This is an exciting time in lung cancer and across solid oncology for the development of more and more antibody–drug conjugates. As we identify targets, how can we deliver therapy directly to those cells and accomplish better outcomes than we can with standard chemotherapy? Today's talk is really focused on TROP2 agents. Just as a moment of background, I just wanted to explain that TROP2 what is it? It is a transmembrane glycoprotein that is overexpressed in a variety of solid tumors, including non-small cell lung cancer. Its normal role is that of an epithelial adhesion molecule, and it regulates stem cell marker associated cell regeneration. You can see the schema to say, this is why you could expect that it might be involved in oncogenic processes.

[00:20:07]

TROP2 Overexpression in NSCLC and Other Cancers

When we have looked across different solid cancers, it is overexpressed in quite a few of them. Non-small cell lung cancer is box, but you can see why this is a very appealing target for drug development. But a non-small cell lung cancer, a strong majority of both adenocarcinoma and squamous cell carcinomas do overexpress this antigen. Again, that has prompted some of the trials that Dr. Yu and I will be profiling this this afternoon.

[00:20:33]

ADCs: Key Principles

Then finally, before we get delve into these, I just wanted to show you, just remind us, get us all level set on a couple of slides. I think a lot of us have seen different versions of. Just to remember, what is an antibody–drug conjugate? First of all, it is a monoclonal antibody, selected for an antigen with high copy numbers on the target tumor cell. The whole idea is to localize to that cell and be internalized. The key decision making and making an ADC is what is our tumor antigen? We want something ideally that is very abundant in tumors and not very abundant in normal tissue. We really want to be able to use this as a selective marker. The hope again, is when it finds an antigen, then this antibody collectively gets internalized. 

Now of course, the antibody is then also composed of a linker. The linker links it to the cytotoxic drug payload. This little molecule or set of molecules of chemo that hopefully this antibody is going to deliver to the tumor. Here are a couple of payload types. That is important as you look at data across all the ADCs is that as we incorporate different payloads that affect sensitivity, affects toxicity, and it affects sequencing because you do not give the same chemo twice in a row. That also might impact even our sequencing of different ADCs in a given patient.

[00:21:45]

ADCs: Mechanism of Action

Now, the most clear cut way that an ADC might work is one through four. The antibody finds the antigen, lands on antigen, binds to the surface, gets internalized, the ADC gets processed in the endosomes and lysosomes, that payload is released, kills the cell directly. That is the classical mode of action. There are some other important ones that we have to think about that may be differential by ADC, by design, or by antigen. One is a bystander killing effect. These payloads are sometimes membrane permeable, so they can also act on adjacent cancer cells to which an ADC had not affixed itself. There can be this local bystander effect. The neighborhood gets affected by the one anchoring of an ADC. 

Then finally, we are talking antibodies. The antibody component can engage with immune effector cells, and so maybe there is an element of anti-tumor immunity that, again, goes past the single tumor cell that the antibody landed on and has a more global effect. Again, a lot to be studied there, but an important thing to keep in mind that may affect our results as we look at different drugs in different scenarios.

[00:22:47]

Anti-TROP2 Antibody-Drug Conjugates

With that as background, these are the three drugs that we are going to be talking about in detail today. These are the three anti-TROP antibody–drug conjugates that have really been studied the most in this space. Datopotamab-deruxtecan or Dato-DXd as we will call it, sacituzumab govitecan, and sacituzumab tirumotecan. All three are antibodies against TROP2. All of them have high affinity binding, and the payloads are slightly different. They are all topoisomerase1 inhibitors but slightly different molecules. Deruxtecan, of course, we know from other approved ADCs in the space. Saci has a SN-38 and then tirumotecan is the belotecan derivative. The other thing that is important just logistically, is these are all given on a Q3 week cycle. Sacituzumab is the only one that has to be given day one and day eight. The other two are just three week doses.

[00:23:36]

Second-line Treatment With TROP2 ADCs

Let us delve into the evidence we have in the second line treatment. This is usually the proving ground for a new drug in non-small cell lung cancer, at least initially.

[00:23:45]

Datopotamab Deruxtecan: TROP2-Targeted ADC

The most high profile work so far has been with Dato-DXd. Again, just a reminder, anti-TROP monoclonal antibody linked to a topoisomerase1 inhibitor an exatecan derivative. This is a high potency membrane permeable payload, short systemic half-life. The hope is that this gets to the tumor, that expresses TROP2 kills that cell, has some bystander effect, and maybe even leverages the immune system.

[00:24:10]

TROPION-Lung01: Dato-DXd vs Docetaxel in Previously Treated Advanced NSCLC With or Without AGAs

What is the evidence that we have? The most high profile study was an intended registrational trial TROPION-Lung01. Basically, this took patients with advanced metastatic non-small cell lung cancer, or stage IIIB and IIIC. They had to have had at least chemotherapy and an immunotherapy, and they could not have had docetaxel. They were randomized 1:1 to Dato-DXd given every three weeks or a standard dose of docetaxel. This is really a common competitor in these second line or beyond trials. Ramucirumab is approved in the US, but because these are often global trials, docetaxel is accepted as the coin of the realm. It is been notoriously hard to beat. 

The co-primary endpoints of this study were progression-free survival and overall survival. As you see on the right, a majority of patients had non-squamous histology, but a good proportion of squamous. We will get in a little bit later with Dr. Yu.  There are a decent number of patients with actionable genomic alterations and specifically the EGFR mutation in about 13% or 15%. The large majority of these patients had only had one or two lines of therapy, so not too heavily pretreated.

