Targeting TROP-2 and TIGIT: Experts Discuss How ADCs and Immunotherapeutic Combinations Are Transforming Lung Cancer Treatment

TROP-2 as a Therapeutic Target

I will be talking about TROP-2, and then I will turn over the discussion to Ben, who will be primarily discussing TIGIT. TROP-2 is a therapeutic target that is being assessed in different solid tumors, in particular, non-small cell lung cancer and small cell lung cancer. TROP-2, if you are not aware, is a transmembrane glycoprotein. It is overexpressed in solid tumors, including non-small cell lung cancer. It is a protein where there is a lot of important action downstream, with cyclin, MAPK, ERK, beta-catenin being important downstream pathway actors. TROP-2 is an epithelial adhesion molecule and regulates stem cell marker-associated cell regeneration. Because of this significant expression in tumor cells and less expression in normal cells, it really sets itself up as a good target for anticancer treatments.

[00:15:21]

Anti-TROP-2 Antibody–Drug Conjugates

We have several anti-TROP-2 antibody–drug conjugates that are currently in clinical development for lung cancer. We have datopotamab DXd, which we will talk about as Dato-DXd. We have sacituzumab govitecan and sacituzumab tirumotecan. They are all TROP-2-directed antibodies. I think in terms of the differences between these active drugs, some have an IgG1 antibody, some have an IgG1 kappa antibody. There are different sorts of binding affinities. The linkers that link the antibody with the payload are slightly different between datopotamab and sacituzumab. One is enzymatically cleaved, and 1 is hydrolytically cleaved. Payload is actually quite similar. They are all topo I inhibitors, so we do see similar across-drug toxicities. The DAR, which is the drug antibody ratio, does vary. The higher the DAR, the more efficacious a drug could be. But also potentially toxicity comes with that as well. Dosing schedule is different where sacituzumab govitecan is Day 1, Day 8, and the other 2 drugs are every 3 weeks. All of these are weight-based drugs.

[00:16:41]

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

First, we will talk about the 1 approval that we have for a datopotamab deruxtecan in lung cancer to date. This is based on a pooled analysis of 2 studies, TROPION-Lung01 and TROPION-Lung05, and really focusing on the EGFR-mutated advanced non-small cell lung cancer population.

Lung05 took patients with advanced metastatic non-small cell lung cancer who had an actionable gene alteration AGA that had received prior targeted therapy, but also prior platinum-based therapy. Lung01, a similar patient population advanced metastatic non-small cell lung cancer with AGAs, needing to have had, again, targeted therapies and platinum-based chemotherapy. Lung05 put all patients on Dato-DXd, and Lung01 was part of that larger randomized study where a portion got Dato-DXd and then another portion got docetaxel. But when pooling these 2 studies together, there were 117 patients with EGFR-mutant lung cancer that were enrolled.

And then in terms of the mutational profile, of course, we see the common EGFR mutations, exon 19 deletion, and L858R. But interestingly, exon 20 and some of the atypical, uncommon EGFR mutations were also included. Actually, this will come into play when we see the ultimate FDA approval label.

Endpoints of the study really were the overall response as the primary endpoint.

[00:18:16]

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

Here is the data. You can see that the overall response rate. In the pooled data, the majority of which had received prior osimertinib, were a response rate in the 43-45% range. Median PFS 5.8 months in both of those cohorts. Median overall survival is somewhere in the 16-18-month range. You can see the Kaplan-Meier curves here showing median PFS as well as median OS for this patient population.

Just 2 months ago, the FDA did grant accelerated approval for datopotamab deruxtecan for patients with EGFR-mutant lung cancer that have received both. One, EGFR-directed therapy, and 2, platinum-based chemotherapy. The label just says EGFR-mutant, so it does include patients with exon 20 as well as the uncommon EGFR mutations.

[00:19:15]

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

In terms of safety, I think that there are certain toxicities like cytopenia, fatigue, nausea that are that run across all of these antibody–drug conjugates. When we think about toxicities that might be unique to datopotamab or to TROP-2 ADCs, they really are these AEs of special interest.

We do see mucositis to some degree in the majority of patients, grade 3 in less than 10%. We also see a summation of these ocular surface events, dry eyes, keratitis. That is about a third of patients, but pretty rare to have grade 3. Of course, for all these ADCs, we do see interstitial lung disease or pneumonitis that was relatively low at 4%. I always like to look at treatment-related AEs that lead to treatment discontinuation. There is a typo there, but it is relatively low at 5%. And then again, here you can see a bar graph form of these different toxicities. Again, we do see alopecia, nausea, fatigue, which really run across the different ADCs.

[00:20:32]

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

Moving on, leaving EGFR-mutant lung cancer behind and focusing on non-small cell lung cancer at large, we will discuss some of the cohorts from TROPION-Lung02, which is a study of datopotamab deruxtecan with pembrolizumab and/or datopotamab with pembro and platinum-based chemotherapy.

There are these multiple cohorts that can be quite complicated when you look at them up here, but really, it is Dato-DXd at 4 mg/kg vs 6 mg/kg, either with pembrolizumab alone or pembrolizumab with carboplatin-based chemotherapy.

