Dr. Patel: So TROPE-2 is a transmembrane glycoprotein. It is highly expressed in solid tumors and the majority of non-small-cell lung cancer. It is an epithelial adhesion molecule and has a myriad of downstream events that regulate stem cell markers associated with cell regeneration but significant effects on cell cycle progression and cellular growth and survival.

[00:18:16]

Anti–TROP-2 Antibody–Drug Conjugates

There are a number of anti-TROPE-2 antibody conjugates which have been developed. And remember that ADCs have an antibody, a linker, and a payload. And all 3 of these pieces can be a little bit different and those changes affect the pharmacokinetics and efficacy of some of these drugs. The 3 that we are going to talk about today include Dato-DXd, sacituzumab govitecan, and sacituzumab tirumotecan.

There are differences in the antibody. So the sacituzumab govitecan, for example, is IgG1 kappa-restricted, whereas Dato-DXd and sacituzumab tirumotecan are just IgG1 restricted. There are differences in cleavability.

So Dato-DXd requires enzyme cleavage. The payloads are all topo 1 inhibitors, but again, the payloads are a little bit different. So we see deruxtecan derivatives, SN-38, and so the toxicities change.

The drug-to-antibody ratio has implications for how much toxin may end up being, or payload may end up being recirculated and how potent the drug is. There are differences in schedule, whereas Dato-DXd and sacituzumab tirumotecan are Q21 day dosing with sacituzumab govitecan. The dose is 10 mg/kg on day 1 and 8 of 21-day cycles.

[00:20:07]

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

We are going to talk about EVOKE-02 and specifically focusing on cohorts C and D. Cohorts A and B have been previously presented at ESMO last year, and the new data that has been presented really is from cohorts C and D. And in those cohorts, patients who are treatment-naive without genomic alterations and good performance status are in different cohorts depending on histology.

So cohorts C, for example, is NEPDL1, non-squamous. Cohort D is squamous only, and these patients are treated with sacituzumab govitecan, pembrolizumab, and carboplatin for up to 4 cycles. So this study was a 2-part study in which the response rate was noted.

There was a safety run-in and then expansion at the dose of sacituzumab govitecan that was decided upon. Remember that both carboplatin and SG caused significant myelosuppression, so there was interest in understanding what the appropriate dose would be for this patient population.

[00:21:35]

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

When we look at the cohorts of patients, so 51 non-squamous patients were treated, we see significant response rates.

And so the hatched lines represent patients that were treated at a 7.5 mg/kg dose. 10 mg was initially used, but then because of toxicity, the dose was dropped. The response rate was 54%. Now, again, this is all PD-L1 status in both arms. There were 41 patients that were squamous that were treated, and the response rate there was 39%.

If we look across the bottom panel, we can see responses by PD-L1 status. And so, I think importantly, in patients who were PD-L1 negative, we see a response rate of over 40% in this patient population. And then a little bit of an outlier with PD-L1 1-49% of 33%, and then a high response rate in patients with high PD-L of over 66%.

[00:22:53]

EVOKE-02 (Cohort C & D): Safety

When we start looking at the toxicity in these cohorts, it is really important to understand, again, what we see with sacituzumab govitecan, and what we attribute to toxicities from carboplatin and how these may be synergistic.

So on the left side, we see patients who received the 10 mg dose, so that was 29 patients. We see a fair amount of neutropenia. With the dose reduction, that has been dropped significantly, so seeing grade 3 rates of 24%. Diarrhea, pretty similar, 10 and 14. We see some stomatitis that is decreased with a lower dose of SG, and so that rate was 1 to 2%. These are the primary toxicities that we attribute to SG.

Generally, these are toxicities that are pretty similar to chemotherapy. Dr. Bazhenova, any comments about these toxicities that we see and to the response rates in this particular cohort of patients?

Dr. Bazhenova: I think that every time we see a new drug in our pipeline, it will take us some time to get used to the toxicities, and I think, honestly, between me and you, where we only see patients with lung cancer, the general oncologists in the community already have exposure to those antibody drug conjugates, so I think at this point, they are probably more comfortable in managing it than I am, in fact, and I think it is certainly an interesting compound that deserves further study.

