This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.

Hello and welcome to the Decera Clinical Education Oncology Podcast. I’m your host, Sharif Morsalin. Today’s podcast features Dr. Helena Yu from Memorial Sloan Kettering Cancer Center and Dr. Matthew Gubens from the University of California, San Francisco. They will be sharing their insights on integrating TROP2-directed therapy in non-small cell lung cancer, including emerging data on antibody-drug conjugates and how these agents may fit into current and future treatment strategies.

For more information on our presenters, along with a link to the full educational program, please visit the show notes for this episode.

Now, let’s get started and hear what the experts have to say.

Introduction

Dr. Helena Yu (Memorial Sloan Kettering Cancer Center): Hello, everyone. Thanks for joining me for this Oncologist On-Call Podcast on integrating TROP2 directed therapy in non-small cell lung cancer. I am Helena Yu. I am a thoracic medical oncologist at Memorial Sloan Kettering in New York, New York, and I am joined by Dr. Gubens.

Dr. Matthew Gubens (University of California San Francisco): Hi, my name is Matt Gubens. I am a thoracic medical oncologist at the University of California, San Francisco. Really good to be with you today.

Dr. Yu: All right, so we are discussing TROP2 as a therapeutic target. Maybe Matt, we can start off by just you explaining why is there an interest in TROP2 and, in particular, why in non-small cell lung cancer?

Dr. Gubens: Sure. TROP2 is a transmembrane glycoprotein that is over expressed in a lot of tumors and that is what is made it really useful as a potential target in developing antibody drug conjugates. For example, in non-small cell lung cancer, fully 75% of squamous cell and 64% of adenocarcinoma have TROP2 over expression. Because it is across a lot of cancers, it really has been something that several companies have looked to develop drugs against. Before we plow into how these have been created, Helena, why do not you give us a reminder of how antibody drug conjugates work and some of the key principles that are involved in their design?

Dr. Yu: Absolutely, Matt. There are more and more of these ADCs in clinical development and also approved for different solid and liquid tumors, but ADCs have three components. There is a monoclonal antibody that is selective for a specific antigen. Today's topic of interest, of course, these are TROP2 monoclonal antibodies. There is a chemotherapy payload. The two most common payloads are MMAE, which are microtubule inhibitors, or kind of topo-1 based payloads, which are DNA damaging agents. The antibody and the payload are linked by a linker. The idea of that linker is that the ADC molecule is brought into the cell and then only when it is brought into the cell is that linker cleaved, and hopefully that payload is released into the cell. There is some amount of what we call bystander effect, which is when some of that free payload might get released a little bit early so that there are potentially other cells adjacent to the tumor cell that can be affected by the ADC, and then there is a question about whether certain ADCs have something called ADCC, which is when there is an immune effect from the antibody that helps illicit anti-tumor effect itself. What are the ADCs that are directed against TROP2 that are in clinical development right now, Matt?

Dr. Gubens: The three that we are going to talk about today that have been developed in a lot of disease types. In fact, some already have approvals in lung and other tumors. The three that you hear us talk about today that are TROP2 ADCs are dato-DXd (datopotamab deruxtecan), SG (sacituzumab govitecan), and sac-TMT (sacituzumab tirumotecan). You get the sense they all have the same version of payload. They are all topoisomerase one inhibitors, though of course deruxtecan for dato-DXd, SM38 for SG and belotecan for sac-TMT. They do have that similarity. They have different drug antibody ratios and, for the most part, are every three week dosing schedules, though SG has a day one and a day eight in the Q3 week cycle.

That sets the stage for the three drugs we will be talking the most about that have the most data in non-small cell lung cancer. Now, a lot of these of course, start in the second line after our established first line therapy. Maybe Helena, if you could start talking about dato-DXd's data for the second line setting.

Dr. Yu: Sure. All of these ADCs were initially looked at in this later line setting with an unselected, non-small cell lung cancer population. Although we will discuss further the only approval we have for one of these TROP2 ADCs is actually in an actionable gene alteration subset EGFR mutant lung cancer. We are thinking that there may be other approvals based on some of the ongoing studies. Dato-DXd was looked at in patients with non-small cell lung cancer that was previously treated with chemotherapy and immunotherapy.

