The Impact of ADCs on Non-Small Cell Lung Cancer Treatment

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Edward S. Kim, MD, MBA: I think this has a great impact on how we are thinking about metastatic non–small cell lung cancer, and again, we’ve got so many things going on. We used to just talk about platinum-based chemotherapy, and Alex and I would argue about which platinum doublet was better, and whether carboplatin was the same as cisplatin, and I’m so glad we’re not even talking about those types of aspects. We’ve had antiangiogenesis agents; we’ve tried for many years with HER2 [human epidermal growth factor receptor 2] with limited success, especially from the antibody standpoint. Targeted therapies have revolutionized what we have seen in non–small cell lung cancer, and that has brought forward this era of precision medicine, which has been great, and then immunotherapy. I don’t know, Alex, your thoughts, but would anyone have predicted how well immunotherapy has transformed lung cancer? Everyone was talking about how it had to be an immune-based tumor, like renal cell and melanoma, but it’s been amazing, right?

Alexander Spira, MD, PhD, FACP: It’s been amazing, and I said it’s revolutionized lung cancer. I do admit, it’s changed, and I’m always amazed, I just saw a couple of patients this week, who are probably cured. They are 5 years out on single-agent immunotherapy right now, like holy mackerel. I’ve even stopped a couple, I’m sure you have as well, who are probably cured. Who would have thought that would happen? These are patients with either complete responses or just good responses and nothing’s grown in 2 years. It’s quite amazing. The only caveat, I will say, is that sometimes people think immunotherapy is the only treatment. I’m sure you get these questions too. They walk in and are like, “I’ve got to get immunotherapy, and it’s the only thing,” etc. And although it works very well, and there are a large number of patients who benefit, unfortunately, most patients don’t benefit as much or not at all, and we’d love to convert those people to responders.

Edward S. Kim, MD, MBA: Yes, and I think we underestimated the impact of the smoking antigen environment with immunotherapy, at least I feel like many of us did.

Alexander Spira, MD, PhD, FACP: Yes, and I will say, we know that in the EGFR mutations or any of the biomarker-selected population, that doesn’t work very well. But I also think that holds true, and I’m sure you would agree, with the nonsmoking population. For what it’s worth, at least in my clinic now, and obviously this depends on where you live, the number of smokers I see has gone down dramatically, and that’s a great thing; the incidence of lung cancer has gone down. When I started here 19 years ago, we had a large military population, a lot of factory workers, and people who smoked. It’s changed over time since the military population has left the area or passed on, and we just don’t have that many smokers anymore, and that’s a great thing. But unfortunately for my clinic, I don’t see all those good immunotherapy responses anymore. I see a ton of EGFR. I actually see more patients with EGFR mutations than I do chemotherapy patients at this point, which is great because we have options there. There’s still this large population for which we’d like to have better immunotherapy options in the future, but hopefully, the things like the antibody-drug conjugates [ADCs] are opening new pathways for them. I think in an ideal world, we’d still like to make immunotherapy work, so how do you combine it with other drugs to make those nonimmune responders respond?

Edward S. Kim, MD, MBA: What’s interesting about some of these targets that you discussed in several of these trials, Alex, is how strong those targets have to be, if they’re quantitative targets. I think we’re learning that you don’t have to be strongly HER2 positive to benefit anymore. What are your thoughts around that?

Alexander Spira, MD, PhD, FACP: As I said, I think we were all humbled at ASCO [American Society of Clinical Oncology annual meeting]. I don’t know if you went to the breast cancer sessions. I did not, but I was able to read all the news. We now have responders in the HER2 1+ and 2+ [immunohistochemistry score] patients for a HER2 drug, which is really cool. We’ve just developed a really good antibody-drug conjugate there, but the same holds for Trop-2. They’ve looked at some of these studies, and we didn’t talk about those data today, but we’ve looked at some of those data in terms of who’s likely to respond to either sacituzumab or datopotamab, based on the preliminary results. We’re not getting that, so you’re right, you don’t need to have huge numbers there. It would be great to know the number because we’d all like that predictive biomarker, who do you give this to, or who do you not give that to. But it’s great to have these options obviously, going forward for them. It’s amazing, because we went through a whole bunch of years with all these new targeted therapies, and I think now we’re going back to some different things. You don’t have to have the EGFR, ALK, ROS, RET, pick your new one of the year. We’re kind of going back to the more agnostic phase, which I think is great for our patients.

