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Drs Edward S. Kim and Alexander Spira answer viewer questions on ADCs in non-small cell lung cancer.

ADCs in NSCLC: Audience Q&A

 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?

: 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.

Yes, and I think we underestimated the impact of the smoking antigen environment with immunotherapy, at least I feel like many of us did.

: Yes, and I will say, we know that in the 

 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 

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?

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?

: 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 

 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.

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 

 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 

 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.

: 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?

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?

: 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.

Yes. Do you think any of these are deal breakers to move them up to the first line?

: 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.

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.

A discussion on how ADCs affect current standards of care in the non-small cell lung cancer treatment landscape.

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

 I’m going to turn it over to Dr Spira now and he’s going to walk you through some of the actual targets of interest.

: Thanks, Ed. It does amaze me; you pointed out [that] there’s a lot that’s already approved. I think what’s lost in this is that the technology to combine an antibody—the linker protein that hooks it all together, and then the warhead of the drug conjugate—seems so simple. And it is right now. You can almost put an infinite number of targets and warheads on, which makes this area ever growing. But here are the main areas of interest as we talk about non-small cell lung cancer in particular. 

, we know about the story in breast cancer and heard a lot of it at ASCO [American Society of Clinical Oncology’s Annual Meeting] a couple of weeks ago. We know that they’re activating mutations, which is different from what we think about 

 breast cancer, you’re really thinking about IHC [immunohistochemistry]. But here, you’re talking about 

activating mutations, which are present in about 2% to 3% of lung cancers. 

, slightly different¼I actually did another talk on this just a few days ago. It’s an antibody-drug conjugate [ADC] against 

. These are targets for a couple of reasons. One, it’s overexpressed, but they’re actually looking at ADCs in these “naked antibodies,” as we like to say, for things such as 

 fusions also. One of the hottest topics [is] there are now approved drugs for certain malignancies, not in lung cancer yet, but TROP2. TROP2 is an embryonal transmembrane protein that sits on the chromosome. It’s expressed mainly in cancer cells, and very overly expressed in multiple human epithelial cancers, and we’ll talk a lot about that today. CEACAM5, so it’s related to carcinoembryonic antigen, the CEA [carcinoembryonic antigen] test that we do. There’s an antibody-drug conjugate against that. And then finally 

, which is very common in lung cancer. Again, slightly different, but also works in the 

 skipping mutations that we already have approved drugs for. But here we’re talking more about overexpression as well. So there are a lot of targets right now, and I’m sure there’ll be many more coming. Here are some in particular that are being looked at in small cell lung cancer: We have trastuzumab deruxtecan and ado-trastuzumab emtansine. The DESTINY-Lung01 studies (NCT03505710, NCT02289833). T-DXd, I think that’s how a lot of us refer to trastuzumab deruxtican. There has been a lot of data on that recently at ASCO and the breast world. But there’s clear evidence in the non-small cell lung cancer world [also]. And I believe it’s already on guidelines for these 

 insertion mutations. TROP2, we’ll spend a little time talking about these today. Datopotamab is an antibody against TROP2 with the warhead deruxtican. Sacituzumab govitecan is actually already for triple-negative breast cancer [TNBC] and bladder cancer as well. None of these have approvals yet in the lung cancer world, but they’re obviously being studied and part of what we’re talking about today. You can see the TROPION-PanTumor01 (NCT03401385) and TROPION-LUNG01 (NCT04656652) studies as well as the EVOKE (NCT05089734) studies. Patritumab deruxtecan is obviously similar to datopotamab, with a similar warhead but a different antibody. As we talked about before, you can mix and match these. This is the HERTHENA-Lung01 study (NCT04619004), and this is actually being studied in the EGFR world. So a slightly different concept that we’re thinking about because EGFR is not 

but there’s an interaction there, and either 

 overexpression or by working alongside as another element of the pathway. There’s some clear activity there. CEACAM5, I mentioned that before, tusamitamab ravtansine, CARMEN-LC05 (NCT04524689) study. And finally, the c-MET drug that we talked about before, ABBV-399, teliso-V [telisotuzumab vedotin]. The LUMINOSITY (NCT03539536) study is ongoing for patients with c-MET overexpression, being studied both in EGFR as well as in patients with c-MET overexpression. Now I’ll talk briefly about the DESTINY-Lung01 study. This is a multicenter, international randomized study looking at 2 cohorts. Basically, you had to have metastatic lung cancer refractory to standard treatments. The typical things; measurable disease, asymptomatic METs [metastasis] in the CNS [central nervous system] at baseline, and then 

 is looked at in 2 ways. Cohort 1 was overexpression. So this is the traditional way we think about 

 overexpression. Either IHC 3-positive or 1-positive. Forty-nine patients at 6.4 mg/kg and 5.4 mg/kg had 41 patients. The second cohort, cohort 2, was 

 mutated. So this is not what you typically think about. And I think it’s important to remember this as we look at the data, that there are differences here when these are 

