This podcast explores the evolving role of HER2-targeted antibody–drug conjugates, exploring their mechanisms of action, and emerging clinical data across genitourinary, gastrointestinal, and gynecologic cancers.
In this episode, Catherine Fahey, MD, PhD; Alexandra Leary, MD, PhD; Funda Meric-Bernstam, MD; and Zev A. Wainberg, MD, explore the mechanisms of HER2-targeted antibody–drug conjugates (ADCs) and emerging clinical data with these agents across genitourinary, gastrointestinal, and gynecologic cancers.
Presenters:
Catherine Fahey, MD, PhD
Assistant Professor
Division of Oncology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Alexandra Leary, MD, PhD
President, GINECO Group
Co-Director, Department of Medical Oncology
Medical Oncologist Gynecology
Team Leader, Gynecologic Translational Research Lab, INSERM u981
Institut Gustave Roussy
Villejuif, France
Funda Meric-Bernstam, MD
Chair, Department of Investigational Cancer Therapeutics
Medical Director, Institute for Personalized Cancer Therapy
Nellie B. Connally Chair in Breast Cancer
The University of Texas MD Anderson Cancer Center
Houston, Texas
Zev A. Wainberg, MD
Professor of Medicine and Surgery
Co-Director of GI Oncology
Director, Early Phase Clinical Research Program
Jonsson Comprehensive Cancer Center
UCLA School of Medicine
Los Angeles, California
Link to full program:
https://bit.ly/42iEDjV
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Hello and welcome to the Clinical Care Options’ Oncology Podcast. I’m your host, Sharif Morsalin.
In today’s episode we are joined by Dr Zev Wainberg from UCLA, Dr Funda Meric-Bernstam from MD Anderson Cancer Center, Dr Alexandra Leary from Gustave Roussy, and Dr Catherine Fahey from Massachusetts General Hospital. They will be discussing HER2-positive disease in genitourinary, gastrointestinal, and gynecological malignancies.
This episode is part of our broader educational program titled, “Emerging HER2-Targeted ADCs in Genitourinary, Gastrointestinal, and Gynecological Malignancies.” For more details on our presenters and to access the full program, be sure to check out the show notes.
Now, let’s get started and hear what the experts have to say.
Introduction
Dr Zev Wainberg (David Geffen School of Medicine at UCLA): Welcome to this podcast, From Concept to Clinical Reality: The Landscape of Emerging HER2-Targeted Antibody Drug Conjugate in Genitourinary, Gastrointestinal, and Gynecologic Malignancies.
Faculty
My name is Dr Zev Wainberg. I am a Gastrointestinal Medical Oncologist at UCLA. I am joined here today by specialists in their respective field.
Dr Funda Meric-Bernstam (MD Anderson Cancer Center): I am Funda Meric-Bernstam from MD Anderson Cancer Center. I run the phase I program, which is the Department of Investigational Cancer Therapeutics.
Dr Alexandra Leary (Gustave Roussy): I am Alexandra Leary. I am a Medical Oncologist Specializing in GYN tumors, so ovarian, cervical and uterine cancer. I am based at Gustave Roussy in Paris, France.
Dr Catherine Fahey (UNC Chapel Hill): Hi. I am an GU Medical Oncologist, so seeing prostate, kidney, and most relevant to this talk, seeing bladder cancer patients. I am at the University of North Carolina in Chapel Hill.
Let us discuss antibody drug conjugates because really we are all familiar with obviously antibodies and now antibody drug conjugates are a very different emerging group of drugs. We have multiple ADCs approved and almost certainly many more to come based on the number in clinical development.
I will ask Dr Leary to give us just an overview of the drug itself and some of the mechanism of action.
Overview and Mechanism of ADCs
Dr Leary: The concept of the ADC, as explained to us initially, is that it is basically a form of targeted chemotherapy, which it is because it is an antibody that targets a membrane-based target that is preferentially and we hope exclusively, although it is not always the case, expressed on tumor cells and not expressed on normal cells. This antibody is then linked via a more or less cleavable linker to a potent cytotoxic.
Often these cytotoxics are so potent that you could not give them systemically. That is the whole point is to deliver these extremely toxic anti-tumor agents very selectively to the tumor cell while sparing normal tissue.