Dr. Patel: Certainly, in the first cohorts, A and B, it was just SG + pembrolizumab. The addition of carboplatin to this particular regimen, any thoughts about in the high PD-L1? Is this something that you think we should continue to study?

Dr. Bazhenova: I think so. Again, even though the patients with a PD-L1 more than 50 have really good results with monotherapy, immunotherapy, but we can still try to improve upon that, so I definitely feel that this is not a closed population at this point, and I think there is definitely room for improvement.

[00:25:30]

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

Dr. Patel: That is great. We will talk about EVOKE-01. This is the Phase III experience in patients who were previously treated, so it is sacituzumab vs docetaxel, which is standard of care. Patients had had to receive platinum and immunotherapy. This was an international study, a large study, over 520 patients.

Importantly, patients could have prior TKIs if they had actionable genomic drivers, so patients with EGFR and ALK, for example, were allowed on study as long as they had received that TKI. Prior brain mets were allowed but had to be treated, and this study was the primary endpoint was OS with secondary endpoints of PFS.

So we look across the arms, 299 patients in SG, 304 in docetaxel. We see more patients with non-squamous, but the arms are pretty well-balanced. Most patients had just received 1 prior therapy, and we see these small numbers of patients with AGAs, so 2% of patients in the SG arm, 4% of patients had prior EGFR therapy, ALK, and then we see others, and those include MET, KRAS, BRAF, NTRK. So again, small numbers, but certainly in a big trial, those patients we can follow over time.

[00:27:00]

EVOKE-01: Overall Survival With SG in Patients With Nonresponse to Last Anti–PD1/PD-L1 Regimen

So this was presented last year at ASCO, and has subsequently been published, but these are the overall survival results.

The trend favored SG. This was not statistically significant, so 11.1 months with SG vs 9.8 months. The hazard ratio was 0.84, and you see the P value. What is interesting, and an unusual subset analysis was they looked at OS in patients who had not responded to the last immunotherapy. And here, again, we see this improvement in survival here, and this is a little bit unusual, but certainly, I think for patients who do not respond to immunotherapy, something that we would like to continue to look at. We see OS across the different histologies as well.

[00:28:10]

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

When we look at subgroup analyses of patients with brain metastasis and those with actionable genomic alterations, so again, with SG, we see an overall improvement in OS compared to docetaxel. That hazard ratio is 0.62, but crosses. It is certainly wide. The PFS is the same, and so there are certainly some questions, but we see response rates of about 10%.

Now, those patients with known actionable genomic drivers, so SG, the median overall survival was not reached at the time of publication. Again, a really robust hazard ratio. PFS, it was pretty close with a hazard ratio of 1 and a response rate of about 10%. Certainly this, I think, helps us understand the question of whether we should be looking at these ADCs in patients with AGAs.

[00:29:09]

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

Now, an interesting drug analysis that is being done is with the drug Dato-DXd. So remember, this is the other ADC directed at TROPE-2.

This is dosed at 6 mg/kg Q3 weeks. There were 2 trials that were combined, and the patients with EGFR-mutated lung cancer were extracted from both of those. So TROPION-Lung01 was similar to the EVOKE trial that we just described, so this was the Phase III study that looked at previously treated patients, and patients who had the actionable genomic drivers had to have at least a prior TKI as well as platinum-based chemotherapy and no prior docetaxel, so they were randomized to each.

And then there was a TROPION-Lung05, which was a Phase II trial that looked at patients exclusively with actionable genomic drivers who had received some kind of therapy. From this, they looked at the EGFR pool, and there were 117 patients. Most of them came from TROPION‑Lung05, but certainly also from TROPION-Lung01.

Recognize that we loosely say EGFR patients. This was a broad variety of patients, so about half of patients had deletion 19, and 30% of patients had L858R. So a fair number of patients had atypical mutations as well as exon 20 mutations, including T790M. However, understand these were all not the same patients and may have had different TKIs.

[00:31:03]

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

So in this pooled analysis, the PFS was 5.8 months in the EGFR patients, and the overall survival was 15.6 months. And you see this really robust response rate of 43% in these patients and a duration of response of 7 months, disease control rate of over 80%, median overall survival at 15.6%. And again, slightly less in patients who had received prior osimertinib, probably because of the therapies that they had gotten prior to coming on trial.

