TROP2-Directed ADCs in NSCLC: Current Evidence, Emerging Therapies, and Future Treatment Strategies

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TROP2-Directed ADCs in NSCLC: Current Evidence, Emerging Therapies, and Future Treatment Strategies

Dr. Christine Bestvina (University of Chicago): Hello everyone. My name is Dr. Christine Bestvina. I am a Thoracic Medical Oncologist at the University of Chicago, as well as Associate Director of Thoracic Oncology Program.

Dr. Joshua Reuss (Georgetown University): I am Dr. Joshua Reuss, Thoracic Medical Oncologist at Georgetown University and Associate Professor of Medicine at Georgetown University.

Dr. Bestvina: Today we are going to be talking about TROP2 antibody-drug conjugates in non-small cell lung cancer. We will talk about the state of medicine as it is today, as well as what is on the horizon. First, I will start by diving in with the unmet need for TROP2 antibody-drug conjugates, and where the interest for TROP2 targeting agents came from is because TROP2 is such a compelling target. When we choose targets for antibody-drug conjugates, one of our goals is to choose things that are expressed highly on tumors while minimally expressed on normal tissue, and TROP2 does exactly that. It is highly expressed in both adenocarcinoma and squamous cell carcinoma, while minimally expressed on normal tissue, and so because of this, there was great interest in developing TROP2 ADCs.

We currently have only one FDA-approved TROP2 ADC in the United States as of this recording, which is Dato-DXd, that is currently approved for patients with EGFR-mutated non-small cell lung cancer who have previously received EGFR-directed therapy, as well as platinum-based chemotherapy. However, there are multiple clinical trials being conducted on multiple different TROP2 ADCs that we will talk about, both in the EGFR space as well as in the non-AGA space in the front line and beyond. With that, let us dive right in.

Our first topic of conversation is where Dato-DXd fits in today. The FDA approval for Dato-DXd came from a pooled analysis of TROPION-Lung01 as well as TROPION-Lung05, which pooled together patients with EGFR mutations who had previously received both a TKI or a tyrosine kinase inhibitor, as well as platinum-based chemotherapy. In this pooled analysis, we saw a response rate of 43% and a median duration of seven months. This is certainly better than what we would have expected for patients who received docetaxel, which would be the historical alternative in this setting.

This leads us with the question of where does Dato-DXd fit into our current treatment algorithm today? Josh, how do you use Dato-DXd in your clinic today, and how do you sequence this compared to other options that we currently have?

Dr. Reuss: It is nice to have another option that is not docetaxel. What do we have first-line and what we give there obviously influences what we do subsequent line. Now we have two frontline options in the EGFR-mutated space, osimertinib with chemotherapy, the FLAURA2 regimen, and then amivantamab with lazertinib, the MARIPOSA regimen. I am someone who I tend to give osimertinib plus chemotherapy, the FLAURA2 regimen upfront, which means that if one gives that and I do not think someone is going to have benefit from additional platinum doublet, there is a lot of things that can go into that timing when someone last received chemotherapy, do we think their organ function can tolerate again. Really, that is oftentimes when I am considering datopotamab deruxtecan as post-chemotherapy with osimertinib.

There is a lot of other things that one needs to look at. Is this oligoprogression? Is it polyprogression? Have you biopsied and found an actual mechanism of resistance? If one is not seeing those things, then oftentimes I am considering it after I have given osimertinib with platinum doublet chemotherapy in the classically EGFR-mutated population. I will say I have not done this as much. I would also probably consider it as a subsequent-line therapy in an exon 20 space, since the approval and the data is not limited to your classical driver populations. It is just not a population that I see quite as frequently.

Dr. Bestvina: Thanks so much for that excellent summary, and I definitely agree with you. I have had the opportunity to use Dato-DXd for two patients with EGFR exon 20 mutations, one of whom had a great response, including an intracranial response for multiple CNS metastases. Very important call out that this extends beyond just classical EGFR mutations. As we are deciding how to use this drug, I think in trying to look at all of the data we have for Dato-DXd, one of the first readouts we had was for the TROPION-Lung01 trial, which randomized patients against docetaxel. This was an interesting trial because it had a positive progression-free survival in the overall trial patient population, but overall survival did not statistically hit an improvement.

