JCO Article Insights: Safety and efficacy of a Novel ADC Targeting TROP-2 in Metastatic Non-Small Cell Lung Cancer (NSCLC)

Journal of Clinical Oncology (JCO) Podcast

In this JCO Article Insights episode, Davide Soldato interviews Dr. Jacob Sands, medical oncologist at Dana Farber Cancer Institute (Boston, MA) and Assistant Professor at Harvard Medical School, on their paper “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01”. The interview offers a deep dive into the safety and efficacy data of this novel drug and puts these data in the context of the current treatment landscape of NSCLC and of the revolution that ADC are bringing into the oncology world.

TRANSCRIPT

Davide Soldato: Welcome to this JCO Article Insights episode for the October issue of Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Jacob Sands, co-author of the manuscript titled, “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.” Dr. Sands is a Medical Oncologist working at Dana-Farber Cancer Institute in Boston and Assistant Professor at Harvard Medical School. His main field of research and clinical interests revolve around improving screening and diagnosis of lung cancer and also on developing novel therapeutic agents for this disease.

So, welcome Dr. Sans, and thank you very much for accepting our invitation today.

Dr. Jacob Sands: Happy to join. Thanks for having me.

Davide Soldato: I just wanted to start with a very general question because I think that we are going to discuss a very important study and the manuscript that you co-authored is going to look at the safety and the efficacy of this novel ADC datopotamab-deruxtecan that is targeting TROP2. But I just wanted to have a little bit of context before starting to discuss the safety and efficacy data. So the population that was included in the study included more or less 60% of patients that received three or more lines of therapy and also 20% of patients who received five or more lines of therapy. So I think that this is a very particular population, especially considering that we are speaking about non-small cell lung cancer. And so I wanted to get from you like a general context, like what are the therapeutic options for these patients normally in clinical practice and what do we expect in terms of outcomes and in terms of toxicity?

Dr. Jacob Sands: Yeah, so as you point out, this is a highly pretreated population in general, which is to say that they've really gotten the most effective lines of treatment up to this point. Now, we certainly do see some efficacy from some of the later lines of therapies in some patients, but inherently there is a decreasing response rate and decreasing durability of these responses as patients get further along in their treatment courses as far as lines of therapy. So it's generally considered to be a challenging clinical scenario, which is part of what makes the data that we're going to discuss, I think, so meaningful.

Davide Soldato: Yeah, I think that especially if we look at the population that was included first, I think that the very particular thing is that included both oncogene-addicted and non-oncogenic addicted patients, and also the great majority of these patients received the most effective treatments that are available because they all received more or less immunotherapy and platinum-based chemotherapy, if I'm not mistaken.

Dr. Jacob Sands: That's right. And that's an important distinction that you're drawing in the patients with oncogenic drivers and, of course, there's plenty of data with this compound with Dato-DXD in that population as well. But broadly speaking, in the non-oncogenic actionable alterations where they've gotten chemo-immunotherapy, those really are the most meaningful. Of course, docetaxel has been a long-standing second line that I'd say there is less and less enthusiasm about that as a line of treatment as we've seen some of these other more novel therapies that have just a better toxicity profile in particular, but also some with really durability that we don't quite see with docetaxel as well. And so once you're getting past that, you're really now reaching a bit deeper to then have something that is well tolerated and has efficacy. That's a setting where we really need it even more.

Davide Soldato: So, going back to the results of the study, as we kind of pointed out, this was a very standard classic with a Bayesian design, phase I dose escalation and dose expansion study of this novel ADC datopotamab-deruxtecan. So I just wanted to go over with you and to provide our listeners a little bit with some data regarding the doses that were explored and then what were the doses that were selected for the expansion. And also to discuss a little bit the safety data. We were discussing the tradeoff between risk and benefit, especially in patients that are very pretreated, searching for these kind of sweet spots between the toxicity and the efficacy. So I just wanted to put in context a little bit the data that you reported in the manuscript.

