HER2-Directed ADCs in Bladder Cancer: Strategies to Personalize Treatment Selection and Optimize Patient Outcomes

HER2 is a surface protein that plays an important role in cancer biology and specifically in bladder cancer biology as well. It is a cell surface receptor that does not have a ligand. It actually dimerizes with other cell surface receptors from the same family to affect cell signaling pathways downstream. Importantly, then, it can also be a target for different drugs, both antibodies, for instance, that prevent dimerization, like trastuzumab, for instance. Now increasingly antibody–drug conjugates as well, which allow us to target cancer cells that express HER2 and basically treat them selectively in a way.

[00:10:56]

HER2/neu (ERBB2)

HER2 is encoded by the ERBB2 gene, which is located on chromosome 17. Again, it is a member of the tyrosine kinase receptor family along with other proteins that are important in cancer biology, EGFR, HER3, HER4.

It lacks a ligand. It dimerizes again with the other receptors to activate cell signaling pathways downstream.

We see HER2 alterations in many different tumor types, and the prevalence of these are also quite different, as shown in this figure. Across the board for different malignancies, there are different prevalences of HER2 amplifications/HER2 overexpression. In bladder cancer we see quite a bit of this as well, as well as actually, mutations in HER2.

[00:11:43]

HER2 Expression in UC

We also see quite a bit of variability in prevalence of HER2 expression across different malignancies. If you look at this figure from a recent publication, actually, bladder cancer is the malignancy with among the highest prevalence of HER2 overexpression. In particular, even if you focus here, a lot of tumors actually have high HER2 expression so 3+.

[00:12:14]

HER2 Expression in Cancers

What does this mean exactly? We describe expression based on IHC scoring. Immunohistochemistry scoring zero is essentially no expression, and it goes all the way up to IHC 3+, which is a pretty strong expression and greater than 10% of cells. We will get into that a little bit later. It is important to note that HER2 expression across different cancers, or the pattern of expression is quite different. In bladder cancer, this expression can often be quite patchy, unlike, say, the more homogenous expression in breast cancer.

The expression on the cancer cells is more circumferential in both bladder and breast, whereas here in more circular, in other words, whereas in gastric it is more U-shaped. Although gastric, just like bladder, actually has more patchy expression of HER2. For this reason, it is generally thought that bladder expression of HER2 resembles gastric more, and that reflects in our scoring guidelines when we score HER2 expression in bladder cancer.

[00:13:22]

HER2 Expression Is Suggestive of More Aggressive Biology in Urothelial Carcinoma

HER2 expression in bladder cancer is potentially prognostic. It is suggestive basically of more aggressive biology. In this study from now, quite a few years ago, they demonstrated that lymph node metastases have higher HER2 expression unmatched primary tumors in urothelial cancer. They also showed that actually in primary tumors here, HER2 amplification is associated with inferior treatment outcomes.

[00:13:53]

HER2 Expression in mUC is Predictive of Response to ADCs

Perhaps even more importantly, HER2 expression in metastatic urothelial cancer is predictive of response to novel therapies like antibody–drug conjugates. These are the results of the DESTINY-PanTumor02 study of trastuzumab deruxtecan. Dr Galsky will actually go over this in greater detail, but this is a study that led to the pan-solid tumor approval of trastuzumab deruxtecan across multiple solid tumor malignancies, including in urothelial cancer.

It was a large study of patients previously treated. Treatment-refractory patients whose tumors had high expression of HER2 IHC 2+ or 3+ here. It included a cohort of bladder patients, 41 bladder patients to be exact, where, in this cohort, the response rate to trastuzumab deruxtecan, an antibody–drug conjugate targeting HER2 with a topoisomerase 1 payload, the response rate was 39% in the entire cohort. It was enriched in patients with IHC 3+ expression, whereas 56%. This is the subset of patients for which this drug received FDA approval. Previously treated patients with IHC 3+ expression in urothelial cancer, which is of course relevant to our session and actually in a few other solid tumor malignancies as well.

[00:15:13]

Testing and Interpreting HER2 Test Results to Individualize Treatment

Next, we will talk about testing and interpretation of HER2 results to individualize treatment.

[00:15:20]

Poll 7: Two Truths and a Myth. Which of the following is a myth?

Here are the next 2 truths in the myth polling question. Which of the following is a myth?

1. Over 50% of patients with urothelial cancer have HER2 IHC expression to some extent, so 1+, 2+, 3+;
2. 15%, or at least 15% of patients with urothelial cancer are HER2-positive, that being defined as IHC 3+ or 2+ and FISH+; or
3. 80% of patients with urothelial cancer are HER2-negative.