The primary objective of this initial study really was safety and tolerability, with secondary objectives looking at efficacy.

[00:21:21]

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

Actually, Dr Levy, my co-discussant, did discuss this data at ASCO. When we looked at toxicities, I think that is in line with what we see with pembrolizumab and what we see with pembrolizumab with chemotherapy, where we do see stomatitis. Again, relatively low rates of pneumonitis. Also seeing fatigue, alopecia, nausea as well. Of course, it is understandably hematologic. AEs were, of course, more frequent in the triplet groups receiving chemotherapy as well.

[00:22:03]

TROPION-Lung02: Efficacy Outcomes for First-line Dato Dxd + Pembro ± Platinum CT

Here is the efficacy data. You can see, focusing on the lighter blue, which is Dato-DXd with pembrolizumab. Response rate ranges from 53-100% of the patients who are PD-L1-high. Looking at the median PFS, right now at 11.2 months. When we look at the triplet combination median PFS, 6.8 months. Confirmed overall response rate of 55.6. So really promising data where we do seem to be adding something to the standard of care of being pembrolizumab and chemotherapy in this space.

[00:22:45]

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

Now, switching over to sacituzumab govitecan, which is a different TROP-2 ADC, we are looking at the EVOKE-02, which is actually similar to the TROPION study we just discussed, where we are focusing on different cohorts, really defined by histology, squamous or non-squamous, and then PD-L1 status, whether it is low or high. And then getting 2 different doses of sacituzumab govitecan, either with pembrolizumab alone or pembrolizumab with carboplatin. These are, again, patients with stage IV non-small cell lung cancer that received no prior therapy. This was first-line treatment and were not allowed to have any actionable genomic alterations. Primary endpoint being overall response rate.

[00:23:33]

EVOKE-02: Antitumor Activity (Cohorts C &D)

Here is the data. The waterfall plot on the left is for patients with non-squamous. You can see the overall response rate being 45.1%. Median PFS 8.1 months. Interestingly, especially with datapotamad deruxtecan not really showing benefit in the squamous cell population, you can see that this combination also seems to be active in squamous cell lung cancer, with an overall response rate of 39%, a median PFS of 8.3 months. You can see that response does track with PD-L1 status, with higher responses and presumed higher PFS with increasing PD-L1 expression.

[00:23:23]

EVOKE-02 (Cohort C &D): Safety

Safety-wise, I think not surprisingly. Patients that received sacituzumab govitecan at the higher dose did see higher or increased toxicities. In particular, some of the cytopenias, diarrhea, and stomatitis being enhanced in the higher group, but expected side effects in both groups. There were less toxicities that led to treatment discontinuation with SG at 7.5 mg/kg.

[00:24:26]

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

The EVOKE-01 study. This is looking at sacituzumab govitecan vs docetaxel, so a registrational study compared to the standard of care. This is similar, a population of patients with advanced non-small cell lung cancer. But these patients actually progressed on platinum-based chemo and ICI checkpoint therapy, and targeted therapy if they did have an actionable gene alteration. Patients were not allowed to have active CNS metastases. They were randomized to either sacituzumab govitecan or docetaxel. In this later line study, the primary endpoint was overall survival. This was a large study with over 500 patients randomized.

[00:25:43]

EVOKE-01: Overall Survival With SG in ITT and Patients Subgroups

Here is the overall survival data. We have seen this before with a numerical improvement in overall survival, but not statistically significant in the intent-to-treat population. There were potentially some subgroups that showed enhanced benefit. One that they highlighted in the presentation was patients who had a lack of response to the last anti-PD1 ICI regimen. You can see again that the hazard ratio crosses 1. Numerically increased overall survival, but not significant.

[00:26:21]

EVOKE-01 Subgroup Analysis: SG in Patients With Brain Metastases and Actionable Genomic Alterations

They did look at other subgroups. Two of the other subgroups they looked at were patients that had pre-existing brain metastases prior to study enrollment. They seem to do better with sacituzumab govitecan, maybe suggesting that there is reasonable CNS penetration with SG, and then also in patients with known actionable gene alterations. I think this is a theme with these ADCs that maybe we can talk about in the discussion about why this AGA population seems to be enriched in response to these different ADCs.

[00:26:54]

Sacituzumab Tirumotecan in EGFR-Mutated NSCLC

Switching gears and talking about sacituzumab tirumotecan, there were 2 single-arm studies that were looked at in specifically EGFR-mutant lung cancer. Both of these looked promising with, again, response rates anywhere from 34-40%. Median PFS ranging from 6-9 months. This is in patients after treatment with EGFR TKI in some of the cohorts after platinum-based chemotherapy.

In terms of treatment-related toxicities, really similar to what we have seen in other studies of sacituzumab tirumotecan. Based on these promising initial studies, last year, the FDA granted breakthrough therapy for sacituzumab tirumotecan exactly in this population of patients with EGFR exon 19 deletion or L858R after TKI and after chemotherapy.

