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Personalizing Treatment of HER2-Positive Advanced Bladder Cancer: Expert Guidance on the Latest Evidence for HER2-Targeted ADCs

So the HER2/neu signaling pathway is actually fairly complex. And the results of - or at least the pathways that are then activated are really dependent upon how the particular HER2/neu dimerizes with another ligand.

So as we see here, HER2/neu can dimerize with EGF, it can dimerize with HER3, it can dimerize with HER4. And it also can form a hetero or homodimer with itself. And these again can activate different signal pathways.

So the MEK, ERK, RAF pathway is basically activated by EGF and HER2/neu. HER3, PI3 kinase, AKT. Same thing with HER2/HER4. And then JAK-STAT pathways is activated by the HER2 homodimer. So the signal transduction pathways that are activated are dependent upon dimerization and activation of HER2 is related to dimerization. The monomers do not really activate these pathways.

[00:10:45]

HER2 Plays an Important Role in Bladder Cancer Biology

So how can we potentially interfere with this? Well, these HER2-targeted drugs can prevent the dimerization of the receptors and then inhibit the potential signal transduction pathways which would normally be activated.

[00:11:01]

HER2/neu (ERBB2)

So what is HER2/neu and what is ERBB2? HER2/neu is the protein. ERBB2 is the gene, and this is located on chromosome 17q11-q12, same place that EGF is - is located. It's a member of the tyrosine kinase receptor family, which includes EGF, HER2, HER3 and HER4. And this is expressed on the cellular surface.

There's no ligand. In other words, TGF-alpha will activate EGF. There is no specific HER2 ligand that's been searched for, for a number of years. It's almost like a search by Captain Ahab for  Moby-Dick. We don't see a ligand for HER2/neu.

So it’s the dimerization that activates it. And this is seen with other receptors. And as I mentioned before, this will activate signal pathways.

HER2 alterations are seen in many tumor types, as we see on the right. Salivary glands, breast cancer, that's where HER2 is really first used as a target for therapy. The stomach, gastric cancer. There is an FDA approval of Herceptin in gastric cancer as well. Uterine cancer, ovarian cancer, cervix.

The 1 that's really been kind of controversial over the years has been prostate. Really the level of expression is fairly low as we see, only 10%; bladder, 12.4%; overexpression, amplification 8.6%; and 9% mutations. So it is seen in bladder cancer.

[00:12:34]

HER2 Expression in UC

And this is another plot which shows the different levels of expression in terms of percentage of 3+, 2+, 1+. As we see, urothelial cancer has a fairly high rate of 3+ expression. It's actually more than breast cancer, salivary gland cancer, endometrial cancer. So it's up there. Gastric seems to be a little bit more than breast as well in the high levels of expression. So this is a legitimate target for the treatment of metastatic urothelial carcinoma.

[00:13:03]

HER2 Expression in Cancers

This slide depicts the immunohistochemical staining of bladder, breast and gastric. As we see, it does seem to be a little bit hotter in the 1s and 2s. And then we start going to the 3s. It's very, very hot. And on the left, of course, is a IHC zero, which really there's no staining at all. And weak staining with IHC1. So all levels of staining and of course the staining means the target is there.

[00:13:33]

HER2 Expression Is Suggestive of More Aggressive Biology in Urothelial Carcinoma

So what about the biology? What does this mean in terms of urothelial cancer? Well, this is actually something that's been known for a long time. And there was a study that was done a number of years ago by Maha Hussain. I was fortunate enough to participate in that, where she looked at a triplet regimen, a chemotherapy regimen of carboplatin, gemcitabine, paclitaxel with Herceptin. And this was a phase I/phase II trial.

And we used all types of methods to assess HER2 status. And what was found was that the volume of metastatic disease and visceral metastases mark for a more aggressive phenotype. And that was where we saw the highest levels of HER2 expression.

So if we start looking at primary tumors and corresponding lymph node metastases, we see that that there is a trend towards more aggressive disease in the primary tumors. The HER2 patients seem to have again overall a higher volume of disease.