[00:25:16]

TROPION-Lung01: PFS in ITT Population

What did we find? Here is the top line data for progression-free survival. On first glance, this is a positive trial. The orange line is higher than the gray line. Maybe modest. The median PFS 4.4 months for Dato-DXd versus 3.7 for docetaxel. The hazard ratio, reflecting the whole shape of the curve, 0.75 and statistically significant. Furthermore, the overall response rate about double in the Dato-DXd arm. On the face of it, this is positive for PFS. There is a really important non-small cell lung cancer point to be made here.

[00:25:50]

TROPION-Lung01: PFS By Histology

When you look at subgroups, and it is a pretty important subgrouping of non-squamous and squamous in all of our treatment decision-making. What we see on the left is that non-squamous patients derived more benefit on this study. The median PFS was just shy of two months greater. The hazard ratio was more favorable at 0.63. On the right, that is not a typo. Those gray and orange lines have swapped. Actually, Dato-DXd underperformed docetaxel a shorter PFS and a hazard ratio favoring docetaxel. This was a disappointment. Remember, squamous actually has more expression of TROP2 when you look at it just in a basic way. This was not an expected outcome from the trial. We will come back to the point of the bottom. AGAs tended to do better, including EGFR. that is why Dr. Yu's Studies will be a little more interesting in just a minute. This was really not showing a consistent benefit across all of non-small cell lung cancer.

[00:26:41]

TROPION-Lung01: OS in ITT Population

When you added in the next slide, which is the other co-primary endpoint of overall survival, there is very little light between those curves. This was a hazard ratio of 0.94 not statistically significant.

In sum, even though there was a lot of enthusiasm to bring this to a phase III trial, this was a negative trial and we do not have a label for all comers in non-small cell lung cancer. More to come on that.

[00:27:05]

TROPION-Lung01: Safety

Just a couple words about safety, and we will have a little section toward the end about toxicity and toxicity management, but in this phase III study compared against docetaxel, which is no one's favorite taxane, but a known quantity, what did we see? The cytopenias were more modest than in docetaxel. It is still chemo, but again, maybe because it is more localized, we do not see as much of an effect on the bone marrow. How about GI side effects? I want to draw your attention to the stomatitis line. This is one of the side effects we have to be very cautious about in this particular compound. What you see here is any grade stomatitis 48% versus just 16% in the taxane and grade three or higher, meaning a lot of management needed and dose delays and discontinuations. We are talking about 7%. We will come back to how we might address that more proactively than they did in this study. But that is something really important in talking to patients about this drug. 

Then boxed on the bottom, any of these ADCs, we want to be very cautious about thinking about the ILD data. This has been seen in the breast cancer literature, in the lung literature, and in lung cancer patients, where there are more comorbid conditions that sometimes can be difficult to distinguish, it really has to be high on our radar of suspicion. What they saw in adjudicated ILD - they have a special panel to look at the data - 9% of patients had any grade pneumonitis or interstitial lung disease versus just 4% on docetaxel. Again, we will come back to some of the management of that. It is not the highest of all the ADCs, but it is notable and again something that requires proactive discussion with patient and very careful attention on symptom review and on subsequent restaging imaging.

[00:28:40]

TROPION-Lung01: AEs of Special Interest

Honing in on that, again I showed you the stomatitis data. Ocular events are also of import. Fortunately, these are usually very manageable. We have a lot of keratitis and dry eye. You see increased lacrimation as part of the keratitis. That is also something that sometimes requires a phoning a friend to the optometry and ophthalmology department. Again, the point about ILDs. ILDs can be asymptomatic, something you see on the restaging scan as an oh, by the way. They can also be grade 5. We take these very seriously, which is why early recognition and handling is very important. In grade 5 adjudicated cases, there were seven cases on the Dato-DXd arm, but I will say that four of those were deemed by the principal investigator in the case to just be progressive disease. There is always that difficult sussing those out especially in a lung cancer case, but it is just something we have to be proactive about across the ADC class.

[00:29:30]

Sacituzumab Govitecan: TROP2-Targeted ADC

Next up, sacituzumab govitecan. Again has an approval in the breast cancer literature, and again it is an anti-TROP ADC. Its payload is also topoisomerase1, but SN-38. Just a little different than the deruxtecan drugs that we have seen here and elsewhere.

[00:29:48]

EVOKE-01: Sacituzumab Govitecan vs Docetaxel in Adv NSCLC Previously Treated With Platinum and ICI

EVOKE-01 is a very similar trial and design to TROPION-Lung01 enrolling very similar patients who have already had chemo and immunotherapy, together or in sequence, and just cannot have had docetaxel obviously, because that is the comparator. Also, randomized 1:1 against the ADC versus docetaxel. The demographics were pretty similar non-squamous dominated, but a significant proportion of folks also had squamous cell disease, but the vast majority were either second or third line. A smaller proportion of patients had actionable genomic alterations. A much smaller EGFR population, for instance. This study had as its sole primary endpoint overall survival. Again, this is a phase III intended to be a registrational trial.

[00:30:30]

EVOKE-01: OS With SG in ITT and Patient Subgroups

What do we see here? Here is the OS. A little bit of benefit numerically for sacituzumab govitecan. Not quite two months at the median. Hazard ratio trending toward benefit but clearly not statistically significant. Again, this was a negative big phase III trial. Great aspirations, a plausible mechanism, but clearly in an unselected population, this is not going to be an approvable drug. There were some subgroups of interest, and this is more for discussion and planning future therapies. This is not something you are going to get a label for. An interesting observation was that in patients who had not been responsive to their last immunotherapy line of treatment, there was a more robust benefit. I do not know what to make of that, but it is out there. Again, it would be hard to design a study in that specific space. Again, hints at maybe differential benefit in different situations. 