-mutated patients. Treated initially the first 42 patients and then expanded for a total of an additional 49 patients. Here are some of the responses in this patient population. This is the 91 patients in cohort 2. In this, the overall response rate was 55%, 1% complete, 54% partial, and 37% stable. Remember, we’re thinking a lot more about stable disease, especially if patients have been through a couple of lines of therapy. Now looking at the disease control rate, which is responses plus stable disease, is 92%, which is actually pretty good. In other words, very few people progressed at that first scan and did not have any benefit. The median time of response is literally the first scan. If you’re going to respond, it’s going to happen early. And the duration is a little more than 9 months. Again, nothing’s perfect in life, but a 9-month duration of response in this patient population. Now we’ll look at datopotamab. This actually started as a phase 1 study looking at patients with refractory relapsed advanced non-small cell lung cancer. Measurable disease, ECOG [Eastern Cooperative Oncology Group performance status scale]1, stable treated METs in the CNS were allowed. Patients were asked for a biopsy—it’s an antibody-drug conjugate against TROP2, what’s the TROP2 expression? It would be great to develop a biomarker. Phase 1 escalation study with an expansion starting at 0.27, got to 10 mg/kg with the MTD [maximum tolerated dose] established as 8 mg/kg once every 3 weeks. You can see the 3 expansion cohorts: 180 patients divided up between 4, 6, and 8 mgs per kg.¼The overall response rate was 24%, 26%, and 24%, so not a lot of difference between the dose levels. The confirmed response rates are for patients that had several scans that showed a response. So a response and then a confirmatory scan, which is usually at least 4 to 8 weeks after. About the same numbers. A couple of people dropped off in that first cohort, and in the second cohort there, a couple also, and the rest are unconfirmed. Disease control rate: 70% to 80% across all arms. Only between 9% and 20% of patients actually did not have a benefit. Duration of response not evaluable/not reached in the 4 mg. In the 6 mg and 8 mg to 9 mg cohorts, the median duration response is between 9 and 10.5 months, so pretty good. If you responded, you went for three-quarters of a year. The median progression-free survival, as you can see, varied between the cohorts as well, between 4 and 6.9 months. Based upon some of that data, the phase 3 randomized study in second-line lung cancer was done, and has completed enrollment. To get into this study, you had to have stage 4 lung cancer without an actual gene mutation. It was actually a separate protocol looking at patients with actual gene mutations. Phase 3 to 4, treated with platinum therapy as well as 

 immunotherapy. They needed to have a screening biopsy looking for biomarkers. And obviously, in the second-line setting, the randomization is versus the standard of care with a drug we never like to give. We tend to give it in clinical trial more than we would probably like to, but it’s a randomization of Dato-DXd [datopotamab deruxtecan], 6 mg/kg was the go-forward dose vs docetaxel. [In] the EVOKE study, as I mentioned before, sacituzumab is approved for second-line triple-negative breast as well as in the bladder world. It’s also an antibody-drug conjugate against TROP2 with a slightly different antibody, a different linker, and a different payload, but the same concept, as we talked about. Stage 4 disease, they need to have progressed past the standard therapies as well. Measurable disease, reasonable ECOG status. Five hundred twenty patients tried to be enrolled in this study, [which is] just getting started. And it’s the randomization of the standard sacituzumab doses. It’s given 10 mg/kg on day 1 and day 8 on a 21-day cycle versus, again, the standard of care in second-line docetaxel. The study is ongoing; I think it just got underway. Now we’re going to talk about the EGFR-mutated world. The ongoing study is called HERTHENA. I know Dr Kim probably came up with all these great names, but the HERTHENA-Lung01 study; he’s shaking his head, patritumab study.¼These are different patient populations. These are patients with EGFR mutations. Remember, EGFR-mutated patients, either 