[00:14:33]

HER2 Expression in mUC Is Predictive of Response to ADCs

And if we look in terms of response to different ADCs, we see that the IHC 3s seem to have the best responses. So on the left is bladder, the middle is other malignancies. All patients. We see that for IHC 3s the confirmed objective response rate is 56%. And for other tumor types 44% for 3s and then 61%. But you do see also responses in the IHC 2s as well.

And this is the DESTINY-PanTumor, which was T-DXd monotherapy in HER2/neu-expressing tumors. And this was in IHC 2+ plus 3+ patients. And these patients had more than 1 line of prior chemotherapy. I'm stuck here. Oh, here we go.

[00:15:23]

Are Patients Who Respond Best to EV the Same as Those Who May Respond Well to HER2-Targeted Treatment?

So what does also biologically HER2 expression mean in terms of the tumor? Well, 1 group which I think, well, this is actually kind of interesting data. It's been found that NECTIN4, of course, we know that it's a target for enfortumab. That NECTIN4 also seems to map along with HER2 expression and ERBB2. So ERBB2 is also overexpressed in the luminal form of urothelial carcinoma, which is enriched for NECTIN4.

The other interesting observation, which I don't have a slide for, is that there's an inverse relationship between FGFR3 mutations and HER2 expression. So low FGFR3, high HER2/neu, and the converse, high FGFR3, you generally don't see HER2/neu amplification. And so that also is something which I think is an interesting observation that's been made.

[00:16:18]

Testing and Interpreting HER2 Test Results to Individualize Treatment

What about testing and interpreting HER2 tests to individualize treatment?

[00:16:24]

HER2 Expression in Urothelial Carcinoma

So as we mentioned before, we have a wide range of prevalence of HER2/neu in urothelial carcinoma. There's heterogeneity between patients, and we'll see that in some specimens. Non-standardized testing methodology, gene amplification associated with increased immunohistochemical expression, but not always. And again, ERBB2 expression. You would think that higher levels of ERBB2 would lead to HER2. That is generally the case, but not necessarily so.

[00:16:55]

Methodologies to Evaluate HER2 Status

So we have different ways of looking at HER2 antibodies, the Dako Hercep test, the Venta pathway, which is an anti-HER2/neu antibody. And of course, there are scoring guidelines which we'll mention in a few moments.

There's also in situ hybridization with Dako as well as the Abbott. And again, there are ASCO guidelines for both breast cancer and gastric cancer. Next-generation sequencing with FoundationOne, Guardant360. And of course, some of us have our own institutional panels using Illumina. And again, there are cut-offs with amplification and pathological alterations.

[00:17:32]

Breast vs Gastric HER2 IHC Criteria

So the staining scores are pretty much similar for both of these groups. So a negative is less than 10% of the tumor cells, staining for HER2/new. And remember, there's a difference between membrane staining and cytoplasmic staining. We look at the membrane staining not necessarily the cytoplasmic, and that - that is indicative of - of course something on the cellular surface.

Negative 1+, faint, maybe more than 10% of the cells. And that again seems to be across the board for gastric and breast. Tumor clusters also can be seen with faint staining as well. Again, faint membrane staining but it's irrespective of the percentage of tumor cells stained.

Then we move on to the equivocal, which is 2+ which is weak. And you can see tumor cell clusters with moderate or complete expression of HER2/neu or lateral membrane reactivity. And then the positives are more than 10% which are strong. And again, the clusters can be strong and complete as well in that situation. So greater than 10% positive—strong staining is positive.

[00:18:45]

HER2 Expression in Urothelial Carcinoma Can Be Heterogeneous

And here is a representation of what we see in terms of the heterogeneity. You see on the left within the same specimen, you have IHC1, IHC2 and IHC3. And this is why you need really an experienced pathologist to help you with the interpretation of these stains, because you can get vastly different interpretations based upon where in the tissue you look.

[00:19:09]

Assessing HER2/ERBB2 Amplification

So I mentioned before, gene amplification of ERBB2 can lead to a higher expression levels of HER2/neu. And you can look at in situ hybridization using FISH either through Dako or through Abbott. And these will examine the tumor cells using these particular probes. And you'll see both positive and negative cells. You see on the right, you see these dots that are the - the - the in situ hybridization.

And on - on the right side, you see up on top from an H&E the amplified cells. But again you can pick these up through FISH amplification.