This is a great example of where we did not just stop with a negative trial. The investigators did a wonderful job, at looking at biomarkers, and found NMR or normalized membrane ratio, which is a computational pathology biomarker that looks at essentially estimating internalization of TROP2. By choosing the patient population that was TROP2 NMR positive, there was a significant benefit with Dato-DXd, with a median progression-free survival of 6.9 months in those patients. Very encouraging to see biomarker development move forward alongside antibody-drug conjugates. Any other thoughts about patient population subtypes or how we should further develop these ADCs?

Dr. Reuss: I will say I am very excited about this QCS-NMR biomarker and utilizing a digital pathology biomarker, which hopefully has implications for being able to utilize a biomarker like that worldwide. If someone can upload something somewhere across the world and it can be digitized and the score provided, it can have some very real impact. It just makes sense mechanistically. If these are antibody-drug conjugates, so-called smart chemotherapy, that needs to be internalized in order to have benefit, finding a biomarker that just does not just stain the surface of the cell but really tries to assess for the rate of internalization and the ability of that drug to be internalized in any one patient's cancer, that just logically makes a lot of sense.

The data that has been presented so far suggests it is predictive and not just prognostic, meaning that this score did seem to predict benefit from datopotamab but did not predict benefit from docetaxel. I know there are several prospective studies that are being done to see really, will this hold water? Will this demonstrate benefit prospectively? That has a lot of hope of patient selection, really selecting those who are most likely to benefit from this treatment.

Dr. Bestvina: With that, I will hand it over to you to transition to future directions.

Dr. Reuss: Thanks, Christine. Datopotamab Deruxtecan, in many ways was one of our first generations of these TROP2-targeted antibody-drug conjugates. We have seen several agents under development. There are more agents than I can even count that are under various stages of development, but one that we have seen a lot of emerging data for that looks quite promising is a drug called sacituzumab tirumotecan. The sacituzumab is the antibody component that targets TROP2, conjugated via a cleavable linker tirumotecan payload a novel belotecan-derived payload with a drug-to-antibody ratio of 7.4. What we saw at ASCO this year was actually data from the OptiTROP-Lung05 study, a phase III randomized clinical trial in advanced non-small cell lung cancer, PD-L1 positive non-small cell lung cancer without EGFR or ALK alterations, so a driver-negative population. In this study, patients were randomized 1:1 to either the combination of sacituzumab tirumotecan with pembrolizumab or pembrolizumab monotherapy, again in a PD-L1 positive population, so 1% or greater. This was a China-only study.

What we saw presented was that the progression-free survival was really quite encouraging. PFS in the overall population by BICR was a hazard ratio of 0.35, so median not reached with the combination compared to 5.7 months with pembrolizumab. Importantly, they did see this benefit across various subsets of PD-L1 high subset as well as PD-L1 low, your 1% to 49% subset. While overall survival data was immature, there was an encouraging trend that was noticed. This was not the first study, I will say, to show promising findings in phase three studies of this drug. The OptiTROP-Lung04 actually looked at platinum doublet chemotherapy versus sacituzumab tirumotecan in an EGFR-positive population post-progression on osimertinib and actually found a positive progression-free survival and overall survival data in that subset. Again, a China-only study.

Actually, though to circle back to OptiTROP-Lung05, very promising data here. What is your take on, in general, phase III studies when you see a population that is a China-only study, does that influence how you think about this data, and what do you think about the comparator arm, PD-L1 positive versus 50% or greater versus where we commonly get use immunotherapy? What are your thoughts on this data?