[00:31:47]

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

If we look at safety with this drug, we see similar sort of toxicities in which we see stomatitis, so grade 3 stomatitis in 9% of patients. Dato-DXd has also been notable for some ocular surface events. So about a third of patients will develop at least low-grade with a small number of patients with grade 3 eye events, as well as ILD.

And remember in the EGFR patients, we always get particularly nervous about that given the propensity for ILD with concerns with combination therapies with osimertinib. What we see again are these higher rates of stomatitis. These drugs certainly cause alopecia as well as some GI side effects.

Mucositis and stomatitis did require dose reduction, and was generally quite responsive.

[00:32:49]

TROPION-PanTumor01 NSCLC Cohort: Datopotamab Deruxtecan

And so there is additional data from the TROPION-PanTumor01 non-small-cell cohort. So again, this was a dose escalation study looking at these different dose expansions. This is essentially looking at MTD. Remember that it got up to 8 mg, but the dosing that has moved forward is 6 mg/kg.

[00:33:15]

TROPION-PanTumor01—Updated NSCLC Cohort: Antitumor Activity

And if we look at this group of patients, again, we will see these lower response rates in the non-small-cell cohort at 26%, but, again, pretty consistent activity.

Based on this data, the combination across a number of trials, certainly I think the strategy of moving Dato-DXd and AGA population is moving forward. Dr. Bazhenova, any comments about that? It is a little bit unusual for us to see smaller subsets of patients being combined in this way.

Dr. Bazhenova: I think there is something unique about the GFR patients who develop resistance and maybe for them, the inhibition of TROPE-2 would be important because we do have some preclinical data that TROPE-2 upregulation in the GFR resistant patients happens. And so maybe this is that sweet spot of the subset analysis which guides us into future development of a TROPE-2 drugs.

[00:34:25]

Sacituzumab Tirumotecan in EGFR-Mutated NSCLC

Dr. Patel: That is great. So the last compound in this space is sacituzumab tirumotecan. And so again, looking at EGFR-mutated patients.

So in the Phase I/II cohort 3 study, there were 43 patients. The response rate was 40%, PFS 62%. Again, a really robust survival, but this is an early phase trial of over 20 months.

Again, seeing the myelosuppression and stomatitis as the primary toxicities. Another study, 08, enrolled 64 patients who had been treated. Again, cohort 1 had prior platinum, cohort 2, no prior chemotherapy.

The response rate in this cohort was a little bit lower, but again, a very nice PFS and similar toxicities.

Based on this data, the FDA granted breakthrough designation for this drug in patients with classical EGFR mutations with progressive disease on a TKI or after chemotherapy. So it would be either patients who were treated with FLAURA2 or sequentially.

[00:35:37]

Select Ongoing Trials With Sacituzumab Govitecan and Sacituzumab Tirumotecan in NSCLC

So these are the ongoing trials with these 3 that go beyond just EGFR patients. And so if we look at EVOKE-03, so this is sacituzumab govitecan. Again, this is a drug that has another approval.

They are looking at the PDL-high population as Dr. Bazhenova previously stated. In this high population, we can still do better. And so this Phase III trial is ongoing.

It is high PDL-1, no actionable genomic drivers randomized to SG + pembro vs pembro alone. There is a Phase II study looking at SG plus bevacizumab in patients with brain metastasis to, again, better understand the activity.

Sacituzumab tirumotecan has 2 studies ongoing. So the Phase III and previously treated AGAs, and so patients are either randomized to ST vs chemotherapy, and the primary endpoint is PFS in the EGFR-mutated cohort. Then TroFuse-009 Phase III that is looking at SG vs chemotherapy. Again, the OS is in EGFR-mutated cohort. So that follows the breakthrough designation.

[00:37:04]

Select Ongoing Trials With Dato-DXd in NSCLC

For Dato-DXd, this is an exciting space right now, I think we are seeing TROPION-Lung02. So this is in high-risk stage 1 patients.

So looking again at different strategies to look at disease-free survival. Lung10 is looking at frontline therapy, again, with different compounds that we will kind of circle back to with different immunotherapies. Remember that many of the decisions about combination partners have to do with particular portfolios, and so we are seeing a number of studies that are coming forward.

