Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to “What I Tell My Patients,” as this afternoon we talk about the use of antibody-drug conjugates in the management of cancer, one of the most exciting topics that we have this week here at the ONS meeting.

We have a great faculty today. We have 3 people with backgrounds in breast cancer, Dr Hamilton and Dr Rugo, but also Ms Carroll from the Mayo Clinic and also we have a lung cancer person, Ms Goodwin from Mass General. So we’re going to be able to get that perspective as well.

We’ve already discussed a number of times antibody-drug conjugates in the initial couple meetings here. Just a reminder we will be talking about the use of, unapproved use of agents so just consult the package insert for specific information.

For the people here in the room on your iPad you have all the slides we’re going to see. There’s a survey for you take and also you can use that to ask questions or present cases to us. The clinicians attending on Zoom, first of all, hi to everybody out there in the E space. All the same functions are available in the chat room where you’ll also find premeeting and a postmeeting 1-minute survey for you to take.

We’re also recording all 10 of these programs here at ONS and we’ll let you know when they’re all ready by email for your colleagues who weren’t able to check it out to see what’s going on here. And we really look at these 10 meetings almost as we always have done. We’ve been coming to ONS for 16 years. This is really a parallel course to the ONS meeting that really focuses on new clinical research, new treatments and how to discuss it with patients, but we’re also, we always talk about patient care, oncology patient care. We’re going to present — the faculty will be discussing a bunch of cases today and one of our themes is, why was it different to take care of this patient than another patient in the same oncology situation but a different person, different attitude, social situation? So what we’ve done for this meeting, which we’ve never before, is we over the last couple of weeks we met with 8 nurses that we’ve worked with in the past at ONS who we weren’t able to get into one of our meetings here this year. We spent about an hour with each one of them asking similar questions to all of them and basically we produced about 85 sound bites. They’re all less than 90 seconds and we’re going to be infiltrating them through social media. If you’d like, we’re going to show just a couple of them here. We’re going to show about 30 in the 10 meetings that we’re doing here today. But if you would like to see all hour and a half of all these comments, check out ResearchToPractice.com/ONS2024Clips. We’d be real interested to see what you think about this type of content and what we, you know, how we might be able to get it to patients.

So here’s where we’re heading today. First we’re going to talk about what antibody-drug conjugates actually are and in particular how they’ve been developed in breast cancer where really as you can see we have 3 breast cancer people here who’ve seen the greatest evolution, but now antibody-drug conjugates are all over oncology, both solid tumors as well as hematologic oncology. We’re going to talk about just part of that today, particularly the breast cancer piece and particularly the stunning pan-tumor approval for the antibody-drug conjugate trastuzumab deruxtecan. We’ve already been talking about the pan this morning. In the endometrial cancer program, we were talking about that. This is an incredibly important thing for everybody here to know about. And then we’ll talk about some of the other ADCs that are coming along in breast cancer and other tumors as well.

But before we get started, just going to kind of take a deep breath here and kind of talk a little bit about taking care of patients.

And Jamie, I don’t know if you know Jessica Mitchell, she is actually a nurse in GI and Mayo. She’s worked with us many times. So I asked all 8 of these nurses this question which is, well, here’s the question.

Listening versus talking.

MS MITCHELL: That is a really good question. Listening is far more important than talking. So I agree with you, you have to give patients the space to really talk about not only their current situation and their disease but often people if given the opportunity will talk about past traumas or family interactions or dynamics, and getting to have the space to be able to get that hurt out I think really helps people feel more at peace with their cancer and their treatment. That’s part of that counseling part of it.

I think people have a lot to say if you give them the opportunity, right, and I think that’s part of our role as health care providers is we are there to support them in any way that we can. So that is the side effects of chemo, the holding your hand when you feel scared, the talking about what happened when you were younger or your problems in your current situation with your family, that’s part of being an excellent provider. Caring about people.

DR LOVE: Jamie, any thoughts?

MS CARROLL: I definitely agree. I think silence is really powerful and giving patients the space to think about what they want to say and as providers I think sometimes it’s really hard to — we want to fill that silence but being able to sit and provide silence to let patients talk and be able to express what they are feeling.

DR LOVE: Erika, any thoughts? We talked last night and we’re going to talk again. One of the topics we talked with the nurses about was avoiding burnout and we talked about that last night and when I went back in my room I was thinking to myself, it’s not just about avoiding burnout, it’s like feeling fulfilled, it’s like feeling good. That’s what we want to do. And I think sometimes connecting with patients the way Jessica was talking about really gives us a greater sense of satisfaction. Any thoughts, Erika?

DR HAMILTON: I completely agree. I think it sometimes can be a double-edged sword because especially in breast cancer we have the opportunity to know our patients for a long time and so sometimes those losses when we really have good relationships with patients can affect us more. But I do think on a day to day, really understanding the life of that person that you’re treating and how their disease may interplay into their life is important and I think it’s a closer relationship that’s more meaningful.

DR LOVE: So we’ve always said that our work is based on rounds and that’s why we don’t really emphasize the slides because we know these people and we get the best people for you to listen to. But we know these people spend years and years explaining things to their colleagues, explaining things to patients, and we’re here to listen to them as well. So let’s get into the meat of what we’re going to talk about because this is extremely important for you and for patients to know about.

Overview of Antibody-Drug Conjugates (ADCs); HER2-Targeted ADCs for Breast Cancer —
T-DM1, Trastuzumab Deruxtecan

DR LOVE: So first of all, let’s just talk a little bit about what an antibody-drug conjugate is and give, paint a little bit of a picture about where it’s being used right now as you’ll see throughout of oncology. And again, we want to talk about this really stunning development. This is the first time this has happened with antibody-drug conjugate which is that this is now an approval based on a biomarker, not on a tumor type. When you look at FDA approvals, often you’ll see this is approved in non-small cell lung cancer or whatever it might be, a lymphoma. This is any person with a solid tumor and any person who has run out of options. And you see that every day. And this drug which we’re going to talk about today is now potentially used in any one of these situations if they’re HER2-positive. We’re also going to talk today about the HER2-low phenomena and the fact that this is really the first time an antibody-drug conjugate not only works if it’s positive but if it's sort of positive but not completely so.

So let’s talk about what these really amazing — we talk so much about immunotherapy but, Hope, to me this is equally fascinating and also a great example of how science can affect what we do. Here, we’re just going to compare 2 antibody-drug conjugates, T-DM1 which was used originally and then the more recent one, T-DXd. Can you explain, Hope, sort of the diagram here and what the antibody-drug conjugate? I mean, people talk about this being a targeted way to deliver intensive chemotherapy.

DR RUGO: Yeah, when we were doing the first work with T-DM1, the idea was a smart bomb, so you would be able to target a specific protein receptor that is on the surface of the cell and the characteristics of that receptor have to be transmembrane so that when the complex of the antibody linked to the payload binds to the receptor, the cell naturally brings that whole complex into the cell and then you could digest the linker and release the toxin and kill the cancer cell. But then this is the T-DM1 era. And since then, there’s been a lot of work and it took a couple of decades to make the right linkers for T-DM1 but there’s been a lot of work on trying to understand the payload, so how much payload do you put in and how much payload per antibody matters. And whether or not it matters whether the payload is hydrophilic or hydrophobic, the idea being that if the payload is a little bit more water soluble, it can leak out of the cancer cell even if it’s not dead and kill neighboring tumor cells. And then the linker, you don’t want to release the payload in the circulation. You want to only release it in the tumor cell but you want to be able to have the cell digest the linker regardless of whether or not it has all the right enzymes because it’s a weird cancer cell already.

So there’s a lot of new things with these new ADCs, the next generation ADCs. The drug to antibody ratio I have to say we thought was a huge advance but it turns out that there are very potent ADCs that have a half that drug to antibody ratio, the same as T-DM1. So it’s an interplay between the antibody, the type of linker you have and the payload.

DR LOVE: So, Jamie, I’m always curious about how people explain things to patients and, Kelly, I’m curious. I was just flashing on last year’s ONS. We did a program on MDS and Rich Stone from Dana Farber, made the analogy of MDS is like if you have a factory with all the workers drunk. The bone marrow is like a factory where all the people are drunk. So how do you explain what an antibody-drug conjugate is to a patient?

MS GOODWIN: Well, similar to Hope, I use like the kind of military analogy of a bomb. I was a history of science major as an undergrad and I’m kind of like a World War II buff so I like to use the military analogies as well of the kind of the targeted bomb. So we have cytotoxic chemotherapy that indiscriminately kills cells that are rapidly dividing and still growing and they’re very toxic because we kill some of the good cells along with the bad cells when we’re trying to keep the cancer. And then within lung cancer, we have lots of targeted therapies, right? And the goal of those therapies is to make more efficient, effective drugs that are more tolerable by targeting say the EGFR receptor on the outside of a lung cancer cell. And these antibody-drug conjugates are somewhere in the middle, targeted chemotherapy. So as Hope was saying, I like to use the analogy of like a guided missile. The drug is designed to link to a protein that is overexpressed or exclusively expressed on the outside of the lung cancer cell. The drug preferentially goes to those cells, binds and the important chemotherapy is internalized and helps to kill the cancer cells.