Dr. Bestvina: For me, this was exciting data, but I do want to see these findings confirmed in a broader patient population including Western patients. Not quite ready for prime time or use in the clinic outside of a clinical trial. As far as the comparator arm for patients who had PD-L1 1% to 49%, in the United States certainly we would use a combination of chemotherapy and immunotherapy for these patients. It did not surprise me that the hazard ratio for this group was very high, because the comparator arm was what we would consider suboptimal as far as practice patterns in the US. However, I did still find it encouraging that in the PD-L high patients of 50% or greater, there was still a really impressive hazard ratio, and those patients seemed to derive very significant clinical benefit at least from a progression-free survival standpoint. Things could have been improved in the clinical trial design, but I still think that there is a lot of encouragement for this approach of immunotherapy plus Sac-TMT.

Dr. Reuss: I completely agree. If you extrapolate and see again in other populations, if this is doing better than platinum doublet, then perhaps that suggests that it is something that can be moved up to the front-line space. I will say, we also do not know in a PD-L1 high population if adding platinum doublet chemo to immunotherapy is better than immunotherapy alone. If some of those trials like INSIGNA and others suggest that there is a benefit for chemotherapy in that space, should we even be revising what the comparator arm is there too. So many open questions.

Dr. Bestvina: Many open questions. We had this question in clinic this past week, and my fellow and I pulled up four different retrospective, large studies, meta-analyses, and still could not come up with the answer. I do not think we as an overall group have figured out exactly what the right treatment strategy is for patients with PD-L high disease. Point very well taken.

Dr. Reuss: One follow-up question on this, particularly for immunotherapy studies, how much stock do you take in progression-free survival data compared to overall survival data?

Dr. Bestvina: We have learned across multiple different studies that overall survival should be the gold standard for this patient population. We learned early on that response rates probably were not going to be the right marker, but we have held on to PFS a bit more tightly. I do think that we are fortunate enough at a point in 2026 where I do expect an overall survival benefit if something is going to be practice-changing.

Dr. Reuss: I agree 100%, particularly if you really want to ask the basic question is, is the juice worth the squeeze? If you are going to add on toxicities, add on frequency of infusions for a patient, you need to know that there is just not lead time bias in delaying progression. You need to know if this is something that is ultimately going to help people to live longer, which is, at the end of the day, probably our ultimate goal here in treating patients with advanced non-small cell lung cancer.

Dr. Bestvina: Particularly for patients who are PD-L1 high, we get so excited when that biomarker comes back, not just because we think patients may live longer, respond better to treatment, or have more durable response to treatment, but also because we know we can spare them the toxicity of chemotherapy. If we are going to change that treatment paradigm to escalated therapy, absolutely we need to see some real significant benefit when that translates to an overall survival benefit.

Dr. Reuss: Agree 100%

Dr. Reuss: There is a lot of exciting data in the TROP2 antibody-drug conjugate space but ultimately, we want to use our best drugs first. We want to move these agents as early on as we can to inform our treatment decision-making. There are several studies that are ongoing with datopotamab deruxtecan. We have multiple studies. We have TROPION-Lung07, TROPION-Lung08. These are both studies looking at various datopotamab combinations in advanced, treatment-naive, driver-mutation-negative disease. Non-small cell lung cancer TROPION-Lung07 is looking at your PD-L1 less than 50% and looking at various combinations of datopotamab with pembrolizumab compared to pembrolizumab alone to see if there is a benefit there in progression-free and overall survival. TROPION-Lung08 is looking at the PD-L1 high 50% or greater population datopotamab plus pembrolizumab versus pembrolizumab alone, a little analogous to the study design of the OptiTROP-Lung05 study. AVANZAR is looking at all-comers of driver-negative non-small cell lung cancer, but importantly, building in your QCS-NMR TROP2 biomarker prospectively to assess benefit. These are studies that are ongoing that hopefully we get information on the potential utilization of this treatment as frontline therapy.