The audience got this correct. The myth is that the majority of patients, 80% are HER2-negative. Actually, both the first statements are true. Over 50% of patients have some HER2 expression and high expression. I see 3+ or 2+ and inside hybridization positive is seen in actually probably somewhat above 15% of patients.

[00:16:40]

HER2 Expression in Urothelial Carcinoma

Historically, there has been a wide range of prevalence of HER2 expression reported in urothelial cancer, and this is accounted for by heterogeneity between patients. Also within individual tumors, where we actually see a lot of heterogeneity of HER2 expression. The amplification of the ERBB2 gene is generally associated with immunohistochemistry expression of HER2, but that is not always the case. There are certainly outliers, as shown in the figure there.

[00:17:08]

Methodologies to Evaluate HER2 Status

There are various methodologies we have to evaluate HER2 status, and these have different clinical relevance. Generally, of course, we use protein expression by immunohistochemistry stain. That is the IHC expression. There are different antibodies that are available for this, including the Dako Hercep Test. There's also the Ventana antibody. There are different scoring criteria as well, which I will get into a little bit, and they differ between gastric and breast cancer.

We also use gene amplification tests. These are variations on in-situ hybridization tests. Also, different tests are available, and the cutoffs for amplification are also different. Then we also have next-generation sequencing. These are with both commercially available panels and institutional panels in certain institutions. These are generally able to detect amplification and ERBB2, and importantly, can also detect other pathogenic alterations such as mutations in the gene, for instance.

[00:18:04]

Breast vs Gastric HER2 IHC Criteria

Here are the breast vs gastric HER2 immunohistochemistry criteria. Again, these are the 2 most commonly used, as there are HER2-targeted therapies approved in these 2 malignancies. Among gastric criteria, specifically, there is also a difference in terms of assessing either surgical sample vs biopsy samples. The main difference really between these 2, between gastric and breast, is that breast cancer, again, the HER2 expression is more homogenous, whereas in gastric cancer, even partial reactivity of the membrane can be considered as positive expression.

[00:18:41]

Pathologist's Advice: Practical Approach for Urothelial Carcinoma

Here is the pathologist's practical approach to urothelial carcinoma guidelines, which generally follow gastric parameters more closely. This is courtesy of my colleague, Dr Ding. If possible, we try to get the most recent specimen for testing HER2, and that is, of course, most relevant to the patient's current clinical status. What that means is that if both primary and metastatic tumor samples are available, we would prioritize metastatic tumor. There is some data, even some data I alluded to earlier, that suggests potentially higher expression in metastatic, with HER2 relative to primary.

If there are multiple histology subtypes present, we generally test all subtypes and may need to score them separately. This is because certain subtypes, such as micropapillary, for instance, can have higher expression of HER2 than some of the other variant histologies. Then if both invasive and noninvasive components are present, this is relevant to radical cystectomy samples. Those may need to be scored separately as well.

[00:19:50]

HER2 Expression in Urothelial Carcinoma Can Be Heterogenous

This is all because HER2 expression in urothelial carcinoma can be quite heterogeneous, as shown in this example here, an individual tumor can have sections that are both IHC 1+, IHC 2+, IHC 3+, and really, depending on the section that you actually get, this can really affect the assessment of HER2 status, obviously, in the sample like this. This really highlights some of the challenges with using this as a biomarker.

[00:20:21]

Assessing HER2/ERBB2 Amplification

We also assess HER2, or specifically ERBB2 amplification. This is done using in-situ hybridization tests. These generally use basically 1 probe to label the ERBB2 protein and another to label the chromosome in which the gene is usually found. Then if there are extra copies of the gene, then this results in extra probes and a positive or amplified test, whereas otherwise it is negative.

[00:20:52]

Defining HER2 Clinical Status (Positive, Low, Negative)

Putting these 2 together. Immunohistochemistry expression and then ERBB2 amplification, we come up with the HER2 clinical status. This is generally what is used for instance, clinical trials of HER2-targeting drugs. Putting these together, we separate patients into those who are HER2-negative, and those are patients with IHC HER2 score of zero. On the other end of the spectrum, HER2-positive patients, and those are basically patients with tumors that are either IHC 3+ or 2+ and in-situ hybridization amplified. Then in between our patients or tumors with low HER2 expression, and those are tumors that have IHC score of 1 or 2+ and are ISH nonamplified.