DR LOVE: So we’ll sort of enter into more of the clinical issues that you talk to the patient about but just to first kind of paint a little bit of a picture where ADCs are right now in terms of oncology. This year we’re not doing a program on bladder cancer but the first-line therapy of metastatic bladder cancer used to be cisplatin-based combination, pretty strong chemo, and an antibody-drug conjugate, enfortumab plus pembro, beat the heck out of it, much better, and that’s now first-line therapy in bladder. Mirvetuximab we’re going to talk in our ovarian cancer sessions, now second-line therapy. That’s another antibody-drug conjugate in ovarian cancer. Another GYN tumor, tisotumab vedotin in cervical cancer is used as second-line therapy ADC.

Actually, one of the first ADCs was used in AML, gemtuzumab, and it’s still used today. So hematologic cancers, you also use it. Diffuse large B cell lymphoma, first-line therapy as of a couple years ago, antibody-drug conjugate replaced a chemo drug in first-line therapy, polatuzumab. Loncastuximab is also used in lymphoma specifically diffuse large B cell.

But that’s just a little bit of a picture of where we’re seeing ADCs right now in oncology. They all have different tolerability issues. We’re starting to see new side effects that we’ve never done before, seen before. We did an entire CME program on ophthalmologic issues in oncology. We’ve had endocrine issues and we’ve had GI, et cetera. So now GI. Anything you want to say, Erika, in terms of sort of globally where you see ADCs heading and also the idea as I mentioned, for example, in bladder cancer the idea of combining immunotherapy in an ADC?

DR HAMILTON: Yeah, I guess my comment may be that we’re really kind of looking at ADCs in a different way than we used to. For T-DM1, it was very important that the tumors had high HER2 expression. And what we’re learning with some of the newer antibody-drug conjugates, trastuzumab deruxtecan for HER2-low when even we have activity in what we call IHC 0s in breast cancer, but sacituzumab we don’t even test for TROP2. Patritumab deruxtecan and Dato-DXd which is HER3 and HER2 targeting, again it doesn’t appear that the level of expression of those targets is important. And so I think we’re going to see more of this really kind of asking the question of how high expression do we need and is this something we even need to test for which ultimately I think the consequences that makes these therapies available to more of our patients regardless of expression of those antigens.

DR LOVE: So I want to get into a couple of cases just to sort of see how this is playing out and actually, Erika, you have a 54-year-old patient who got an interesting strategy in general. This has been out for 5 years but just to bring it out which I call it the KATHERINE strategy which does involve an ADC. So can you talk a little bit about what happened with this woman and kind of what the KATHERINE strategy was?

DR HAMILTON: Yeah, absolutely. So this was a 54-year-old woman that was involved in childcare as a profession and she had a node-positive locally advanced HER2-positive breast cancer. It did not express estrogen or progesterone receptors and she received neoadjuvant TCHP chemotherapy and had a very nice response. She had about a 4 cm tumor and with less than about 0.5 cm left but still did have a little bit of residual disease in her lymph node as well and so in the adjuvant setting we discussed the KATHERINE trial. Now KATHERINE was a trial of using T-DM1 and really replacing those adjuvant antibodies that we otherwise would have been given, either trastuzumab or trastuzumab and pertuzumab. And initially, we thought that there was about 11% improvement in disease-free survival, 77 to 88%. But we’ve just seen an 8.5 year follow-up data now from the KATHERINE trial and there’s actually a 13.7% benefit in disease-free survival. So really quite meaningful and anybody with any residual disease after neoadjuvant therapy regardless of what they got in the neoadjuvant setting is a candidate for this. And so if you just think about the number of patients that were potentially then translating to cure, I think that this is a really meaningful number. A lot of times in breast oncology we talk about a 2 or a 3 or a 4% benefit and so really to be able to explain to patients out of 100 women that 14 more women won’t have the disease recur is quite meaningful. So she did receive T-DM1. She had a little bit of thrombocytopenia, did not need to have a dose reduction, that tends to be a side effect of T-DM1, and also had some cumulative fatigue. It ends up kind of completing a year of T-DM1 and so towards the end of that she did have a little bit of fatigue but completed this quite nicely and continued to work full time.

DR LOVE: So just to emphasize Erika’s point, in the past we would use adjuvant therapy, so you do the surgery first and then try to reduce the risk of recurrence. This way you give the treatment before and you see how it works. If it completely gets rid of the tumor, you’re good and keep the same strategy going but if you still see tumor in spite of giving treatment then you switch to this antibody-drug conjugate and then you drop the recurrence rate almost in half by doing that. Hope, and this theoretically can be done in many situations but I’m not too sure that it's been done outside of breast and in this situation where you have this — there are a couple of situations kind of like that. Any thoughts, Hope?

DR RUGO: I think that actually many of our colleagues and with other, who specialize in other solid tumors are using the neoadjuvant approach, I mean, to make — but in general, the neoadjuvant approach the way it started was to make tumors more surgically accessible so you could convert somebody from needing a mastectomy to a lumpectomy. And there are still people out there who are focused a little bit on that in breast cancer where you’re thinking about, okay, if a patient could have breast conserving surgery or they’re going to need a mastectomy anyway, you might as well just go to surgery. But because of data like the KATHERINE trial, there’s also I think we have information in triple-negative and hormone receptor-positive disease as well that suggests that if you know what’s happening to the tumor that that tells you what somebody’s risk of recurrence is and you can modify the treatment after surgery to improve outcome. KATHERINE was very exciting because it was the first study we had that showed that you could actually do that, change based on knowing response.

And I just had a patient with a big triple-negative cancer who I think we explained it to her 5 times so then I thought, well in different settings and different people why she should have neoadjuvant therapy and get pembrolizumab which you can’t give in the adjuvant setting, right, if you’ve gone to surgery. And it was interesting because what I think patients need to hear is that this isn’t a disease that’s just in your breast or nodes, there are cells elsewhere. And that’s a concept that’s really important to help our patients understand and I realize that even though we think we’re explaining it in the right way, the nurse practitioner was very frustrated that the patient wasn’t getting it time after time but this is, even pictures, things like that can really help patients understand what the rationale is in doing this sort of educated neoadjuvant approach. I hope we’re going to move to, you know, we do neoadjuvant therapy and it not only allows us to give more treatment or less after surgery but potentially to give less or more before surgery. That I think is a really exciting next step for us.

And we’re also looking at T-DXd versus T-DM1 in post neoadjuvant therapy and adding tucatinib to try and reduce the recurrence in brain to T-DM1 and those 2 trials I think are going to be really important for us next.

DR LOVE: I was just going to bring that up that initially I think people maybe thought all antibody-drug conjugates are the same and we actually had a study in the metastatic setting, here it is right here, comparing 2 different ADCs, the 2 that we’ve just been talking about, T-DXd and trastuzumab emtansine and you can see there’s a big difference. The higher the curve is, the more people are remaining without progression. You can see there’s a big difference in the patients who got T-DXd. Any comments about T-DM1 though in terms of — it’s actually used in the adjuvant setting as well. What do you see quality of life wise? Do you see nausea, acute issues? Actually I think you had a patient who developed pneumonitis or somebody, right? Oh no, that was, sorry, we were talking about that in the room. Anyhow, any thoughts, Jamie?

MS CARROLL: Yeah, so I was just going to mention that I think for patients that will be getting T-DM1 in the adjuvant setting, it’s important to talk about how this will affect them from a side effect profile. These patients likely got pertuzumab in the neoadjuvant setting and suffered from diarrhea. That is not something that we would anticipate that they would have on T-DM1. So from a quality-of-life perspective, T-DM1 is pretty well tolerated. I would anticipate that these patients would have Grade 1 nausea and we do see some Grade 1 elevations in their ALT and AST. Usually it does not progress to Grade 2 and does not usually require a dose reduction.

DR LOVE: So maybe we can get into, actually Kelly has a case, a lung cancer patient who got T-DM1. I guess we were aware that other tumors, you can see HER2. That’s sort of the beginning that led to what happened 2 weeks ago with every tumor being considered for it but lung, I think you guys were kind of early on the scene there in terms of getting into anti-HER therapy. I think the T-DM1 study actually didn’t work that well in lung but I was curious you had a patient. How did the patient do on the T-DM1? Was that the one that had the pneumonitis?