[00:19:48]

Defining HER2 Clinical Status (Positive, Low, Negative)

And then looking at the HER2 status, positive, low or negative. Again, 1+, 2+, 3+. 3+ is the strongest which has complete basolateral lateral membranes reactivity in more than 10% of the tumor. And generally, the 2+, you could look at DISH non-amplified as well as the amplified, which would be positive in this particular situation. That, again, is a way of stratifying that particular group.

[00:20:15]

Prevalence of HER2 Expression in Advanced UC

So in advanced urothelial carcinoma, HER2/neu is seen at reasonably high rates using more than 2,000 specimens and standardized testing for HER2/neu 13% with IHC 3 would qualify for treatment with trastuzumab deruxtecan, more than 50% with HER2/neu expression, as we see the 3+ are 29% in the metastatic lesions and 13% in the primary lesions. And that again is indicative of the fact that this marks for a more aggressive form of the disease.

[00:20:53]

ERBB2 Amplification and HER2 Clinical Status

Does ERBB2 status always correlate with HER2/neu expression? The answer is, there is a trend towards that, but there are some specimens that are not amplified which have high levels of IHC 3 positivity. So it's not necessarily correlated with that particular observation.

[00:21:13]

Relationship Between HER2 Alteration by NGS and HER2 Expression by IHC

And then we start looking at the correlation between sequencing and HER2/neu expression. We see that ERBB2 alterations, both pathologic as well as amplifications were identified in the MSK IMPACT in 20% of urothelial cancer cells, and 2+ or 3+ expression is seen in about 52% of those cells.

[00:21:37]

HER2 Expression Does Not Always Correspond to ERBB2 Amplification

And I mentioned before that the HER2 expression does not always correlate with ERBB2 expression. ERBB2 can be amplified in about 40% of IHC 3 tumors, 27% of IHC tumors do not have ERBB2 amplification. And these have been examined by looking at copies of GATA3 and PPARG. Five will have GATA3 amplification, 1 will have PPARG amplification as well.

And this shows that, you know, again, the way this marker is manifested is either through amplification or upregulation.

[00:22:14]

HER2-Directed Therapies in Bladder Cancer

So what - what do we do with this information? Well, we have HER2-directed therapies for urothelial carcinoma. It - it was very disappointing to see that a lot of the TKIs that target HER2/neu and there have been adjuvant studies in that setting do not really show activity. I mean, it’s really a big negative.

Trastuzumab lacks clinical benefit. And although I think it's never been adequately examined in terms of combination therapy with chemotherapy. But the next-generation agents include trastuzumab deruxtecan which targets - which has targets HER2/neu. The linker is a tetrapeptide. The payload is topoisomerase I inhibitor, DXD, and it has a tumor-agnostic approval in HER3-positive patients.

Disitamab vedotin administers MMAE and it has been evaluated in tumor in urothelial carcinoma. It's not yet FDA approved. The question is going to be can we sequence this with enfortumab based upon toxicity? That's going to be an interesting question that turns out later, because prior exposure to MMAE may lead to more neuropathy.

[00:23:35]

          Posttest 1

Okay. So let's go on to the post-test. 72-year-old patient with metastatic urothelial carcinoma started treatment with EV plus pembro but experienced disease progression. Based upon current guidelines, what molecular testing strategy is most appropriate to determine the potential eligibility for approved HER2/neu ADCs?

1. Tumor tissue on NGS is the most recent biopsy to assess ERBB2 amplification;
2. ctDNA from a recent blood draw to assess ERBB2 amplification;
3. HER2/neu immunohistochemistry on the most recent tumor biopsy to assess HER2 expression; and
4. HER2/neu immunohistochemistry on archival primal tissue to express - to assess for HER2 expression.

So what's your vote?

Okay. Most recent tumor biopsy. I think that that would agree. And we see that because we saw a difference in the metastatic vs - vs the primaries and also in terms of the lymph nodes.

[00:24:48]

          Posttest 1: Rationale

So the right answer is the most recent tumor biopsy. And again, that's the most appropriate strategy for looking at this. Next slide, please.

[00:25:02]

          Challenges in the Community #1

What's the biggest barrier to obtaining HER2/neu results in advanced urothelial carcinoma in your practice?