[00:21:42]

Prevalence of HER2 Expression in Advanced UC

What is the prevalence of these categories? This is a recent study, actually, that I was involved with that looked at HER2 expression in advanced urothelial cancer using a large, commercially sourced global cohort of tumor samples. Over 2,000 patients, mostly with advanced primary tumors, but some metastatic as well, almost 60 metastatic samples. We use a standardized testing approach to define this HER2 status with both IHC and amplification of ERBB2. What we found is that 13% of these tumors had IHC 3+ HER2 expression. They would, in other words, qualify for trastuzumab deruxtecan.

A much larger percentage, actually over 50%, had HER2 expression to some extent. At least 1+, 2+, or 3+. This is a population that is right now being enrolled in different clinical trials of HER2-targeted drugs and can potentially benefit with HER2-targeted therapy as well. What we also saw is that potentially the HER2 expression in metastatic samples, or more extensive HER2 expression, so IHC 3+, is even higher, up to 30% here.

[00:22:58]

ERBB2 Amplification and HER2 Clinical Status

We also looked at ERBB2 amplification in the same data set. Overall, about 12% of samples were amplified, and these differed significantly based on IHC expression. IHC 3+ tumors over 50% were ERBB2 amplified. This dropped to 10% for IHC 2+, and those with low expression, so IHC 0 or 1+, still 3-4% had ERBB2 amplifications. Also important to note that these amplifications were enriched again in metastatic samples or were higher in metastatic samples than primary tumors.

[00:23:40]

Relationship Between HER2 Alteration by NGS and HER2 Expression by IHC

We also have some data on the relationship between HER2 alterations and HER2 IHC expression. This is data from a group at Memorial Sloan-Kettering where they found that in patients again with high HER2 expression, so IHC 3+, the majority of them actually had either ERBB2 mutations or amplifications. Also notable here that HER2 2+ or 3+ expression in this data set was present in over 50% of the tumors.

[00:24:12]

Not All Increased HER2 Expression Associated with ERBB2 Amplification

My group at UCSF, we also looked at other amplifications potentially associated with high HER2 expression. We found that in patients who have IHC 3+ tumors that are non-ERBB2 amplified, they actually often have amplifications of other potentially relevant genes such as GATA3 and PPAR gamma luminal markers. This highlights the utility, potentially, of NGS testing, when to potentially identify additional tumors with high HER2 expression when HER2 IHC data is otherwise not available.

[00:24:54]

HER2-Directed Therapies in Bladder Cancer

Finally, this brings us to HER2-directed therapies in bladder cancer. There is actually a long history of this, of multiple trials, which were negative, but we still learned quite a bit from them. What we learned is that single-agent, HER2-targeted tyrosine kinase inhibitors have limited activity in bladder cancer. Trastuzumab deruxtecan also has limited activity, certainly not in breast cancer, for instance, where it has been the mainstay of therapy for a couple of decades.

Now we have this newer generation of drugs to target ADCs that are showing significant promise, and there are again, 2 in particular. One, trastuzumab deruxtecan, that already has FDA approval for a narrow subset of patients at this point. These are IHC 3+ patients, and then we have some pretty promising data with disitamab vedotin as well, which is a very different antibody–drug conjugate. It is a different antibody targeting HER2 different from trastuzumab, and importantly, has a very different payload. MMAE, the same payload that enfortumab vedotin has. The drug that has really transformed care in urothelial cancer in many ways. I think Dr Galsky will discuss some of the trial data and ongoing trials with these drugs in the next sections.

[00:26:16]

Clinical Trial Updates in HER2-Positive Bladder Cancer

Dr Galsky: Thank you. Good morning. Thanks for coming this morning.

[00:26:22]

Poll 8: Two Truths and a Myth. Which of the following is a myth?

Let us talk a little bit about the clinical data. Now that you have heard about how to test and interpret HER2 in bladder cancer. We will start with 2 truths and a myth again. Which of the following is a myth?

1. Antibody–drug conjugates directed at HER2 have an FDA approved indication in bladder cancer;
2. Small molecule inhibitors directed against the HER2 kinase are associated with response rates of greater than or equal to 30% in patients with bladder cancers harboring HER2 mutations; or
3. HER2 protein expression in individual bladder tumors is often patchy.

Which 1 is the myth? We have small molecule inhibitors directed against HER2 kinase associated with objective response rates were or greater than or equal to 30%. That got the largest vote at 50%, and yes, that is the myth, as we have already heard.