MS GOODWIN: It was, yeah. So I had a lovely 69-year-old woman with metastatic lung cancer who had pretty aggressive disease which she had had a metastatic recurrence within a year of surgery for a 1A lung cancer and over the course of her treatment she actually got 7 lines of therapy and lived almost another 4 years with appropriate sequencing of drugs and I’d like to think good supportive care. But she did have a HER2 mutation which we see rarely in lung cancer, about 2 to 4% of our patients though, and she initially got our first-line carbo/pem/pembro, so platinum doublet plus immunotherapy. She did well for over a year. When she progressed, she went on a HER2 targeted therapy on a clinical trial, a pill which was discontinued for intolerance. She had significant rash, diarrhea, fatigue. And then she went over to one of the other institutions across town because they had a clinical trial available for one of the newer drugs that’s actually still available on clinical trial now, Dato which I think we’ll talk about in a bit. She went onto Dato and had a good response for about a year but when she —

DR LOVE: That’s another ADC.

MS GOODWIN: Yeah. But when she —

DR LOVE: Dato-DXd.

MS GOODWIN: When she progressed, she transitioned back to us. We had another ADC clinical trial available but she was ineligible because she had just received the Dato on trial so we petitioned to get T-DM1 off label for her which she tolerated reasonably well. I would say just like Jamie’s patient a bit of fatigue, some mild transaminitis, some mild nausea and she had a nice response to treatment on her first set of restaging scans but unfortunately she also had evidence of ILD.

DR LOVE: Interstitial lung disease, which has been associated with a lot of things including T-DXd. And Erika, can you kind of explain a little bit more about what interstitial lung disease is? We’ll come back to Kelly’s case in a second, but what we know about interstitial lung disease and how it’s managed and prevented.

DR HAMILTON: Yeah, so ILD also sometimes called pneumonitis, is essentially inflammation in the lungs. We can get this from a variety of therapies. There’s actually a lot of therapies in oncology that can cause some degree of ILD. It really became more of a concern with the drug trastuzumab deruxtecan because in the initial study, we saw fatal cases of ILD. So really this idea that if we don’t catch the ILD very early and intervene, once it becomes kind of Grade 3 or greater that oftentimes those cases could be fatal. The good news about that was with increased education, awareness that ILD was a side effect and really guidelines about when to hold drug, when to permanently discontinue drug, we’ve really been able to all but eliminate any fatal cases and the majority of our cases are kind of Grade 1 and Grade 2 now. What’s important to remember is that we treat ILD with trastuzumab deruxtecan differently than we do other tumors. For checkpoint inhibitors for example, we don’t make any big deal about Grade 1 or really even Grade 2 ILD often but with trastuzumab deruxtecan, Grade 2 or greater ILD is discontinuation of the drug permanently without a rechallenge. In Grade 1 which is ILD seen on a staging scan in the absence of any symptoms is a hold, wait for this to resolve kind of within 4 weeks and then restart. So it’s really a little bit of a paradigm shift with trastuzumab deruxtecan having to be more vigilant about the ILD and how this affects us in clinic is that we often keep our scans at a little bit shorter interval because we want to find the ILD when it’s Grade 1 and the patient can go back on the drug instead of them having to come to us with symptoms and then they can’t go back on drug.

DR LOVE: Yeah, that’s a really great point. We’ll get back into that as we talk about some of these cases. Also just to sort of enlarge the sphere as we get deeper and deeper into this is kind of related to what we were talking about before and what you see here on the slide, this so-called bystander effect and how that affects so-called HER2-low breast cancer. This is a whole entity that just came out in the last couple years. I think a lot of people were surprised that this came. It was like very interesting. Hope, can you kind of paint a little bit of a picture? I’ve spent a couple years now since we’ve started hearing about this of at least in breast cancer how it’s playing out. Outside of breast cancer, there’s a whole other story. We’ll get to that in a second. But what about HER2-low, the bystander effect in breast, Hope?

DR RUGO: It’s an interesting thing because there are 2 topics there, so HER2-low and the bystander effect. The idea is that as Erika was saying earlier, we were so focused on having HER2-positive disease and it was like, 15 years of trying to figure out what was the right HER2 test and how can we define it so much so that there’s a whole panel of ASCO with the College of American Pathologists that work together to try and make guidelines for what we called HER2-positive and you would give HER2 targeted therapy to. But we understood that all these, the reason why it was so hard is because there was a little expression or a medium amount of expression and from those very early days, we were trying to decide, you got a little expression if you had gene by doing an antibody test and looking at immunohistochemistry then you would do a gene amplification test or FISH or ISH and look to see if the tumor was really HER2-positive. So if it was HER2-negative, you knew there was protein but it didn’t meet the criteria. So there was a lot of interest in whether or not those patients would respond to HER2 targeted therapy. So we had a metastatic trial with T-DM1. Didn’t work. We had an adjuvant trial unfortunately, big large adjuvant trial giving trastuzumab to those patients. That didn’t work either. So it didn’t change outcome. So then the idea was, if you had a HER2 — it’s the same trastuzumab. It’s a biosimilar with T-DXd. But you were delivering more toxin that maybe you could target tumor cells that have lower expression and that’s what Erika was talking about earlier which is a fascinating concept. And also along with the bystander effect, you would kill the neighboring cells. Tumor cells like to hang out together so there’s a lot of cells nearby. They might have very low expression. You could kill them because you have this tumor, the payload, the toxin leaking out and killing them. And these toxins are very potent in small amounts. You can’t give them as naked drugs. That’s the sort of a whole herald of what the payload is.

So the studies that were done with T-DXd started with an umbrella trial and it was such a cool trial to participate in because we gave T-DXd to people who had really heavily pretreated HER2-positive disease and 1 of my patients stayed on it for 4 years. It was really remarkable. And for HER2-low, the same thing. Mostly an HR-positive, hormone receptor-positive, great responses. And that of course then led to this trial that Neil is referring to, DESTINY-Breast04 where we looked at T-DXd in patients who had HER2-low disease. But it’s also opened another whole can of worms. How do you define HER2-low? Maybe the antibody test isn’t really good enough and the pathologists say, well, it just depends on which pathologist is looking at it. Some studies say 80% agree, some say 50% agree. Anyway, it’s an area that’s under continuous investigation. But what we’ve also found is people who are low, like 1+ HER2, if they’re below that, there may be a group of patients who still have some HER2 but it doesn’t fit into those ASCO CAP guidelines. That’s actually being studied in a trial that we should hear for results from later this year.

DR LOVE: So to be continued. Let’s get back into the clinical issue and just note though that that patient got T-DM1 and got pneumonitis so it’s not like T-DXd is the only drug as Erika was saying that causes pneumonitis. It was interesting. One of the GYN docs was saying, oh, we never see pneumonitis. But yeah they use taxanes and a lot of other stuff so maybe kind of interesting. Anyhow, let’s back to this case because this actually was a patient who was HER2-low, Jamie. What happened with her? She was a 44-year-old woman.

MS CARROLL: Yeah, so my patient has de novo metastatic disease, ER-positive. HER2 was 1+. So her first-line treatment was AI and CDK4/6 inhibitor. Unfortunately, she progressed within 3 months of being on treatment and she had cord compression. She was being treated at an outside facility but came to us with numbness and tingling down her legs and inability to walk so she was hospitalized. We found the cord compression and then she had surgery for the cord compression and then ended up inpatient rehab with other comorbidities that occurred, pulmonary embolism. And then we put her on second-line trastuzumab deruxtecan with her HER2-low. And so her case involved multidisciplinary players because she needed social supports. She went from a healthy 44-year-old woman with a 14-year-old son at home and then needed a walker, she needed van support back and forth to clinic and so I think it’s really important that you involve social work, multidisciplinary folks to help with all aspects of patient care. So I think that’s really important when we’re caring for our patients.

DR LOVE: Kelly, spinal cord compression is of course one of the most tragic complications that we see in cancer and we can see that in any tumor particularly ones that go to the bone. Any thoughts about picking these up early, managing those cases? What’s your experience at MGH?

MS GOODWIN: Yeah, I think it’s really challenging and I think the most important thing is a good baseline assessment of your patient’s functional status when they’re starting treatment and always having in the back of your head that that’s a potential risk when you’re teaching patients about the side effects of their therapy. Also trying to teach them to call for signs or symptoms that might be concerning for progression of their cancer. We tell them that it’s encouraging if you are starting to gain weight, if your energy is improving on treatment, if your breathing is improving and your cough is less productive, but also we want you to call us if you start losing weight or feeling more tired, if you’re experiencing new aches or pains and we try to restage folks every 2 cycles or so but certainly want to see them urgently or if they’re having new issues. CAT scans unfortunately aren’t very helpful for investigation of nerve issues so we’ll get restaging scans which may underestimate really the degree of bony metastases and then unfortunately a patient might call a couple weeks later with significant pain, lower extremity neuropathy or weakness, bowel or bladder changes, numbness/tingling around their hips, loss of bowl or bladder control and then we have to rush to kind of an emergent MRI and palliative radiation which may have to interrupt their systemic therapy so it’s really difficult for our patients as well.

