This podcast explores the role of HER2-targeted antibody–drug conjugates (ADCs), evolving safety considerations, and future directions 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, discuss the evolving safety considerations and future directions of HER2-targeted antibody–drug conjugates (ADCs) 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
To claim credit for listening to this episode, please visit the podcast online at the link above.
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 current considerations for monitoring and managing adverse events associated with HER2-targeted ADCs as treatment for patients with 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.
Dr Zev Wainberg (David Geffen School of Medicine at UCLA): Hi. My name is Dr Zev Wainberg. I am a Gastrointestinal Medical Oncologist at UCLA.
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.
Dr Meric-Bernstam: So current HER2 antibody drug conjugates that are approved as well as those in development, differ quite a bit in their adverse event profile.The predominance you know, determinant appears to be the payload, although some of these toxicities we're seeing may be target related.
Dr Wainberg: The way I explain it to my patients is you are going to have two different categories of toxicity on an antibody drug conjugate. The one is something you are very familiar with, which is the cytopenias, the anemias, we are going to watch counts. Then the other, the alopecia, which is I have seen in a number of antibody drug conjugates, some people have hair loss and some people have the intense cytotoxic side effects.
Then there are others that are, like you said, neuropathy with vedotin and with exatecan and topotecan derivative payloads, we see a lot of GI toxicity. We warn patients certainly about diarrhea and nausea and making sure that they are managing it.
There is a whole other group of side effects which are a little bit unusual and outside of the typical stuff we would see with chemo, which includes either interstitial lung disease as the predominant one, but even some other more obscure ones.
I think that has been shown in the clinical trials, in the large clinical trials that have looked at these drugs and breast cancer, certainly in gastric cancer and others. It is very important that we warn patients about these toxicities. They have also been manifested in real world evidence studies.
Dr Leary, I wonder if you could go over some of the differences between on-target and off-target toxicities. Does the linker matter? Does the DAR matter? Of course the payload matters. Maybe you can help us talk through some of that.
Dr Leary: Yeah, I mean I think we have to say humble because I think we do not understand all of it quite yet. For example, in terms of on-target effects, I find it fascinating. It is reassuring, fascinating that we do not get more cardiac toxicities with HER2-targeted ADCs. Can someone explain? It is great, but myocardial cells express HER2. It does not really seem to be an issue.
We have other ADCs that have these curious ocular side effects. We thought initially it had to do with the target. It probably has more to do with the payload. I think we are learning, but I think we are still far from understanding all of these.
I think it is going to be important as some of these ADCs are being proposed in the maintenance setting. We have talked about combining them with chemo, but a lot of studies are using them after chemo as maintenance. While we are used to maintenance, we use it a lot in GYN cancers.
Maintenance with something like an immune checkpoint or bevacizumab is not the same as maintenance with an ADC. It is, and it still remains cytotoxic. To some degree, while our patients are willing, they live with a little bit of lymphopenia, thrombocytopenia, anemia, that does not bother them so much, probably except if it is grade 3 or 4. But grade 1/2, nausea, diarrhea, those effects bother them more.
I think we still have a lot to learn about this. I do not think we understand everything about these side effects. They do not make sense always from an even biological or pathophysiological basis. I do not always make sense of them.
I think we have to keep being very cautious. As you said, we know some of these dangerous ones like ILD. People are really learning, thanks to other tumor types where ADCs are much more used to really intervene early in the case of a suspicion of something like interstitial lung disease because some of them can be fatal if you do not take them seriously.
Dr Wainberg: Yeah. I mean, first of all, really good point about the echos. I mean, should we be doing them at all is a fair point. I think this is not trastuzumab. I mean in breast cancer it is a little different, right? Because these drugs are incorporated off in the adjuvant setting. In breast cancer, women will have been on these drugs and have an expectation of survival of many, many years. Whereas in advanced disease, sadly in gastric cancer, at least where I have used trastuzumab for a long time, we do not necessarily even see the long-term toxicities of cardiomyopathy because sadly patients do not survive that long, the majority of the time.