Edward S. Kim, MD, MBA: I agree with that, it’s almost like you have to get really detailed and specific before you can start looking broad again. I still remember when ROS1 was being debated, whether we should test it, because the incidence was 1%. And any other person would be like, “Wow 1%, 1 out of 100, especially with the number of patients with lung cancer, why wouldn’t you test that?” So, we have gotten into these very nuanced markers, with TRK fusions and ROS1 where we had to go really deep. Now we’re going back out into a landscape of saying, it’s OK to look at some of these other nuanced overexpression markers again because we have different techniques to deliver cytotoxic therapy specifically to these areas, so I like the way it’s evolving.

Alexander Spira, MD, PhD, FACP: Do you think you’re going to see some of these move up into the front line? I guess that’s a loaded question because there are a lot of different questions here. I’ll start with the easy one, I do think the HER2 ones are going to move up into the front line, it’s biomarker driven, it’s given as a single agent. I have to look, I can’t remember what it is on the NCCN [National Comprehensive Cancer Network] guidelines as, I think it’s for patients who received first-line therapy already. I think, candidly, as you look at it, it makes sense kind of like it does for osimertinib. What do you think about some of the Trop-2s? How do you think that’s going to play out? My only comment, and I will throw this out to you as well, so you can answer the hard part of the question. Carbo Pem Pembro [carboplatin, pemetrexed, pembrolizumab] works pretty well, so if you look at first-line adenocarcinoma, which is most of what we see now in the United States, it’s actually pretty well tolerated with very good disease response rates, as well as a very good disease control rate. So what do you think the future is for things like these Trop-2 drugs in the frontline setting?

Edward S. Kim, MD, MBA: I would say, and you showed some of these data last year, let’s still make sure we biomarker test everyone. Regardless of what we think the first-line treatment is preferred, let’s please do genomic testing on every patient who comes through, and up front. I view that as essential as having a histologic diagnosis, as essential as having staging; you’re incomplete until you have that information to go forward. Let me start there. I believe that it’s all going to be based on tolerability and adverse effects. This is what I’m going to pick your brain about as we do these. As we think about moving these agents forward, and up into the frontline setting, it really is about tolerability and adverse effects. And just as you mentioned KEYNOTE-189, that pembrolizumab, carboplatin, pemetrexed regimen, has really been a great regimen for people to use because the adverse effect profile has been very tolerable for a chemotherapy and immunotherapy combination. You have this maintenance therapy that continues, that’s very easy to take, and so high adoption and high efficacy.

I think we’ll have to see the same thing for these. If these drugs prove that their adverse effects are very manageable and that they can be effective, I agree with you. I think absolutely, it’s a natural step for them to move forward. But based on your experience, and you’ve had a ton of experience with these drugs; the adverse effect profiles, what do you worry about? Do you think these will be pretty easily integrated as an initial therapy?

Alexander Spira, MD, PhD, FACP: I do, because I’ve given all these drugs somehow, I think a couple of thoughts. Some people do really well with chemotherapy. We’ve all had those patients who have no adverse effects whatsoever, and then we’ve had that patient population that just doesn’t do as well. I’m about to see somebody as an add-on today. So, I think there is clearly a role for some of these newer treatments, No. 1. No. 2, is, there’s something very appealing. Patients just don’t like the word chemotherapy; you talk about chemotherapy and they fall apart. If you can tell them they can have a nonchemotherapy option, for example, a lot of what we’re looking at now with these studies. You saw some of those later designs, the second-line and beyond vs docetaxel. But now we’re asking the question, what happens if you combine it with immunotherapy in the frontline setting? What happens if you do carboplatin and one of these drugs as well, to keep them on platinum-based therapy? I think that’s probably going to have improved outcomes over time.