, are the 2 most common EGFR mutations. They need to have gotten osimertinib as well as at least 1 platinum-based chemotherapy regimen. Progression of stable brain metastases was allowed, and tumor tissue is required. There were 2 parts to this early cohort: fixed dose 

 DXd, so fixed dose patritumab/deruxtecan is given at 5.6 mg/kg, or the other set of patients started at 3.2 and then up-titration to either 4.8 or 6.4 mg/kg. This is a randomized phase 2 study, randomized in different doses, trying to optimize the doses, but everybody gets drug on the study. We’ll now talk about a different antibody-drug conjugate, the tusamitamab ravtansine or the antibody against CEACAM5. CEACAM5 is expressed in lung cancer cells. This is a little bit more complicated study to do because to get on the study, the Sanofi folks have developed what looks like a biomarker. You have to have a high CEACAM5expression. Obviously, that’s a little bit of a challenge because you need to have CEACAM5 expression before you enroll in the study, and this is not something currently being tested on next-generation sequencing. I know they’re trying to work on blood-based assays to come up with a good marker, but this has to be done by central testing as of right now. No EGFR, BRAF, ALK, ROS aberrations, and no treatment for metastatic disease.

 exclusion criteria; unresolved corneal disorders. That’s something we see a lot of in the antibody-drug conjugate world. A lot of the warheads get secreted in the eye so you can get some eye irritation and corneal irritation in particular; a lot of them have eye exams, and that’s because of the payload, the maytansinoids are notorious for that. Cannot have gotten any therapy before. It’s a 3-part randomization to pembro [pembrolizumab] plus tusa [tusamitamab], platinum-based therapy plus pembro plus tusa. And then in moderate expression, tusa plus pembro plus platinum plus pemetrexed. So there are a few different arms of the study. It actually gets to be fairly complicated. The primary objective here is to really get the tolerability and then look at the recommended doses as it moves forward. But great study. I think one of the challenges with the study is trying to get these results back. Central testing with limited tissue is always a challenge. But it’s a great concept, and they had really good single-agent activity beforehand. Here is some of that data right now. So, here’s some of the safety, tusamitamab, in long-term treated patients with non-squamous, non-small cell lung cancer expressing CEACAM5. Among 11 patients treated greater or equal to 12 months, 7 had a PR [partial response] and 4 patients had stable disease as the best overall response. That’s 11 out of 12 had disease control, which is pretty remarkable. The median duration of response here, for those 7 patients with response, was almost 2 years. In the lung cancer population, we don’t typically talk [about] almost 2 years. That’s almost unheard of. And one of the things that are being looked at is the CEACAM5 expression level. And in this patient population, the confirmed PR occurred in patients with both moderate and high CEACAM5 expression levels. So, again, one of the things being looked at on this clinical study is, what’s the CEACAM5 expression you need for efficacy because it does look like we have a biomarker. Finally, we’ll talk about the LUMINOSITY study. This is telisotuzumab or teliso-V, the second or third line in c-MET positive non-small cell lung cancer. Two patient populations here, either non-squamous withEGFR wild type or non-squamous with EGFR mutated. And the patients had to have c-MET expression as well, by IHC by central confirmation. You could not have gotten more than two lines of prior therapy. The reason we look at two populations here is that c-MET is actually one of the major resistance pathways for patients who receive EGFR inhibitors. So it’s not uncommon that they develop c-MET overexpression as a mechanism of resistance; this is trying to overcome that. As part of the central assay here, looking at c-MET expression across the 2 different cohorts, several different levels here, breaking it down. And then go/no-go decision depending on the initial response rate and then expanding thereafter. There’s a separate population for squamous cell population as well, who are also overexpressing the c-MET. The dosing here of the drug teliso-V is given 1.9 mg/kg every 2 weeks. Here are some of the results in the first 23 patients, the median progression-free survival was 2.4, months and the median overall survival was 5.6 months, again very preliminary data. Polling question: Which target do you think holds the most promise for non-small cell lung cancer? I’ll open it up to the audience. Looks like we have about 70 people on. We’ve got 5 different answers here, so 

 looks like number 1, I think that’s a very good option there, but the other ones obviously have some positives as well. So it looks like most people voted for 

 and I think that’s probably true, at least in my humble opinion, just based on some of the data we see. As I mentioned before, TDxD [trastuzumab deruxtican] is actually on NCCN [National Comprehensive Cancer Network] guidelines right now.