Once the antibody drug conjugate binds to the membrane receptor, it is then endocytosed into the tumor cell, where there the antibody is cleaved from its cytotoxic payload and cause a cell death. Obviously, what differs among ADCs are the target. Here we are talking mainly about HER2, but as you said, there is a huge number of targets already approved or development.
Then the type of linker and how it is cleaved, what makes it dissolved to release the cytotoxic agent? The next big difference is the payload, and there are classes of payloads. Some of the most common are Topo 1 inhibitors, microtubule inhibitors. These are chemotherapies that defer by the mechanism of action. Even though within a class, some of them have different names, they are very similar within each class, but let us say in the broad classes are Topo 1 inhibitors, microtubule inhibitors.
The final difference among these ADCs are how many payloads we can stick onto a single antibody. In some cases two, it is four, it is eight. That is basically how many molecules will be delivered by each antibody. That is what distinguishes these antibody drug conjugates.
I think probably one of our biggest frustrations is while we have a huge multitude of targets, so antibodies, we have fewer different classes of payloads and that is probably where we are going to really have to start working over the years to come so that we can hopefully get better at sequencing these agents.
Dr Meric-Bernstam: This is a really exciting area because several of the newer ADCs have had so much activity. Especially, now that we started seeing activity in solid tumors, there is a lot more drug development in this space.
There is a lot still unknown from a mechanism of action standpoint, the importance of things like bystander effect, the importance of relative target selection, antibody development, mechanism of intrinsic and acquired resistance. Clearly over the next several years, we will be seeing a lot of development in the space, areas especially that are rapidly developing include development of bispecific ADCs as well as novel payloads.
Dr Wainberg: Very good synopsis. I certainly agree with your final point there is that we need more payloads. I think we are getting exhausted by the MMAE and Topo 1 payloads. I have seen that at least at the last few conferences, some more emerging payloads with other, whether they are microtubule inhibitors or other type of chemotherapy. It has got to be on some level cancer specific, right, for example.
In GI cancers, we tend to prefer these exatecan/topotecan derivative payloads because those are cytotoxic that work in those cancers. So I think it really must be centrally, depending on what cancer you treat, maybe the payload would be of different interest.
The bystander effect. Dr Fahey, I mean this is a term we throw around a lot. This seems to imply that, at least on the outside, the way I simplistically think about it is you are getting into the sale of interest, but then of course your payload is destroying anything adjacent to it. I think that with these HER2 1+, that is certainly the hope. How would you explain this bystander effect?
Dr Fahey: Yeah, I think that is a really good way of thinking. When I talk to my patients, the metaphor that I have been using with them is like an antibody drug conjugate is a boat that goes to the dock that is waving the right flag and then the chemo is on the boat. That has worked for people.
If we think about the bystander effect, eventually the boat is making it into the tumor micro environment and then we are shooting cannons, which is the chemo into the nearby cells. We got to have that flag to get us to the area. Then you are exactly right, we get into the right microenvironment, the linker that Dr Leary described so well, it is cleaved and we are able to release our cytotoxic payload, hopefully predominantly in that tumor microenvironment and not hitting anything else.
Dr Wainberg: Let us get into the specifics. Maybe you could just go over high level some of the ADCs, HER2 target ADCs. You have got data with trastuzumab deruxtecan and others.
Dr Meric-Bernstam: DESTINY-PanTumor02 was a phase II study of trastuzumab deruxtecan asking the question of whether T-DXd would have efficacy in all tumor types expressing HER2.
In this setting, patients that had advanced solid tumors that were second-line plus, that had HER2 expression, either 2+ or 3+ were enrolled either with a local test or if not available with a central test.
Patients received T-DXd at 5.4 milligram per kilogram and they were assessed with the primary endpoint of confirmed objective response rates. We enrolled multiple tumor types including endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, biliary tract tumors, pancreatic cancer, and we also had other tumor cohort which excluded these disease types including breast cancer and gastric cancer, where there were already approvals, and lung cancer and colon cancer where there were ongoing dedicated trials.
This was a really important study because it really showed that T-DXd had activity across a variety of tumor types. Overall, the objective response rate in the study was 37.1%. For patients that had centrally confirmed 3+ HER2 expression, the objective response was 61.3%.
Importantly, these were durable responses. Really very exciting to see across the board this tumor activity, especially the 3+ patient population.
