know, I think it's important to be able to do clinical trials and understand how we can increase the impact of these new agents for all of our patients who are underserved as well.

Herbst: Excellent. Okay, well my take is in the absence of any new IO agents that work in the resistance setting, we've relegated ourselves back to chemotherapy, but it's 2023 chemotherapy: better payloads with more directed ways of attacking and linking to the tumor. Do we fully understand why some of these work so well? No. Will resistance be an issue, I suspect yes, but we need to interchange and try combinations. Yes, but we're inching forward with progress in lung cancer, which is what we have to do, given that it's the number one cause of cancer death worldwide and of course in the United States.

It's been a pleasure talking with all of you today. Really exciting to hear all these updates. Look forward to getting together again soon after some of the fall meetings because the literature will be populated with even more data that will help us to do a more informed treatment of our patients.

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