Dato-DXd + osimertinib, certainly looking at that for PFS. And then finally, TROPION-Lung15. So this is patients who have EGFR lung cancer, who have had progressive disease on osimertinib, and then are randomized to Dato-DXd plus osi, Dato-DXd alone, or platinum-based chemotherapy. And this is a Phase III study with the primary endpoint of progression-free survival.

[00:38:21]

Posttest 1: Based on Cohorts C and D in the EVOKE-02 trial, which statement best describes the clinical activity of sacituzumab govitecan + pembrolizumab + carboplatin in treatment-naive patients with metastatic NSCLC?

Dr. Bazhenova: Okay, thank you, Dr. Patel. So now we are going to test how effectively you were listening. So the posttest 1: Based on a cohort C and D in the EVOKE-02 trial, which statement best describes the clinical activity of saci plus pembro plus platinum doublet in patients with metastatic non-small-cell lung cancer? And you have 3 options.

1. Similar;
2. Better in squamous; or
3. Better in non-squamous.

You can vote. Okay, can we see the results?

And so, Jyoti, can have you comment on the right answer here?

Dr. Patel: Sure, so we see similar response rates in progression-free survival, regardless of histology. So the response rate was 45% in non-squamous, and in patients with squamous, the response rate was 39%. So regardless of histology, they are pretty similar, perhaps a few degrees numerically higher.

Dr. Bazhenova: Perfect. Thank you so much. So let us move on.

[00:39:54]

And we already discussed that, the answer to that question. So the correct answer was (A).

[00:40:06]

TIGIT Axis Inhibits Innate and Adaptive Immunity Through Multiple Mechanisms

Okay, so I will take you over the second part of our presentation, which is talking about TIGIT. So TIGIT is important in both innate as well as adaptive immunity because the TIGIT axis is able to inhibit multiple mechanism of tumor kill, mainly going through a T and NK cell intrinsic inhibition, as well as upregulating immunosuppressive dendritic cells. So by removing TIGIT axis, you are reactivating T and NK cells, and you are also minimizing the presence of immunosuppressive dendritic cells.

[00:40:50]

Anti–TIGIT Therapies in Development

So currently, there are several drugs in development which has anti-TIGIT properties. Here on this table, I am presenting 3. I am going to be talking about the fourth drug, tiragolumab, and I will explain to you later what that drug is.

So domvanalimab, as well as belrestotug, is anti-TIGIT Ig1 monoclonal antibody. Rilvegostomig is slightly different. It is actually a bispecific PD-L1 and TIGIT.

There is also additional special features that distinguish those anti-TIGIT antibodies. So the main distinguishing characteristics is silent or active FC. The FC portion of monoclonal antibody is responsible for cellular cytotoxicity.

So if you silent an FC, you are theoretically decreasing the chance of that monoclonal antibody in addition to activating the T and NK cells, also killing it by just ADCC. All of those drugs have different Phase III clinical trials. Belrestotug has been discontinued based on the results of the trial I will show you in a second.

[00:42:070]

Phase II ARC-7: Domvanalimab + zim ± Etrumadenant vs zim in 1L metastatic PD-L1–High NSCLC

So we will first start with domvanalimab, so I will call it dom, and zimberelimab, I will call it zim because it is easier. So dom is an anti-TIGIT antibody. zim is an anti-PD-L1 antibody similar to pembrolizumab.

So there was a clinical trial called ARC-7, which is a Phase II clinical trial, which had 3 arms, but the arms I am going to be discussing is dom + zim vs zim alone. Etrumadenant, it is an adenosine receptor inhibitor and just preface it, the triple arm had very similar efficacy as a double arm, so I am not going to be discussing that.

And as you can see here, looking at the progression-free survival, the dom-zim showed PFS of 9.3 months vs zim alone showed 5.4 months. And just a reminder that this clinical trial was specifically designed for patients with PD-L1-high non-small-cell lung cancer, which is defined as PD-L1 expression more than 50. The common side effects that we saw in that trial was nausea, fatigue, constipation, dyspnea, pneumonia, and diarrhea.