But in these ADCs, it is interesting. We are supposedly targeting HER2 and yet we are not having a meaningful impact on ejection fraction. I have noticed that too and I have not heard a great explanation either.
Dr Leary: No.
Dr Wainberg: I think the ILDs are important to spend a few minutes on, because the ILD is really the stuff that we are warned about. We knew very early on in the development of these drugs I remember from the phase I with T-DXd at least that it was a clear.
Dr Meric-Bernstam: For trastuzumab deruxtecan, an important adverse event of note, is there potential risk for pneumonitis or institutional lung disease? This is something that could be monitored closely during imaging that is done routinely at the time of restaging. It is important to evaluate the pulmonary fields to see if there is any pneumonitis related changes, because the goal would be to be able to catch any early pneumonitis when it is still grade 1 that is asymptomatic.
If there is signs, radiographic changes that are suggestive of pneumonitis, the recommendation is to hold treatment and then do a full assessment looking for alternate causes, including infections, potentially get infectious disease or pulmonary consultations, consider bronchoalveolar lavage, consider early re-imaging and consider steroids treatment.
Dr Wainberg: There is a scale of what we consider to be clinically ILD. The first scale is obviously that it is not something that is identifiable only on imaging, essentially, a pickup on imaging which has no clinical manifestation. It really is something that the radiologist points out and that we see on the imaging, these ground glass opacities perhaps some degree of interstitial findings that are a bit different and those patients are often monitored.
Then from grade 1 through 4, it gets progressively worse and you have symptoms whether it is low grade symptoms like shortness of breath on exertion or more serious symptoms like hypoxia and requiring oxygen.
We know now that we have guidelines and how to manage these, when we should stop the drug, when we should give supportive care. I think it is critical, at least in my opinion, to get a good pulmonologist to work with so that you can get a good feel about that.
I think early on we did not have a good feel about that, which is why if you look at the early studies, and we did some of these studies in colon cancer and in gastric cancer. We saw grade 5 events. We saw grade 5 ILDs on these earlier reports that are really sad and not an insignificant number. If I recall in the original study, there were up to 5% of patients and there were a number of deaths associated with this.
I think now we have a much better handle on this and it is a much more multidisciplinary situation, so we can get more specialists engaged. I do not know Dr Fahey, if you have experience with this ILD, but it is a very tricky toxicity to manage and I do not know if you have a protocol there or pulmonology team that you work with to help.
Dr Fahey: Yeah, it is really tricky to deal with and I really appreciate your point that we need to recognize these things promptly so that we can start treatment as quickly as possible. And pointing out that there is a risk of death. In the DESTINY-PanTu, there were three deaths from ILD, including one of the bladder cancer patients.
We do work really closely with the pulmonology team here. There is a group of people who have a particular interest in immune checkpoint inhibitor toxicities. Obviously, the overlap between the ILD of an antibody drug conjugate and the pneumonitis of a immune checkpoint inhibitor, there is some overlap in interest there as well. We have some really excellent pulmonology colleagues that we definitely get involved when we are dealing with patients with new severe hypoxia concern for ILD from a HER2 drug.
Dr Wainberg: I think the adjudication has been really good. Overall in the programs, I think there has been enhanced recognition and comfort. That is true of any drug we all know. It sometimes takes time for us to you know to understand to understand the toxicity and learn how to manage it. This certainly is no exception.
I think to the points made earlier with checkpoint inhibitors, we are going to see more ILD. That is one of the things we have to brace ourselves for and how to manage those, particularly when to start steroids is going to become important in the next few years.
Dr Wainberg: With immunotherapy, it has not been easy I have to say, but. One thing we worry about obviously is overlapping toxicities. With cytotoxics, the overlapping toxicities and antibody drug conjugate are usually going to be cytopenias and all of these things that we are more familiar with.