The Incidence and Management of Interstitial Lung Disease with ADCs

DR LOVE: So one of the things about lung cancer is a lot of your patients already have pulmonary problems and I’m kind of curious if, Erika, when you have a patient who already has asthma or some kind of a pulmonary problem and then you’re giving a drug that has the potential to cause ILD. You’re doing CAT scans, et cetera, but you — what about the clinical management of a patient like that? And is it helpful, particularly outside of breast, I hear people going, oh we ask these people, are they short of breath, walk them around, et cetera. Any thoughts about that?

DR HAMILTON: Yeah, I think it can be really challenging especially for somebody that has that cough as baseline, et cetera, because sometimes kind of new cough can be a sign of ILD. I think it goes back to what they were saying of really kind of understanding what’s normal for that patient at baseline. I actually had a case of Grade 3 ILD that occurred in a patient only 2 weeks after a CT scan that was clear and her only complaint to me was, well I’m short of breath carrying the laundry up the stairs now and I wasn’t before. And I kind of thought, well I don’t know, I think I’m short of breath carrying the laundry up the stairs sometimes too, but we ordered the scan and low and behold she had ILD. So I think it’s really just letting your patients know that any change in pulmonary symptoms, cough, shortness of breath, that you want to hear about that and then kind of investigating is important.

DR LOVE: So Jamie, I don’t know if you saw this paper, “The Five “S” Rules” to minimize the risk and impact of ILD. This did come out of breast cancer, people at Dana Farber, screen, scan, synergy, suspend treatment and steroids. Can you kind of talk a little bit about that?

MS CARROLL: Yeah. So the most important is catching the ILD before it becomes symptomatic so hopefully you’re able to catch it on a scan and so that’s why Dr Hamilton brought up doing scans more frequently in these patients when we know ILD is a higher incidence and so we will check every 6 to 12 weeks like it says in the scan section there because if you are checking just every 12 weeks, so more or less frequent then your patient’s going to become symptomatic and then they’re going to have to come off drug and so we want to try to do it more frequently so that it’s a Grade 1 toxicity or asymptomatic. And so for those patients, you can pause drug, consider steroids and then hopefully it resolves and you’re able to restart.

DR LOVE: So Hope, last night we did a program on hormone therapy of breast cancer and we sort of brought it right up to the edge and said, okay, next tomorrow at lunch we’re going to kind of pick up on sort of where things take off after that. You have a 35-year-old woman who presented with metastatic disease, not the most common way that people have metastatic disease. What happened? She ended up getting T-DXd. Can you talk a little bit about what happened when she got T-DXd. First of all, we haven’t talked too much yet about acute side effects that you see, nausea and vomiting. How did she do from that point of view and then what happened?

DR RUGO: Yeah, I think that it’s certainly across a spectrum in terms of those acute side effects and our supportive care colleagues, I do a lot of work in supportive care, have actually given this a new term because the most common toxicity from T-DXd is nausea and it can be quite delayed. So we tend to think of nausea as being up-front, right, and then there’s the platinum delayed nausea. That’s about 5 days. And then there’s this very long delayed is the new term that they’ve coined. We’ll have to see if we can make that a little bit shorter but, and that’s the idea that these patients can be nauseated for 10, 14 days, sometimes even the day before. Of course, it’s not helping that they’re coming in to see us but they might be nauseated then. And I have a patient who’s on now with HER2-positive disease. I’ve even dosed reduced her and she’s just nauseated for 3 weeks. Thankfully it’s a small number of patients and they’re more like this patient that Neil was talking about which is a patient who had 2 lines of therapy before and had a progressive brain met. It’s been a remarkable treatment for her so she likes that but it caused this nausea and so we worked really hard on managing the nausea.

We actually in the NCCN made it highly emetogenic so we could use a triple drug regimen which is really important, but then the rescue part for this delayed nausea is really important so we’ve been big fans of olanzapine which is, you know, you have to tell your patient when you give them olanzapine that they’re not psychotic. That’s not why you’re giving it to them. It is because the pharmacist will say to them, why are you getting this drug? And then we started a really low dose. I was very grateful our colleague in India did a study looking at the 2.5 mg versus higher doses that had been studied primarily in men because our patients just don’t tolerate those high doses. And we tell — that’s the funny thing with education. You say to patients, okay, you need to take it for 3 to 5 days, but then 5 days come, they stop the drug, and then they’re nauseated for the next 5 days. So I’ve really tried to switch our education to say, you can keep taking it. There’s no issue here. It’s not addicting. The main side effect is sleeping and it doesn’t cause constipation or headaches like ondansetron. So there’s a lot of benefit in giving patients olanzapine. I make sure everybody has it who starts on T-DXd and it’s made a huge difference in managing it. And then for people who are still nauseated, dose reduction does help a lot. But I’ve found that with this new cocktail, we really haven’t had to do that. There’s just 1 patient.

DR LOVE: I was telling you that we did a program on HER2 ADCs at the GU ASCO meeting and they didn’t know, you know, and now it’s approved. They have data on it. They didn’t know anything about it. And so we actually showed video of breast cancer investigators and I remember because I was thinking about it. We showed a video. It was just exactly like what you just described and then when they turned to the GU faculty person and said, well how do you manage acute GI toxicity, he goes, I’d do what she just said. And that’s what everybody’s doing right now is talking to them, the breast cancer people because they’re the only ones who know it and it’s onboard everywhere. Every subspecialty is trying to figure this out right now. It’s so interesting. Jamie, any thoughts about your, the representative of the other world here? Any thoughts about how we can get through to these other disciplines and kind of get them up to speed and also the challenge, for example, in your patients where they already have pulmonary symptoms?

MS CARROLL: Yeah.

DR LOVE: Any thoughts about, Jamie, about this?

MS CARROLL: Well of course they have to attend Research To Practice, right? That’s how they get educated.

DR LOVE: Good one.

MS CARROLL: So I think — I forgot your question, I’m sorry.

DR LOVE: I can’t remember the question either. I’ve been asking so many questions this week, I’m kind of — my brain is on — anybody remember what I asked her? Kelly? Anybody in the audience?

MS GOODWIN: How we get the rest of the people like me on board —

DR LOVE: Right, right, right.

MS GOODWIN: — with your science?

DR LOVE: Right, right, right.

MS GOODWIN: I mean, I think it’s important to understand that there are a lot of commonalities between solid tumor types and our treatments, right? So I have the benefit of working at MGH and being in a really specialized clinic but the majority I think of oncology providers in this country are in community settings and they’re responsible for taking patient, taking care of patients across tumor types and you have to fill your head with a lot of information. So the more that you can think like thematically about class effects I think is really important and then you talk to your colleagues who might take care of more breast cancer patients or more GU patients and you have to share amongst each other and I think forums like this are great, also talking to physicians in other disease centers who you may not necessarily overlap with in the direct management of your patients. Like creating those relationships is important, looking outside of your primary tumor type when you are researching how to best care for a patient. And we know that from NCCN guidelines there are standards for taking care of VTE across disease types, nausea across disease types, managing oncologic emergencies across disease types so, and you always have to stay on top of the new therapies but also bring your experience into that and the relationships you’ve formed into that. And I think also listening to your patients about what is most distressing to them so that that’s kind of the symptom that you’re focusing on is really important. The video that we saw at the beginning about listening rather than talking. I think I can do a review of systems with a patient in 8 minutes so what else am I going to fill my 22 minutes with? I hope learning about my patient and what’s important to them and what’s distressing to them. They all have a different level of tolerance for certain side effects so if someone is really worried about nausea because of their sister’s experience with breast cancer 10 years ago then that’s what I’m going to focus my teaching on and my follow-up visits on.

DR LOVE: So I want to get back to Hope’s case because actually it turns out cycle 6 she got some, she picked up some ground glass opacities on a CT of the chest but she felt fine. But first, Erika, you had a thought?

DR HAMILTON: Yeah, I mean, I think this is one of the areas where nurses can be really helpful to us in the clinic because there’s a lot of times you guys are treating patients across tumor types where we may be siloed. And a lot of times a patient may not tell us something in the room and then they get in the treatment room and they’re sitting there for a couple hours for their treatment and they raise something so to say. Hey, the breast cancer doctors are doing X and she’s still struggling with nausea. To be quite transparent, we stole the olanzapine trick from the GI oncologists so I think that’s one of the places where our nurses can really help us.

DR LOVE: Yeah, exactly right. I’ll tell you who else knows about this is the general medical oncologists. They know much more about T-DXd than a lot of these subspecialties who’ve never heard about it. They’ve used it in breast all the time. So Hope this is kind of a classic scenario. The patient gets T-DXd. Was she benefitting?