This came at a time we also had information coming in from DESTINY-Lung01 and DESTINY-CRC02. Both of these studies show significant activity in HER2-positive tumor types. Altogether the activity of T-DXd in these three trials led to the FDA approval in the accelerated approval for patients that had unresectable or metastatic HER2 3+ cancers.
The activity of T-DXd was explored in other scenarios as well. In the DESTINY-PanTumor01, the activity was tested in patients with HER2 mutation. There was also activity in that setting, yet a little bit more information in that setting I think as needed. T-DXd is already FDA approved for patients that have HER2-mutant lung cancer.
Dr Meric-Bernstam: What did you think about the activity in DESTINY-PanTumor02?
Dr Fahey: Yeah. They looked at patients with HER2 3+ or HER2 2+ and the FISH positive and treated them in a pan tumor way with trastuzumab deruxtecan. When they looked at the urothelial cohort among all patients, the response rate was about 40%. In the IHC 3+ group, the response rate was actually 56%.
Based on this, we now have an approval for HER2 3+ in bladder cancer to use trastuzumab deruxtecan.
That being said, we are also using a newer HER2 antibody disitamab vedotin. This has an approval in China for use for our HER2 positive bladder cancers. DV, it is a anti-HER2 antibody that is conjugated to an MMAE, the vedotin, MMAE.
This has been studied in HER2 positive and some phase Is, phase IIs. China actually has some phase IIIs opening. We are opening a trial for patients with metastatic urothelial frontline for DV with immune checkpoint inhibitors. This is a drug I anticipate we are going to be seeing more of in urothelial.
The data from the muscle-invasive cohort they are looking at was actually presented at GU ASCO this year, so just a few months ago. The pathologic complete response rate for patients who got DV and toripalimab in muscle-invasive bladder cancer was 75%. 66% pathologic complete response and 75% just pathologic response, which is a really outstanding and exciting trend.
I am excited to see where this drug goes. I anticipate we are going to be seeing it more and more, but it is not technically one that is approved. It is only in clinical trials currently in the United States.
Dr Wainberg: You guys are spoiled there by those vedotins, I guess, because I have seen that data with EV, such quickly adopted as a standard of care in your disease, if I am not mistaken.
Dr Fahey: You are very not mistaken. The data comparing EV pembro to cisplatin-based front-line metastatic therapy was game-changing performance. Progression-free survival increasing from six to 12.5 months. It is just incredible. I think it gets to the point Dr Leary was making earlier about the payloads. We are going to run into issues with these vedotins in the neuropathy that we develop. How many vedotins are we going to be able to give one after the other as we are moving forward?
Dr Wainberg: I guess that on some level for that Nectin-4 ADC, if I am not mistaken, then you start to question about, I do not know if there is any data that has emerged already. Maybe you can comment on overlap of biomarkers and what happens when you have both of these and how do you sequence these and all of the questions that are probably top of mind.
Dr Fahey: So overlap. Nectin-4 is expressed in over 90% of urothelial carcinomas. That is why it has got the approval just for front-line therapy. We are not actually routinely sending Nectin-4 testing upfront, whereas HER2 is a much smaller cohort. Patients would definitely have overlap. I think the question is going to be, in the patients with HER2, do they benefit from actually doing the HER2 first?
Then there is also some evidence that possibly what is actually happening on progression is resistance more to the payload and less to the target. I do not know, I would love to hear in your cancers if there is similar thoughts, but that will be an issue then when we are looking after vedotin.
Dr Wainberg: In GI, we have a number of approvals. From an antibody drug conjugate perspective, we have also an approval based in DESTINY-PanTumor studies, as you alluded to. In those cancers, we also had a fair amount of the non-classical, so the BTC was in there, and BTC as I mentioned, biliary tract cancer is usually gallbladder and there is about 10% prevalence. There also the same eligibility applied. There was a pretty high response rate upwards of 50%. In the United States, you got a tumor-agnostic approval, which covers BTC.
What is interesting in BTC is there is also some data with other anti-HER2 agents, which is positive and not yet maybe meeting the threshold of approval, but including tucatinib trastuzumab. Also in some recent evidence with a bispecific antibody that blocks two epitopes of the HER2 domain known as zanidatamab, which had pretty compelling data.