[00:43:20]

Phase II ARC-10: Domvanalimab + Zim vs Zim vs CT in 1L PD-L1 High Stage IIIB–IV NSCLC

If you look at another trial, which is a Phase II seamless into III design, we only have the results of a Phase II clinical trial called ARC-10.

This trial also has 3 arms, also was developed for patients with PD-L1-high, and it basically it is dom + zim vs zim vs chemo. And you can see here that the double arm, the D-Z arm, showed improvement in progression-free survival, in overall survival based on a hazard ratio of 0.64. The median OS was not reached for the double arm, and it was 24.4 months in the zimberelimab arm.

And then looking at the progression-free survival, you can see the PFS was 11.5 on the D-Z arm and then 6.2 on Z arm.

[00:44:17]

Phase II ARC-10: Safety of Domvanalimab + Zim vs Zim vs CT in 1L PD-L1–High Stage IIIB-IV NSCLC

Going into the side effects, you can see that adding dom to zim slightly increased treatment-emergent adverse events or treatment-related adverse events. The majority of the increase happened due to early grade toxicity, the grade 3 toxicity. The differential is not as significant compared to the all-grade toxicities.

[00:44:42]

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

Then looking at ARTEMIDE-01, which is a rilvegostomig, which is again, as I mentioned, is a bispecific PD-L1 antigen. This is a slightly different setting. So the ARTEMIDE-01 trial was used in the patients who were checkpoint inhibitor-naive and then showing the differential and overall response rate, as you can see on the right side of the slide, patients with PD-L1 more than 50.

So again, we are having the same pattern that people that have a PD-L1 expression over 50 may be benefiting more by addition of TIGITs. And you can see here that overall response rate was 61% for PD-L1 more than 50 and 29% for PD-L1 1-49%. And you can see the waterfall plot here.

[00:45:37]

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

Next, we are going to move on to the GALAXIES trial, belrestotug. As I mentioned before, unfortunately this compound has been discontinued based on a negative results of the GALAXIES Lung-202 study. And this is kind of unfortunate because based on the overall response rate, you can see that there was a quite meaningful, in my opinion, improvement in overall response rate compared to about 40% with PD-L1 by itself, the dosta vs dostarlimab + belrestotug showing the overall response rate of about 60% to 70%.

And you can see there was actually a pretty meaningful difference in the complete response rate as well. However, unfortunately, the progression-free survival, which was another endpoint of that trial, did not show a significant difference and therefore the company decided to discontinue development of this compound.

[00:46:42]

GALAXIES Lung-201: Safety

So looking at the safety, you can see here that there was no dramatic increase in toxicities, although numerically some of the toxicities were higher in the dual arm.

[00:46:57]

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

Next, we are going to go through 2 other TIGITs that were not on my table initially. Tiragolumab is a monoclonal antibody against TIGIT, which also does not spare FC.

So we expect ADCC potentially killing the cells that we are trying to stimulate. So there are 2 clinical trials, SKYSCRAPER-06, which is shown here. This was for patients with all expression of PD-L1, and then basically they were randomized to a KEYNOTE-189, which is a chemo-pembro placebo, vs the same chemotherapy and addition of tiragolumab as a maintenance built-in for both of those trials.

And you can see down there in the green box that the SKYSCRAPER-06 failed to meet the primary endpoint. They had 2 coprimary endpoints, PFS and OS, and the numbers are listed below, and you can clearly see that the hazard ratio is actually trending the wrong way. And then there was no statistically significant improvement in PFS or OS.

[00:48:06]

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

And then we have SKYSCRAPER-01. SKYSCRAPER-01 was for patients with a high PD-L1 expression. Again, showing you that a majority of the studies that I presented today with TIGITs were mainly looking for the patients with PD-L1-high, and SKYSCRAPER-01 basically randomized the patients to ateza vs ateza plus tira.

And you can see here that the median progression for survival was not different statistically because that was a co-primary endpoint. And while numerically you can see that there was improvement in OS and PFS, that did not meet statistical significance.

[00:48:51]

Select Phase III Trials of Anti-TIGIT Therapies in NSCLC

And then we have other clinical trials still looking at anti-TIGIT therapies, and I listed them here. We do not have the results of those trials yet and eagerly waiting to hear what they will show.