DR RUGO: Yes, I mean, she was very young when she got diagnosed with de novo metastatic disease, HER2-positive and ER-positive to bone but then she progressed in brain while she was on trastuzumab/pertuzumab maintenance after an induction with docetaxel on the antibodies. And so we treated her and actually kept her on HP and then she progressed again and got radiation necrosis, had to have surgery. There’s all this stuff for this single lesion in her brain, really unfortunate situation. So at the time, we didn’t have T-DXd and she went on the HER2CLIMB regimen with tucatinib, capecitabine and trastuzumab. But she had a lot of side effects from that. It was interesting, I mean, a lot of fatigue and other issues. And she had another progression in her brain but also she just had more bone pain and we had a really hard time seeing her bone disease so we decided to change treatment and she’s had a reduction in her bone pain, she’s more functional, her brain has been stable for the longest that it ever has been. So it’s been really — and once we managed her nausea, she’s done really, really well. But when we got a — we tend to get our scans every somewhere between 6 to 9 weeks in the first year depending on risk. A little easier to do it every 9 weeks. So when she had a scan, I think it was her second scan over the course of her treatment, she had ground glass opacities that were new and I’ve taken to — and I didn’t used to pull up all the CTs but now we have the electronic health record. I can look at it on my phone. We pull up the CTs and look to see what does this really mean because maybe they had a virus last week or something like that and you want to be sort of balanced. But she really had nothing and she had new ground glass opacities and this sort of fuzziness on the CT scan so we put her on 0.5 mg/kg of steroid and repeated her scan and I tend to taper a little bit in those 3 weeks because people don’t like the steroids and then she had a repeat CT, missed 1 dose, right? So then 6 weeks after her last dose, the new scan showed almost complete clearing of her opacities. So we restarted the drug and interestingly it hasn’t come back. We taper the steroid over about a month and she hasn’t had recurrence of those ground glass opacities.

I will say that there is still mortality from ILD and across the studies except for the one that Neil showed, DB03 in patients with HER2-positive disease, every single study has shown some mortality. Even with these really new guidelines it’s about 1%. So anything that we can do on our side to try and pick this up early is really important to understand risk factors as well. People have had lots of prior therapy, are older, have renal insufficiency. Those 3 things have really been called out as risk factors for ILD but that’s not the only patients.

DR LOVE: But what you just heard is what we want to see happen on these patients. We want to get it picked up with Grade 1.

So we want to move on and talk about some of the other ADCs that are being used and also in development but just 1 other point back to you, Erika, with this patient who had brain METs and that’s been of course a big issue in oncology in general, breast cancer specifically, particularly HER2-positive disease. And initially there was the thinking maybe these ADCs wouldn’t get into the brain, it wouldn’t be beneficial, but that doesn’t quite seem to be the case. Any thoughts?

DR HAMILTON: Yeah, I feel like we continue to humble ourselves. I think we all thought that antibody-drug conjugates were too big in size to really cross into the brain. We had some reports of brain activity with T-DM1 but really with trastuzumab deruxtecan increasing data among patients with active brain mets that we can really see quite good responses. We actually just published an update to DESTINY-Breast03 which was the trastuzumab deruxtecan versus T-DM1 in the second-line setting but just of patients that had brain mets and the progression-free survival difference was really quite marked there. It was 15 months with trastuzumab deruxtecan versus just 3 months with T-DM1. So certainly these drugs are active. They do get into the brain. In fact we’re being maybe a little bit conservative, more conservative about radiation now for the smaller asymptomatic brain mets.

DR LOVE: Yeah. And actually, Jamie you have talked — Kelly, you were talking about targeted therapy of lung and we’re doing a program tomorrow on EGFR where they will use systemic therapy and not use radiation to the brain because it works. That’s a common practice in lung cancer with these, what we’ll talk about. But hopefully that’s going to — that’s starting to happen with breast cancer, but we’ll see whether it does.

ADCs Targeting Other Signaling Pathways in Breast Cancer — Sacituzumab Govitecan, Datopotamab Deruxtecan, Patritumab Deruxtecan

DR LOVE: So let’s talk about other ADCs that are being looked at particularly in breast, or that are being used and looked at in breast cancer. One that’s been out there for a little while is sacituzumab govitecan. So before we go back to the 2 investigators who actually did the work, particularly Hope, I’m just kind of curious, Jamie, what do you say to patients who are about to begin sacituzumab? What’s your experience with it?

MS CARROLL: Yeah, so with sacituzumab govitecan, I really stress to patients that diarrhea is one of the biggest side effects. This treatment is given 2 weeks on, 1 week off and so we really — if you’re really worried about the patient and their side effects, use your multidisciplinary team if you’ve got other people that can see the patient for day 8. So if you’ve got a clinical pharmacist, utilize your nursing colleagues for — if the MD or the APP can see the patient day 1 and then if you’ve got a wonderful nurse that can see them day 8 or the pharmacist, then you can have several touch points along the way during that cycle so that you can understand what side effects your patients are having so that they don’t have horrible diarrhea and then they’re not telling you about it.

DR LOVE: So, Hope, can you talk a little bit about what sacituzumab govitecan as commonly called saci is and what we know in terms of its benefits and risks?

DR RUGO: So this was a first in class TROP2 ADC that has as its payload the active metabolite of irinotecan. And that was very cool, called SN-38. Irinotecan is metabolized to be active and that’s created a lot of interest in the pharmacogenomics of each individual patient in being able to metabolize the drug to detoxify it more than creating SN-38. But this was a very clever idea. The idea was in breast cancer patients they really weren’t at that time seeing topoisomerase 1 inhibitors so it was a new drug who one might not have had resistance to and then a new target, TROP2. And TROP2 is expressed in about 95% of at least triple-negative in hormone receptor-positive breast cancers. And it’s not a test that we normally do but it does give you an idea that it might be active against a broad range of tumors. And it was tested first in very heavily pretreated triple-negative breast cancer which is a terrible prognosis. I mean really survival after 3 lines of months and was an improvement, a dramatic improvement in both response, progression-free survival, and overall survival. And then the next data was in hormone receptor-positive heavily pretreated disease were not quite as dramatic but also a significant improvement in both progression-free and overall survival compared to standard chemo. And in 50% of those patients on the treatment of physician choice arm got eribulin which had been our standard rescue, better than the — it was shown to be better than the other chemos so it was helpful to have eribulin there in the control arm. But there’s been a lot of interest in this idea of how do you manage the toxicity from these drugs? And pharmacogenomics clearly play a role and it’s increasing interest now to understand which patients have UGT1A1 polymorphisms that might affect their primarily diarrhea risk with sacituzumab.

DR LOVE: So, Erika, maybe, and I want to hear, Hope, you had a patient and particularly I want to hear about what happened with her in terms of her counts and growth factors as that is 1 issue that I hear about sacituzumab. But just to go back to you, Erika, in terms of Hope referred to the fact there’s studies looking at an ER-positive as well as triple-negative disease. When do you start thinking about sacituzumab? And now that we have HER2-low both ER-positive and triple-negative like what comes first, T-DXd or sacituzumab?

DR HAMILTON: You’re going to ask me the tough question. So yeah, there are quite a few patients that are eligible for both sacituzumab and trastuzumab deruxtecan. So more patients that are ER-positive are actually HER2-low than patients that have triple-negative disease that are also HER2-low. So the data really kind of looks good for both. The data for sacituzumab, there’s a little bit of a bigger body of evidence with triple-negative breast cancer compared to the DESTINY study in HER2-low that was predominantly included hormone receptor-positive disease again because there are more patients that have hormone receptor-positive that are HER2-low and so I think a lot of us may use trastuzumab deruxtecan first for our patients that are HER2-positive and may use sacituzumab first for our patients that are triple-negative. But the reality is that both these drugs are options and right now we don’t have a lot of data about sequencing one after the other but we do have data that chemotherapy is pretty crummy in these settings and so I think a lot of us are doing that but that’s going to be a big field moving forward is really mechanisms of resistance and how to sequence these drugs.

DR LOVE: So Hope, you had this patient who got saci and I’m kind of curious. So this is a I think 30 — is this the 32-year-old? No, no. In any event, she got saci. Can you maybe talk about what happened in terms of neutropenia, what you did in terms of growth factors, what you typically see with neutropenia from saci and how you prevent or manage it?

DR RUGO: Neutropenia is the most common toxicity for sacituzumab and, although there’s going to be a new sacituzumab being studied in Phase III trials that has a T as the second word. And it is MK-2870 so we’re going to have to say SG or something to differentiate them now. But so I’m going to switch now, SG. So SG, neutropenia is the most common toxicity but remember we studied it in patients who had a median of 4 lines of prior systemic therapy and 3 in the metastatic setting. And the same was true with HR-positive disease. So you’re seeing patients who’ve been pretty heavily pretreated, a lot of Grade 3 or greater, Grade 3/4 neutropenia, we managed it very well actually using growth factors and we’ve been trying to use pegfilgrastim after day 8. So first cycle if they need growth factor we give it 1 or 2 days after day 1 to try and get them to day 8 and then after day 8 give pegfilgrastim and sometimes that’s all they need, right, for the rest of the cycles. But now that we’re moving the drug a little bit earlier in line of therapy for triple-negative disease and HR-positive disease, I’ve seen a lot less early neutropenia so it’s a much later phenomenon. Of course unless somebody couldn’t get through their AC in the neoadjuvant setting. There are individuals who are sensitive.