1. Insufficient tissue/need for repeat biopsy;
2. Turnaround time;
3. Coverage; or
4. Discordance (IHC vs NGS) or uncertainty interpreting results.

So discordance uncertainty seems to be the most common problem. Coverage, next. And the turnaround time in insufficient tissue. My experience has been insufficient tissue, because we're using the tissue for FGFR3, next-generation sequencing, potential clinical trials. So we've actually had to rebiopsy some patients to look for this.

But I think the turnaround time also can be abrogated by doing the test right at the development of metastatic disease. This way, if and when a patient progresses on their current treatment, you're ready to go and you don't have to wait. And it really does reduce stress and anxiety for the patient as well as the physician.

So coverage and - oops, go back to that again. Coverage and discordance between the IHC and the NGS are the most common reasons - common barriers. Next.

[00:26:34]

Integrating Established and Emerging HER2-Targeted ADCs Into Treatment Sequences for Advanced Bladder Cancer

So Dr Koshkin. I'm sorry, you should be - you're the moderator.

Dr Gupta: No, no, no, you have to pass it.

Dr Petrylak: Okay.

Dr Gupta: You can sit there too, if you want.

Dr Vadim Koshkin (University of California, San Francisco): All right. Great. Well really glad to be here today to talk about this. And having discussed, well, the importance of testing and testing methods.

Now it's a good time to discuss the HER2-targeted antibody drug conjugates and some of the options we have. And we actually talked about this a little bit already, at least, you know, some of the available data for trastuzumab deruxtecan.

[00:27:09]

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

But at first it's important again to highlight that these are actually, you know, pretty complex drugs. So an antibody drug conjugate consists of an antibody that, you know, targets a specific target hopefully on the tumor and present on the tumor and not on normal tissue. And that's linked via stable but cleavable linker to a chemotherapy payload. So a cytotoxic drug which essentially gets into the cancer cell and actually kills the cancer cell.

[00:27:40]

Select Anti-HER2 ADCs

There are a few anti-HER2 antibody drug conjugates that are either in development or actually already have pretty good data. In the interest of time, I'll focus on just a couple of them, the trastuzumab deruxtecan, which actually has an FDA approval in this disease, and actually for pan solid tumor indication. And then disitamab vedotin, which has a pretty promising data, not yet approved in the US, actually approved in China. But really good data, including, again, some updated data that was presented this morning at this conference.

[00:28:12]

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

But trastuzumab deruxtecan was approved based on phase II DESTINY-PanTumor02 study. Dr Petrylak went over this a little bit already. But this was basically a large multicohort phase II trial which included patients with many different solid tumor malign - solid cancers, solid tumor malignancies. All patients in this trial had tumors that had high HER2 expression. So IHC 2+ or 3+. All were also pre-treated.

So these were treatment refractory patients. And they were, as part of this trial, treated with trastuzumab deruxtecan at the standard dose, given every 3 weeks.

The primary endpoint here was investigator-assessed confirmed objective response rate. And of course, key secondary endpoints are progression-free survival, overall survival, safety, things like that. And importantly, this trial also had an exploratory analysis looking at outcomes based on HER2 status. So basically comparing 2+ and 3+ patients.

[00:29:16]

DESTINY-PanTumor02: Efficacy of T-DXd

The results shown here again highlight that pretty robust response rate 37% across all patients. Again, in this 267 patient trial. And this was pretty consistent in the bladder cohort specifically. So the 41 patients in the bladder cohort had a response rate of 39%. This was enriched not shown on this slide, but Dr Petrylak showed earlier, in patients with HER2 IHC 3+ expression where it was actually 56%.

Most of these were partial responses. Only 1 complete response was seen. The responses here are not always very durable. Median duration of response is about 9 months. And then we do see when comparing again 2+ and 3+ or outcomes in 2+ and 3+ patients that even though the response rate was actually higher for 3+ patients, the PFS and OS actually was quite similar in the 2 groups.

So the FDA approval for this drug is again for IHC 3+ patients. But based on this data, actually IHC 2+ patients do do reasonably well also.