[00:27:31]

HER2-Targeted ADC Design, Mechanism of Action, and Implications or Adverse Events

Let us talk a little bit about HER2-directed ADC. ADCs, of course, are complicated drugs, and they are really combinations of 3 key components. There is the antigen that the antibody is directed against. There is the linker, and there is the cytotoxic payload. Depending on the characteristics of each of these, that will determine both the activity and the safety of these drugs. The linker is oftentimes, at least historically, not considered as prominent as the target or the payload, but it is actually critically important. We will talk about that a little bit more.

[00:28:07]

Select Anti-HER2 ADCs

Here are some select anti-HER2 ADCs. There are many on this list. We all know about T-DM1, approved for breast cancer and used pretty extensively. There have been limited studies in bladder cancer, but the 2 studies in metastatic bladder cancer showed somewhat different results. One showed really no activity, the other 1 showed a little bit of activity. I will note that T-DM1 has a noncleavable linker, and we have already heard that patchy HER2 expression is characteristic of bladder cancer.

If you have a linker that is noncleavable, and so your cytotoxic payload is not cleaved in the tumor microenvironment, you have patchy expression, then you might expect a drug with a noncleavable linker to not have as much activity in urothelial cancer. This has been nicely shown in model systems. Actually, there is a beautiful study in mice where different concentrations of HER2-positive vs HER2-negative cells were combined, and then xenografts were developed based on those tumors.

It was really nicely shown that if you had a high concentration of HER2-negative cells, then drugs with a noncleavable linker did not work that well. If you had a cleavable linker, the ADCs worked better. We have trastuzumab deruxtecan. We are going to talk about that more,. Disitamab vedotin, and I will talk about that more, and then a couple of new drugs that are in development where we are just seeing some clinical activity.

I am going to start with trastuzumab deruxtecan.

[00:29:47]

DESTINY-PanTumor02: Phase II Trastuzumab Deruxtecan in Selected HER2-Expressing Tumors

We have already heard that trastuzumab deruxtecan is the trastuzumab antibody linked to a topoisomerase payload. This was studied in the DESTINY-PanTumorO2 study. This was a Phase II basket study testing trastuzumab deruxtecan in different cohorts of patients with advanced solid tumors. The patients had to have either IHC 2+ or 3+ expression in their tumors. They had to have progressed on prior therapies. There were smallish cohorts of about 40 patients and all these different tumor types. The primary endpoint was objective response rate.

[00:30:27]

DESTINY-PanTumor02: T-DXd Efficacy Summary

Here you can see the results in bladder cancer vs other cancers. In the bladder cancer cohort, a response rate of 39%, that compared favorably to all the other solid tumors, which showed a response rate of about 30% combined. You can see that actually not on this slide, but we have already seen on a prior slide that there was some correlation between expression and the degree of activity, acknowledging that these are very small sample sizes. A HER2 2+ expression, 35% response rate, HER2 3+ plus expression, 56% response rate. Pretty high response rate for a group of patients who are heavily pretreated with metastatic urothelial cancer.

On the basis of this study, there is a tumor-agnostic approval for trastuzumab deruxtecan, which includes patients with HER2 3+ expressing metastatic urothelial cancer. We should now be testing all of our patients for HER2 expression with metastatic urothelial cancer.

[00:31:35]

DESTINY-PanTumor02 in HER2-Expressing Solid Tumors: TDXd Responses Across Tumor Types

Here is the waterfall plot, showing the activity across different tumor types, and also the swimmers lane plot, showing the durability of activity. You can see just by looking at the visual here that across all the different tumor types, the activity is pretty similar, and the durability of activity is pretty similar, so that is nice to see.

[00:31:56]

DESTINY-PanTumor01: Advanced, HER2-Mutated Solid Tumors

There was a second study called DESTINY-PanTumor01, and this was very similarly designed, but looking now at patients with metastatic disease who had HER2 mutations. You can see the list of prespecified HER2 mutations there. HER2 mutations, as we have already heard, are actually pretty common in urothelial cancer, and HER2 mutations in urothelial cancer have been somewhat of a hard nut to crack because HER2-directed small molecules, as we have already heard, just have not shown a lot of activity in urothelial cancer compared to many other solid tumors.

Initially, we explain that, based on the fact that we did not select patients correctly. Initially, it was based on HER2 expression and then maybe based on FISH in not a lot of activity. Then we said, well, maybe it is the mutations. Maybe it is the patients with mutations who we really need to select for. Studies with HER2 small molecules in patients with metastatic urothelial cancer selected based on HER2 mutations actually showed very limited activity as well. Why this is not exactly clear. It might relate to the co-alterations that occur in urothelial cancer compared to some other cancer types like breast cancer.