The randomized study TROPION-Lung01, looked at dato-DXd compared to our standard of care second line treatment, which is docetaxel. It was a large study more than 600 patients, that were enrolled. We had expected that there would be, reasonable efficacy with dato-DXd based on the phase 1 and phase 2 studies. In terms of the PFS, which was the primary endpoint of the study, dato-DXd had a median PFS of 4.4 months compared to docetaxel at 3.7 months. I think the interesting data was really in the different histology subsets, because this is where the big difference was. When focusing on non-squamous non-small cell lung cancer, the benefit with dato-DXd was actually greater with a median PFS of 5.5 months compared to 3.6 months.

The somewhat surprising data was when we looked at the squamous cell population where really they seemed to have a lack of benefit with dato-DXd, with a median PFS that was shorter than what was seen with docetaxel. Dato-DXd with a median PFS of 2.8 months compared to 3.9 months with docetaxel, and then, one might not be so surprised that, with those more modest or lack of benefit in PFS, we really did not see a statistically significant difference in overall survival. That really led to, a segue or a change in the clinical development for this agent that led to its ultimate approval.

We talked about how this is a TROP2 ADC. Matt, maybe you could go through some of the common side effects that we see with dato-DXd since they are a little bit unique from some of the other ADCs that we are familiar with.

Dr. Gubens: It is so important, as we get to see more of these ADCs in clinic, to get familiar with the very unique set of toxicities each of them have. With TROPION-Lung01, it was a big study. We had a lot of patients compared against docetaxel, a drug we know and maybe do not love, but one thing I always think of is how many patients had to come off study specifically for toxicity. The discontinuation rate was about 8% compared to 12% with docetaxel. Even though there is some side effects I will talk about often, these are ones we can mitigate through proactive management or certainly addressing as they come up.

One thing that is important to mention is that this is an ADC. It is meant to deliver a chemo more acutely to the tumor site and the microenvironment, but these are still chemo side effects. Some of the side effects are similar to other deruxtecan based ADCs we have across cancer indications. One of them is stomatitis and oral mucositis. This was more than double the incidence in dato-DXd compared to docetaxel. This does require some anticipatory guidance to our patients. It is more than docetaxel, but it is manageable often with steroid mouthwash.

Another unique thing to this drug is ocular events, and this is something that we do not see as much in our standard of chemo, so we have to be very aware of it. Again, talking to our patients about it. Most common are things like dry eye, increased tearing, but a subset of patients do get keratitis, sometimes ulcerative in nature. Some people have conjunctival hemorrhage, visual acuity reduction. Not large numbers, but enough that we really should have ready access to optometry/ophthalmology in the care of these patients on an ongoing basis.

A final thing I wanted to call out, and this is important as we think about all the ADCs, is the incidence of interstitial lung disease. This is so important in our lung cancer population where sometimes it is harder to discern what is pneumonitis versus lymphangitis spread versus infection viral or bacterial. This is of course why a lot of the studies have formal adjudication. The formal rate assessed was about 9% in the dato-DXd arm versus 4% in docetaxel. In terms of the incidence of grade 3 or higher, we are talking about 4%. It is a minority, but it is one you really have to be looking out for. First of all, for asymptomatic ones that you see on imaging you are doing for restaging, but also any new symptoms because these pneumonitides you really want to be discovering early, treating early so that fibrosis does not set in. There were grade 5s on both arms. Granted, some of them were ultimately ruled progressive disease, but I really think about these strongly when I use any of our ADCs. Again, these are seen in all of our studies of TROP2 and other ADCs.

Dr. Yu: I think, having a very reasonably high pretest probability for pneumonitis, especially with our lung cancer patients who already have potentially shortness of breath, cough, hypoxia, it becomes really tricky to diagnose it and you have to always be thinking about it as top of mind. With the toxicities, any personal experience with having patients with the stomatitis or the ocular events, and any experience about how you managed it?

Dr. Gubens: I think especially with the stomatitis, a prophylactic steroid mouthwash has been really invaluable. That is one thing. Cryotherapy actually having people suck on ice chips during their infusions, is really helpful and very easy to manage. For ocular events, mostly they have been things that we can handle topically. Luckily, I have not personally had to refer a patient to an ophthalmologist or optometrist for any more significant eye toxicity, though it certainly is reported in the trials.