[00:30:28]

DESTINY-PanTumor01: Trastuzumab Deruxtecan in Advanced, HER2-Mutated Solid Tumors

Further, there was also DESTINY-PanTumor01 study. This was also in trastuzumab deruxtecan. But patients were selected for this trial differently. So this trial included patients with ERBB2 mutations, so a gene that encodes HER2, rather than being selected based on, again, higher HER2 expression. The prespecified ERBB2 mutations are shown in the table there. These were again pretty diverse, included both mutations in the extracellular domain and a transmembrane domain in the kinase domain as well.

And all these patients again were treated with trastuzumab deruxtecan at the standard dose every 3 weeks. This was also a trial including many different solid tumor types, many - across many different cohorts of patients. And the primary endpoint here again was confirmed objective response rate.

[00:31:24]

DESTINY-PanTumor01: Best Percentage Change in Target Lesion Size and Confirmed Response by ICR

In terms of outcomes, we see again actually, you know, pretty good responses in the majority of tumors in breast. Especially, you really see that in these tumors with mutated ERBB2, you see pretty good reduction in the tumor bulk. Urothelial cohort here was small. It's in the middle of the slide there. It was only 7 patients, but some responses were seen there as well. And actually all patients had, you know, reduction in their tumor bulk there.

And so this is intriguing data suggesting that also mutations in ERBB2 may predispose to responses to trastuzumab deruxtecan. But this is not what the drug is approved for right now.

[00:32:09]

Select Anti-HER2 ADCs

Next we focus on disitamab vedotin. And that's, of course, a different ADC from trastuzumab deruxtecan. So the antibody is different. It's still a HER2 antibody but not trastuzumab. And importantly, the payload is different. So trastuzumab deruxtecan of course includes a topoisomerase I payload. Disitamab vedotin, the payload here is vedotin, which is MMAE, the same again exact payload as enfortumab vedotin, the drug that really has, you know, transformed the landscape of urothelial cancer.

[00:32:46]

Disitamab Vedotin in HER2 2-3+ mUC

This drug initially was developed in China, and the initial really promising data was from studies in China. So this is data for disitamab vedotin monotherapy in patients with IHC 2+ and 3+ expression. All were also treatment-refractory patients. And in this pretty sizeable cohorts, over 100 patients, response rate was over 50% in these, you know, high expressing tumors.

So really promising. You further see enrichment of responses. Actually the higher the expression of HER2. So IHC 3+ or IHC 2+ and FISH positive. Their responses were over 60%. We also see pretty good outcomes in patient populations that are typically difficult to treat. So those with liver metastases with visceral metastases as well.

[00:33:44]

RC48-ADC: Disitamab Vedotin in HER2-Negative UC

There was also data in HER2-negative patients. This was a slightly different trial, much smaller, only 19 patients, that had lower expression of HER2. So IHC zero or 1+. And here the response rates, as perhaps would be expected, were lower at 26%. All responses here were actually seen in IHC 1+ patients. Among those 13 patients with IHC 1+, the response rate was a bit higher. But all patients with IHC zero, so no HER2 expression, still actually had stable disease here.

[00:34:24]

RC48-ADC: Disitamab Vedotin in HER2 0/1+ mUC

Focusing a bit more on IHC or on the subsets again in this smaller trial, IHC 1+ patients. So that's again just a 13% subset. But response rate is still 13 patient subset. The response rate is still pretty good. So almost 40%. And it's also, you know, pretty remarkable that this data actually looks pretty similar to the data that was actually presented this morning in IHC 1+ patients. Again, it was about 40% response rates or so.

[00:34:54]

RC48-C014: Response to Disitamab Vedotin + Toripalimab

Then there were further trials that combined disitamab vedotin with immune checkpoint inhibitors. And here's where we begin to really see really good activity with this combination. So this was a trial that included a mix of patients both treatment-naive and actually pretreated as well, and all received a combination of disitamab vedotin with toripalimab. It's an immune checkpoint inhibitor, a PD-1 antibody that's used in China, we don't use it here so much.

But, you know, the response rate with this combination was over 70%. Really robust, really impressive as shown in this slide here. And it's also really actually remarkable how similar this data looks to a combination of, for instance, pembrolizumab and enfortumab vedotin. So a different ADC in an unselected patient population, but with the same payload.