We have got a few different HER2 strategies, not all ADCs. In gastric cancer, which is we have large randomized data sets. We have at the moment an approval for second-line and beyond, which included basically patients who progressed already on trastuzumab in front-line metastatic disease and randomized to either trastuzumab deruxtecan or investigator’s choice of chemo. We have had that approval in place for a few years.
More recently we have a press release, although we have not seen the data that even in second-line showed a survival advantage compared to standard chemotherapy alone. We data to be released actually in this ASCO. That will be probably another expanded indication of trastuzumab deruxtecan in gastric cancer.
We have a specific colorectal cancer, a cohort of patients that enrolled two separate colorectal cancer trials, DESTINY-CRC01, DESTINY-CRC02. Those were single agent studies of trastuzumab deruxtecan. But the second study actually randomized to two different doses, which is extraordinarily challenging. We will talk about doses later. It is 5.4 and 6.4 milligrams per kilogram of trastuzumab deruxtecan. The consensus was that the 5.4 was as good as the 6.4, but with a lot less toxicity.
With respect to DV and the other ones, and there is a bunch of others that we all know and we see pretty much every ASCO, ESMO, many HER2 ADCs. Most of the data in GI is emerging from China. Some of it is hard to interpret often in my opinion, but we are seeing more and more of these newer ADCs like DV starting to trickle in data with comparable response rates.
I will start with you Dr Leary. We see a dataset coming from China with X response rate in this ADC. How do we interpret that? How does that correlate with some of the data that we tend to generate in the western world?
Dr Leary: I think that is not necessarily specific to ADCs actually. I think that response to anti-cancer agents can vary across the world, whether it be TKIs, whether it be traditional chemo in terms of toxicity and efficacy, which is why I think it is always so important to reproduce data across geographical subsets and ethnicities because metabolism, CYP enzymes and variants will probably affect this.
Plus it is also possible that the prevalence of a biomarker might change across geographical and ethnic backgrounds. I think it is always going to be important to reproduce these data. In any single arm signal finding, you often get the best data first and then you need to reproduce this in a larger randomized setting to really confirm it.
Dr Wainberg: Yeah, it is a fair point. I think it is something that, because we use response rate now and response rate is the first thing people look at and the first thing people point to and it is the easiest and quickest readout. It is interesting how we see a response rate reported constantly and frequently and sometimes it is hard to interpret. I totally agree.
In your cancers, in the gynecological malignancies, maybe you could give us a high level overview of the HER2 ADCs?
Dr Leary: Yeah. GYN malignancies were included in the DESTINY-PanTumor. The response rates were really nice in cervix and ovarian and endometrial. I have to say the winner of the PanTumor trials is endometrial. It has an 85% response rate in 3+. I think that is probably a combination of factors, but one is probably coming back to what you said earlier about the payload. Actually, even regardless of the payload, it is also chemo sensitivity in general.
If we were to test ADCs, probably regardless of the ADC and low rate, slowly proliferating relatively chemo-resistant tumors, your response rate is also going to be lower. It so happens that in endometrial cancer, the subset that has high HER2 is aggressive high-grade chemo-sensitive endometrial cancer.
I think there is a combination of factors that are going to make these agents work well. It is going to be the target to how well it is expressed and how chemo-sensitive the tumor is and whether it is chemo-sensitive to that particular payload, exactly as you said earlier.
In terms of approvals, there is an approval in the US based on the PanTumor study for GYN cancers as well. In Europe, we still require phase III trials, but they are ongoing. DESTINY-Endometrial01, 02 are ongoing, and 02 interestingly is about to start. That is exploring the benefit of trastuzumab DX in HER2 2+ or 3+ in the adjuvant setting in patients with no residual disease, which is a bull jump.
Again, because these are the most aggressive tumors among endometrial cancers, those that are high-grade, they are very high risk of metastatic relapse. Improving the efficacy of our adjuvant treatment is important, and this could truly move the mark.
Dr Wainberg: Is there a control arm there?
Dr Leary: Yes. Compared to standard of care.
Dr Wainberg: Wow. Okay.
Dr Leary: It is [inaudible]. We are testing some of the other ones, including the DV as well.