[00:27:55]

OptiTROP-Lung03: Phase II Trial of Sacituzumab Tirumotecan in EFGR-Mutated NSCLC

At ASCO this year, we actually saw some of the results from the OptiTROP-Lung03 study. This is, again, looking at sacituzumab tirumotecan vs docetaxel in this EGFR-mutant AGA-positive population. The data that we saw looked very promising, where the overall response rate for sac-TMT was 45% compared to docetaxel, 15.6%. A near tripling of the response rate. When we look at PFS, the PFS was 6.9 with sac-TMT and 2.8 with docetaxel. The overall survival data was immaimmature but seem to be a significant hazard ratio improving OS with sac-TMT. We await that final OS data.

Okay. That ends our section looking at TROP-ADCs in non-small cell lung cancer.

[00:28:58]

Posttest 1: When discussing new clinical data with your colleagues, in which of the following patient populations with locally advanced or metastatic NSCLC would you tell them datopotamab deruxtecan is currently FDA approved?

When discussing new clinical data with your colleagues, in which of the following patient populations with locally advanced or metastatic non-small cell lung cancer would you tell them that datopotamab deruxtecan is currently FDA-approved? Please vote.

We close the poll. I think we will be able to see results now. Perfect. You guys did great. The majority of you voted for EGFR-mutant lung cancers after EGFR-directed therapy and after platinum-based chemotherapy. That is exactly where the approval is for datopotamab. At this point, there is an ongoing study, TROPION-Lung15, which is looking at datopotamab immediately after progression on TKI, and randomizing against chemotherapy. Those results are not yet out. Exactly the right indication. Good job, everyone.

[00:30:12]

Here is the rationale.

Going to talk about TIGIT. Take it away, Ben.

[00:30:22]

TIGIT Axis Inhibits Innate and Adaptive Immunity Through Multiple Mechanisms

Dr Levy: Before we start on TIGIT, maybe we can layer in some discussions here on TROP-2. Helena, you did a great job of going over that. I guess I will start with a question. Maybe you can pepper questions to me here. We have got a lot of conflicting data. Do you think the EGFR space is where these TROP-2 ADCs will really land? Are there other possibilities and an all-comer approach in the second line? Where do we see this going?

Dr Yu: I think it is the million-dollar question. I think these drug companies are thinking about spaces to go in. I think that using this aging population is low-hanging fruit. We have seen before that EGFR, ALK-positive lung cancers are more sensitive to chemotherapy and presumably more sensitive to ADCs. I think there is some degree of biomarker selection by AGA. I do think that that is certainly a subset that might benefit. The other thing I know some of the companies are looking at is TROP-2 expression, not just by IHC, but by QCS or some of these other methods. Maybe, Ben, you can explain to all of us what is being looked at.

Dr Levy: I will try. This is a complicated way, at least on the surface, of measuring TROP-2. Just to take a step back here, it seems like for IHC, most of these ADCs do not predict response to ADCs. Now, maybe HER2 is an exception and MET is an exception, but at least in the TROP-2 space, these TROP-2 overexpression by IHC historically and consistently has not enriched the patients that are more likely to respond, which does not make a lot of sense, because we think that the more expression of the protein you have on the cell surface, the more likely there is engagement of that monoclonal antibody and more cell kill. But that has not been the case.

One of the things that has been looked at is a new biomarker called QCS or TROP-2 QCS, or NMR. I could spend 20 minutes trying to explain it, but the bottom line is this, it is trying to measure accurately the level of TROP-2 expression, not on the cell surface, but more inside the cell membrane. The question is, why would that make a difference? Why would a TROP-2 expression or content inside the cell really enrich patients that are more likely to respond? I think we have to go back to the mechanism of action of these drugs, which is that, yes, they bind to the cell surface, but they really do their damage when they are internalized. If you can measure that internalization of TROP-2, that may be a better way to do it.

Now, the way that this is done is by sophisticated computational pathology. It is an artificial intelligence approach to doing this. I do not want to get too much in the weeds here. When this was presented, I think people were, Is this something that you can really do in everyday clinical practice? The bottom line is, it will be something that we are able to do in clinical practice if this biomarker holds true. It is just a software program that can be used that digitize the cell can measure the levels of TROP-2 inside the cell. You come up with a ratio. But the bottom line is that may be a biomarker that holds true. It may force us to look at other places for biomarkers outside of just IHC.

We will have to see how this goes, the long-winded answer. But the data, at least from TROP-2, from the first line, looks fairly encouraging so far.

Dr Yu: What are your thoughts or your knowledge on whether this is scalable? I think TROP-2 is not in isolation. There are a lot of different ADCs with different targets. The ideal thing would be some multiplex test, where we test each tumor for these different markers to really select which ADC might be the best.

Dr Levy: It is the holy grail. I think you have hit the nail on the head. Can we do something reproducible, it is scalable, and generalizable, that can be at our desk after the biopsy is done that we have this result within a reasonable amount of time? I think this is where there are a lot of challenges.

We are in the infancy of artificial intelligence. I think that may create complexities as it relates to scalability. You are right. A multiplex would be great. One-stop shop, multiple stains. You find your answer very quickly from 1 or 2 slides on which ADC you leverage. I think we will get there over time. I think we are still trying to understand how these drugs work. By trying to better ,understand, and maybe we will have an understanding also of biomarker identification and enrichment strategies. Very interesting times.