Maybe it is a drug issue. We now have this next generation of more potent and selective, irreversible HER2 small molecule inhibitors showing nice activity in diseases like lung cancer. Maybe we will see something different in urothelial cancer, but so far, small molecules just have not been that active.

[00:33:34]

DESTINY-PanTumor01

Now testing the strategy of antibody–drug conjugates in HER2 mutated disease, and here you can see the cohorts, much smaller cohorts now because these patients are more difficult to find typically. You can see 7 patients with urothelial cancer were included. You can see there is some activity. In fact, there are regressions in most of the patients, but most of those did not meet the criteria for objective responses. Annotated below is the HER2 IHC expression in those patients. I know it is hard to see, but I will just point out that the patient who had the best response also had HER2 IHC 3+ expression. Do the mutations really matter, or are the mutations just a surrogate for IHC expression, as we saw from the data from Memorial? Showing that there is some enrichment in HER2 overexpression in patients with HER2 mutated disease.

[00:34:38]

Select Anti-HER2 ADCs

That is trastuzumab deruxtecan-approved pan-tumor indication, including urothelial cancer, now a standard treatment for our patients., And we test all our patients with metastatic disease. How about disitamab vedotin? Disitamab vedotin is a distinct antibody directed against a distinct epitope on HER2 now linked to MMAE as a payload, a microtubule agent. We are all familiar with MMAE, the payload that is involved in enfortumab vedotin, an antibody–drug conjugate that really has transformed the way that we treat metastatic urothelial cancer.

[00:35:15]

Disitamab Vedotin in HER2 2-3+ mUC

Disitamab vedotin was initially developed in China. It is approved for use in China. Here is a study pooling 2 different studies. Phase II studies, very similarly designed, exploring disitamab vedotin in patients with HER2 2+ or 3+ metastatic urothelial cancer. You can see that these patients were heavily pretreated. 64% had greater than or equal to 2 lines of prior therapy, and you can see that the response rate in patients with what has been often called HER2 high, which is 2+ expression with positive FISH or 3+ expression. The activity in that group was 62%. In patients with 2+ IHC FISH negative was 39.6%. Again, activity in a heavily pretreated population you can see down on the table showing prior therapies that the responses really were seen across different groups of patients with prior exposures. Certainly, an active agent.

[00:36:23]

RC48-ADC: Disitamab Vedotin in HER2-Negative UC

How about in patients with HER2-negative urothelial cancer? This is a cleavable linker, so back to our point about patchy expression. Maybe if you have a cleavable linker, you do not need a lot of HER2 expression. This was a smaller study looking at disitamab vedotin in patients with metastatic urothelial cancer who had either zero ITK expression or 1+.

Dr Galsky: Now we see the response rate in this cohort was 26%. Virtually, all of the activity was seen in patients with 1+ expression. There was really no activity in patients with no HER2 expression. Really lines up with this concept that you need at least some HER2 expression, but even a little bit is probably enough to generate anti-tumor activity in some patients.

[00:37:12]

Disitamab Vedotin in HER2 1+ mUC

Here is the waterfall plots, again, color coded by IHC expression. The lighter blue is 1+ and the darker blue is zero. Based on the promise of a single-agent disitamab vedotin, and based on the data that had been emerging with enfortumab vedotin plus PD-1 blockade that raised the issue, should we be combining disitamab vedotin with a PD-1 inhibitor? Here is disitamab vedotin plus toripalimab in patients with metastatic urothelial cancer. Most of these patients, 60%, had no prior therapy, and a subset had at least 1 line of prior therapy. You can see really marked activity for this combination response rate of 71.8%. You can see again color-coded the waterfall plot, based on HER2 expression, so activity is seen across different HER2 expression levels, although mostly in patients with 1+ expression or higher. You can see in the spider plots that a lot of these responses were quite durable. Really lining up with what was seen with enfortumab vedotin plus pembrolizumab.

[00:38:25]

RC48-CO14: Phase Ib/II Dose-Escalation and Expansion with Disitamab Vedotin + Toripalimab in HER+ Adv UC

Exciting data with this combination leading to the initiation of a Phase III study in China. This is the Phase III combined pretty similarly to the EV302 study. These are patients with metastatic urothelial cancer who were previously untreated. I had HER2 at least 1+ expression. They were randomized to receive disitamab vedotin plus toripalimab. DV plus a PD-1 inhibitor vs platinum-based chemotherapy, and that chemotherapy could include gem-cis or gem-carbo depending on what a patient was eligible for.