[00:35:50]

RC48-C016: Disitamab Vedotin + Toripalimab in HER2+ Advanced UC

And this promising data with this - with this combination of checkpoint inhibitor and disitamab vedotin then led to this larger randomized trial that enrolled in China and actually just presented the results recently, a few months ago at ESMO.

And so this is a phase III study of treatment-naive patients in the metastatic setting who were randomized 1-to-1 to receive either standard of care, which would be basically platinum-based chemotherapy, or this combination of disitamab vedotin and toripalimab. And all patients, I should say in this study, had at least some HER2 expression. So 1+, 2+ or 3+. That had some HER2 expression basically to enter the study and be randomized.

The co-primary endpoints were progression-free survival and overall survival. And the results, you know, when they came out were actually quite impressive.

[00:36:44]

RC48-C016: Objective Treatment Response

Disitamab vedotin and toripalimab combination outperformed platinum-based chemotherapy both in terms of across all endpoints actually, starting with actually response rate. You see higher response rate here 76% vs 50% with—so 76% with the combination, 50% with chemotherapy. Disease control rate with combination over 90%. Again, very - you know, data that's very reminiscent of EV pembro data.

[00:37:16]

RC48-C016: PFS

And then, of course, importantly, DV and toripalimab outperformed chemotherapy in terms of progression-free survival. One of the co-primary endpoints, really impressive hazard ratio of 0.36. The curves separate early on and really shows the benefit of this, this combination in this selected patient population. So HER2 expressing patients.

[00:37:39]

RC48-C016: OS

And of course, most importantly, there was a significant overall survival advantage as well with DV and toripalimab vs chemotherapy with again a hazard ratio here of 0.54. Almost doubling of median overall survival. So 31.5 months vs 17 months. Again, remarkable how similar this data actually looks to something to the data from EV 302 actually, where at least on the initial readout, EV pembro median OS was exactly 31.5 months as well. And the chemotherapy outcomes were - were about the same as well.

[00:38:14]

RC48G001: Phase II Study of Disitamab Vedotin in Locally Advanced or Metastatic UC

There was additionally a phase II study, which—well, cohorts A and B finished enrolling, cohort C and were actually cohorts A and B were presented earlier this morning by Tom Powles. And then also cohort C which is still enrolling. But this phase II is a global study now where cohorts A and B include patients again with either high or low HER2 expression, respectively, that were treated with disitamab vedotin monotherapy. And these were treatment-refractory patients.

And again we saw the data this morning, which again was at a pretty robust response rate. And actually pretty similar response rates between cohort A and cohort B, perhaps surprisingly.

And then there was cohort C, which were actually patients also with metastatic disease, but treatment naive. And as part of the initial safety run and they received a combination of DV and pembrolizumab. Those were the initial 20 patients. And now the cohort C is in the randomized portion, where they're enrolled patients are getting DV and pembrolizumab vs just DV monotherapy.

[00:39:34]

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

The initial safety run-in data. So initial 20 patients was actually presented by Matt Galsky about a year and a half ago at ESMO 2024. And here, again the response rate with this combination was 75%. So it was 15 out of - out of 20 patients with response and 19 out of 20 patients with response or stable disease. So really robust numbers we see with this combination. As a result of this or this actually informed the design of now a global phase III study which randomizes patients again with HER2 expression to receive DV and pembrolizumab vs platinum-based chemotherapy. And that trial just finished enrolling, and we hope to see results in a couple of years.

[00:40:17]

          Posttest 2

So now we move on again to post-test questions. So this is post-test question number 2. And based on the data, so just presented, which of the following HER2-targeted ADCs in combination with toripalimab demonstrated improvements in both PFS and OS compared to platinum-based chemotherapy in a randomized phase III trial that was enrolling patients with previously untreated advanced HER2 expressing urothelial carcinoma? And yeah, the options again are:

1. Disitamab vedotin;
2. Trastuzumab deruxtecan; or
3. Other ADCs that are also in development, or at least had some preliminary data, which is MRG002; and
4. SYD985.

All right. Yeah. And I think this is probably what we should see, which is now that everyone gets the right answer. So that's great. Yeah.

[00:41:29]

          Posttest 2

So now our second post-test question. So which of the following HER2-targeted ADCs in combination with toripalimab, again an immune checkpoint inhibitor, demonstrated improvements in both PFS and OS vs platinum-based chemotherapy.