Another important point is that this is, like a Dato-DXd, a TROP2 ADC. It has a different payload, but it is not that different substantively when you think about it. The key point I wanted to show here is that between squamous and non-squamous, it is really not a difference in benefit. Both had a very modest non-statistically significant benefit with the same hazard ratio. It is not a TROP2 phenomenon that squamous cell cancer patients are going to do less well. Again, it is just important to look at these subgroups in our study designs as we go forward.

[00:31:49]

EVOKE-01 Subgroup Analysis

Also important, and maybe this abridged into Dr. Yu's section, first of all, brain metastases. Part of the discussion around ADCs early on, the question was whether these bulky constructs are going to get past the blood brain barrier. Especially in lung cancer where brain metastases are so prevalent, are we going to have a meaningful clinical benefit for these patients? It is really good to see them reporting out these data, allowing brain metastasis patients. What we see is that there was a better, more robust hazard ratio in the brain metastatic population with a hazard ratio of 0.62. It does point to benefit in brain as we have seen in other ADCs and other situations. An important subpopulation to always keep an eye on when data are reported out. Then again very small numbers and actionable genomic alterations. Most of them EGFR. Several of them KRAS, which of course totally different clinical scenario. It is I always get leery about lumping all those together. But again, a better hazard ratio at least with this small numbers to suggest that maybe there is a differential benefit in those settings. I think that is a nice segue into Dr. Yu's section to really think about some data in the EGFR space.

[00:32:57]

Use of TROP2 ADCs in EGFR-Mutated NSCLC

Dr. Helena Yu (Memorial Sloan Kettering Center): All right. Exactly that I think Dr. Gubens set me up.

[00:33:02]

Background: EGFR-Mutated Lung Cancer

I think in the light of negative all comers studies, I think that there is some interest to look at those subpopulations where there might be benefit. This slide really tries to orient us. When we think about EGFR mutant lung cancer, a lot has changed in the last couple of years. We now have, not just osimertinib monotherapy as a first line treatment, we also have the option of giving platinum-based chemotherapy and osimertinib via FLAURA2, or the combination of amivantamab, which is an EGFR met bispecific antibody, and lazertinib, which is another third generation EGFR inhibitor. These are our three treatments of choice that all have FDA labels and recommendations. Then, there are different types of progressions. I think something that is a point to note, in many cases about a third of cases that I have seen, patients have oligoprogression where there is only one or two sites that are growing. We treat those growing sites, continue the osimertinib. If patients do have true symptomatic multi-site progression, we often recommend biopsy at this point. About 20% of the time we can find an acquired alteration that may be the reason that the cancer has begun to grow on osimertinib. Some potential findings include meta amplification and acquired ALK fusion and a KRAS alteration. Some of those lend themselves to dual targeted therapy, like adding in a met inhibitor to osimertinib. For the majority, about 80%, we have multi-site progression, no mechanism of resistance identified on either tumor tissue biopsy or liquid biopsy. Then we move on to second line. 

In the second line setting, it really depends on what you got in the first line setting. If chemotherapy was not a part of first line treatment, then there is the ability to either do chemotherapy on its own or partner with some targeted therapy. The MARIPOSA-2 study looked at amivantamab plus chemotherapy as a really valid option in the second line setting. The recent COMPEL study looked at continuing osimertinib after progression when adding in platinum-based chemotherapy. Then now, post-chemotherapy and post-osimertinib, we do have the Dato-DXd label, which we will talk about. One thing to note, amivantamab and lazertinib really only has the first line label. In the later line setting for these common sensitizing EGFR mutations, we really only have the option of adding amivantamab to chemotherapy. Then third line, there are of course other chemotherapy options we have. If somebody gets chemotherapy in the second line, of course, datopotamab-deruxtecan is a third line option.

[00:36:03] 

EGFR-Mutated Lung Cancer and Brain Metastases: Retrospective Analysis of Patients at MSKCC

Matt mentioned this, that the idea for non-small cell lung cancer is brain metastases are quite prevalent. They are even more so in EGFR mutant lung cancer. We published this past year looking at what is the natural history of patients with EGFR mutant lung cancer. You can see there is about a quarter or a third of patients that will have brain metastases at diagnosis. When you get out to five years, more than half have brain metastases. This is a really important lens through which to look at drug development. When we have multiple TROP2 ADC options, understanding which might have better CNS penetration and CNS efficacy really becomes a treatment-defining efficacy point. Then this is also a point where, if patients develop brain metastases on treatment, those are often more recalcitrant to treatment because they grew on osimertinib, a very good CNS penetrant drug. I think understanding that those patients in particular really need an efficacious second line treatment that penetrates the brain.

[00:37:19]

Pooled Analysis of TROPION-Lung01 and TROPION-Lung05 in EGFR-Mutated Adv NSCLC

These are studies, or at least TROPION-Lung01 is one that Dr. Gubens the registrational All-Comers study that he recommended, or that he discussed. Then there was a different study on TROPION-Lung05, which really focused on, again, because of that signal seen in actionable gene alterations, focused on patients with metastatic lung cancer with AGAs. Then both of those studies had a significant minority of patients with EGFR mutant lung cancer. That data was pulled together to try to get a robust number of patients with EGFR mutant lung cancer that could be assessed. I do not think it came up here, but in terms of this mutational profile, I think one thing to note is patients with atypical or uncommon EGFR mutations were also included, as well as patients with EGFR exon 20 insertion. Really looking at all EGFR mutant lung cancer.