Dr. Jacob Sands: Yeah, that's right. So, like phase I’s go, we started with a low dose at 0.27 milligrams per kilogram, and dose escalations occurred up to 10 milligrams per kilogram. The 10 milligram per kilogram dose did have toxicities that really made it not considered to be tolerable, and that mostly being mucositis and skin. And so it was then back down to 8 milligrams per kilogram. And then there was a dose expansion at 4, 6, and 8 milligrams per kilogram. The 4 and 6 milligram per kilogram doses had 50 patients enrolled within those cohorts and 80 patients within the 8 milligram per kilogram cohort to then get much more data, of course, for efficacy and tolerability within those levels. Ultimately, each of them really demonstrated some efficacy as well as general tolerability. The 6 milligram per kilogram dose was really the one selected overall for further testing and future trials based upon the data out of this one that we're going to discuss further.

Davide Soldato: What were the main side effects that you observed in the trial? And particularly, do you think that there is some kind of special toxicity that should be looked at when using this novel type of ADC?

Dr. Jacob Sands: Certainly there are some novel toxicities to really pay attention to. And maybe I'll just point out before diving into the toxicities, that this is in many ways chemotherapy. The antibody drug conjugates, as listeners probably know, are an antibody that has a linker bound to chemotherapy, what's called the payload. And in this case, it's a topoisomerase I inhibitor with the antibody, the TROP2. So the cells on the surface, when there's TROP2 expression, the drug binds to that, gets pulled into the cell and releases that chemotherapy intracellular, but it is still chemotherapy. And so some of the toxicities are things that we commonly see with chemotherapy drugs. Although, broadly speaking, I would say we're able to deliver higher doses of that chemo to the cells in this kind of targeted dosing of chemotherapy to give the chemo intracellular.

Now, that being said, some of the toxicities that we see from this drug in particular that are a bit different is the stomatitis, mucositis. That is something that has occurred. Now, I've found that if it's really severe, then with a dose reduction that has really substantially improved any toxicities with future dosing. And at a 6 milligram per kilogram dose, a dose reduction to 4 milligram per kilogram is still within a dose range where we saw plenty of efficacy within the trial that we're discussing. That being said, if one can help patients tolerate it better, if it's more mild symptoms, if it's not severe, then that's better in maintaining that dose. And interesting things like ice chips at the time of infusion, so cold within the mouth, kind of like the cold caps to try to reduce alopecia at the time of infusion of the chemo may help some steroid rinses also can be helpful. But really these are things to help prevent stomatitis from being severe. It's harder when that occurs, then the treatment for improving it is a bit different.

We do know, though, that that does improve with time. So even when it was severe with that infusion, it does improve as patients get further out from those doses. Of course, another one is dry eyes or irritation within the eyes. And if that is severe, then or even mild actually, I'd say when there's any known toxicity like this is to involve ophthalmology. Now, within this trial, ophthalmology was involved and patients had to get a baseline eye exam and they would get checked at different time points throughout the course of the trial. And so they were being monitored. I did not have anyone who needed to stop the drug because of this. The patient I had with the longest standing response to therapy did have some dry eye. It was not bothering him so much. And he had this real aversion to using eyedrops. It was very hard for him to make himself use these. But when I told him, “Look, if this gets worse, you might have to come off the trial, that it might not be our decision just by the way the trial describes it, if this gets worse.” And so for him, the fear of having to come off the drug was really the thing that helped him to then start using his eyedrops, which really helped to control that a bit more. And so that is something to monitor for.

But the biggest thing really is interstitial lung disease. This is something that is a complex topic, I think because it's something that we need to be very aware of and monitor for. At the same time, a diagnosis of interstitial lung disease can be challenging. There really were not cases where we had pathologic confirmation of this diagnosis. These are clinical diagnoses in the cases on this. Now there was an adjudication committee that would review all of the data and come to a determination of whether this looked like drug related ILD or not. But for clinicians, when you see a patient whose scan shows some inflammatory markings or inflammatory appearing markings on a scan, we see that all the time with other drugs too. And so determining what is potentially incidental versus drug related, I think in most cases on a trial when we're unsure, we lean toward drug related. And in some cases there are reported out severe cases of drug related ILD.