So here, again, disitamab vedotin is the right answer. So we I think can move on to the next one now.

[00:41:57]

          Posttest 3

Okay. So earlier we discussed the case of the 72-year-old patient with metastatic urothelial cancer, disease progression on EV and pembrolizumab, who then starts treatment with carboplatin, gemcitabine chemotherapy, experienced disease progression then on this second-line therapy. HER2 testing in the metastatic sample shows IHC 3+ expression. Based on, of course, current evidence and expert recommendations, which of the following would you recommend as the most appropriate next treatment? So again, patient progressed on EV pembro, then platinum-based chemotherapy. High HER2 expression. Would you consider:

1. Disitamab vedotin-toripalimab;
2. Taxane-based chemotherapy;
3. Sacituzumab govitecan, a TROP2 targeting antibody drug conjugate; or
4. Trastuzumab deruxtecan.

Okay. Awesome. Yeah. We're basically almost knocking it out of the park. Yeah. So trastuzumab deruxtecan is the most common post-test answer. And that is the right answer here.

[00:43:20]

          Posttest 3: Rationale

So in this basically third-line setting with high IHC 3+ with high HER2 expression, so IHC 3+. This is exactly the situation where you would use trastuzumab deruxtecan. So, and that's the basically the FDA approval for this drug right now.

[00:43:42]

          Challenges in the Community #2

Now on to challenges in the community. So for an eligible HER2 IHC 3+ patient, what is the biggest barrier to initiating trastuzumab deruxtecan? So is it that:

1. It's not in the formulary or there are payer restrictions;
2. Is a - is there concern about side effects? We haven't discussed side effects yet. Dr Gupta will do that next. But is there concern about ILD or pneumonitis;
3. Are there limited infusion resources or staffing; or
4. Are there delays or are there concerns about delays in HER2 testing and reporting.

Okay. So no one is resource limited, which is great. But there are concerns about formulary or, I guess, the drug being available. Concern about side effects and also some delays in HER2 testing and reporting. And yeah, I will say, I mean, regarding delays, yeah, if you have, again, a patient who is now third-line setting, right? They've progressed on 2 prior lines of therapy. You do - usually it's a situation where you want them to get them started on treatment pretty soon. So waiting for the result is not ideal, which is why it's great to actually probably have this information already and probably test early.

And now regarding things like, well, concern about side effects, I guess that's probably our - our next topic. So this is a good time to hand off to Dr Gupta.

[00:45:25]

Mitigating and Managing AEs Related to HER2-Targeted ADCs

Dr Gupta: Thank you, Dr Koshkin and Dr Petrylak. We have time remaining. So you guys are really ahead of time. So very nice segue into mitigating and managing adverse events so people feel more comfortable prescribing this available option to our patients.

[00:45:48]

DESTINY-PanTumor02: Safety Summary

So Dr Koshkin, you presented the DESTINY-PanTumor02 study. And if we dwell on the safety summary, you can see here that any drug-related treatment-related adverse events were seen in majority of patients. Almost 85%, but grade 3 or higher were also seen a lot of patients, 40%. So what was, you know, the ejection fraction decrease, unlike the older HER2-directed agents that we used in breast cancer, you know, that was seen in very few patients, just 2.6% and grade 3 or higher was in 0.4%.

So cardiac toxicity is not the big concern. But in ILD and pneumonitis, any grade ILD pneumonitis was in 10% patients, of which about 1.5% patients had serious. So - and left ventricular dysfunction was in 4% patients, of which 3% was related to T-DXd. And other toxicities can be nausea, fatigue, neutropenia and anemia, all pretty well managed.

[00:46:54]

RC48-C009 and RC48-C005 Trials: TRAEs With Disitamab Vedotin in HER2+ Locally Advanced or mUC After 1L CT

And when we look at the RC48-C009 and the C005 trials, these are the side effects that we see most commonly. Again, with peripheral neuropathy being the most common side effect, grade 1 being 32%, grade 2 or higher being in totality about 36% or so. And we can see some leucopenia and LFT abnormalities.