These drugs do have unique adverse effects, and they can’t be overlooked. They are antibody-drug conjugates, and the drug there is chemotherapy, and don’t forget that, because what happens is the drugs are only as good as they sit on with their linker proteins, and some of that ends up as free drug in the body. You do see some chemotherapy adverse effects. With sacituzumab, it’s mainly GI [gastrointestinal], diarrhea, it’s similar to irinotecan, so you get a lot of diarrhea, you get some cytopenias, and you can get some hair loss. There are some of those adverse effects. With datopotamab, you get some of that, not as much, but you get some pulmonary toxicity. You get pulmonary toxicity with sacituzumab govitecan as well, which has been higher than we would like, and is concerning. The challenge is that it shows up as an ILD-like picture, interstitial lung disease, and it’s really hard to diagnose. Who doesn’t have a patient with lung cancer who says they are short or breath and coughing? It’s sometimes very hard to see on the scan, and what happens is it’s often irreversible. You give steroids to people, you treat them supportively, but it’s hard. I think it’s going to make headway into the frontline setting because I think overall it’ll be better tolerated, but there are some unique adverse effects that we really have to think about as well.

We have a slide, what are some of these toxicities? Hematologic, thrombocytopenia, anemia; GI adverse effects; fevers and fatigue; LFT [liver function test] abnormalities; and keratopathy. A lot of these drugs fall off through circulation and they end up in the eye, so you can get some irritation of the cornea. The pneumonitis I think is the big one. Almost everything else is reversible, but if you do a look at some of the studies, the datopotamab study is the farthest along for Trop-2, there are some grade 5 events—grade 5 is death—due to pneumonitis. This was also seen with trastuzumab deruxtecan [T-DXd] as well. We do believe that the lung cancer population is more prone to this than the breast cancer population, probably due to prior radiation or because they had lung damage as well. But it cannot be overlooked, and it’s sometimes hard to even pick these up in clinical practice. But again, a long answer to the question, I do think it’s going to make it into the frontline setting for many reasons. At least in the second line, it’s going to offer a lot of hope as well. We’re waiting for some of those confirmatory studies to read out, but I think we would all be shocked if they weren’t positive.

Edward S. Kim, MD, MBA: Yes. Do you think any of these are deal breakers to move them up to the first line?

Alexander Spira, MD, PhD, FACP: I think pneumonitis is a deal breaker for some of these, especially T-DXd. I do think that’s going to be a concern because while you have increased responses, as a physician, nothing hurts more than life-threatening toxicity on either a study or on a drug. We’ve all given drugs, and when I started, I think we’re about the same age, maybe I’m a year older, Ed. When we started, we gave people chemotherapy, and I remember doing rounds. Some people succumbed to adverse effects from chemotherapy. I had somebody who got typhlitis from docetaxel. It was my partner’s patient on a clinical study, and she died, with cytopenia. And we have a very high threshold to never let that happen. None of us want to be guilty of that. I am concerned about the pneumonitis across this right now because nothing hurts more than somebody doing really well, and then ending up either on oxygen or having a major adverse effect. So to me, that’s going to be the big one. Again, in my challenge of managing this, it’s been hard to diagnose, because you’re looking at the scan, is that pneumonitis, is it not pneumonitis? Is it ILD? How are they feeling, is it just the cancer? Then if you continue to dose them, you just make matters worse, as well.

Edward S. Kim, MD, MBA: I agree. I’m hopeful that for a disease type that has made it through immunotherapy, and combination immunotherapy, and there were a lot of cautions as you know, and there are still a lot of cautions, but I think people take many more liberties now when treating folks. It’s been a good thing and helps us manage that.

Transcript edited for clarity.