Dr Yu: Very interesting. The other thing to think about with all of these coming down the pipeline is sequencing. We are seeing a lot of TOPO-1 backbone ADCs, but we know that there are other ADCs in development. Radio conjugate ADCs. I think there is a lot of different space. But understanding what component makes a tumor resistant to 1 of these ADCs, and how that tells us what we can do down the line, I think it will also be an important question.

One more for you. I know you have had some experience with datopotamab and sacituzumab. What about the mucositis and the eye tox? How much do you see that? How does that impact patients?

Dr Levy: A great question. Something that everyone needs to have on their radar now that datopotamab deruxtecan is approved in the EGFR space, as you mentioned, Helena. I think the stomatitis is real. I do not want to undersell it. It is there. It occurs in more than half of the patients. Most of these are grade 1 or grade 2. A grade 2 stomatitis is not the easiest thing to deal with, with a patient. Being proactive in the management of stomatitis is important, specifically for Dato-DXd. We do not see it a lot with sacituzumab govitecan, but we see it with Dato-DXd. I would say preemptively that the steroid rinses and the ice chips during the infusion may make a difference, with the operative word being 'may.' I think it is important to at least try. Is this an overmedicalization for the patient? Maybe. But given that this drug is now approved, it does make a lot of sense to try those proactive strategies.

I think the ocular stuff is interesting. I would just ask the community, investigators, and doctors, even the academic folks out there, to just be mindful of asking these questions about dry eyes and blurry vision, and challenges with eyesight. Those are the things that I think we are not used to asking. I would also say, remember to partner with your ophthalmologist. Find a good 1. We had a tough time for a while at Hopkins. I think they are hard to find sometimes. They are all great doctors, just maybe a little bit more difficult to find. But it is really important to partner with an ophthalmologist so that they can be seen. There are strategies to mitigate these.

I am not too concerned about the ocular more than the stomatitis. I think the stomatitis is where we need to get really proactive. That can be a rate-limiting step in getting patients getting them the right dose on the right schedule. I think it is really important.

ILD, as you mentioned, Helena, it is there with Dato-DXd. I think we have to be very careful. We have learned a lot from trastuzumab deruxtecan and HER2 about ILD. I think we are still trying to understand the mechanism of action of the ILD in the lung, and potentially mediated by macrophages in the lung. I think that it is also important to note when you are treating patients.

Dr Yu: I think it is a class effect with these ADCs. We are adding in PD-1 inhibitors. We are adding in targeted therapies that have their own risk of pneumonitis. So, really being careful during these studies of making sure that there are maybe additive tox but not synergistic tox, like we have seen with some of the targeted therapy PD-1 combinations. We will have to look at that.

Dr Levy: Yes.

Dr Yu: Over to you to start the talk about TIGIT.

Dr Levy: Yes, a great segue here. The TIGIT Axis. Similar to PD-L1, this is an axis that allows for tumor cells to have immune escape, immune evasion, similar to PD-L1. It does this by a variety of mechanisms that you see on this simple schematic here. It makes a lot of sense biologically. It makes a lot of sense scientifically to try to abrogate the signaling, similar to what we have done with checkpoint inhibitors with PD-1 and PD-L1 inhibitors, given that these are similar in the way that they behave, this pathway behaves. TIGIT has been front and center for a while. We have got some mixed data here. I think it is important to hit the pause button here, in August, as World Lung comes up and Asthma comes up, to see where we are and potentially where we are going with TIGIT.

[00:39:50]

Anti-TIGIT Therapies in Development

These are the anti-TIGIT therapies in development. There are a couple that have been discontinued, belrestotug and tiragolumab. We will go over that data first. Both of these are anti-TIGIT IgG1 monoclonal antibodies. And then we have got drugs that are still ongoing. Lots of clinical trials with domvanalimab and rilvegostomig. Domvanalimab is an anti-TIGIT IgG1 monoclonal antibody. Rilvegostomig is a little bit different. It is a bispecific. It inhibits both PD-1 and TIGIT. Some of the unique features of domvanalimab and rilvegostomig are that the FC portion of the monoclonal antibody is either reduced or silent. The potential theoretical advantage of having a silent FC portion of that monoclonal antibody is that it may limit toxicity, it may limit some of the immune-related toxicities that can be seen. A lot of drugs here to look at. Think appropriately, going over the ones that just are not going to make it first would be important.

[00:41:01]

GALAXIES Lung-201: Efficacy of Dostarlimab ± Belrestotug in Metastatic NSCLC

The GALAXIES Lung-201 was looking at the efficacy of belrestotug + dostarlimab, which is a checkpoint inhibitor, so similar to pembrolizumab. A very straightforward study, a Phase II study evaluating belrestotug + dostarlimab in patients with high PD-L1, greater than 50%, and looking at different doses of this anti-TIGIT molecule.

It looked fairly good when you are looking at response rates here. We are looking at single-agent dostarlimab. This is a checkpoint inhibitor given to patients who are treatment-naive with a high PD-L1 response rate of anywhere from 30-40%, which is what we have seen with pembrolizumab in KEYNOTE-024. Looking at the addition of this TIGIT, it seemed like it did improve response rates across the doses.