Back to you, Dr. Patel.

[00:49:11]

Posttest 1: Based on Cohorts C and D in the EVOKE-02 trial, which statement best describes the clinical activity of sacituzumab govitecan + pembrolizumab + carboplatin in treatment-naive patients with metastatic NSCLC?

Dr. Patel: Great. Thanks so much. So posttest 2: Based on current clinical trial evidence, which of the following biomarkers is most consistently associated with potential benefit from TIGIT inhibitor combinations in non-small-cell lung cancer?

So please vote. It would either be:

1. High TMB;
2. High TIGIT expression by IHC;
3. PD-L1 proportion score greater than 50%;
4. STK11/KEAP1 mutations; or
5. Low CD8 T-cell infiltration.

[00:49:59]

Dr. Bazhenova: Yes, so basically, again, it is hard to answer the question because the TIGIT was not a biomarker of entrance for the trials that I discussed. A majority of the studies did involve the patient with PD-L1 more than 50, so the correct answer, based on the trial eligibility criteria, is PD-L1 more than 50.

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

[00:50:38]

Dr. Patel: I think we are going to skip the discussion for now and do it all at the end. We will keep moving as we have gone a little bit over. However, we want to talk about both of these approaches for small-cell lung cancer and some of the data that is been presented.

[00:50:44]

TROPiCS-03 ES-SCLC Cohort: Study Design

So TROPiCS-03 was looking at SG in patients with extensive stage small-cell. So this is patients who had received had chemotherapy with immunotherapy. The primary endpoint was response rate. 40 patients were treated until progressive disease.

[00:51:05]

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

And so here you see the waterfall plot.

So certainly in the second-line small-cell cohort, we are seeing a response rate of about 42%, with a duration of response about 4.7 months, and OS of 13.6 months. So certainly, I think this is interesting for us and certainly of note. There were just a small number of patients who were enrolled who were chemotherapy refractory, carboplatin refractory, and those patients did not respond to this strategy.

[00:51:45]

TROPiCS-03 (ES-SCLC Cohort): Safety

If we look at safety, it is pretty similar to what we have seen in the non-small-cell cohorts. Again, patients with small-cell lung cancer are often a little bit more fragile or have a greater number of comorbidities. What we see is about 37% of patients needed dose reductions. And again, primarily the high-grade toxicities are myelosuppression with neutropenia, some GI effects, as well as myelosuppression.

[00:52:17]

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

We have also looked at TIGIT in patients with small-cell and have a couple of trials we would like to highlight. So in this study, the OC is anti-TIGIT, and we are looking at ICI post-chemo radiation in patients with limited-stage disease. So they were getting immunotherapy concurrently with radiation and then maintenance afterwards. The primary endpoint of this Phase II trial was PFS.

[00:52:55]

AdvanTIG-204: Efficacy

And what we see in terms of efficacy is there was a trend to improvement with immunotherapy, but the arms between A and B look pretty similar.

We are seeing high response rates, good duration of response, but toxicities that are in line with what we see in this intensive treatment platform. Importantly, we did not see a difference in efficacy with PD-L1 or TIGIT expression. And that has been across the board, I think, with small-cell.

[00:53:33]

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

SKYSCRAPER-O2 was presented at ASCO last year and this was tira and atezolizumab with chemotherapy and extensive stage disease. Unfortunately, there was no improvement with the addition of TIGIT, really no difference in progression-free survival or overall survival. And so certainly I think this was disappointing to many of us, but probably no pathway forward for this compound in small-cell.

Q&A

I think at this juncture, we can take a few questions. Before we move on to questions about trial enrollment. So there is 1 question that came up in the chat for our EGFR patients.

Dr. Bazhenova, so post-osimertinib, what do you think is going to be the best strategy for patients? Will it be chemotherapy? Will it be MARIPOSA-2 or 1 of these new compounds like Dato-DXd or SG?

Dr. Bazhenova: I think right now we have to discuss, again, what is available to us, right? So the TROPE-2 drugs are not yet approved in lung cancer. We do have preliminary results of the combination of 2 trials.