Dr Wainberg: Yeah, I mean I think we need more randomized data. Completely agree. Some of these accelerated approvals in the United States have made that challenging, which is why at least in gastric cancer, when the FDA approved and we got accelerated approval of T-DXd in second-line and beyond, we could not enroll anymore in the randomized study.
That study, which was, as I mentioned earlier, DESTINY-Gastric04, it will be read out at ASCO, we know it is positive for a survival advantage. They had to do that study exclusively in Europe and Asia, because at that point we already had the drug FDA approved in the United States. It is really important to generate randomized data.
What about upfront? What about newly diagnosed? You mentioned adjuvant, that is a really bold move. I agree. Do you have any ongoing trials in newly diagnosed HER2 positive or are there trials out there in HER2 positive endometrial?
Dr Leary: Yeah. It is in the adjuvant setting. It is in the first-line metastatic setting, and it is in the second-line post platinum setting.
Dr Wainberg: It is covering bases. Dr Fahey, in newly diagnosed bladder cancer, you mentioned you have something or there is a trial going on somewhere?
Dr Fahey: Yeah, we are in the process of opening up Cohort C of the RC48 G001, which is the trial of disitamab vedotin alone or with pembrolizumab. There are several different cohorts. Cohort C, which is looking at disitamab vedotin for front-line therapy of urothelial carcinoma.
Dr Wainberg: In gastric cancer, we do have a front-line study. One of the challenges became combining ADCs with other agents. There is a whole different challenge when you start to think about these drugs as combination partners, both combination partners with others cytotoxics and with immunotherapy. For example, the standard of care upfront in gastric cancer is chemotherapy with FOLFOX 5-FU based therapy or platinum-based therapy and immunotherapy PD-1.
What they did was a very large phase I study to try to find the optimal partner because you really cannot add any antibody drug conjugate so simply to a regimen like FOLFOX. You have got already two cytotoxic and an ADC and immunotherapy. It has become challenging both because of obviously tolerability.
Also the second question is, is it altogether necessary in advanced disease at least? The study took a while, the DESTINY-Gastric03 study. Now has come up with some 5-FU combination essentially with trastuzumab deruxtecan and immunotherapy moving to the front-line.
The phase I did show some unique side effects and also some challenges in phase III development. Finally, now there is a plan, a new study, DESTINY-Gastric05, if I am not mistaken, to test this in the front-line compared to the standard of care.
Dr Meric-Bernstam: It is going to be a very interesting time over the next several years to see how these agents evolve.
The combination therapy is an area also that looks very exciting. There has been exploration, a combination with immunotherapy, but there is especially an interest in combination therapy with small molecule inhibitors. This includes a combinations with HER2-targeted agents with the thought that there may be enhanced internalization with such a combination strategy, but also a lot of interest in combinations that may enhance the activity of the payload, including agents that modulate DNA damage repair.
I expect over the next few years, we are going to see a lot of trials read out, so it should be very interesting.
Dr Meric-Bernstam: Thank you very much for listening to our podcast today. I hope that you were able to learn and gain some insights into the Landscape of Emerging HER2-Targeted ADCs in Genitourinary, Gastrointestinal and Gynecological Malignancies.
Come back to listen to our next installment in this series on Uncovering Safety and Signposts to the Future: Assessing Safety Profiles of HER2-Targeted ADCs and Future Obligations.
If you missed our first podcast on the Lay of the Land: The Biology of HER2 in Genitourinary, Gastrointestinal, and Gynecological Malignancies, please go back and listen to our discussion on this topic.
Thank you, Drs. Wainberg, Meric-Bernstam, Leary, and Fahey for a great discussion, and for sharing your valuable expertise with us. And of course, many thanks to you, our listeners, for joining us today. As a reminder, you can access the full program, “Emerging HER2-Targeted ADCs in Genitourinary, Gastrointestinal, and Gynecological Malignancies,” by clicking the link in the show notes.
Be sure to check back soon for more episodes in this series, including: Episode 3: “Uncovering Safety and Signposts to the Future”—a look at the mechanisms of toxicity with HER2-targeted ADCs and how HER2-directed therapy may evolve moving forward. And if you missed our previous episode, be sure to listen to Episode 1: “The Lay of the Land”—an overview of the biology of HER2 in genitourinary, gastrointestinal, and gynecological malignancies. Thanks again for listening and we’ll see you next time.