[00:42:02]

GALAXIES Lung-201: Safety

When we look at toxicity, we do see perhaps more grade 3 treatment-related adverse events with belrestotug plus dostarlimab vs dostarlimab alone. Nothing here to me would be treatment-prohibitive here. There were more grade 5 serious treatment-related adverse events in the combination arm vs the single agent. The most common treatment-related adverse events were subcutaneous tissue disorders and endocrine disorders.

[00:42:42]

SKYSCRAPER-06: Tiragolumab + Atezolizumab + Chemotherapy in Untreated Metastatic NSCLC

Moving on to tiragolumab. I think we have learned a lot about this compound. It has been in the news. Obviously, we have gotten presentations now, high-level presentations. A lot of promise with this compound, given again the scientific rationale.

This was SKYSCRAPER-06, a very straightforward, very clinically meaningful Phase III study asking a clinically relevant question. Patients with advanced non-small cell lung cancer without an EGFR or ALK mutation were randomized to either the KEYNOTE-189 regimen of carboplatin + pemetrexed + pembrolizumab, or cisplatin, with placebo. That is the control arm or the addition of tiragolumab in this patient population. There was a lot of promise in this study. This was all PD-L1s because KEYNOTE-189 is approved for all PD-L1s. The question was, can you add an anti-TIGIT molecule and improve outcomes? Maintenance pembrolizumab was given in the control arm. You got maintenance here, tiragolumab in the experimental arm with the atezolizumab. Unfortunately, no improvement in median PFS and no improvement in OS. This was a little bit of a disappointment. I think we thought maybe there would be something here. Hazard ratios of 1.27 and 1.33, respectively, for PFS and OS. Really, no benefit there.

[00:44:13]

SKYSCRAPER-01: Tiragolumab + Atexolizumab in Untreated Metastatic PDL1-High NSCLC

And then SKYSCRAPER-01, which is similarly the KEYNOTE-024 analog here of looking at the addition of tiragolumab to atezo vs atezo alone for patients with PD-L1 greater than 50% advanced age who were treatment-naive. Again, similar to the prior study, once again, the addition of this anti-TIGIT monoclonal antibody to atezolizumab vs atezolizumab alone showed a small benefit in PFS, but really no benefit in the co-primary endpoint of OS here. Based on these studies, to my knowledge, tiragolumab is no longer continuing development in the non-small cell lung cancer space.

[00:45:09]

Phase II ARC-7: Domvanalimab + Zim ± Etrumadenant vs Zim in 1L metastatic PD-1L-High NSCLC

Moving on to domvanalimab. Again, this is an anti-TIGIT monoclonal antibody. It has a reduced FC effector function. This was the Phase II ARC-7 study. This was evaluating domvanalimab plus zim vs zim alone. Zimberelimab is an anti-PD-1 monoclonal antibody. This was in treatment-naive patients with a PD-L1 greater than 50%. What we have seen, at least based on the abstract presented by Melissa Johnson a couple of years ago, is an improvement in progression-free survival. We see 9.3 months in the dom plus zim arm vs 5.4 in the zim arm alone. These curves look encouraging. These are small numbers of patients. It is a randomized Phase II study. But certainly looks encouraging, at least initially.

[00:46:07]

Phase II ARC-10: Domvanalimab + Zim vs Zim vs CT in 1L PD-1L-High Stage IIIB NSCLC

And then we move to the Phase II Arc-10 study. Very similar design. It was a 3-arm study looking at chemotherapy as another arm. We will ignore that arm for now, but very similar. Domvanalimab plus zim vs zim alone, and patients that were stage IIIB-IV non-small cell lung cancer, once again with a PD-L1 greater than 50%. This is a big study. It is a global, multicenter, randomized study. We are seeing, again, improvements in progression-free survival. These again are smaller numbers right now. We have roughly 40 patients in each arm. Perhaps ticks towards overall survival here, too. Looks encouraging. We will have to see more mature data. We will certainly have to look at more of the OS and see what happens there.

[00:47:00]

Phase II ARC-10: Safety of Domvanalimab + Zim vs Zim vs CT in 1L PD-1L-High Stage IIIB NSCLC

Finally, looking at the safety of domvanalimab, I think this is a theme with the TIGITs, at least with dom and rilvegostomig, is that we are not seeing that much more toxicity additively when you add this drug to a checkpoint inhibitor. We did see a little bit more grade 3 treatment-related adverse events in the dom/zim arm, 21% vs 15% in the zim arm. But we do see that most of these are grade 1 or grade 2. I think that these drugs are fairly tolerable. We will just have to see if they translate into meaningful benefit for patients.

[00:47:37]

ARTEMIDE-01: Efficacy of Rilvegostoming in Checkpoint Inhibitor-Naive Metastatic NSCLC

Finally, the rilvegostomig. This is a bispecific. This is a little different than the other TIGITs we are talking about. This is a PD-1 TIGIT bispecific. We have got a lot of data that is forthcoming with this compound. This is looking at single-agent rilvegostomig in patients who are heavily pretreated, and who were also checkpoint-inhibitor-naive. These patients had never seen a checkpoint inhibitor.