[00:38:21]

Pooled Analysis of TROPION-Lung01 and TROPION-Lung05 in EGFR-Mutated Adv NSCLC: Efficacy

Here is the pooled analysis. When looking at the 117 patients treated in those two studies, the overall response rate was 43%. You can see the median PFS was 5.8 months and the median OS was longer at 15.6 months. These are all numbers that are higher than the intent to treat population of TROPION-Lung01. You can see the PFS curve here on the top right, and then also see a really significant median OS benefit of 15.6 months. This is again after EGFR mutant lung cancer patients have seen TKI as well as chemotherapy. Based on this pooled analysis, the FDA granted accelerated approval to datopotamab deruxtecan for patients with EGFR mutant lung cancer who have received prior EGFR directed therapy and prior platinum based chemotherapy. As of now, this is the only approval for a TROP2 directed ADC, actually, within non-small cell lung cancer.

[00:39:23]

Pooled Analysis of TROPION-Lung01 and TROPION-Lung05: Safety in EGFR-Mutated Adv NSCLC 

Here is safety data. This is similar to what Dr. Gubens has already talked about. When I look at treatment related AEs, I look at the rate of treatment related AEs that are associated with treatment discontinuation. That was relatively low at 5%. About a quarter of patients did require either a dose delay or dose reduction due to toxicity. These are similar toxicities that were already mentioned, but I think the two or three that are key to note are the stomatitis, because for patient of quality of life, this really is something that leads to the inability or difficulty with PO intake and can be quite challenging to manage. The ocular surface events, just because this is a more novel toxicity that we do not see with a lot of our anticancer treatments. Then, of course, that adjudicated drug related interstitial lung disease which is really a class effect for the deruxtecan ADCs. As Dr. Gubens mentioned, not the highest with datopotamab deruxtecan, but still significant.

[00:40:34]

Sacituzumab Tirumotecan (MK-2870; SKB264): TROP2-Targeted ADC

Moving on to sacituzumab tirumotecan, I think this is the next generation of a sacituzumab TROP2 based antibody ADC. Again, one good benefit is that this is given every three weeks, which is certainly more patient friendly in terms of dosing, and very similar, again has a topo1 inhibitor payload. There really are questions about whether topo1 inhibitor ADCs can be sequenced or not. I think time will tell there. Then of course potential for bystander effect as well as an immune effect with these ADCs.

[00:41:13]

Sacituzumab Tirumotecan in EGFR-Mutated NSCLC

A lot of text on this page, but it is summarizing two different studies with sacituzumab tirumotecan in EGFR mutant lung cancer. Again, there is this real signal that actionable gene alterations, in particular EGFR mutant lung cancer, have maybe greater sensitivity to chemotherapy, but that leads to a greater sensitivity to these ADCs. First, there was a phase I, II study of sacituzumab tirumotecan that enrolled patients with metastatic lung cancer, where about half had EGFR mutant lung cancer. Then we again see this differential where in all comers, the overall response rate was 40%, but when looking at the EGFR mutant subpopulation, it was 55%. The median PFS in the study in all comers was 6.2 months. Then the EGFR mutant lung cancer population, interestingly had a PFS of 5.3 months. Again, we are getting into really small numbers here. Only about 20 patients with EGFR mutant lung cancer. Then the median OS seen in this study was 22 months. 

With sacituzumab tirumotecan, you see more of the traditional chemotherapy related toxicity. You can see cytopenias like anemia and neutropenia and leukopenia. You do still see stomatitis, which does seem to be more of a class effect with these TROP2 ADCs. Another study, again seeing that EGFR mutation signal, enrolled 64 patients with EGFR mutant lung cancer, again treated with sacituzumab tirumotecan.

There were two cohorts looking at two different lines of therapy. Cohort one patients were progressive on both EGFR TKI and platinum based chemotherapy. Cohort two, these tumors have progressed on TKI but have not received prior chemotherapy. Usually, the earlier line we bring these agents, oftentimes there can be an increased efficacy there. In this patient population, again, the overall response rate was 34%, median PFS 9.3 months, and the median OS not yet reached. Similar toxicities were seen. Based on the sum of this data with sacituzumab tirumotecan, in December of 2024, the FDA granted breakthrough designation to sacituzumab tirumotecan in patients with EGFR mutant lung cancer after TKI and platinum-based chemotherapy.

[00:43:49]

OptiTROP-Lung03: Sacituzumab Tirumotecan in EGFR-Mutated NSCLC After EGFR-TKI and Platinum-Based CT 

Those early studies led to this larger study OptiTROPLungO3, which is again looking at sacituzumab tirumotecan exactly in that patient population that got breakthrough designation: EGFR mutant lung cancer after an EGFR TKI almost always osimertinib and platinum-based chemotherapy. These patients were randomized 2:1 to get sac TMT versus docetaxel. Patients with brain metastases were allowed and the primary endpoint was overall response rate by BICR. I think one thing to note that is not present in a lot of studies is that crossover was allowed where patients who got docetaxel were allowed to cross over to sac TMT upon progression.

[00:44:37]

OptiTROP-Lung03: Efficacy With Sac-TMT vs Docetaxel

Here are the efficacy data. I think, first looking at the overall response rate quite striking with a threefold increase in response rate with sac TMT compared to docetaxel. Then looking at duration of response was higher with sac-TMT seven months versus five months. Then the median PFS was 6.9 months with TMT versus 2.8 months with docetaxel. That an early interim analysis there did also appear to be an improved overall survival wit sac-TMT, but that data are not yet mature.

[00:45:17]

OptiTROP-Lung03: PFS and OS

Here are the Kaplan-Meier curves looking at PFS and OS. Again, a hazard ratio of 0.23 for that median PFS, 7.9 versus 2.8 months, and then looking at OS not yet reached but there does seem to be some separation of the curves. When you look at the 12 month OS, 73% versus 54% with docetaxel. So promising, and we are looking to see more mature data and potentially an approval of another TROP2 ADC in this space.