So this patient actually has a very unfortunate situation, a 40-year-old woman with triple-negative breast cancer received a KEYNOTE-522 like regimen with pembrolizumab and chemotherapy as neoadjuvant treatment but had a lot of disease at the time of surgery and then got capecitabine and continued pembro. But while she was on capecitabine and pembro developed a lung lesion, she was being followed on a study with testing ctDNA actually and that’s what drove them to do the CT. So they took out the lung nodule but then she presented less, I think about 6 weeks later with brain metastases and multiple lung nodules, so very rapid progression while still on pembro. Interestingly PD-L1 positive disease also. So we don’t have approval for sacituzumab, SG, in the first-line metastatic setting but she had such resistant disease, didn’t respond to taxane/carbo and AC as well in the neoadjuvant setting so we started her on first-line SG which it’s interesting. There’s a little bit — whenever we start these drugs, people have said, when are you going to start chemo versus an ADC? And I’m like, no, no. ADCs are chemo. It’s a more effective delivery mechanism but this is chemo. So managing exactly how to manage her side effects was really important, fatigue, et cetera, when to take a week off so she could go to Sweden and visit her family. But she had a fabulous response and responded for a long time. During that time, she had additional treatment for her brain METs. So she got peg — she hated filgrastim and she just got bad symptoms when she’d get the injection so we put her on pegfilgrastim after day 8 and she stayed on it. She’s like so sold on it, she wants it with all of her chemo regimens now. But, you know, could I get just pegfilgrastim. She likes the on body device. But, and it worked really, really well for her and she had a little diarrhea but not much, very easily controlled. So that was great. And responded for — I think as we move these drugs earlier, we’re going to see even longer responses.

DR LOVE: So, Jamie, I see you have a 36-year-old woman who also got saci and I think you had a thought also about what Hope was saying.

MS CARROLL: Yeah, so one other point that I wanted to make is that with sacituzumab, we started using it in the triple-negative setting and now we have data to use it in the ER-positive setting and so the thing that I think is important for us to know as we’re talking to our patients about this drug is, some of our patients have not yet gotten drugs that cause alopecia and so this drug does cause that. And so for some patients, they haven’t seen chemotherapy before. Maybe they’re de novo metastatic disease or maybe they were diagnosed ER-positive but didn’t need to receive chemotherapy initially. Maybe they just got tamoxifen or maybe they got an aromatase inhibitor and didn’t have hair loss. And so this drug will likely cause hair loss for them and so that’s something that I think we need to counsel our patients on and it’s important.

DR LOVE: So important and I don’t think people would even think about it, so really great point. How about this 36-year-old woman? It sounds like she’s kind of an interesting person.

MS CARROLL: She is. And I think this case study is important as Kelly pointed out earlier to really know your patients, know their social history, and know what’s important to them. So for this patient, she’s a 36-year-old woman who works for a travel agency and so for her, we were putting her on sacituzumab govitecan, or SG, and so it’s really important that she is able to continue her work balance where she is going to be traveling long distances and the importance is if she has diarrhea, it’s not going to be easy for her to be working and getting to a bathroom that’s the size of 2 x 2 inches and continue to work where you have 150 other people that need to use the same bathroom at the same time when she can’t wait 10 minutes, right? And so it was really important for us to do extensive counseling with her on the side effects of sacituzumab govitecan and making sure that she has antidiarrheals with her. I think it’s one thing to educate your patients that diarrhea can be a side effect and here’s a prescription we’ve sent to your local pharmacy but making sure that it’s serious. You need to fill that prescription because Saturday night when you get diarrhea, you don’t want to drive to the pharmacy at that time, right? So you need to fill that prescription and making sure she knows how to take the medication and so really sitting down and understanding her, her social situation, and being sure that she knows how to take the antidiarrheals effectively was really important for this patient.

DR LOVE: I was flashing back to listening, you know, listening about symptoms too. Your story, you’re obviously a listener for sure. Alright let’s talk about some new ADCs out there that perhaps by next year we’re going to be using starting with what we call Dato. Erika, what is Dato-DXd?

DR HAMILTON: Yeah so this is another TROP2 targeting antibody-drug conjugate so it’s kind of the same target as sacituzumab and then it has the same payload as trastuzumab deruxtecan so you can think of it almost as a somewhat of a bizarre combination between the 2. So yeah I think we’re going to have a second TROP2 antibody-drug conjugate. I hope one of the things that you’ve taken away from this is that although we loop all of these antibody-drug conjugates into 1 class, they really have very different side effects. So trastuzumab deruxtecan we really, I think about nausea and the worry about ILD. Sacituzumab govitecan we really think about diarrhea and the counts issue. Datopotamab deruxtecan is an interesting one because a very prominent side effect is stomatitis or sores in the mouth. And it tends to be very hard to treat once people have them. We can use a steroid mouthwash to help prevent them but it’s really effective in preventing them. It’s hard to treat it once it happens and so I think that this is really a place where educating our patients is really important. I’ve had patients that use the steroid mouthwash like I recommend for a week and they don’t have mouth sores. They decide, oh, I don’t need it, they stop it, they get mouth sores, and then we’re in trouble. So to really say if you don’t have mouth sores, it’s because it’s working. Please don’t stop it. So I think that’s important to remember.

DR LOVE: It’s interesting too at the big European meeting, the so-called ESMO meeting they have every fall, there was a big paper on Dato in breast but there’s also a big one on lung. And the lung people are like, mucositis? And the breast people are like, oh, yeah, we’ve dealt with this with everolimus. They’re like — but you guys I’m not sure where — did you ever kind of get it?

MS GOODWIN: Yeah, with some of our EGFR inhibitors, right, earlier generation EGFR inhibitors like erlotinib and afatinib can cause quite significant mucositis. Not so much with the newer third generation osimertinib. We don’t see it as much. But I do have a patient who went on a Dato trial, a Dato plus ongoing osimertinib and she had significant mucositis. It was really profound on physical exam but she was quite a stoic woman with a high tolerance for discomfort and she always tried to minimize the side effects but it was, I mean, it was difficult to listen to her talk sometimes, right, because her lips where chapped and cracking and swollen and you could, as she was speaking, you could see the kind of ridging along her tongue. We tried the dexamethasone rinses prophylactically and she thought that they stung unfortunately when she did get the mouth sores so she wasn’t as compliant with them so then a lot of it’s diet modifications, avoiding anything that’s spicy or acidic, baking soda rinses, ongoing steroid rinses. We would get viral cultures intermittently because she did have a history of cold sores just to make sure that she didn’t need a course of an antiviral.

DR LOVE: So I like to make the joke that being in oncology you wake up in the morning and you check your phone and you see what’s been approved and then you start thinking about how it applies to your practice. And those days happen not uncommonly. And maybe in the next year you’re going to wake up and check your phone and you’re going to see Dato is approved. And you’re going to read about mucositis but remember what the people who use it tell you. So let’s hear about a couple of people who actually got it. I mean, again, this is a common problem in oncology. A drug is used in a trial and boom it’s in practice and all of the sudden you’ve got to deal with something that maybe you weren’t quite aware of. So Erika, you have a 57-year-old woman on Dato. What happened when you gave her the Dato? Did you use preemptive anti-mucus?

DR HAMILTON: We did. We worked with this compound in Phase I so luckily kind of knew about this. It’s interesting. Most of the protocols don’t mandate the steroid mouthwash because in some places especially outside the US it’s not readily available and so they’ve tried other things like bland saltwater rinses and things like that but yes, we did use the steroid in a prophylactic fashion. She had a little bit of Grade 1 stomatitis, not bad at all, not affecting what she was eating, et cetera. And then she also had a little bit of Grade 1 nausea that was well controlled with antiemetics. She ended up having stable disease for about 6 months on this therapy and was heavily pretreated so that was a win for her.

DR LOVE: So Hope, you also had a patient on a trial of Dato. It’s the only way you’re going to get Dato nowadays obviously. The TROPION-1 study, a 32-year-old woman, what happened with her?