Tough to make heads or tails of this, given that these patients have never seen a checkpoint inhibitor, and whether inhibiting the PD-1 axis in and of itself is enough here, and how much the TIGIT is doing, given that this is a bispecific. But we are seeing here encouraging response rates. Even in the 1-49%, that is a 30% response. Again, these are small numbers. The PD-L1 is greater than 50%, roughly 60%. Again, is that being pushed with the PD-1 arm of the monoclonal antibody? Clearly, we have a lot of work to do here with this compound. But the waterfall plots look encouraging in -high pretreated patients. I think, Helena, you and I were discussing before how many studies are ongoing with this compound. I think we will have a lot more answers in the next 12-24 months on where this compound fits, if at all. I think we have to see what larger data sets show.

[00:49:00]

Select Phase III Trials of Anti-TIGIT Therapies in NSCLC

Again, these are ongoing studies looking at multiple anti-TIGIT therapies. There are a lot of them. I would say the domvanalimab and rilvegostomig are really where we are looking ahead for some of these studies. Tough to keep up with all the arms and all the therapeutic strategies here. I think hopefully we will have some answers, again, in the next year or so with some of these compounds.

Let us do the post-test. Maybe then, after the post-test, you and I can discuss what is going to happen with these compounds. This is post-test question 2.

[00:49:41]

Posttest 2: Based on ARC-10 trial in patients with treatment-naive PD-L1–high NSCLC, which statement best describes the clinical activity with domvanalimab + zimberelimab vs zimberelimab alone?

Based on ARC-10 trial in patients with treatment-naive PD-L1 high non-small cell, which statement best describes the clinical activity with dom zim vs zim alone?

This is a tough one. I think PFS and OS both trended to better outcomes here. I think the majority of you got it right, if you look at the percentages. I think that is right.

[00:50:20]

Let us move to post-test 2. There is your rationale right there. Again, these are early signals of efficacy, and I think we will have to wait and see if this is statistically significant and meaningful after a larger data set and events occur in more maturity.

Panel Discussion and Audience Q&A

[00:50:38]

Helena, TIGIT, makes a lot of sense. We were all in love with tiragolumab data, at least before it was presented. We thought this was an idea that worked. The drug was well-tolerated. I am going to ask you an unfair question here. Do you think these existing drugs will make it? Do you think, given the early preliminary data we have with domvanalimab, and the preliminary data that is very early with rilve, is there traction with these compounds?

Dr Yu: It is, again, another million-dollar question. I think that the bar is very high because we have seen similar drugs fail in the past. I think there is a scientific rationale. We have great preclinical data. There was just this expectation that this would take us to the next level, past PD‑1. I do not know. Again, the biomarker question looms large. Some people say there is the TIGIT ligand, PVR, is that something that might come into play? Is there a subset of patients? Not the ones that have PD-L1-high expression, who we expect to respond to PD-1 inhibition alone, but a different group that is not as immune-sensitive. That might be the right population. I guess these larger studies are done. Maybe we can do a little bit of stratification and subgroup looks to see. I do not know. What are your thoughts?

Dr Levy: Yes, those are my thoughts. I think you hit the nail on the head. It is really challenging. It is like drinking from a fire hose, trying to understand. The biological rationale looks so sound. But as we know, that which is scientifically reasonable, does not play out in our clinics every day. I will say this, the data with tiragolumab was really tough for us. I think there was so much promise there. They did the right studies. They did the Phase III studies and the all-comer approach and combination with chemotherapy. They did the Phase III studies with greater than 50%. I am wondering what is different about these other drugs, like domva and rilve, that will say this is different.

Taking a page out of the ADC, we learned that datopotamab deruxtecan is no better than docetaxel. We have learned that sacituzumab govitecan is no better than docetaxel second-line. We learned that patritumab deruxtecan is no better than chemo in the second-line. How many times are we going to do these studies now in the second-line in an unenriched patient population for ADC? Now, that is my argument there. I am just borrowing it here.

I do think that potentially the bispecifics, and just seeing early signals with some of these bispecifics, look promising. Maybe you do have to abrogate 2 different signaling pathways at the same time with an antibody that holds on tight and does not elicit toxicity. Maybe that is the way it goes, and maybe you do not even need a payload with the bispecifics. Maybe the ADCs go away because you just have that bispecific engagement, and that is all you really need. I am excited potentially about the bispecific. I am. More than the anti-TIGIT monoclonal antibody with domva. We will see. We are participating in some of these studies with domvanalimab in the stage III setting with PACIFIC-8. But I am very encouraged or excited, let us say, about rilve.

Helena, what do you think? Is there any difference between the bispecific? We got amivantamab. Now, it is a challenge with the tox, but it is a bispecific that has made it in lung cancer.

Dr Yu: There is clear activity. I think the rationale is there. With a bispecific, you have just a more specific tumor target engagement. It might be hand-waving. As you said, there are so many studies ongoing, we will have the answer. But I think ultimately, looking at biomarkers and some subset populations, and that is not all we are looking at. I think there is a big push into cellular therapy, T-cell-directed therapy. I think pursuing a lot of different avenues to move the bar to the next level makes a lot of sense. The jury is out.