[00:45:53]

OptiTROP-Lung04: Sacituzumab Tirumotecan in EGFR-Mutant NSCLC

This is a very similar study, but moving up one line forward, where OptiTROP-Lung04 is looking at sac-TMT in EGFR mutant lung cancer patients after a TKI, but before platinum-based chemotherapy. Patients are randomized 1:1 to receiving sac-TMT versus platinum-based chemotherapy. The primary endpoint of this study was PFS by BICR.

[00:46:22]

OptiTROP-Lung04: PFS by BICR (Primary Endpoint and OS)

Here are the data for this study. Even moving up a line forward and now comparing itself to platinum-based chemotherapy, we can see a median PFS of 8.3 with sac-TMT compared to 4.3 with chemotherapy. Hazard ratio there is 0.49 with a nice separation of the curves. Then looking at OS which is not yet mature, but does appear to be trending towards a benefit with sac-TMT, with a hazard ratio of 0.6. Now we have OptiTROP data with sac-TMT really demonstrating an improvement in PFS and response rate against both docetaxel and then one line earlier with platinum based chemotherapy.

[00:47:09]

OptiTROP-Lung04: Safety

When we look at safety of sac-TMT, the rate of treatment discontinuation because of treatment related AEs was actually low at really zero with sac-TMT. The toxicities that are most prominent and actually are not so distinguished from chemotherapy, are cytopenia so anemia, leucopenia, neutropenia. We also see stomatitis. Again, just like Dato-DXd it is about two-thirds, half to two thirds of patients that have that. You can see some other GI side effects like nausea, anorexia, but one thing that we do not see with sac-TMT is ILD or pneumonitis. There were no reported cases of this. Two things being really TROP2 class effects are those ocular surface toxicities which were lower with sac-TMT than Dato-DXd but still present. Again that stomatitis.

[00:48:12]

Posttest 1

Question one. Posttest question. For patients with metastatic non-small cell lung cancer with EGFR exon 19 deletion and progression after first line osimertinib and platinum-based chemotherapy, which of the following approved treatment options would you recommend for this patient based on available evidence and currently approved indication?  Please vote.

Let us see how we did. Remember, with datopotamab deruxtecan, that being the only FDA approved TROP2 ADC, sacituzumab tirumotecan, and to a lesser degree, sacituzumab govitican, both have shown some efficacy, but Dato-DXd is the only approved agent, and ami-lazer is only approved for first line treatment. Any use of ami-lazer in the later line is really off label and not always reimbursed. So, Datopotamab Deruxtecan. 

Here, just again saying that the FDA granted this accelerated approval. The other ones are interesting and intriguing with early data but not yet approved. Docetaxel is really the comparator arm is inferior to Dato-DXd in this patient population.

[00:49:41]

Posttest 2

Which of the following most accurately describes currently approved and investigational TROP2 directed ADCs for patients with advanced non-small cell lung cancer? 

1. Dato-DXd shows a statistically significant improvement in OS versus docetaxel in all comers with non-small cell lung cancer;

2. Dato-DXd is associated with ILD pneumonitis and ocular AEs;

3. Saci govitecan is associated with ILD and stomatitis; and

4. Sac-TMT is FDA approved for patients with EGFR mutant lung cancer and brain metastases; 

Please vote.

Let us see what the answers were. Again, I think the issue with Dato-DXd in all comers is that patients did not show, or the cancers, did not show a statistically improvement, significant improvement in OS with docetaxel - did not show a statistically significant improvement in OS in all comers. Dato-DXd is associated with ILD and ocular AEs. The sacituzumab govitecan really has lower rates of stomatitis and ILD, and then sac-TMT is not yet approved by the FDA for patients with EGFR mutant lung cancer. Only Dato-DXd has the EGFR mutant lung cancer approval.

[00:51:26]

TROP2 ADC Combinations in the IL Setting

Now I am going to go over the TROP2 ADC combinations in the first line setting.

[00:51:33]

TROPION-Lung02: Phase I Study of Dato-DXd + Pembro ± Platinum CT in Advanced NSCLC

Whenever there is activity, as Dr. Gubens said, in that second or later line setting, that is the proving grounds and then we move forward to the first line treatment. This TROPION-Lung02 study is a very unwieldy study with a lot of different cohorts. It is really looking at Dato-DXd combined with immunotherapy in indications where immunotherapy alone, pembrolizumab alone would be given. Then looking at a combination of pembrolizumab with carboplatin taking out the pemetrexed or the carbo companion and putting in Dato-DXd in these different cohorts. This was a small study. This was just signal finding looking to see if there was activity in this first line space.

[00:52:26]

TROPION-Lung02; Efficacy Outcomes for First-line Dato-DXd + Pembro ± Platinum CT

Here you can see, looking at the two arms or two of the groups of arms, looking at Dato-DXd with pembrolizumab, we typically do this combination or would do this combination or would do pembrolizumab in patients who have PD-L1 expression greater than 50%. Looking at that second column, you can see that in all comers, the median PFS was 11.2 months but not yet reached in the high PD-L1 expression. Then the median OS not reached. But 100% response rate in patients that have high PD-L1 expression to this doublet. Then when looking at the triplet, the median PFS 6.8 months, confirmed overall response rate of 56%. I think enough early data to suggest that there might be activity in this first line space leading to larger registrational studies.

[00:53:24]

TROPION-Lung02: Select TRAEs in >20% of First-line Dato-DXd + Pembro ± Platinum CT

Then treatment related AEs. Again, I think one thing that we always look for when we combine two agents together for the first time is are there any synergistic toxicities? We really did not see that. One thing to look at is the pneumonitis rate which was higher. Maybe some additive toxicity with adding pembrolizumab to Dato-DXd. Stomatitis stayed about the same. Then again we saw some chemotherapy related toxicities. Besides that additive potential pneumonitis signal, nothing that looked different with these combinations. Of course, when you are giving carboplatin plus Dato-DXd, you are going to have more hematologic AEs as well.