Dr. Yu: Maybe segueing a little bit, datopotamab deruxtecan is not the only TROP2 targeted ADC. Another one that has been looked at in lung cancer is sacituzumab govitecan. Maybe you could run us briefly through what data we have for sacituzumab govitecan in non-small-cell lung cancer.

Dr. Gubens: Another TROP2 ADC. Some of you listening or maybe are using this in other indications. We also had to go at it in lung cancer and the trial EVOKE01 was very similar to TROPION-Lung01. Patients who had already had their first line chemo immunotherapies, they would have had targeted therapies if they had an actionable genomic alteration. But again, randomized to the ADC, sacituzumab govitecan given days one and eight every 21 days versus our old standard, docetaxel. Unfortunately, even though there was maybe a numerical improvement in overall survival by about a month and a half, 11.3 versus 9.6 months, it was not statistically significant. Again, we have a trial that maybe showed a hint of benefit, but in the all comer population, unselected for TROP2 status, we really did not see enough to get this drug across the approval line.

There were some interesting kind of subsets and we will talk about that, especially in terms of folks who did have these actionable genomic alterations. I also am always interested as these studies report out their subset of patients with brain metastases. I think it was not obvious before we looked at all these ADCs, they have brain activity, but each of these studies has shown some of that benefit, and, as with dato-DXd, have shown some benefit in the brain metastasis subpopulation. Again, not enough in this big phase 3 to carry it over the line to approval.

With that said, maybe it is a nice segue, Helena, to maybe think about how this fits into this EGFR mutation space. Such an interesting and multifaceted area, so many new options in the first line, but it seems that ADCs have had an outsized benefit in the EGFR subpopulations in these big trials, enough that the sponsors have pursued studies specifically with these patients. Maybe you can lay out some of the EGFR specific data for dato-DXd and sac-TMT.

Dr. Yu: Yes, absolutely. I think that was a clear signal with, these TROP2 ADCs, but also with other ADCs. Some of the AGA positive lung cancers have maybe a greater sensitivity to chemotherapy in general. I think that translates to some of these ADCs and perhaps maybe enrichment of the protein targets of interest as well.

For first-line therapy for EGFR mutant lung cancer, we now have three options. We can give osimertinib monotherapy, which is that third generation EGFR tyrosine kinase inhibitor. We can give osimertinib with platinum-based chemotherapy. Rather than sequencing the two we give both chemo and osimertinib upfront. Then another option is amivantamab and lazertinib. Amivantamab is an EGFR met bispecific antibody, and lazertinib is a different third generation EGFR TKI.

Based on what you get in the first line setting, there may be an opportunity to proceed with second line chemotherapy, either as a first exposure or perhaps as a re-treatment if they received platinum chemotherapy some time ago. After EGFR TKI and after chemotherapy, then that is where I think some of these ADCs come into play. That is exactly where dato-DXd is approved.

The approval for dato-DXd id EGFR mutant lung cancer really came from a pooled analysis of that TROPION-Lung01 larger non-small cell lung cancer study that I briefly went over and then TROPION-Lung05. Lung01, of course, was randomized where half the patients received dato-DXd, and half the patients received docetaxel. Then, TROPION-Lung05 was a single arm study that really focused on those actionable gene alteration positive lung cancers. In some, it was more than 300 patients that were treated with dato-DXd with different actionable gene alterations. Of that, about 117 actually had actionable mutations in EGFR.

Based on that pooled analysis, we saw that there was a median progression-free survival benefit with dato-DXd of 5.8 months and an overall survival of 15.6 months. Based on this pooled analysis, the FDA did grant accelerated approval to dato-DXd for patients with EGFR mutant lung cancer that have received prior EGFR-directed therapy as well as platinum-based chemotherapy.

One interesting point, which maybe is something that distinguishes this therapy from other available therapies is that the approval was a little bit broader, where it really included all different EGFR mutations, including the atypical or uncommon mutations as well as EGFR exon 20. I think, unlike some of the indications which really focus on the common mutations of exon 19 deletions in L858R, dato-DXd is, available for use, in the different types of EGFR mutations.