Then with immunotherapy, PD-1 inhibitors or other checkpoint inhibitors, we are encountering, other toxicities like interstitial lung disease and ADC-associated toxicity. So it would not be so simple.
Dr Wainberg: Dr Fahey, I mean you commented on the DV toripalimab study, which is maybe one of the good ones out there.
Dr Fahey: Yeah, I think the big question is the pneumonitis. With the trastuzumab deruxtecan in many of the trials, the pneumonitis rates were consistently between 8% and 10%. You all can correct me if in some of your disease groups you are seeing different rates. But everything that I have seen has been in that range, which is quite high. I think when we are talking about HER2 therapies, we are often dealing with aggressive cancers, risk benefit wise, it makes sense, but it gets really hard to tease out if we are going to combine the trastuzumab deruxtecan with an immunotherapy pneumonitis. Is it from the HER2? Is it from the PD-1?
We are giving steroids either way. Does it change if it is from one or the other? I will say in bladder, we are not combining them at this point the trastuzumab deruxtecan with an immunotherapy. Right now the approval is for monotherapy based on the PanTumor.
Then the disitamab vedotin with PD-1, we do not see the same pneumonitis to my knowledge. Now, I will be fully transparent. I have not gone through all of the trial data from the phase I/II, but to my knowledge, we do not have quite the same levels of pneumonitis.
I am anticipating the toxicity should be similar to what we see with enfortumab vedotin, where really the neuropathy and rash are the biggest things we deal with now.
Dr Wainberg: You do not have a big pneumonitis problem in EV plus pembro?
Dr Fahey: No, I have not seen substantially higher rates of pneumonitis with EV pembro than with pembro by itself. Certainly we have our risks of any of the itises with our immunotherapies.
Dr Wainberg: That is interesting. Different ADC, different construct, obviously different payload or the same payload for vedotin, but different than the payload for trastuzumab deruxtecan certainly. I think the section of toxicity is challenging because you have off-target/on-target toxicities you can tolerate, some you cannot.
I will start with GI cancers where like I mentioned, we are trying to combine these drugs upfront now with chemo. One thing that we are encountering is a lot of cytopenias which are requiring dose reductions, which is challenging because you do not know what dose to reduce when, you do not know what drug to reduce, you do not know how to restart. We are all kind of learning on the fly with these ADCs.
Future of ADCs
I wonder if we could talk a little bit about the future. I think that how far can this go with these antibody drug conjugates? How far can we push it? Or can we move all these drugs upfront? It is a big question I think in a lot of cancers. Dr Leary, you talked a little bit about ovarian cancer moving it even earlier. I mean, do you think this is a wise decision or what do you think?
Dr Leary: I mean, I think it has to be tempered with the risk of the disease. If you are going to be moving drugs like these into the adjuvant curative setting, then it has to be guided by the prognosis of these patients. It so happens that we are moving it into a high-risk.
Although these patients will benefited from complete surgery, we know by their histology that they are at a very high risk of metastatic relapse. I think it has to be balanced by the risk of metastatic relapse for these patients.
I think that as a medical oncologist, I always want to increase cure rate rather than spend my time treating relapse metastatic disease. I also think that at least in breast cancer, where they have used HER2 ADCs for a long, long time and they can stop them and patients are in complete response, I think we also have to keep our eye on the ball whether in some instances we may be in curing metastatic disease with some of these agents. It will be a rare instance, but that is a fantastic thing.
I mean cure still remains a priority. I think it is important to safely move them into the curative setting in diseases that have a risk of relapse, that justifies that approach.
I think the next question will be how long? What is the duration of these? When you are treating a disease that you can see and that is shrinking and know your eyes, that is one thing. But if we are moving them into adjuvant setting where we do not see the disease, what is the right length? There, it is going to require a lot of fine tuning.