[00:54:11]

TROPION-Lung02: Safety Summary for First-line Patients

Then again, looking at the discontinuation of any drug as a good measure of treatment related toxicity. That was higher at anywhere from 29% to 33% to 37%. These are more toxic drugs given in combination. That will be something to look out for, and then the AEs of special interest again, mucositis, ILD and ocular surface events, which were all relatively similar except a little higher rate of pneumonitis.

[00:54:45]

EVOKE-02 (Cohorts C and D): Sacituzumab Govitecan + Carboplatin/Pembrolizumab in Untreated NSCLC

Next is EVOKE-02. You can see parallel drug design and drug development between these different TROP2 ADCs. Very similar study where we are looking at sacituzumab govitecan with pembrolizumab or with pembrolizumab and carboplatin. Again, doublet or triplet. The primary endpoint of EVOKE-02 was overall response rate.

[00:55:09]

EVOKE-02: Efficacy of SG + CP (Cohorts C and D)

Here you can see the waterfall plots. This is focusing on the triplet, and you can see the non-squamous on the left and then the waterfall plot of the squamous patients on the right. Again, highlighting that point that Dr. Gubens made that, it is not that squamous cell lung cancers cannot have activity with TROP2 ADCs where we really saw potentially slightly less benefit, but pretty comparable benefit in both squamous and non-squamous for this triplet, with response rates 40 to 45%, median PFS 8.1 and 8.3 months, respectively. Not surprisingly, the higher the PD-L1 expression, the better the response to these drugs.

[00:55:54]

EVOKE-02: Safety of SG + CP (Cohorts C and D)

Here is a plot that compares the safety. This is really actually looking at two different doses of sacituzumab govitecan 10 mgs per kg versus 7.5. The things that are higher with the higher dose of SG really are neutropenia, diarrhea, which is, I think, a more unique toxicity with sacituzumab govitecan, and then stomatitis. Slightly higher tox with the higher dose of SG. 

[00:56:22]

Biomarkers for Assessing Effectiveness of TROP2 ADCs

I will turn it over to Dr. Gubens to discuss biomarkers to help us again further select which patients might benefit from TROP2 ADCs.

Dr. Gubens: Thanks Dr. Yu. Again, aside from moving to the first line, getting patients and their tumors when they are more naive, the other question is can we do a better job of selection.

[00:56:40]

TROP2 Normalized Membrane Ratio (NMR) Positivity: A Novel Predictive Biomarker

Unlike HER2, where either an activating mutation or high overexpression can yield benefit to trastuzumab deruxtecan or met in non-small cell lung cancer where IHC3+ yields to benefit in to solve, the question is what about TROP2? Really all the early studies did not show that just plain old TROP2 IHC was effective in selecting for patient benefit. It is really unfortunate to be very straightforward mechanistically. But there has been some efforts to try to do a better job here. This was an interesting study that was shown by Ben Levy at ASCO last year. The idea here is that maybe there is an opportunity to be more nuanced in how you evaluate the surface staining that we see on our pathology. The idea here is AI, if you will. You can bring in the IHC that you have done at the local lab, you image these slides and then you feed them into an automated imaging analysis system. The hope is that the computer pathologist, can do a very discreet job of differentiating tumor from non-tumor, looking just at the tumor cells, measuring this optical density of the staining. How this 1+, 2+, 3+ that is very subjective under human eyes. Can we really quantify this meaningfully? Basically this metric gives a cutoff 75% of cells with a low nuclear membrane ratio positivity distinguishes a positive population. Can this be a discriminator in these trials?

[00:58:07]

TROP2 NMR Positivity in TROPION-Lung01 With Dato-DXd

In TROPION-01 [?], that study I showed you that was modestly positive for all comers PFS, if you apply this NMR testing the people designated high, which is 107 patients in this sample, it was a meaningful proportion of patients. You really could distinguish that these patients had more Dato-DXd benefit than those who were negative. Even if IHC is not, maybe this metric, which does require some automation, but presumably can be operationalized to send slide images to a central repository where the computer can do its work, maybe this could be a way you could design a trial to enrich for benefit. Also, noticeably this is a predictive marker not prognostic. Because you notice the docetaxel did not matter what your NMR status was.

[00:58:56]

TROPION-Lung02: TROP2 NMR* for First-line Biomarker Evaluable Subset Measured by QCS

In further study in TROPION-Lung02 which is a study Dr. Yu Just showed us they looked at these first line regimens. Either the doublets or the triplets. Similar theme emerged. These were not comparative trials. These were just nominally looking at these interventions. What they saw was that the median PFS was significantly longer in patients who had this TROP2 NMR positivity in their tumor. Really a promising biomarker, enough that the sponsor actually has started enrolling a phase III registrational trial that looks like TROPION-Lung01. It is called TROPION-Lung17, which shows how much development is happening in this space, but actually randomizes people in the same way against docetaxel if, in the second line and beyond, if they have this NMR positivity. That is very promising and maybe a better way to do precision oncology than saying, "It is highly expressed but maybe not meant to be an all comer drug." As of today there is no IHC discriminator in the label. The only label, of course, is in the EGFR space. That is the biomarker we are using for now. For now, no TROP2 focused assay is involved in us selecting patients but stay tuned for the future.

[01:00:06]

Posttest 4

With that question four posttest, which of the following statements best reflects the evidence for TROP2 normalized membrane ratio NMR positivity in the therapeutic use of ADCs for non-small cell lung cancer? 

1. Is associated with improved PFS in patients receiving Dato-DXd; 

2. Can it be used to predict resistance; 

3. Does it identify patients at an increased risk of AEs or toxicity; or 

4. Is TROP2 positivity by NMR required per the FDA label to give this drug, Dato-DXd; 

Mark your answer.