There are ongoing clinical trials for TROPE-2 ADC and specifically for that population. So at this point, my choice, since TROPE-2 is not available, is going to be MARIPOSA-2 or chemotherapy, depending on the patient's desire to go through the side effects that MARIPOSA-2 offers. However, the majority of my patients, I do give MARIPOSA-2.

I think the 1 interesting question will be, is we will never have a head-to-head, right? So we will have to be comparing, doing a cross-trial comparisons. And the MARIPOSA-2 combinations have a completely different side effect profile compared to the TROPE-2.

None of them are a walk in the park, to be honest with you, but it is a different profile. And I think once we, as thoracic oncologists, get more experience with TROPE-2-ADC, I think we will decide which treatment would be more tolerable or more palatable by our patients.

Dr. Patel: That is great. And I feel like the goalposts continue to change, right? The incorporation of new therapies makes it very difficult to predict what the strategy will be in 2 or 3 years when patients may unfortunately experience progression on their frontline regimens.

You know, 1 piece in the EGFR space, we have spent so much time talking about precision therapy and biomarker testing, where does biomarker testing land for TROPE-2 therapies? Do we have any companion diagnostics, thoughts about efficacy based on TROPE-2 expression?

Dr. Bazhenova: I think you probably know more about that answer since you were more involved with the TROPE-2 study, so I will start. So I think multiple companies who have a TROPE-2 ADC looked at TROPE-2 overexpression as an ability to distinguish which patient population will benefit from the drugs. And uniformly, the TROPE-2 expression has not been associated with improvement in the outcome.

However, I think it was last ASCO was presented the quantitative TROPE-2 score, which is a complex formula looking at the ratio between the TROPE-2 surface expression vs TROPE-2 cytosolic expression. And I think that the data on that presentation from the TROPE-2 trial, from the data, was actually very encouraging. And I know there are ongoing studies right now which specifically enter the patient based on a level of that quantitative TROPE-2 score.

I do not think this is commercially available, neither at this point, even if it was commercially available, without a prospective study which entered the patient based on this biomarker rather than just a post hoc analysis of the biomarker. I am not making my decisions based on that, but we might in the future.

Dr. Patel: Right. I mean, certainly I think now our patients have become, or the histologic and pathologic assessment for our patients, even as of last week, got another layer added. So not only are we asking for NGS, we are looking for RNA expression and now IHC for both HER2 and MET for ADCs.

And so certainly we will see how this paradigm of TROPE-2 kind of fits in because certainly, as you correctly pointed out, conventional IHC has not been so helpful in distinguishing efficacy.

A Focus on Equitable Access: Clinical Trial Enrollment Strategies

[00:58:37]

So I think we need to probably, let us get to this other piece that I think is very important and really exciting because there seems, so often there is a disparity between what we see in clinical trials and what we all experience in our clinics and how we treat our patients. And thinking about how representative our clinical trials are is absolutely important to how we evaluate these compounds.

So with that, Dr. Bazhenova, I will take it away.

[00:59:13]

Ensuring Access and Equity

Dr. Bazhenova: Thank you so much. So I will be, it is a very brief discussion looking at clinical trial enrollment strategies. We know that in general, patients with non-small-cell lung cancer who reside in rural areas are less likely to receive immunotherapy.

We also know that patients who are non-white, when they have non-small-cell lung cancer, they have lower survival rates and very often diagnosed at a more advanced stage. And taking that into account, ideally we would want to enroll those patients in the clinical trial so we can learn and study the drugs in a not uniform population of patients. However, unfortunately, we have a lot of barriers for those patients to participate, including cost barriers for molecular testing, and cost barriers for traveling to the site where the clinical trial is open.

[01:00:14]

Clinical Trial Enrollment

And this is actually supported by the data. So if you look at this publication, so they looked at almost 30,000 patients who participated in 147 clinical trials. The majority of those patients were white and only 3% were black and 10% were Asian and Pacific Islanders and 3.4% were Hispanic Latina. So we clearly see that that patient populations are underrepresented in clinical trials. And trying to dissect and understand what is the reason, you can see that 1 of the problems is that Hispanics and Black patients were also 30% less likely to be willing to participate and also 40% of Chinese patients were less likely to participate. So we have a 2-pronged problem.