I think the really difficult thing that I'd want people to take away from all of this, though, the bottom line is, yes, we need to be very aware of the potential for drug related ILD while at the same time, we need to not reflex, just call things drug related ILD and really make sure that we're doing a workup when feasible rather than just that bottom line conclusion. We see it at a rate related to the drug, and I do think it's real. But we also need to, when treating individuals, try to identify any other potential etiology. I did have one patient that really looked absolutely classic for this diffuse drug related ILD that ended up ultimately really being what looked more like tumor progression in just a radiographic pattern that looked more like an inflammatory process than it did the way we would typically see cancer progression. And so this has really, for me, I think, highlighted this as a topic where I'm diving a bit more into that description.

Davide Soldato: And I also think that in the population of lung cancer patients, as you were saying, this is even more complicated because frequently these are patients who had a history of smoking, who can have concomitant infections where progression is easier in the lung. If I think, for example, other ADC that have already been tested, for example, in breast cancer, it might be far easier to detect and to adjudicate an ILD to the drug that we are using compared to what could be, for example, for lung cancer patients.

So if I understood correctly, the toxicity that in your opinion as a clinician, they are more complicated to treat, let's say on a more daily basis, are more stomatitis and inflammation, but maybe the one that you experience as potentially more severe are always related to lung toxicity.

Dr. Jacob Sands: Well, I think the scary thing about the ILD is that we have higher grades of ILD, and this is a toxicity that then can become life threatening. When we see a grade I or a grade II ILD reported in numbers, where we see, okay, this looks like it's really happening, and then see some really higher grade toxicities, I think the concern amongst clinicians then is if they're seeing lower grade, which of those can potentially progress to those higher grade, which then becomes life threatening toxicities. Whereas dry eyes certainly can become a nuisance, we didn't see any blindness or something like this, and the stomatitis resolves as you hold the drug, and in some cases, really before the next cycle even comes, it's just more a matter of controlling the discomfort, which can be severe. I'm not minimizing that. I think that's why ILD stands out so much, is that that becomes a potentially life threatening thing.

And to your point exactly, these patients with a smoking history on other drugs, we see these inflammatory findings. Now, in some cases, we know it can be from the drug. In other cases, we see it and know that it's essentially incidental. And I'll say to patients, “Hey, we see this. It's something we'll monitor on future scans, and these can wax and wane.” When you have a patient on a drug with a high attention towards something like ILD, there can be- what I'm cautioning against is a reflex attribution to that drug. In all cases. I'd urge clinicians to individually assess each of these patients to get a sense of whether they think that that's going on for that person, knowing that it's often not possible to say with 100% certainty in any of these cases. But we often see waxing and waning inflammatory findings. And in many of these patients with heavier smoking histories, in particular, there can be waxing and waning respiratory symptoms. So the question is, are there instances where there is what really is an incidental inflammatory findings and incidental respiratory waxing and waning that then suddenly we call a grade II?

At the same time on the other part of that, if there is something that seems like it really may be drug related ILD, is doing that work up and really evaluating and diagnosing that before it progresses to a point that really there are severe symptoms. And it's kind of trying to do both of those things on the opposite ends of the spectrum that I'm speaking toward at the same time.

Davide Soldato: Just on a personal note, do you think that, as we continue the development of these drugs that are associated potentially with lung toxicity, do you think that we also need to pay attention to the drugs that were immediately previously received by the patients? What I mean is, do you have the feeling that the previous treatment could potentially impact on the risk of developing this type of toxicity in the lung?

Dr. Jacob Sands: I don't know that we yet have data to draw any real conclusions around that. But you raise an important question within this, and what potential toxicities could be related to prior treatments or synergy across those. Of course, we see inflammatory findings within the lungs and pneumonitis with prior immune-related therapies, and that it would be a good prompt to the question you're asking. And that in particular, we also see this in some of the targeted treatments, although not nearly to the same percentages. I don't know that we can draw conclusions from this. I would speculate that the mechanisms of action of each of these drugs are so different that I would not hypothesize real synergy in those toxicities. But it is certainly something to be aware of and an important question that you're raising.