Great. We do see some delta from when we started. More people answered the correct answer, which is association with improved PFS in patients getting Dato-DXd. That is the promise of it, and hopefully that will be validated in a phase III trial that enrolled patients selected for that positivity. A couple of you still were tempted to say TROP2 positivity was required per the FDA label. Again, there is no FDA label for most patients. It is just for the EGFR patients. And no, there is not a TROP2 discriminator. These are not used to predict resistance. They are not used to identify increased risk of AEs at this time.

[01:01:25]

TROP2 ADCs: Toxicity Management

Finally, we have been talking a lot about toxicity. This is so important as we try to incorporate new drugs into our paradigm for non-small cell lung cancer, especially when there are competing choices like in the EGFR space. The patient experience of toxicity is so important and so is proactive management of these toxicities.

[01:01:41]

TROPION-PanTumor01 Substudy: Prophylactic Mouthwash for Mucositis/Stomatitis

We have stressed multiple times that stomatitis is a feature of these drugs at a variety of grades of AE, but higher than at least thoracic oncologists are used to for the vast majority of the chemo drugs we already give. What is really, I think, useful is that as we have gained more experience with these drugs in the standard of care, not just in the lung cancer space, but also in study development, there has been emphasis by the sponsor to not just say, "Oh, a steroid mouthwash is useful PRN," is to say, "Why do not we actually work it into the instructions for the trial?" This is, among other studies, this is a substudy of TROPION-Pan Tumor01, which basically randomizes patients to A, prophylaxis, not waiting for something to happen, but to do it proactively. But also to see if we can demonstrate a benefit of a steroid including mouthwash over a non-steroid mouthwash. Because anecdotally, this really has been helpful for our patients. I will admit, in my institution, as we wrote our epic Beacon orders for Dato-DXd, we added in as a mandatory premed, prophylactic steroid mouthwash. I already believe the data but this will be nice to have validation and some numeric weight behind that, and also to make sure we can get an insurance approval and the like.

[01:02:54]

Management of Stomatitis/Mucositis Associated With Datopotamab Deruxtecan

Just to some helpful hints about stomatitis and mucositis. What are we looking out for? Again, we know this as oncologists, but you know lips and mucosa appearing redder, the appearance of sores. Sometimes actually I have had patients with mouth pain without any sores or obvious redness, but very much affecting chewing and swallowing and dysphasia. I think the key here is just to recognize it, identify it, and be very proactive about it. If there is just mild symptoms, we usually do not change the Dato-DXd. We just want to make sure are they really doing all the things we are asking them to do? The next slide, we will have some other practical hints. When we start getting to ulceration, we are delaying dose. We want to let that heal. The half-life of these drugs lets us have a little time off and really get a patient back to a manageable state. Then there is an option at level two. But at grade 3, really, if we are going to go back to the drug upon resolution, we are going to resume at a reduced dose. That is something to really consider and really has made a difference in the grading of these on an ongoing basis. Then finally, if you are getting to oral intake, not possible life threatening consequences, of course, this is not the drug for your patient. We really should be moving on to other things.

[01:03:58]

Supportive Care and Management of Stomatitis/Mucositis 

Secondly, and also just some supportive care things. Some of these are obvious, but I think it just bears mentioning again. Just ring a bell, and in our patient education materials, we started to have a dot phrase in epic to encapsulate some of these, avoiding spicy, highly acidic foods, soft liquid diet. Artificial saliva can be useful when people have dry mouth. Viscous lidocaine can be useful, especially if you are trying to get people back from that grade 2 and 3, in addition to the steroid action, and mouth rinses as well are very straightforward. Again, as I mentioned, I do not do reactive oral liquid dexamethasone. I do it proactively.

[01:04:34]

Management of Ocular Surface Toxicities Associated With Datopotamab Deruxtecan

Aside from mucositis again Dr. Yu stress as I mentioned it that ocular surface toxicities, just because they are not as common in the other drugs in the non-small cell lung cancer armamentarium. Just what are we looking out for? What are we counseling patients on? The elements of dry eye like redness and stinging and blurred vision and sensitivity to light. Then the keratitis piece where there is a lot of lacrimation, difficulty opening the eyelid. Of course, it is tough when patients have a predilection for brain metastases in non-small cell lung cancer, we are also just always remembering blurred vision, vision changes. Let us make sure we think about the differential. Really I think the key message here is to make sure that you have an optometry or ophthalmology offer to them. Sometimes we suggest that patients, if they have not seen their docs recently, to get back in touch. And again, to have a number in the institution to say, "Hey, I have got someone who has got an issue now, can we get them in quickly?" Those are very busy clinics in our neck of the woods. Having that relationship and getting people in and treated quickly lets us stay on longer or not have to come off it altogether if we can be proactive in managing them. Again, most of these are reversible. That is important. But perforation you are off this drug. Of course I have not seen that yet.