Dr. Gubens: It is great to have this new option. I am curious, you really are an EGFR guru and if you have these patients in your clinic, let us say just a canonical EGFR exon 19 deletion patient, maybe you put them on FLAURA2 and they had osimertinib and chemotherapy for a good two years, maybe about the median on that study. What is your approach when they progress? Are you going straight to dato-DXd? What is your thinking? What is your process in clinic?

Dr. Yu: This is a really practical question that we are now facing or will be facing soon as we put more and more patients on first line FLAURA2, the regimen. A lot of patients on FLAURA2 and clinically, in practice discontinue the chemotherapy sometime during their treatment course. Of course people get three months of the platinum-based therapy, but the median time of exposure of the platinum, even on the study was just over eight months. As you said, most of our patients are on maybe two plus years, and so there is certainly a chemo free period where I think that consideration of retrial of chemo might be appropriate.

If people have been off the chemotherapy for greater than six months, but certainly greater than a year, one of my first things that I might turn to is actually retrial of the chemotherapy. At that point, I probably would pair it with something. I would think about adding in amivantamab if they have not seen that in the first line setting, based on the MARIPOSA2 data, or I was compelled by the COMPEL data for patients that have perhaps existing but well controlled CNS metastases that may be continuing the osimertinib and adding back the chemotherapy could also be appropriate. Then, after the chemotherapy and maybe after they have seen amivantamab, that would be when I would think about adding in dato-DXd. Certainly before docetaxel or some of our later line treatment options.

Dr. Gubens: Such a increasingly complex area. Glad to have options, but it really gets messier, and that is to say nothing of rebiopsying along the way to see if there are other actionable resistance mutations.

One final, very practical question about the dato-DXd approval is when you do eventually start it, do you leave on the EGFR TKI?

Dr. Yu: Yeah, that is also a tough question. I think we know that there can be additive benefit potentially for keeping on the TKI while starting new therapy, but certainly additive toxicity as well. The ORCHARD study did treat a small cohort about 50 to 60 patients with a combination of osimertinib plus dato-DXd, and it certainly was doable. There did seem to be significant efficacy with the combination, but definitely additive toxicity. And there are some ongoing studies that will help us decide how much of an added benefit continuing the osimertinib is. There is the TROPION-Lung 15 study, which is looking at dato-DXd versus dato-DXd plus osimertinib compared to chemotherapy in that second line setting. Generally, again, if patients have well controlled CNS metastases, where I am concerned about removing the osimertinib, those would be people that I would think about continuing the osimertinib while adding in dato-DXd. For patients that do not have CNS metastases and have systemic progression only, I might just do the dato-DXd. What about you, Matt?

Dr. Gubens: That sounds very reasonable. I think I have a similar approach and appreciate that nuance. This is, again, so complicated. Every patient in front of you has such a different constellation of metastatic disease and velocity that you really take all these into consideration. More to come on all of those fronts.

Are you excited about any of the other ADCs in the AGA and specifically EGFR space?

Dr. Yu: I am. There are certainly a lot of drugs that are in clinical development. I think taking a lesson maybe from dato-DXd. There is this focus of development of some of these ADCs and the actionable gene alteration positive lung cancers. There are, as you mentioned before, there is the sacituzumab tirumotecan, which has been looked at in EGFR mutant lung cancer in a similar setting post TKI post chemotherapy, and does look quite similarly active like dato-DXd, that agent has breakthrough therapy designation. We await additional studies. In the OptiTROP-Lung03 study, the median PFS with sac-TMT in EGFR mutant lung cancer was 6.9 months compared to 2.8 months with docetaxel.

I am looking forward to and expect that there will likely be additional approvals of ADCs in general and TROP2 ADCs in particular in the space. I think one thing that will help us distinguish between these different agents is, as you mentioned earlier, CNS penetration. I think in non-small cell lung cancer at large and, in particular for EGFR mutant lung cancer, we do see a really high incidence of CNS metastases. That could be a distinguishing factor as to whether we choose one drug over another. More to come there.

The development of these TROP2 ADCs does not stop at EGFR mutant lung cancer though. There is a push to consider these in the first line setting in addition to potentially chemotherapy or in combination with immunotherapy. Matt, perhaps you can go over some of those first line studies just so we have some anticipation of what might be coming.