DR RUGO: She’s another unfortunate patient as many of ours are but with ER-positive de novo metastatic disease, very luminal B, didn’t stay well controlled on endocrine therapy for very long. And in the second-line setting, she was on TROPION-Breast01, the study that was submitted to the FDA for this BLA as you can see here on the slide. And she was randomized to Dato-DXd. We put a bunch of people on there and she was the only patient randomized to Dato-DXd. It was really frustrating. But we’ve given quite a lot of Dato in the neoadjuvant setting in our I-SPY2 randomized trial in patients with high-risk triple-negative and hormone receptor-positive disease. And so we have quite a bit of experience both alone and with a checkpoint inhibitor. And so it’s interesting. This patient had been on everolimus before so we gave her the steroid mouthwash because I was already sold on this was the way to go and she had not gotten any mouth sores on everolimus so she made the decision, and we see this all the time, she didn’t use the mouthwash. So she came in with like Grades 2 to 3 stomatitis. I mean, she really had terrible stomatitis. So we had to delay her treatment, started the steroid mouthwash, and she continued without a dose reduction and never had more, I mean, a little sensitivity in her mouth with each cycle but nothing that prevented her from eating and had a remarkable response. I mean, really stayed on for almost a year and then really nothing else worked after that which was an interesting thing. I mean, you get these windows of time which in the end you’re so grateful for that you could offer something to a patient that was effective. But nobody can really manage with a year of mouth sores so I think it’s going to be really important for us to manage this up-front with prevention. It’s fascinating about the steroid mouthwash because it actually in our hands even in the neoadjuvant setting worked really well. Some people still had mouth sores so they would have a sore throat so I had them actually gargle with the steroid mouthwash and that worked. Their sore throats went away. So I think that we can manage these things up-front. We’re actually going to present some data, combined safety data from TROPION-Breast01 at ESMO Breast in the next month or so. There’ll be a lot more information out in the press before the drug is approved.

DR LOVE: So, Erika, as we hear about more and more ADCs, we can imagine and in fact it’s happening. People are going to get multiple ADCs. You just talked about whether you’re going to give sacituzumab or T-DXd first, whether you’re going to give both, and then you get into a big issue in oncology which is resistance and how do you sequence these things. And if you’re going to use one ADC, should the next one have a different payload, a different target? Any thoughts about where that’s all heading, Erika?

DR HAMILTON: Yeah, we don’t have a lot of definitive data. So far in kind of very small looks, it looks like it’s probably more important to use a different target than to use a different payload. So there’s a lot of studies ongoing that will look at that. There’s also a lot of antibody-drug conjugates in development so I think a big need is ones with different payloads and different targets so we’ll see some of that coming as well.

DR LOVE: So one other ADC, this is to HER3, patritumab deruxtecan. You can see it has the same last name, the same payload, and I hear people now calling it HER3-DXd. That’s the new name? I wanted them to call it trasthreesomab.

DR HAMILTON: That was a good one.

DR RUGO: Yeah. That’s a good one.

DR LOVE: Anyhow, so what about this? And we’re going to talk about this tomorrow in lung, EGFR-positive, like where does that come from? But what about HER3 and HER3-DXd, Erika?

DR HAMILTON: Yeah, so you figure it out which family it belongs to with the deruxtecan last name, so this is similar to trastuzumab deruxtecan, datopotamab deruxtecan, but now we’re targeting HER3 with the same payload. What’s really interesting about this compound and you’ve already heard from sacituzumab as well as T-DXd that we had activity in both ER-positive and triple-negative. In this initial study, they actually looked at HER2 as well, so all 3 types of breast cancer and there was activity across the board. And another interesting thing about this along the themes of what we’ve been talking about for antibody-drug conjugates is that it doesn’t appear that we need to test for HER3. Other patients have less than 25% expression of HER3 on the cell surface, 25 to 74 or over 75%, all of these patients really get meaningful responses. So this is another one we’re probably going to hear more about and makes it a little bit more tricky when we think about how we ultimately may sequence these drugs.

DR LOVE: So and you see down there on the slide down towards the bottom EGFR-mutated non-small cell lung cancer which is what we’re going to be talking about tomorrow. But actually, Hope, like EGFR and HER2 are kind of in the same axis. I think EGFR1 is actually —

DR RUGO: HER1.

DR LOVE: HER1. I get them confused. But any thoughts, Kelly, about I don’t know whether you’ve been involved with trials of patritumab and actually Erika has a patient who got it I want to hear about. But what about in lung. Are you seeing it in people who progress on like osimertinib?

MS GOODWIN: I do have a patient who received this combination on a clinical trial and we had talked before about TKIs being wonderful drugs, small molecules that can penetrate into the brain, and so most of our patients who come to us with an EGFR mutated lung cancer despite how bulky or extensive their disease is can get a really nice response in a very short period of time with first-line osimertinib. And then when patients with metastatic lung cancer and an activating mutation start to progress, we can often continue them on the treatment post progression while we await additional biopsy information that might tell us why they started to progress on that treatment and give us another molecular target to add to the osimertinib or to switch therapy and regain control of their disease. Unfortunately once folks have sort of progressed and we don’t identify a new actionable mutation or they have run through our standard of care targeted therapies or clinical trials, were often jumping to chemotherapy for these patients so a platinum-based chemotherapy with or without ongoing osimertinib. And so these are really exciting drugs in that it’s still a little bit smarter than our platinum-based chemotherapies which are really toxic.

So I did have a patient who responded to first-line osimertinib with really nice control for nearly 3 years and then at the time of progression we re-biopsied her cancer and it continued to show her original L858R mutation but no other actionable mutations. And she was eligible to receive patritumab with ongoing osimertinib on a clinical trial. She tolerated it fair, a lot of cytopenias which folks are not used to if they’ve been on targeted therapies. We don’t really think of targeted EGFR therapies as causing myelosuppression so having to check CBCs routinely and talking to folks about calling us with a fever is a much bigger deal, right, when you’re getting this kind of therapy versus something like osimertinib. So a lot closer observation and more frequent lab checks with these patients. So I think fatigue and cytopenias were her main complaints. Unfortunately she did progress after 2 cycles of therapy and she was coming to us for the clinical trial from quite a distance so after she discontinued therapy and didn’t have any other actionable mutations on repeat biopsy, she transitioned care closer to home and is just getting vinorelbine in combination with her osimertinib.

DR LOVE: So Erika, you have a 62-year-old patient who actually you say responded to patritumab. And when you have these people who progress with metastatic disease, just to see response is fantastic and I’m curious too what do you think it’s going to take to bring this and also data into practice. What do you need to see in a clinical trial in these situations in order to actually have it approved?

DR HAMILTON: Yeah, I think that’s a fantastic question. Yeah, this lady had previously received sacituzumab govitecan and then received patritumab. She had about a 36% shrinkage in her liver lesions. Unfortunately it wasn’t particularly long lived. She progressed at about the 6-month mark. So I think right now in this BRE 354 study we have, we’re enrolling specifically patients that have already seen antibody-drug conjugates, who have already seen trastuzumab deruxtecan and already seen sacituzumab govitecan. Because really these drugs are being tested in earlier lines now. They’re being tested in the first-line setting. They’re being tested in the adjuvant setting. So we really need to see what the activity of some of these newer antibody-drug conjugates are after already receiving an antibody-drug conjugate.

ADCs for Other Tumor Types and Toxicities Associated with ADCs

DR LOVE: So Hope, again, any thoughts about in both, with both of these agents, what are we looking for? Just to elaborate more on this question of how much benefit do you need particularly in view of what the patients have to go through. What are we looking for in these trials in order to say, bring a drug that’s been tested in the metastatic situation actually into practice?

DR RUGO: I think it’s a great question because bringing a drug that’s been tested in the metastatic setting into practice I think really depends on the strength of the data in the Phase III trials that we’re looking at and then in the early days of ADCs, SG was really approved initially based on the idea that it was a rescue drug when none others existed. But those days are behind us thankfully. I think now you really have to have a randomized trial. So the challenge with HER3-DXd and people are only calling it that because they can’t patritumab but it’s always a problem with our drugs. We practice a lot. But the HER3-DXd problem is it’s DXd. So we have T-DXd and that’s our drug of choice for HER2-low breast cancer. Maybe we’ll give SG first for triple-negative disease but if they have any HER2, we’re going to give T-DXd next, right? So now all of these patients have seen deruxtecan has half of the HER2-positive patients. So then you have Dato with deruxtecan and you have HER3 with deruxtecan.

So I think the question is really, can we still deliver the same toxin with efficacy and will it be worth it for the patient? So we’re balancing that degree of efficacy against side effects. I will say I’d rather give a sequential ADC than give vinorelbine late-stage breast cancer which doesn’t work except for maybe in HER2-positive disease and some others, lung. It just doesn’t work in our patients and so giving something that might give a little benefit and occasionally I’ll see a patient and we’ve seen this in the registry sequential studies where most people have a longer progression-free survival on the first ADC than the second ADC, right? But then there’s a few patients who do better on the second ADC. They have a longer PFS. We don’t really know why that is and it’s going to be incredibly complicated to figure it out. They found in 1 patient studied at Mass General who had these fresh autopsies where you can get samples from the different sites that there were 2 mechanisms of resistance to TROP2 ADC in the same patient in different organs. So it’s a really complicated area. And I think what the data in the late-stage setting may do for these later drugs like HER3-DXd is to move the drugs into the early stage setting as quickly as possible because of course what we’d like to do is prevent metastatic disease.