There are also some words of caution here in the sense that EVOKE-03 which was a study of sacituzumab govitecan plus pembrolizumab versus pembrolizumab in a PD-L1-high population, this ended up being a negative study that we saw presented at World Conference of Lung Cancer 2026 in South Korea. Christine, when you see this and you see there is a lot of exciting studies, there is some positive data that we saw China-only data, there is some negative data, how do you break this down? What are you most looking to see from these studies that we are waiting on, and what do you think that maybe EVOKE-03 did not meet the endpoint that we wanted it to?

Dr. Bestvina: There is a couple different things when we look at these studies as a whole. One concern that I have will be how tolerable the triplet regimens are that are using a combination of PD1 inhibitor, platinum chemotherapy, and antibody-drug conjugate. We are essentially for the non-squamous patients substituting out an antibody-drug conjugate for pemetrexed, which is generally very well tolerated for patients. There are real cytopenias that we see with antibody-drug conjugates across the board to varying degrees, but certainly across the board. I am interested in the tolerability of the triplet regimens. Fortunately, a couple of the trials are also including just the doublet of antibody-drug conjugate plus immunotherapy. I will be interested to see if that ADC can substitute for the platinum doublet or both agents because my suspicion is that that is going to be better tolerated, and we will see if the efficacy can hold up.

Dr. Reuss: I agree entirely. You do not necessarily want to extrapolate from other studies, but I definitely have the question that, okay, if datopotamab deruxtecan was not better than docetaxel in an all-comer population, are we going to be able to replace platinum doublet with that when that is a chemotherapy combination that we know at least when utilized in an upfront population, has better efficacy than docetaxel? You are looking at one various step removed here, and perhaps that is why I am probably most excited to see what the TROP2 NMR-positive subpopulation and perhaps when stratified prospectively, is that going to be the subset where it makes sense to pursue this doublet or even pursue a triplet combination? Because otherwise, it begs the question, is the juice worth the squeeze?

Dr. Bestvina: Absolutely. As exactly as you said, getting some prospective data using this highly novel biomarker, is going to be important for the field of ADCs as a whole and how do we move forward in the incorporation of these agents or even substitution into the frontline from what we currently are using.

Dr. Reuss: These agents are not just being utilized in a driver mutation subset. Again, we are trying to see how do we utilize these therapies either as frontline treatment or as subsequent line. TROPION-Lung14 is actually looking at frontline osimertinib plus datopotamab deruxtecan versus osimertinib. I will start there. The question on that, is this the right study? It is hard when a study is accruing, we get data and then we automatically are looking at a paradigm that may be out to date. If this study is positive for progression-free survival or when we get that data readout, how are you going to look at this data knowing that our control arm in most cases now is probably osimertinib with chemo or amivantamab plus lazertinib?

Dr. Bestvina: Absolutely. It is hard to penalize the study because I think at the time this study was developed, the majority of us were still using osimertinib monotherapy. I will call out that I was a late adopter for chemo osimertinib frontline just because of the additional toxicity. It is going to be tough to try to figure out how to compare that since I am using chemotherapy plus osimertinib or the FLAURA2 regimen for the large majority of my patients. Unfortunately, we are going to be left looking at hazard ratios, median progression-free survival, doing all the cross-trial comparisons that we espouse never to do. Unfortunately, it is just going to be a real-world, messy interpretation of the data and how we apply it to our clinic.

Dr. Reuss: Absolutely. I agree entirely. We cannot fault the design of the study and at the very least makes for great conversation and debate about what the right option is for the patient in front of you. Obviously, we are also trying to get higher-level data on the subsequent line space. Our datopotamab deruxtecan approval is based off of pooled data, but it is pooled single-arm data. Essentially, we need better data to confirm the efficacy of this in this setting. There is several trials ongoing, TROPION-Lung15, looking at that subsequent-line population. Interestingly enough, again, a product of study design datopotamab deruxtecan by itself or datopotamab with osimertinib or platinum doublet chemotherapy.