Dr. Gubens: Sure. All of these drugs, aside from being tested in these big phase 3 second line trials, have also been looked at in a whole bunch of combinations in the first line. First line is complicated, right? We are all very comfortable with the immunotherapy for the right patient, chemoimmunotherapy, while trying to suss out the subdivisions of squamous versus non squam, high PD-L1 to low or non-expressing PD-L1. It gets very complicated in terms of what partners you might put with dato-DXd. For example, in dato-DXd there is a phase 1 study TROPION-Lung02, that is looking at a variety of combinations with either pembrolizumab or pembrolizumab plus chemo in different subsets of first line patients.

These are very early. They are smaller numbers, but there were really encouraging signals that when you looked at these first line patients, in 35 patients with dato-DXd and pembro alone. In PD-L1 expressing, you were seeing a response rate of 55% median PFS 11 months. You are pretty respectable and I think we are going to look for more signals over time. Then you can add in chemo as well, especially for the patients who do not have that PD-L1 expression at baseline just to make sure they are fully covered with chemo. We are seeing, good response rates in the mid 50% range. We are seeing relatively good tolerability. Nothing we did not expect in terms of additive toxicity, including in pneumonitis, which again, such an important thing to look at when you are starting to add it with immunotherapy. We will soon be seeing phase 3 studies report out. We would not do this right now off the cuff. This is something we really have to see the data for, really be able to look at it in comparison with our standard of care first lines already.

Sacituzumab govitecan same thing. EVOKE02 is the study there that they are looking at different combinations in different settings. Again, combined with pembrolizumab and carboplatin, they are seeing response rates in the 45% range in non-squamous, for example, PFS of 8.1 months. Enough to get the drugs to phase 3 trials, which we all eagerly await the results of.

Of course once they come out, we will have a lot of data to parse the next couple years to think about how it fits into our current paradigm. Is there enough additive benefit? Is the toxicity profile reasonable enough to give these combinations to our patients? I really eagerly await these, but there will be lots more of these podcasts to come to try to suss out those results. I think they are going to be coming at us fast and furious in the next year or two.

I think one question, Helena, I have is one of our very first successful ADCs in lung cancer was actually trastuzumab deruxtecan. That drug is only approved in HER2 mutation tumors and in HER2 highly overexpressed 3+. Very careful niches where you know that the patient's tumor is so clearly driven by HER2, whether it is overexpression or mutation. In TROP2, as we have discussed, the studies have been really all comers. Granted TROP2 is expressed and overexpressed in a majority of non-small cell lung cancer, but has there been any effort to try to figure out the actual extent of TROP2 expression and to actually use it as a predictive biomarker and maybe a selection point for enrollment in trials?

Dr. Yu: This has been a really frustrating aspect of ADC drug development. I think we all thought intuitively that cell surface expression of these proteins would predict response. You would think that the more TROP2 you have on the cell surface of the tumor, the more likely you would be to respond to a TROP2 directed ADC. As you mentioned, we really have not seen that, where all of the large studies have post-hoc looked at TROP2 expression and really have not seen a clear association between, at least, immunohistochemistry based expression of these different protein markers and response. Hence that push to look for other biomarkers such as these actionable gene alterations that might enrich for a population that might benefit.

With dato-DXd, there has been some effort to look at other ways to measure protein expression on a cell surface. One such effort is something called NMR positivity, which is the TROP2 normalized membrane ratio. It is a computational approach that is utilizing some amount of AI to help us measure TROP2 expression. By doing so using this TROP2 NMR, they were able to find some degree of correlation with TROP2 expression by NMR and response. More to come here to see if this can be scaled, if it could be relevant to other TROP2 ADCs. Of course we do appreciate this effort to really help look for subsets that are going to benefit more from these therapies. Because, as we have more treatment options, really finding a biomarker to help select the right patients for the right treatment certainly becomes important

Dr. Gubens: You are right. I think that it is so appealing to think there might be a good biomarker to really predict the patients who are going to have better benefit, but already the logistics of getting NGS testing, doing IHC for HER2 for MET, is really getting more and more complicated. It really requires a lot of communication with our multidisciplinary team to make sure we get the tissue we need to answer all these questions. I think that NMR is really exciting.

Helena, in your clinic, any other helpful hints and practical advice you have about how to give dato-DXd and other ADCs emerging in the TROP2 space?