Co-primary endpoints were progression-free survival and overall survival, and this is really the first Phase III study of an anti-HER2-directed ADC in metastatic urothelial cancer. Presented at ESMO a few months ago. Now published.

[00:39:20]

RC48-C016: PFS

Here is the PFS endpoint. Marked improvement in PFS with a hazard ratio of 0.36.

[00:39:29]

RC48-C016: OS

Here is the overall survival data. An improvement in overall survival with a hazard ratio of 0.54. Impressive results, and compares quite favorably to what we have seen with enfortumab vedotin vs chemotherapy and the EV302 study. There are some nuances, some differences between the 2 studies.

[00:39:49]

RC48-C016: Objective Treatment Response

There is a little bit of a higher proportion of patients with upper tract disease in this cohort compared to EV302. There is a little bit of a lower complete response rate compared to EV302, and a lot has been made of that. I can tell you that in some other data sets, including with single agent therapy, we see CR rates that are comparable to what we see with EV. I think this is probably just an aberration of the data set rather than a real difference between the 2 therapies.

[00:40:23]

RC48 G001: Phase II Study of Disitamab Vedotin in Locally Advanced or Metastatic UC

This drug and combination therapy is being explored now globally, and this is the RC48 G001 study. It is a Phase II study of DV in patients with metastatic urothelial cancer that has several cohorts. There is the HER2 2+ or the HER2 high cohort, cohort A. Cohort B is a HER2 low cohort, so this is single-agent deviant patients who progressed despite prior therapies, and then there is cohort C which is the combination of disitamab vedotin now with the PD-1 inhibitor pembrolizumab.

This involved a safety run-in phase and then a randomization of DV plus pembrolizumab or DV alone, very similar to the development strategy that we saw a few years ago with enfortumab vedotin plus pembrolizumab, to really provide us with some understanding of the contribution of components of this combination in patients with metastatic urothelial cancer or previously untreated.

[00:41:24]

RC48G001 Cohort C: Disitamab Vedotin + Pembrolizumab in Naive HER2-Expressing Advanced or Metastatic UC

We have seen data from the run-in phase of this study, so here you see DV plus pembrolizumab in a small run-in phase study. You can see lots of activity with this combination, including many complete responses, and that really gets back to that point that I was making about the Phase III in the somewhat lower CR rate than we have seen with EV plus pembrolizumab might be an aberration. We certainly see a high CR rate in this small run-in phase of this study.

[00:41:57]

Select Anti-HER2 ADCs

Now there is a Phase III study also ongoing comparing DV plus pembro with platinum-based therapy. International Phase III study to try and replicate the results of the Phase III that was seen in China. Just 1 point about some additional agents. This is MRG002, and the only reason that I showed this is, this is a different antibody. Again, an MMAE payload, cleavable linker, and I only point this out to show that yes, there are other HER2-based ADCs that are showing activity in metastatic urothelial cancer. This was from ASCO a couple of years ago, comparable response rates to what we are seeing with other agents. This is certainly a field that is ripe for the development of additional antibodies, additional payloads, and different linkers.

[00:42:53]

Managing Treatment-Related Adverse Events in HER2+ Bladder Cancer

I am going to shift gears a little bit in the time that I have left. Just go through some of the key adverse event information that you need to know if you treat patients with metastatic urothelial cancer with these agents.

[00:43:06]

Poll 9: Two Truths and a Myth. Which of the following is a myth?

First, 2 truths and a myth. Which of the following is a myth?

1. Patients receiving trastuzumab deruxtecan should have a baseline echocardiogram.
2. Trastuzumab deruxtecan could be resumed after resolution of grade 1 pneumonitis.
3. Disitamab vedotin can cause peripheral neuropathy.

A, B, or C. Patients receiving trastuzumab deruxtecan should have a baseline. Echo was 38.9%, so the majority answered.

[00:43:56]

DESTINY-PanTumor02: Safety Summary

Let us talk briefly about safety. Trastuzumab deruxtecan, there are side effects related to the payload, so you can see here drug-related treatment-emergent adverse events in the bar charts. You can see things that we see with topoisomerase inhibitors: nausea, fatigue, neutropenia, diarrhea, and then a couple of things, of course, to know about this drug in particular and HER2 agents in general.

We know that HER2 agents can occasionally cause an impact on ejection fraction. This seems to occur less commonly with ADCs than we saw with naked antibodies in the past. There was a very small subset of patients who had decrease in LV function with this therapy and you can see 4.5% there.