DR LOVE: So I want to show a slide and actually ask Erika to comment on it because again I think it’s relevant to all parts of oncology. On the top there is this so-called waterfall plot. So each one of those sticks is a patient and represents which way the tumor goes. So if it goes up it means it’s increasing in size. If it goes down it means it’s decreasing. And so waterfall plots like this where most of the patients the tumor is going down is what we like to see. And then you can see how they try to correlate it with what kind of mutations they have. Erika, anything you want to say about like kind of the waterfall plot, how you look at it and even how you explain it to a patient?

DR HAMILTON: Yeah, I think a gross way to look at the waterfall plot is are there more bars that are going below the line or are there more bars going above the line, right? So we really see here maybe an excess of 3/4 are at least kind of below the line and then these patients that are green on the right are really getting substantial benefit. Especially in a disease like lung cancer where we haven’t had a whole lot of wins outside immunotherapy, I think this is pretty impressive. When you look down at all of these pretty little colors on the bottom, that first row is showing kind of what kind of EGFR activating mutation is present in each of these individual patients that represent a bar. But if you go all the way to the bottom, you can see HER3 expression and you can see that there’s not a pattern there. There are patients that have very low HER3 and very high so again that gets back to the point that I was making that it really doesn’t appear that you need to have high levels of HER3 to get benefit from a drug like patritumab.

DR LOVE: So Hope, I-DXd, so another member of the family potentially coming on. Again, we did an entire program on B7-H3 ADCs. You could imagine being in oncology we did a 90-minute program on these kinds of ADCs but any thoughts, Hope, about where this is heading?

DR RUGO: Well, we have a whole group of new ADCs and we talked about the fact that we’d like to get a different antibody and a different payload so we have more ability to sequence or figure out what’s better for what specific tumor type and what specific tumor even within breast cancer. And so this is really a fascinating area. We’d like to see something other than deruxtecan as the payload and there are eribulin actually ADCs that are in clinical trials now and one that’s a little bit more advanced than another. But the idea here is that you would use sort of an immune affecter target so that potentially you could activate the immune system with an antibody and deliver the toxin at the same time almost like you’re giving an immunotherapy along with a chemotherapy.

There are early results from these. They do appear to have some efficacy and this one, ifinatamab shows as you can see from these waterfall plots some efficacy in a variety of settings in different cancers. But, and we’ve seen that across the board with these new ones. There’s even ADCs that have an immune payload. That’s going to be fascinating to see as well. So where these are going I think will be fascinating. Obviously, the interest is studying some of the immune ADCs, more immune sort of either targets or payloads in cancers that respond really well to immunotherapy but maybe we can overcome that. I mean, there’s a whole area of study giving immunotherapy with ADCs. Maybe this would do it all at once.

DR LOVE: Yeah, somebody said that to me. I didn’t quite get it but putting an immune targeted package onto an ADC, super cool. Here’s another one, again, I’m not even going to begin to pronounce it. We’ll just call it Ralu-DXd. What can I say? Things are going in the right direction. So a lot of reason to be optimistic. Again, Erika, any thoughts about this one? I know you see ovarian cancer as well.

DR HAMILTON: Yeah, this is a CDH6 targeting antibody-drug conjugate and ovarian tends to be one of our tumor types that really just has a very unfortunate prognosis so to see a waterfall curve where almost all patients are getting some benefit here I think really was impressive. This study actually enrolled both ovarian cancer as well as renal cell cancer and we saw responses across both.

DR LOVE: Do you see ILD with these other deruxtecans?

DR HAMILTON: You can. I mean it’s not as high as we see with trastuzumab deruxtecan but definitely we do see it, yes.

DR LOVE: And we were talking about whether autoimmune toxicity of IO predicts benefit. What about in this situation? Does ILD predict benefit or not really?

DR HAMILTON: No, it does not.

DR RUGO: And the HER2 ADCs, so deruxtecan clearly has some toxicity there but it does appear that HER2 is expressed on lung so that may be why we’re seeing the ILD with T-DXd but we see very low levels with, say, Dato-DXd but you see stomatitis. So then there must be TROP2 expression on the mucosa and you’re delivering the potent toxin. So it’s fascinating to think about the mechanisms.

DR LOVE: Alright, well let’s finish out by talking a little bit about taking care of patients and, Jamie, I’ll be curious to see what you think about what Mr Stein has to say.

MR STEIN: Only one thing, and this is for all the nurses out there whether you’re a registered nurse or an advanced practice nurse, a nurse practitioner, a nurse clinical specialist, a nurse anesthetist, don’t forget you were new at one time and you were learning and I think it is so very, very important to give back to the profession. Take new nurses under your wing, mentor them, precept them, teach them. You will be doing a fabulous service not only to them but to yourself, as well, because it will — at least what I found it’s refreshing to see new blood going into this field. It’s refreshing to know that you still know what you’re talking about, and you can offer this to somebody and potentially let that legacy of oncology nursing live on.

DR LOVE: So Jamie, if you know that you’ve got a nurse who’s going to be starting in your clinic and you’re going to sit down and talk to her, what are some of the things you’re going to be chatting with her about?

MS CARROLL: Well, I couldn’t agree more with what Ron was saying. I think we all had a day 1 ourselves and we all appreciated that person that sat down with us and explained oncology and walked through cancer care and so I think we all talk about burnout and I think variability in our work also helps with burnout and so if you’re providing care to our patients but then you’re also doing education and mentorship, that’s variability in your work and it also helps decrease burnout. And so I think that that also is very important in being a well-rounded nurse. So it’s super important.

DR LOVE: And I’m going to come back to the physicians with their thoughts about educating in their colleagues but I just want to bring up 1 other issue and get Kelly’s thoughts on it and a bunch of the nurses comment on this which is humor in oncology. Here’s what Ms Burns has to say about that.

MS BURNS: I feel that humor is really important and some days it’s just lost on most of us. I did a 12-year stint in a radiation oncology practice and our children’s hospital and I think we can learn a lot from pediatric cancers in that you need to make that experience fun. With kids it’s different. You always have a remote-controlled spider in your desk or a fart machine, whatever it is. You make things light and happy and I think we can learn a lot from taking care of kids in that not all of these experiences that our patients go through are happy but if you can joke about it and make light of it, it just makes everything easier. There are going to be people on that team that maybe that might be the only way you can connect with them is through humor. A little bit of sarcasm sometimes goes a long way.

DR LOVE: Kelly?

MS GOODWIN: I agree completely. I laugh every day at work with my patients and with my colleagues. I think when I first started practicing in thoracic oncology and as Erika said we don’t have a ton of wins, right? Our progression-free survival or overall survival is very different than the population you treat in breast cancer and so you would feel a little guilty laughing with your colleagues or making a joke in the office and you’d close your office door and then the longer you practice and the more that you experience patients and meet them where they are and learn about what’s important to them and identify with them as people not just as patients, they like to hear you laughing in the hall. They like to have me come in and be sarcastic and use foul language about the traffic coming into clinic in Boston. Like, their blood pressure is always going to be elevated and you make them laugh when they finally found a parking space and you reassured them with their blood counts and then you recheck their blood pressure and they’re fine.

I did have a patient who, the sweetest gentleman ever, he passed away about 2 weeks ago, but he had really horrible disease when he first met us and he got 3 great years that I think surprised us as well. And about 6 months ago he was sitting in our exam room and he moved his chair too close to the wall and when he moved the back of his chair up, it hit a corkboard behind the chair which hit a clock which fell on his head. Right? And I mean, I just, I didn’t know what to do. He was on therapeutic anticoagulation. It smacked him. I mean, we needed to get a CT of the head, we needed to, just to be on the safe side. And he joked that it wasn’t his time yet. And he must have made that joke every week I saw him for the last 6 months of his life. And he made that joke the day that we put him on hospice. And he didn’t like to use the word hospice. He said the hockey team was coming over instead of the hospice nurses. I mean, we laughed throughout the 3 years together and that’s what I’ll remember about taking care of him.

DR LOVE: In a way, Erika, I can connect the 2 comments by in terms of sort of preparing your colleagues or being in oncology obviously is a big challenge but then maybe humor is a big part of getting through it. Any final thoughts, Erika?

DR HAMILTON: Yeah, I mean, I think it’s a privilege of taking care of our patients and they’ll surprise us, right? I mean, they’re facing some of the hardest days of their lives and they come in with humor. I had a patient last week that said, I did great this last cycle, I only vomited once. Now it was in aisle 3 right beside the tortilla chips at the grocery store. But you know it’s that adage: you either laugh or you cry, right? So it’s good to have humor.

DR LOVE: So faculty, thank you so much. Thank you for attending. Come on back tonight. We’re going to talk about lymphomas and CLL. Thank you.