Dr Wainberg: Yeah, I completely agree. I mean in GI for example, this is a big debate because I think one of the things that we are all saying is HER2 is different in different cancer. We can learn only so much from breast cancer in my opinion. We can learn, for example, about toxicity profile to some extent. We can learn about expectations, but we also know that HER2 is a different thing in gastric and breast and ovarian and bladder.
Just because the drug worked exceptionally well in HER2 1+ and breast cancer does not mean it is going to do the same in these other cancers by any stretch. In gastric cancer, because I have been doing HER2 trials for a long time in gastric cancer and we were very tempered because early on there was this expectation with anti-HER2 trastuzumab would worked in the advanced setting, it is going to work in adjuvant setting or perioperative setting. A lot of those studies were very negative. There was no clear evidence that moving a HER2 inhibitor upfront and there still is no evidence that moving a HER2 inhibitor upfront in a disease like gastric cancer helps survival.
Now some of the studies were a little inconclusive and some of the studies were probably not selecting patients the way we ought to be in this era. But nonetheless, we did not have a clear signal that there was any evidence that moving these drugs upfront. They are trying to change that. Particularly in the perioperative setting, which is what we do in gastric cancer, we are trying to treat neoadjuvantly before and then adjuvantly after.
But there, the standard of care is multi-agent chemotherapy. We have to figure out how we are going to possibly incorporate this into that context. With surrogates, I think like you mentioned pathological response rate, and Dr Fahey, you talked a little bit about that in bladder and we are trying to think if we can extrapolate that.
But I think the point is really well taken that these are different expectations and we have dual challenges. First, just because we have new drugs does not mean we should use them in everybody. It certainly should not mean that when we go into an adjuvant context, we expect the same benefit across the board. I think that is a really good point.
I am sure Dr Fahey, in bladder cancer, you are in line with what we are saying here.
Dr Fahey: Yeah, I could not agree anymore with the points that the two of you just made. Very well said.
Dr Wainberg: I really want to thank both of you. I know that we are all excited about this field, antibody drug conjugates, HER2 targeting across the board. It has been really fun for me to learn a little bit about bladder and endometrial and cancers I do not know much about. It is exciting to see that. We are all excited. I am happy to see that we are all excited about this field. I do not if any parting thoughts, Dr Leary from Paris?
Dr Leary: I would say it is a tsunami of ADCs. We need help to know how to sequence them. That is going to be our major, major, major problem is how do we sequence them. We need to understand.
Dr Wainberg: I think we are going to need global studies. It is not going to be sufficient to, just as we talked about earlier, show response rate in one region. We have to do these big global studies I think to answer this.
Dr Funda Meric-Bernstam: Yeah, thanks. Well, HER2 remains a really exciting target. And there are several different strategies being developed. Other monoclonal strategies as well as small molecule inhibitors in development. In addition, there's a lot of drugs in development that have a immuno-oncology strategy, and some of these include engagers, car T cells by specifics. So it's going to be a very interesting time over the next several years to see how these agents evolve.
Dr Wainberg: Dr Fahey, I will let you have the parting word.
Dr Fahey: I think that this has been just a wonderful conversation. It has been so interesting learning about the perspective each of you have. I really appreciate all of the points about making sure we are selecting the right patient populations with the right HER2 biology to go after. Also the points about not all diseases are the same that were made by you about making sure we are thinking about this correctly and moving forward correctly.
The tsunami is coming. The tsunami is here, and it is going to be a lot of work to figure out the right way to do these things.
Dr Meric-Bernstam: Thank you very much for listening to our podcast today. I am going to try it again. 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.
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 our previous episodes in this series, includingEpisode 1: “The Lay of the Land” – An overview of the biology of HER2 in genitourinary, gastrointestinal, and gynecological malignancies.As well as Episode 2: “Taking a New Path,” Evaluating Current and Emerging Clinical Data With HER2-Targeted ADCs in Genitourinary, Gastrointestinal, and Gynecological Malignancies. Thanks again for listening and we’ll see you next time.