Dr Levy: The jury is out. We have 2 really good questions in the question box that I just want to tackle real quick. We will start with the second one. Do you see the NCCN Pathways Committee re-reviewing data for the broader FDA-approved label or limiting recommendations to specific deletions and insertions? I am on the guideline pathway. I am going to back off here. Helena, you can give us your take.

Dr Yu: The reason I brought it up and pointed it out during my section was I actually thought that the label was L858R and exon 19 deletion, as the NCCN guidelines are. I am almost a little surprised that they got the full EGFR mutation label, because if you look at that pie in the very beginning, it was probably 10 or 15 patients treated with uncommon or exon 20. I think that was already pooled data. I would imagine that the bar might be a little bit higher for wanting to see a more robust data set. I am just not aware if that is upcoming. I think the question asker brings up a good point in terms of, a lot of the EGFR novel treatments are focused on L858R and exon 19 deletion. But then, when they get approved, we are like, what about uncommon? What about exon 20? The biological rationale of these things working is similar. It does leave us with, clinically, what should we do?

Dr Levy: Yes. I think you are right. This is a little bit difficult to discern right now. I was surprised as well. I think we need further clarification here. Let us move to this other question about with the coming advent of AI, when can we expect an individualized chemo-immune drug regimen?

I will start. I do not know if we will ever get to that level of sophistication, at least over the next 5-10 years. Maybe in the next 20, we can get there. It seems so complicated when you talk about artificial intelligence-assisted biomarkers, because the question comes back over and over again, is it scalable? Can you do this in everyday practice? The answer to that question is yes, you can. It is going to take a little time. But I do see a day when this will become more and more relevant for us. How it gets pushed in the context of the other biomarkers, though, does it supersede some of these other biomarkers like PD-L1? Are we looking at something else? That is where I think things get really tricky.

Helena, that was a hedge of an answer by me, by the way. Helena, your thoughts on this?

Dr Yu: I do not know either. Maybe the beauty of AI is integration, though. Right now, we think about PD-1 expression. We think about TMB. We think about radio mix, all that sort of isolated potential biomarkers. But I think some of the power of AI might be integrating these different biomarkers into something that is multimodal, that takes into account a lot of different aspects of the tumor. I do think it is scalable as well. I think AI a year ago is different than it is going to be next year. I hope that we can become that sort of precise with our precision medicine.

Dr Levy: My running joke is that I went into lung cancer because it was easy. In 2008, there were 3 drugs, pemetrexed, bevacizumab, and erlotinib. Wow, how the world has changed better for our patients, better for physicians. But it is complicated. It really is complicated for the practitioner out there who has to integrate all of the things that are currently going on. I doff my cap to you. It is hard work. It speaks volumes to the importance of programs like this.

I think we have got about 5 minutes left here, 5-10, and I will just zoom forward here on the small cell data that we have.

Applications for Targeting TROP-2 and TIGIT in SCLC: Show Me the Data

[00:59:18]

We have learned a lot about where we are in TROP-2 ADCs for TIGIT, for non-small cell, and the conflicting data. Obviously, small cell, we have learned from ASCO, we are making gains with either novel cytotoxics or making gains with BiTE engagers like tiragolumab.

[00:59:54]

TROPiCS-03 ES-SCLC Cohort: Study Design

I want to go over the role of potentially TROP-2 ADCs with extensive stage small cell with TROPiCS-03. This was an open-label, multi-cohort Phase II study looking at SG potentially in the second-line of extensive stage small cell lung cancer, and the primary endpoint being objective response rate. You can see here the key secondary endpoints.

[01:00:17]

TROPiCS-03 (ES-SCLC Cohort): SG After Platinum-based Chemotherapy and Anti-PD-1/PD-L1 Therapy

The results look fairly encouraging. This is a nice waterfall plot, I would say, for refractory patients with extensive-stage small-cell lung cancer. Response rates north of 40%. Disease control rate north of 80%. A PFS of 4 months and an OS of 13 months. It is pretty incredible to see OS in the second-line for more than a year, which is what we are seeing with tarla as well. A lot of encouraging data with this compound in small cell.

[01:00:50]

TROPiCS-03 (ES-SCLC Cohort): Safety

We have gone over the talks of SG. I would say just the big ones, obviously, are the febrile neutropenias, diarrhea, and cytopenias that you have to keep in mind. This drug has been used in other disease states, like breast cancer. I think there is a lot of familiarity with this compound.

[01:01:10]

EVOKE-SCLC-04: Sacituzumab Govitecan vs Standard of Care in Previously Treated ES-SCLC

There is EVOKE, a small cell lung cancer 04 study. This is looking at SG vs standard of care in the second-line. It makes a lot of sense to do this study, given the Phase II results that I just shared with you. These are patients with small-cell lung cancer. Extensive stage randomized after progression of disease on a platinum-containing regimen with a PD-1 drug. Either standard of care. Take your choice. Pick your choice of topotecan. There are other options as well for in Asia vs SG, with a primary endpoint being objective response rate.

[01:01:48]

AdvanTIG-204: Ociperlimab (BGB-A1217) + Tislelizumab + cCRT in Untreated, Limited-stage SCLC

And then, other TIGITs that are coming out. Ociperlimab plus tisleliumab. This is another checkpoint inhibitor. This is looking at limited-stage small-cell lung cancer. The point here is that there are multiple different compounds that are coming out. I would say that the extensive stage small cell lung cancer space is probably a little bit more advanced in terms of learning about these drugs than we are in limited stage.