There are also several studies at a global population looking at the drug sacituzumab tirumotecan, sac-TMT, what we discussed earlier, in the EGFR-mutated space and as well as the EGFR-mutated and other driver space compared to platinum doublet in a previously treated population. I want to ask you, Christine, for these designs of these studies, what do you think? Do you think that continuing osimertinib is going to be important here? Are there any toxicities that you might be worried about with various of the combination strategies being tested?

Dr. Bestvina: I do think that there is a lot of compelling reasons to continue the osimertinib post-progression. We always worry about CNS progression with taking off the EGFR-directed tyrosine kinase inhibitor. We have now seen data from COMPEL that there is a reason to keep the EGFR TKI backbone going. From an anti-cancer perspective, absolutely, combination therapy is compelling to me where the big question is going to be though, is can this be a tolerable combination? Interstitial lung disease is a big concern with antibody-drug conjugates. Can we potentially amplify that ILD signal with the addition of EGFR TKIs, is the big worry. Stay tuned. Some much needed data, but I am glad that this arm was included in the trial.

Dr. Reuss: I could not agree more. There is some data that has been published. One of the arms from the ORCHARD basket study suggested that the combination of osimertinib with datopotamab deruxtecan in the subsequent line has PFS values that are numerically higher than what we are seeing for datopotamab deruxtecan alone, which I think biologically makes sense. At least in that data, there was not a significant increase in the rates of ILD. I agree that is a concern that definitely needs to be fleshed out in a prospective fashion.

Dr. Bestvina: Now that we are using antibody-drug conjugates more in the clinic with Dato-DXd and potentially some of these other TROP2-directed ADCs on clinical trial, I would like to share a little bit about practical adverse event considerations. This is a class of drugs where counselling and supportive care are highly important. We see higher rates of stomatitis and ocular toxicities, but what we have seen throughout the clinical trial development of Dato-DXd is that with a prophylactic regimen, we can decrease the rates of some of these adverse events. As our patients are starting on Dato-DXd, we do extensive counselling on stomatitis. Here, prevention is definitely the best strategy. We discuss dexamethasone mouth rinse four times a day with patients.

There has also been some emerging data for oral cryotherapy using ice chips and ice water during the IV therapy period. As far as ocular toxicity prophylaxis, using eye drops four times daily can prevent some of these. Using eye drops up to eight times daily should symptoms occur, can also be highly effective. I am very lucky to have the benefit of oncology pharmacist who does additional counselling with our patients. This is also where we can incorporate physicians assistants and nurse practitioners to help do counselling with our patients ahead of starting these therapies to try to minimize some of the toxicities that can affect quality of life.

Lastly, we also do counsel them extensively on calling us should they experience new cough or shortness of breath because we know that early intervention for ILD is extremely important in the outcomes of these patients. We want them to call us if they start seeing their pulse ox dropping at home after their daily walks, or even if they develop a new cough, because again, early intervention can be quite important.

With that, I am happy to go ahead and wrap up today's podcast. Thanks so much for listening to the end with us. Both Josh and I will give one key takeaway, as well as one unanswered question that we are looking forward as the field develops. For me, my key takeaway is that I do think TROP2 ADCs have helped actually guide biomarker development in non-small cell lung cancer with the development of NMR. My unanswered question is how as we escalate therapy, patient preference and quality of life will tie in to first line treatment preferences. Josh, go ahead and finish it up for us.

Dr. Reuss: Thanks, Christine. Thank you for this very engaging discussion. My big takeaway is that these TROP2 antibody-drug conjugates are here to stay. I do not think this is a flash in the pan. We are going to be seeing more of these therapies work their way into more frontline treatments and probably more settings in non-small cell lung cancer, so definitely encourage providers to gain experience with these therapies. My main unanswered question to watch is similar to yours. We just need to see more prospective randomized data in a global population for these therapies. I am also very excited to see if QCS-NMR prospectively can be validated as a biomarker that is reliable, that then hopefully can be scaled to be utilized on a global level.

Dr. Bestvina: With that, thank you so much for joining us on this session on TROP2 ADCs.