The other side effect that can occur with trastuzumab deruxtecan, that is not common but potentially serious is pneumonitis. We take pneumonitis quite seriously with antibody–drug conjugates, and specifically in those with a little bit of a higher frequency of pneumonitis. You can see here that ILD of any grade occurred in 7.5% of patients in the PanTumor02 study.

[00:45:11]

RC48-C009 and RC48-Coo5 Trials: TRAEs With Disitamab Vedotin in HER2+ Locally Advanced or mUC After 1L CT

Here is the adverse event profile with disitamab vedotin, and this has a different side effect profile. It is a different linker. It is a different payload, and that dictates the side effect profile.

[00:45:24]

Factors Influencing the Toxicity of ADCs

I am going to skip this slide because I am going to show you a little bit about the comparing and contrasting adverse events depending on the target and the payload. Here you can see that the different factors that influence toxicity, which we already discussed, the antibody matters, the payload matters, and the linker matters. With the noncleavable linker, you might expect less free drug in circulation and maybe less systemic toxicity that was at least a thought when ADCs were initially being developed. On the downside, you have less of that bystander effect potentially.

[00:46:02]

AEs: Related to the Anti-HER2 ADC Payloads and Target

This is what I was referring to. We have this really nice example in urothelial cancer where we have 3 drugs, and across these 3 drugs we either have the same target, or we have the same payload. You could compare and contrast toxicity and really start to get a sense for what might be more target-related vs more payload-related vs a combination. Trastuzumab deruxtecan has already mentioned pneumonitis is something that we think about. Not that common but can occur.

Pneumonitis can actually occur with any ADCs, but occurs probably less commonly with some vs others. Disitamab vedotin, on the other hand, we see neuropathy. It has an MMAE payload. We do see some transaminitis. We see some rash, but the rash seems to be less than we see within enfortumab vedotin. Remember Nectin-4, the target of EV is expressed in the skin, and so, probably at least responsible for that. We do not really see a lot of hyperglycemia with trastuzumab deruxtecan or any to speak of, but we do see this with MMAE payloads on occasion.

[00:47:12]

Management Pearls

Just 1 quick case of this 78-year-old patient who had metastatic urothelial cancer, progressed on platinum-based therapy, had a tumor that was IHC 3+, and he was treated with trastuzumab deruxtecan. He has a great response to treatment, received 16 doses, and then has the CT. You see on the CT these patchy ground glass appearing infiltrates, so this is a patient who has developed pneumonitis.

[00:47:41]

Administration Considerations for ADCs in GU Tumors

Our management strategy with trastuzumab deruxtecan-related side effects is pretty well-defined based on the studies that have been done to date. There are some really nice treatment dose modifications that are spelled out for managing various toxicities, including pneumonitis.

You can see here an algorithm for managing pneumonitis, including interrupting the drug with any suspicion of pneumonitis. Getting a CT, pulmonology consultation, should certainly be considered. We think about starting steroids pretty quickly if we are suspicious of pneumonitis in patients on trastuzumab deruxtecan. Patients with grade 1, we hold until grade 0 and then potentially resume with same dose vs lower dose, depending on when the side effect resolves, and patients with grade 2 or higher, we permanently discontinue trastuzumab deruxtecan.

[00:48:40]

Experts in the Hot Seat

We are going to move on to some questions that there are a variety of choices for the questions that you would like us to discuss, and then we will provide some input on these.

[00:48:52]

Poll 10: Audience, please vote. Which of the following questions would you most like the experts to discuss?

Which would you like us to discuss?

1. HER2 is amplified, expressed, and mutated in bladder cancer. How does this influence the need for next-generation sequencing in addition to HER2 IHC?
2. How do you incorporate routine testing into your clinical practice? Or
3. How do emerging clinical data results of HER2-directed ADC therapies affect current standards of care in bladder cancer?

A, B or C, what do you want to hear more about? How do you incorporate routine testing into your clinical practice, Dr Koshkin?

Dr Koshkin: This is an important question. I think especially with these emerging new therapies for a new target in bladder cancer, which is HER2 expression, it is important to test as early as possible. By the time patients get to the metastatic setting, I try to make sure that I know the HER2 status of their tumor, basically. That often involves testing the tissue that is readily available. That is usually more archival samples from radical cystectomy. As I also highlighted, I think it is important, if possible, to test the metastatic sample if you have it.