[01:02:21]

AdvanTIG-204: Efficacy

This is just looking at the efficacy of the arms here. Some preliminary activity here. I think this is just too early to tell what is going to happen with TIGIT in the limited-stage. Nevertheless, ongoing efforts that I think are important and to learn from.

[01:02:38]

SKYSCRAPER-02: Atezolizumab + Carboplatin/Etoposide ± Tiragolumab in ES-SCLC

We have learned already about tiragolumab in non-small cell lung cancer. Unfortunately, we have very similar results in small cell lung cancer. This was the SKYSCRAPER-02 presented, Helena, by your colleague, Charlie Rudin, and published. A very clean study, looking at platinum etoposide + atezo placebo control arm vs platinum etoposide + atezo with tiragolumab. Asking the question, can you add an anti-TIGIT monoclonal antibody to existing regimens and improve outcomes? Unfortunately, we did not see an improvement in PFS or OS. Not all is lost. Hopefully, we will learn more from other TIGITs in the small cell space.

[01:03:22]

Posttest 3: Based on eligibility criteria for the phase III EVOKE-SCLC-04 trial with sacituzumab govitecan vs SoC, which of the following patients with ES-SCLC could be considered for enrollment on this trial?

Based on eligibility criteria for the phase III EVOKE-SCLC-04 trial, which I just went over, with SG vs SoC, standard of care, which of the following patients with extensive stage small cell lung could be considered for enrollment on this trial? There are your answers.

Dr Yu: Tough question.

Dr Levy: Tough one here. I think they got it. This is a sophisticated crew here.

[01:04:06]

There is a rationale, I think, here. Ongoing study. Very important. Will ADCs land in the second-line with a small cell?

Panel Discussion and Audience Q&A

[01:04:15]

We have gone over these questions, I think, already. We have hit the audience questions.

A Focus on Equitable Access: Clinical Trial Enrollment Strategies

[01:04:22]

I think there are a few more slides to tackle here on equitable access clinical trial enrollment strategies in the last 2 to 3 minutes.

[01:04:29]

Ensuring Access and EquityClinical Trial Enrollment

This is just some data here on the challenges that we have and the attitudes and beliefs about patients of minority or underrepresented in clinical trials.

The importance of having these patients enrolled in our clinical trials. I think this is very important.

[01:05:02]

Posttest 4: Now, how confident are you in addressing disparities in access to novel therapies and clinical trials for rural, Black, and underserved patients with lung cancer?

Now, how confident are you in addressing disparities in access to novel therapies and clinical trials for rural, Black, and underserved patients with lung cancer?

Good. I think that is important. I think we are gaining confidence as we begin to understand the data and we begin to understand the challenges and hurdles of enrolling minorities, and underserved patients into these clinical trials, which is so very important.

[01:05:50]

Poll 4: Do you plan to make any changes in your clinical practice based on what you learned in today’s program?

Do you plan to make any changes in your clinical practice based on what you have learned in today's program?

1. Yes;
2. No, or;
3. Uncertain.

The last poll 5 here.

[01:06:18]

Poll 5: Please take a moment to enter 1 key change that you plan to make in your clinical practice based on this education.

Please take a moment to enter 1 key change that you plan to make in your clinical practice based on this education.

Dr Yu: While they answer that, Ben, I am going to leave it to you to say, with the data that we discussed and/or other stuff that is going to be imminently presented at World Lung or ESMO, what is something that you are excited about in terms of a novel treatment that you think might have promise?

Dr Levy: I would say I am very selfishly curious at how ADCs will be incorporated in the frontline, if at all, and what biomarkers may be used. Secondly is I think the biomarker search has to be on. I look for these ADCs in an intent-to-treat population just does not seem to do what we want them to do or what we expect them to do. I think enrichment is going to be important. I think those studies, looking at biomarker enrichment strategies, are going to be important.

I will go back to what I said before, which is just the bispecifics. The more I hear about these bispecifics, and the more I see preliminary data on bispecifics, I am not sure you even need a warhead. I do not know. I think we will see with rilve what happens here. But I am encouraged. Amivantamab led that story. I think we will get more sophisticated in the biochemistry of these compounds and how they are generated. Those are the things that I am looking forward to. Helena, how about you?

Dr Yu: Just to feed off of what you are saying, I think that allows us to personalize these treatments better by combining EGFR and MET inhibition with amivantamab when we know both of those proteins and signaling are important in EGFR-mutant lung cancer. I think similarly, that allows us to potentially be more targeted. I think ADCs are on that first wave. But looking forward to, as you said, patient selection.

And then I guess upcoming at World Lung, seeing that FLAURA2 survival data just helps. That is the key. Helping our patients live longer with these diseases. Anytime we can see a nice survival benefit, that is something to definitely hold on to.

Dr Levy: Yes. You mentioned it in your first section about sequencing drugs. We are trying to treat this as a chronic condition, not a cancer. How to sequence these strategies, I think, is going to be paramount for this to be a chronic condition and not a cancer.