Dr. Yu: I think what you described earlier, I will reinforce it and say that I agree. I do think that the prophylactic steroid mouthwash is really critical in terms of both prophylaxis as well as treatment when early grade mucositis does occur. This prophylactic steroid mouthwash does require creation at a compounding pharmacy, where not every pharmacy might have this, but certainly any compounding pharmacy can make these dexamethasone mouth rinses. I do prescribe that before I initiate treatment with dato-DXd or any of these TROP2 ADCs. The idea is to do more minimal use prophylactically and then more escalated or intensive use should there be any signs of mouth sensitivity or symptoms.

Then I do think the ice chips is something practical that patients can do on treatment. I do think that is helpful. Then for the ocular surface toxicities, I have had one patient that had a significant toxicity. I think one thing, the package label for dato-DXd does recommend an ophthalmology eval before making sure that they have seen the eye doctor within the last few years and then have access to somebody more quickly. Because it is not something that you want to escalate at the first sign of symptoms if there is issues with vision. You want them to see one of your eye colleagues right away. I think with that and with steroid drops and lubrication, I was able to continue the dato-DXd after the acute event resolved.

Then finally I think pneumonitis is a class effect with these ADCs and in particular with the deruxtecan backbone. I think at any sign or concern for pneumonitis, just hold the drug, right? We obviously do need to rule out progression of disease or infectious causes, but I think it never hurts to hold the drug, get a CAT scan, and then maybe more quickly involve some of our colleagues, like our pulmonary colleagues who might be able to do a bronchoscopy to really get a more definitive diagnosis. Especially because, for any symptomatic ILD, you are really supposed to discontinue the drug permanently. It is a decision that you do not want to make lightly, but something that we know that very early treatment and intervention for ILD really does improve outcomes and can prevent mortality with this toxicity. I think really important.

To end, we mentioned obviously some of these first line trials, but that is not the end of what is going on with these TROP2 ADCs. Maybe, Matt, do you want to just select a few studies with these TROP2 ADCs that are ongoing that you are interested in seeing results of?

Dr. Gubens: It is just tremendous the investment in these large phase 3 trials to get answers in the very near future. Again, aside from some of these first line combinations in just standard variety stage 4 patients, we also are seeing phase 3 studies in other areas. One I was interested in is that stage one where we have high risk pathologic features, positive liquid biopsies, or ctDNA, there actually is a trial randomizing patients including rilvegostomig, but also with dato-DXd. That is an interesting option. Another thing is looking deeper into the AGA space, and we alluded to this being approved after EGFR directed therapy and after chemo, as you reminded us. Trying to bring it earlier in treatment in that setting too. TROPION-Lung14 is actually looking at dato-DXd plus osimertinib versus osimertinib. A phase 3 study. It will be very interesting to see how that pans out. Then also in the second line setting, so maybe instead of going to chemo, actually using it as a continuation with osimertinib, or as dato-DXd, alone compared against platinum based chemo. That is another phase 3 trial TROPION-Lung15.

Then finally, to your point before about NMR positivity is maybe a good predictive biomarker for benefit. There is something called the TROPION-Lung17. This is taking the same approach as TROPION-Lung01, but refining the population to the NMR TROP2 positive patients. The hope is that these are patients of a better pretest probability of having benefit, and that in this setting, dato-DXd will win out over docetaxel in that important second line setting. All these are phase 3 studies. These will be practical applications if they turn back positive. Really excited over the next few years to see advances in this field as they emerge.

Dr. Yu: Absolutely, and I think the TROP2 ADCs are not in isolation. We also have development of HER3, EGFR, all sorts of other ADCs. And so, figuring out how they all fit in a very similar space will be hopefully a fortunate problem that we will have in the future.

Matt, thank you so much for joining me. Hopefully we got the listeners excited about these different TROP2 ADCs, and really as you mentioned, there are a lot of potentially practice changing studies that we hopefully will get results from in the near future. We will be eagerly awaiting those.

Dr. Gubens: To claim CME credit, for this activity, please click on the claim credit button on your screen.

Thank you to both, Dr. Yu and Dr. Gubens, for a great discussion and for sharing your expertise with us. And many thanks to you, our listeners, for joining us today. Be sure to check back for more episodes on important oncology topics!