Davide Soldato: I think that, apart from the safety data that I think we dissected, the other end of the spectrum would be finding a drug that this very pre-treated population could still give us some efficacy data. So you already mentioned that, in the dose expansion cohorts, so 4, 6, and 8 milligrams, we had more or less signals of activity and of efficacy of these novel drugs. So the therapeutic options, as you were mentioning, are potentially docetaxel or other types of mono chemotherapy. But we know that the objective response rate is not that high, and that progression-free survival is not that long with these types of drugs. And potentially the safety profile could also be complicated in patients that are also pre-treated. So I just wanted to discuss a little bit the efficacy data and to see if there is really promise in this type of delivery of chemotherapy as you were saying with the ADC.

Dr. Jacob Sands: We saw response rates of about 25% across all three of those cohorts. The manuscript outlines the 4, 6, and 8 milligram cohorts within a chart showing the efficacy outcomes. And really it's around 25% across the three of those, which in this patient population, as we've discussed, heavily pre-treated, to have a response rate of 25% is really quite promising that there really is a substantial treatment effect. On top of that, we also see a duration of response of really around 10 months. So, in the patients that are having a response, there really is some durability. Now, it's tragic that 10 months is considered durable within this population and it really highlights the ongoing need for further drug development because I don't think anyone would say that 10 months is enough, we need dramatically better. But within the context of what we currently have, a 10-month duration of response is really quite meaningful and a response rate of 25%.

Now, it also describes a disease control rate. And I always have to put a little asterisk to this. I think we see this increasingly - the disease control rate being reported - and it always looks quite a bit better than the response rate. And that's essentially incorporating stable disease. And although I would never claim that everybody with stable disease is truly benefiting from a drug, across all of the studies where this is reported out, there is a spider plot which really highlights a number of patients that are not considered responders, but with responses, a handful of them beyond six months of disease control, even though they're not considered responders, and one of them beyond a year with still ongoing disease control. So, even within that stable disease group, I'd say there are some who are really clinically benefiting from the drug, which is to say that really, even beyond the 25% response rate, we are seeing some others that are truly benefiting from this.

Davide Soldato: Yes, and I also think that for these patients, especially when they can develop very rapidly symptoms that can potentially also impact quality of life, having a drug that achieves this level of stability - with maybe no deterioration in clinical symptoms - I think that it's still probably a very meaningful objective to obtain for this type of population. Of course, I think that with future studies we will also have probably health-related quality of life data that will tell us more about the impact of this type of drug in this setting. But I still think that this could be potentially a relevant endpoint, even if we don't achieve what we officially consider as a response as per resistor criteria.

So I think that we have talked a little bit about the efficacy data. So, we are kind of entering a novel area where more and more ADCs are being tested, are being included in clinical practice. For example, if I think about breast cancer, we already have two that are approved that can be used, the same in bladder cancer. So, as you participated in this phase one trial, I just wanted to have your opinion: if you think that, in the future, we are going to evolve completely towards this type of delivery of chemotherapy, using what we call now "smart drugs" in terms of delivery of these cytotoxic agents.

Dr. Jacob Sands: It'll be interesting to see. We certainly will see other generations of ADCs. I mean, I think we're really just at the beginning with this technology. We certainly have now a very solid foundation to build upon, where we have effective targets and effective payloads. We've highlighted some of the toxicities we're seeing from that. Also, I'd highlight within this drug with TROP2, the amount of expression has not seemed to really be a driver in this. And some of that may be the bystander effect, which I'd call a real benefit of the drug, where the payload as a drug goes through apoptosis and lysis, that payload that releases then into the surrounding- toward the surrounding cells is membrane permeable and crosses into other cells, leading to potentially more efficacy. That technology in itself, I'd say, is something that we may see incorporated further into next generations of ADCs. Whether there can be improvements in preventing toxic drug in other sites like the stomatitis, for example, with newer generations that evolve from this, we'll see.