[01:05:39]

Management of Interstitial Lung Disease/Pneumonitis Associated With Datopotamab Deruxtecan

Then finally again as Dr. Yu You mentioned this is across ADCs and all the deruxtecans have an element of this. Just especially in lung where we have people who have preexisting COPD and emphysema, you have lymphangitic carcinomatosis. There is a lot of differential aside from pneumonia, that you just have to be mindful and looking out for shortness of breath, dry cough.  Things that happen between restaging scans, I listen for very carefully. A, because it could be progression, but also because maybe they are doing great cancer wise but we are seeing some of this pneumonitis evolve. We do sometimes see patients with pneumonitis on restaging scans where the patient feels great, there is not a symptom, we do hold for that. Even if we are not totally sure on the differential, I hold for that. Carefully follow them for symptoms and offer to do very close follow up at three to four weeks so I can hop right back on to treatment with a patient where that resolves. But we do not continue, even with grade 1 localized pneumonitis. That is why we also do not usually start steroids or anything. We really just want to watch that, but there is an offer to give steroids, maybe if it is more extensive. As soon as patients are symptomatic, we are seeing oxygen fall, we are seeing a cough, we are seeing anything that starts limiting care, then we are going off Dato-DXd. This is a little more dogmatic than maybe our management of pneumonitis in other settings like TKI. Really the recommendation is, if you have to invoke steroids for anything symptomatic, you probably should not go back to Dato-DXd. It is important, especially to establish that differential diagnosis, make sure that is the cause, but just want to emphasize that asymptomatic things, we hold drug for, hopefully, go back on when it resolves on its own, plus or minus steroids. Once you are symptomatic, once you are having severe symptoms, you really are off drug.

[01:07:20]

Posttest 3

With that, we will do the question number three. Based on current guidelines, how would you manage grade 1 asymptomatic ILD on Dato-DXd? 

1. You continue with close follow up at the current dose and add the steroid then; 

2. To continue with close follow-up but dose reduce at this time;

3. Do you delay the next dose until resolution; or

4. Do you delay and also add infliximab now; or 

5. Do you stop Dato-DXd for this asymptomatic ILD; 

All right. The largest number, you said delay next dose until resolve that. That is what I can see as the right answer. I think a few people did think we should continue, adding a steroid. You can add a steroid, but you really, even at grade 1, we should stop and hold. Does not mean we cannot go back on. I do see resolution of these infiltrates on a four week scan, and I hop right back on therapy. You really should not continue with close follow up with or without additional drugs. Not even with dose reduction. You really should delay until resolution, but you do not have to discontinue altogether. Some of these do resolve on their own.

[01:08:34]

Future Directions for TROP2 ADCs

With that, I will hand it back to Dr. Yu for just a couple of words about future directions for our TROP2 ADCs.

Dr. Yu: Yeah, I will only spend a minute on this so that we can answer questions. So, please enter questions in the chat if you have anything related to TROP2 ADCs.

[01:08:48]

Select Ongoing Trials With Sacituzumab Govitecan and Sacituzumab Tirumotecan in NSCLC

Here is a select group of ongoing studies that are still going with different TROP2 ADCs. I think one strategy is combining these ADCs with other novel therapies. You can see there is this bevacizumab, sacituzumab govitecan. The ongoing studies, of course, looking at the first line with the sacituzumab govitecan and pembrolizumab. The sacituzumab tirumotecan development plan really is focused on EGFR mutant lung cancer, where we are seeing, again, the more registrational or confirmatory studies looking at sacituzumab versus chemotherapy. We will see those studies and then, looking at studies with Dato-DXd, there is that study that Dr. Gubens mentioned looking at TROP2 NMR positive non-small cell lung cancers without AGA, really to see if we can recapitulate TROPION-Lung01 but in patients that are hopefully selected to have more of a greater benefit. There is a first line study in EGFR mutant lung cancer combining Dato-DXd with osimertinib versus osimertinib alone. That is the TROPION-Lung14 study. Then the confirmatory study TL15 that is looking at chemotherapy versus dato or dato plus osimertinib. Some confirmatory studies, some combinations in the first line, and then we are interested to see that TROP2 NMR study that comes out.

[01:10:24]

Summary

Just a quick summary, and then maybe we can get to a question or two. TROP2 is a compelling target in non-small cell lung cancer. There are obviously multiple ADCs, and these are not all of them that are being actively investigated. Dato-DXd is approved for EGFR mutant lung cancer. All comers, irrespective of TROP2 expression after TKI and chemotherapy. There is no TROP2 biomarker currently used to select patients for these ADCs although some are in development. Then again, many combinations and moving the TROP2 ADC to the first line setting. Then I think really proactive intervention but also surveillance for these toxicities because both mucositis ILD and the ocular toxicity. The sooner we diagnose these, they are much more manageable and obviously maintaining the quality of life for our patients.

[01:11:17]

Poll 3

Two more polls too. Poll three. Do you plan to make any changes in your clinical practice based on what you learned in today's program? 

Please vote. Let us see the answers. Maybe we do not see the answers for these ones.

[01:11:39]

Poll 4

One more. Please take a moment to enter one key change you plan to make in your clinical practice based on this education.

[01:11:47]

Questions?

Any questions? Maybe we take one, or do you have a question? I can ask you a question.

Dr. Gubens: Dr. Yu, as a world leader in EGFR, I am curious, your use of Dato-DXd, and the thought of ADCs and the sequencing, both specific things in these non-canonical mutations. How are you using it in exon 20? Is it something you are enthusiastic about, or you will add it to the list? Are you willing to extrapolate some of the AGA data outside of EGFR at all?

Dr. Yu: Yes, I think those are both great questions, Matt. I think I am surprised that the label was broad and covered all of these different EGFR mutations with pretty small subsets. That being said, I will take advantage of it. I do not see any biologic rationale why this should only work for EGFR L858R and exon 19 deletion. Absolutely, I think exon 20 and uncommon mutations both have less treatment options. I would think of this, again after a targeted therapy like amivantamab or sunvozertinib after chemotherapy, this would be next step in that space. 

Then yes, I think that the AGAs really I think it comes down to likely a greater sensitivity to chemotherapy. I think that if these were more widely available, I do think that the benefit in EGFR likely would be recapitulated in, say like ALK positive lung cancer, RET positive lung cancer. Just like in the adjuvant setting, when we have these really small genomic subsets, we are not going to be able to do a full study. I think that we can extrapolate to some degree.