Alexander Spira, MD, PhD, FACP, and Edward S. Kim, MD, MBA, shift their focus to the use of antibody-drug conjugates in non-small cell lung cancer treatment with a review of ADC clinical trial data.

ADCs in Non-Small Cell Lung Cancer

Good afternoon, everyone. I’m really pleased that you could join us for this 

® seminar titled “On the Horizon in NSCLC: Antibody-Drug Conjugates.” We’re excited that you’re able to join us. Hopefully, we’ll be able to share some knowledge regarding this interesting area of therapeutics. I’m Ed Kim. I’m at City of Hope [in Newport Beach, California], where I serve as a physician-in-chief at City of Hope in Orange County and vice physician-in-chief for the [National Medical Center]. I’m joined by my good friend and an old colleague, Dr Alexander Spira. He’s the codirector of the VCS [Virginia Cancer Specialists] Research Institute and the director of the thoracic and phase 1 program. He is a clinical assistant professor at Johns Hopkins [University School of Medicine in Baltimore, Maryland] and also a very experienced lung medical oncologist. Welcome, Alex. It’s great to be with you.

 Thanks for having me. Good to see everybody.

Let’s jump right in. We know multiple things happening in lung cancer. We’re going to take an in-depth look at what these antibody-drug conjugate [ADC] technologies are and why they’re so impactful in the treatment of non–small cell lung cancer. We’ll also review the strategies for managing the adverse events that can occur. Feel free, at any time, to ask questions. We’ll get to them as we go along. Let’s begin the program.

First, what’s an antibody-drug conjugate? There are 3 components: an antibody, which is the drug delivery portion; the linker, which connects the antibody to the payload; and the drug or the payload that destroys the tumor cells. You want these antibody portions to have a high affinity for their target. That way, you can get the binding done. Of course, delivering this drug or payload is an effective way to kill cancer cells.

When we look at the overall mechanism of action of an ADC, you can see that you start with binding to the cell surface. You want that high affinity and avidity. You get endocytosis of the ADC, which leads to lysosomal degradation. You get cleavage of this payload and release of it, which causes DNA or microtubule damage. That leads to a programmed cell death. You can also get this bystander effect as you have seepage into other nearby environmental areas that could kill other cells with the effect that occurs within the cell. We see that bystander effect occurring with neighboring cells in the vicinity.

There have been a lot of key milestones in ADC clinical development. Everyone talked about the magic bullet concept [in the early 1900s]. That was very different from what we’re seeing with some of the targeted agents or precision medicine, but they’re a variation of it. In the 1980s we had first ADC human clinical trials using an anti–CEA [carcinoembryonic antigen] antibody, a vindesine conjugate. Then there was the first approval of a monoclonal antibody preventing the rejection of kidney transplants. Gemtuzumab ozogamicin for recurrent refractory AML [acute myeloid leukemia]was approved in 2000. We’ve seen additional approvals in 2013 and 2019 of drugs with trastuzumab-based, HER2 [human epidermal growth factor receptor 2]–based ADCs with emtansine, deruxtecan, and brentuximab vedotin. There’s a lot of acceleration, as you can see. In 2022, we have 12 approved ADCs for cancer. The technology, as well as the specificity of how we’ve been developing these with the minimization of adverse effects, has led to a lot of different approvals.

Here’s the list of FDA-approved ADCs. It’s an expansive list. I’m not going to go through each 1, but they should look familiar. You can see where their target is and the diseases with these HER2 or hematology-related malignancies. We’re seeing more of them expand, especially in areas like solid tumors that are outside breast cancer. We’re hopeful that that can continue.

First polling question is, do you have experience with ADCs in your clinical practice? Please answer yes or no. I don’t think we have any 

We don’t want to disengage the audience this quickly. I’ll have my daughter sing. She’s a good singer. Let’s see what we’ve got, and what the results are. We’ll send them out so everyone can see them. You can see here that the majority of folks have experience, but we still have a high number of folks who do not. It’s a no that we have some experience there.

Edward S. Kim, MD, MBA, and Alexander Spira, MD, PhD, FACP, provide an overview of antibody-drug conjugates, including mechanism of action, historical milestones in development, and the approved ADCs for non–small cell lung cancer treatment.


Edward S. Kim, MD, MBA

Articles

ADCs in NSCLC: Audience Q&A

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

ADCs in Non-Small Cell Lung Cancer

ADC Technology and Mechanism of Action