I will also say that actually because there is a lot of experience and expertise from the pathology and in terms of doing this for breast cancer. Now, for gastric cancers, the adoption of this testing for urothelial cancer, at least at my institution, has been pretty seamless. They are ready and able to do it, and now many actually commercial panels, like Foundation, Tempest, are able to do it pretty reliably as well.

Dr Galsky: We have been doing it pretty routinely as just a reflex test on cystectomy specimens over the past couple of years, so it is nice to have that information available and planning ahead, but certainly a test unlike some of the others that we order that can be done locally and come back quite quickly. Oftentimes if it is not done and we request it, we get results back within a matter of days.

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Poll 11: Audience, please vote. Which of the following questions would you most like the experts to discuss?

How about the next topic?

1. Do you envision HER2-targeted ADCs affecting future clinical practice, and where will they fit in within clinical guidelines?
2. What is the potential for HER2-targeting in earlier lines of therapy?
3. Do you foresee the incorporation of HER2-directed ADCs with TKI therapy, bispecific antibodies, or even CAR T-cell therapy and future treatment of HER2-positive bladder cancer?

Which topic would you like to hear more about?

How do you envision HER2-targeted ADCs affecting future clinical practice? Will they fit in within clinical guidelines, Dr Koshkin?

Dr Koshkin: They are already affecting current clinical practice. We are, of course, obviously using trastuzumab deruxtecan in treatment refractory patients with high HER2 expression. I see 3+, and with the really encouraging disitamab vedotin data, we are probably going to be using it more and for a broader subset of patients, so not just those with IHC 3+ expression, but based on trial results, potentially will expand its use to, again, a broader population of patients.

Based on available data, again, it is probably over 50%, 60% of patients with some degree of HER2 expression that may qualify for therapy with something like this vedotin in combination with pembrolizumab, for instance, if that combination is eventually approved. Now the question is in what setting we would use that in there. If the currently ongoing global trial of disitamab vedotin with pembrolizumab vs chemotherapy reads out with the same encouraging results that the study in China that was presented at ESMO showed, then it may be an option in the frontline setting.

Then we will have to make a decision of who gets that vs, say, getting informed of vedotin and pembrolizumab, which has become the mainstay for frontline treatment. Then, moreover, we potentially would consider using it even earlier, like we are using it in vedotin pembrolizumab earlier now, for patients with muscle-invasive disease. There is some data for DV and with checkpoint inhibitors also as monotherapy in the muscle-invasive setting as well from China. Going forward, that may be something to explore further as well.

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Poll 12: Audience, please vote. Which of the following questions would you most like the experts to discuss?

Dr Galsky: Thank you. Sorry. One more. Please weigh in on which of the following we should discuss:

1. How important is sequencing of therapies in the evolving treatment landscape of bladder cancer?
2. What strategies do you use to foster better coordinated care for the recognition and treatment of treatment related adverse events? Or
3. What clinical strategies may help to mitigate treatment related adverse events in patients undergoing therapy with HER2-targeted treatments?

Which 1 should we discuss? We have a tie. We have how important is the sequencing of therapies, and then what clinical strategies to mitigate. Dr Koshkin, which 1 do you want to discuss?

Dr Koshkin: We can maybe quickly address both. Starting with the first 1. The sequencing of therapy, very important question for which, with the currently available therapies, we have limited data. We have trastuzumab deruxtecan, somebody that is approved for patients with metastatic disease and the treatment-refractory setting. That patient with HER2 IHC 3+ expression who had progressed on prior therapy, usually the frontline therapy for these patients now, will be in the form of vedotin and pembrolizumab. Then we have to make a decision whether they get trastuzumab deruxtecan or, say, platinum-based chemotherapy. We really do not necessarily have the data to support either approach. I generally try to go with the targeted drug earlier on because, again, we see pretty good activity with this therapy. I do not know if you want to comment on that as well.

Dr Galsky: No, I agree.

Dr Koshkin: Then, in terms of clinical strategies to mitigate treatment-related adverse events. Again, it is important to be aware of the specific toxicity associated with the drug. With trastuzumab deruxtecan, again, we worry about cytopenias quite a bit, and those can happen even early on in treatment. Monitoring for that, and of course, addressing it as, needed. For many patients, I actually use G-CSF support. I do not know if you do primary prophylaxis, but that is an important approach.

Then, of course, keeping in mind pneumonitis, which is a rare side effect, it does not happen in most patients, but is potentially a significant side effect. Anyone with any suggestive symptoms, I think we try to jump on that pretty quickly and really assess any dyspnea cough with pretty urgent imaging, and to make sure that we address it if it happens.