I don't know that I would anticipate all chemotherapy ultimately going through ADC technology, but I certainly believe that this is the beginning of what I would call a whole new class. But would future cytotoxic treatment happen more so through ADC than just broad circulating payloads? If we can call it that. And I certainly think we'll see a lot more development like that. But you know, we may see other ways of developing the cytotoxic drugs in other forms of delivery as well. It'll be exciting to see as we go forward.

Davide Soldato: I also think that one of the major challenges that we probably will have to deal with, in probably not so long, is also the sequencing of these types of agents. We are starting to have, as I was saying, accumulating data regarding the efficacy of these drugs. And some of them share either the same payload or they target the same antigen on the cell. And so, do you think that we will need as a new line of research to really go into the field of cross resistance when we are using and trying to sequence these types of novel agents?

Dr. Jacob Sands: We're seeing that across various tumor types. I mean, to stick with lung in particular and small cell lung cancer, we've seen DLL 3 really be a demonstrated target for small cell lung cancer. And now we have a handful of drugs being developed that target DLL 3. How would we potentially utilize those drugs? In what orders and which ones over others is going to be an area for discussion, much like the area you're raising here, where we see TROP2 directed treatments. And so which one would you choose? On top of the fact that there are other targets, in this case, we're talking about TROP2, but of course, there's HER3 that we've seen, and especially when we're talking about an EGFR population, EGFR mutation population, we've seen good efficacy with this TROP2 antibody drug conjugate, as well as the HER3. And so how would we order those? And they both are using the same payload.

If we're talking about both of the deruxtecan compounds, this is going to take some sorting out. I think with time, it'll be tough. I don't know if we'll end up seeing head to head studies in this or if this is going to end up being shaped more by expert committees and their descriptions. But I imagine we'll see some heterogeneity in the treatment pathways at different centers just based upon preferences and familiarity with these different drugs. Of course, assuming that they all end up ultimately being approved and then that efficacy and tolerability that we're seeing continues to pan out in future trials.

Davide Soldato: So we were mentioning before that there is a very big line of development for this novel ADC. And I think that there are also some trials that are exploring the role of data DXD so the datopotamab-deruxtecan in lines where patients have received less therapy or in combination with other agents. So I wanted to ask you if you could give us some insights regarding the ongoing trials, if you know about them. And also what do you think could be the area of a met need where this drug could potentially give the most effect?

Dr. Jacob Sands: It'll be interesting to see. In the first line setting we have TROPION-Lung07 and TROPION-Lung08. These are studies with PDL-1 expression of less than 50% or greater than or equal to 50%, the greater than equal to 50% being plus pembrolizumab versus pembrolizumab alone. The less than 50% essentially being an incorporation with or instead of chemotherapy along with the platinum-based therapy plus pembro. And so that one is a more complicated three-arm study. Now, essentially what this is looking at is incorporating this antibody drug conjugate in place of chemotherapy for potential tolerability when given concurrently with the platinum and pembro. Whether or not we'll see some synergy with the chemo and the pembro, I guess I would hypothesize that we would likely see at least similar to when giving the chemotherapy, or at least that's the hypothesis driving the trial design.

If anything, whether we note improved tolerability relative to those getting, I'd say the carboplatin component, because certainly within non-squamous, non-small cell, pemetrexed is generally very well tolerated. And so that's a bit tougher to beat out from a toxicity standpoint. The trials are really designed based upon the efficacy that we've seen from this trial you're pointing out. I think by the time that this podcast is heard, we'll have the data from TROPION-Lung01 that'll be reported out as well in the second line setting versus docetaxel as that data is near release. These are areas for ongoing attention, certainly.

Davide Soldato: Thank you, Dr. Sands, for being with us today. This concludes our episode of JCO Article Insights. We discussed with Dr. Sands the results of the manuscript titled, “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.”

This is Davide Soldato. Thank you for your attention and stay tuned for the next episode.

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