So 1 of them is those patients are not willing to participate in the trials but also having difficulties in accessing clinical trials because of additional visits and additional costs that could be encountered when we do the clinical trials. So I think it is important for us as physicians who do participate in trials is to make sure we re-educate our patients because without our involvement, the situation is not going to change.

And so back to you, Dr. Patel.

[01:02:00]

Posttest 3: How confident are you in your ability to identify patients with advanced lung cancer who are eligible for enrollment in trials involving TROP-2- or TIGIT-targeted therapies?

Dr. Patel: So for our final posttest, how confident are you in your ability to identify patients with advanced lung cancer are eligible for enrollment on either TROPE-2 or TIGIT-targeted therapies? So please vote. Very confident to not at all confident.

Hopefully, we have given you the data to get to very confident. And can we see the results? So we are getting there.

Almost 70% of you are somewhat confident. So here we go.

[01:02:43]

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

Dr. Bazhenova: And so the next poll we have is, do you plan to make any changes in your clinical practice based on what you learned in today's program?

Okay, and looks like we are not going to show the results for that poll. Can we move to the next poll?

I will give you a little bit more time to respond. Okay, Dr. Patel, I think we have 1 more question there in Q&A and I will maybe ping it to you. Do you think TROPE-2 or TGIT, or both of them, are more promising in non-small-cell or small-cell lung cancer?

Dr. Patel: This is a great question. I mean, it is tough after seeing the number of TGIT studies that we have had that have not panned out as we would have hoped. Luckily, most of them do not have increasing toxicity.

However, without a path forward with a biomarker with TGIT, my suspicion is that it is going to be an uphill battle and that likely TROPE-2 is something that I think we can pivot on. We are seeing consistently there are patients who respond. I think the real issues are going to center around patient selection.

And so some of these novel platforms to look at differential response, cytoplasmic vs membrane, to look at other mediators of response. However, my sense is that we are probably going to see TROPE-2 drugs available in clinical practice in non-small-cell lung cancer in the not-so-distant future. What is your take on it?

Dr. Bazhenova: I have a very similar take. I think in TROPE-2, at least we maybe identify the subset of patients like AGAs who will benefit or maybe there is a new biomarker we might be able to predict better than we were to this point which of the patients are going to respond to TROPE-2 ADCs. The TGITs, there are 4 drugs that I mentioned.

We have 1 stopped being developed. One, the SKYSCRAPERs, 2 studies were negative. And there is a difference between those TGIT compounds or FC-silent or FC-active. And how much is that FC silence truly make a difference? It is really hard to say because many, many times in oncology we see a perfect outcome in preclinical studies, and we can explain why this drug is better than another drug and then we put it in the patients and things do not work the way we would expect based on mice model.

So I think the, honestly, the non-FC-silent TGITs, I do not think we should explore anymore because we have 2 negative studies, 3 negative studies with 2 different compounds in non-small-cell plus if you add small-cell there.

However, I think the FC-silent, I definitely want to see the dom-zim combination to be looked a little bit further. It is hard to know if it is going to be positive or not, but I think preclinically it makes sense to develop it further.

Dr. Patel: I would say, what has been, I think, really nice about the development of some of these drugs we have talked about, the trials, I think have had a good degree of representation from around the world, as well as patients, again, like allowing patients who had treated brain metastasis or who have had a prior AGA, that is given us real insights into what might happen instead of clinical trials that are overly rigid in their inclusion criteria and exclude patients that we may really learn from if they volunteer to go on clinical trials.

You know, this, again, is a huge effort between industry, academia, and practice and how we talk about clinical trials to patients, how we really think about them as a first standard rather than something that is a last resort. Any words you want to say about that?

Dr. Bazhenova: I agree. And I think I honestly believe that clinical trial enrollment comes from us, right? So if I am dedicated, and I think it will truly make a difference, then I am able to spend that extra time.

Of course, we all understand that if you are a clinical investigator on a trial, your work is pretty much outcomes uncompensated because of everything else that needs to be done on a trial. However, if you truly believe that this is necessary for the patients and that is how we move forward, I think you will be able to convince the patient that this is indeed important and hopefully enroll the patient in a clinical trial.