[00:47:22]

Factors Influencing the Toxicity of ADCs

So what are the factors influencing toxicity of ADCs? There's a lot of different factors. You know, it could be antibody-related, payload-related, linker-related. And then the patient-related factors like comorbidities. Patients starting out with baseline neuropathy will obviously have more exacerbation in that, organ function at baseline. How there's the pharmacogenomic polymorphisms, body composition, ethnicity, etc.

[00:47:49]

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

And when we try to break it down with the payloads and target. Trastuzumab deruxtecan, for those of you who also treat breast cancer, are pretty familiar with that. The - one can see neutropenia and diarrhea and pneumonitis is the key toxicity. For disitamab vedotin, which we know the vedotin payload is pretty notorious for neuropathy and some liver dysfunction and can cause also rash. And we see that here and hyperglycemia.

And this we see is somewhat similar to enfortumab vedotin, where we believe rash could be because of the NECTIN4 expression in the skin. But these are some common side effects.

[00:48:39]

Management Pearls

So in terms of management pearls. 78-year-old man with long-standing history of non-muscle invasive-bladder cancer develop metastatic disease in the lung, as we can see. And then treated with gemcitabine/cisplatin, had a good response initially, but then developed progressive disease. Tumor was tested to be HER2 3+ positive by immunohistochemistry and started treatment with T-DXd. Achieves a response to treatment but after 16 doses develops progressive shortness of breath and this was the CAT scan.

As you can see, we see a lot of ground-glass opacities. And this is pathognomonic for ILD or pneumonitis. And we also see pneumonitis with immunotherapy. And with this, we see this really exacerbated here.

[00:49:27]

Administration Considerations for ADCs in GU Tumors

So administration considerations for T-DXd. These are the guidelines. Antiemetics should be routinely given. Starting dose is 5.4 mg/kg every 3 weeks until progressive disease or toxicities. And dose reduction, there are guidelines about the first dose reduction, second dose reduction, and when patients get to still adverse events that can't be managed, we have to discontinue the drug.

For ILD pneumonitis, we have to stop at the first sign of that symptomatic or on imaging, and start steroids for grade 2 or higher and maybe start IV steroids. It's even more severe for neutropenia. It's quite preventable if patients is demonstrating neutropenia with each dose, then can consider prophylactic growth support. And again for thrombocytopenia modify the dose. And for left ventricular ejection fraction issues consider dose modification.

For DV, the starting dose is 2 mg/kg every 2 weeks and dose reductions. Again, the first level is 1.5 mg/kg, second dose reduction level is 1 mg/kg and third is should be discontinued.

So peripheral neuropathy is really the key side effect. And we see that a lot with EV also. And really when it is grade 2 that already means patient has some disabilities in day to day activities, they can't probably button their shirt or take credit cards out of wallet, or they can't - if they have motor neuropathy, they probably not feeling the ground. They're dropping objects if they have more peripheral neuropathy. So we should not really let it progress beyond that. That is already pretty disabling.

And we have to hold the drug for grade 2 neuropathy, resume at a lower dose. Once the neuropathy resolves to grade 1 or lower and permanently discontinue for recurrent grade 3 or grade 4. And it is very important to not only keep asking the patient every time you see them. Also, ask their caregivers if there are any falls at home or patient has started using cane and do a quick gait test or a grip test. These are quick things to look for neurologic exam. It doesn't need to be head to toe, but quick exam.

And for neutropenia, hold it for grade 3 or higher. Reduce the dose for anything more and consider G-CSF.

[00:51:50]

Detecting and Managing T-DXd–Related ILD: The 5 “S” Rules

And T-DXd has boxed warnings for ILD, and it can also be fatal pneumonitis in less than 1% patients. So this was from a review based on the data from this drug being used in breast a lot. The 5 S's, you know, be on the lookout for this toxicity, screen patients, ask questions about their shortness of breath and obtain imaging immediately if there's some concern for shortness of breath different from baseline.

And obviously there's a lot of multidisciplinary care involved, refer to pulmonary. Do other workup for treatment if - if there's some question about infectious causes, do that workup, start antibiotics, refer to infectious disease. So really a multidisciplinary specialty team is required.

Always hold drug when you are seeing any evidence of ILD, there's really no need to keep pushing and be quick to use steroids.

[00:52:53]