Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to “Understanding the Current Paradigm and New Approaches in the Care of Patients with Cancer.” This is a first of 11 meetings we’ll be doing here at the ONS Congress.

We have a great faculty today. We’re going to talk about antibody-drug conjugates in the management of cancer. From our faculty, closest to me is Marianne Davies from the Yale Cancer Center in New Haven, Connecticut; Ms Marissa Marti-Smith from the Texas Oncology-Baylor Charles A Cancer Center in Dallas; Dr Eddie Garon from the David Geffen School of Medicine at UCLA, Johnsson Comprehensive Cancer Center; and Dr Tiffany Traina from the Memorial Sloan Kettering Cancer Center in New York.

As for all of these meetings, we will be talking about the use of agents and treatments that are not approved, so check out the prescribing information for more information.

Check out our podcasts. Just go to podcasts on your phone and type in “Oncology Nursing Update” and follow us. There are a couple programs. Now we’re going to put all 11 of these programs on the podcast feed as well.

So we are really thrilled today to be joining the ONS and celebrating their fiftieth year here. As I said, this is our seventeenth year working — coming to the ONS Congress. I wanted to just show you how I actually — this is something I sent to my daughter, she runs our company, as you all know, this is what I sent to her when she turned 50.

MOLLY SHANNON: Ladies and gentleman, my name is Sally O’Malley. I’m proud to say I’m 50 years old. I’m not one of those gals who’s afraid to tell her real age. I like to kick, stretch and kick! I’m 50! 50 years old.

DR LOVE: Congratulations.

So as I mentioned, these are the 11 meetings we’re doing here, but we really envision this as an immersion oncology experience for you now and on replay for the next couple of months. We’re not only going to be talking about the specific issues and cancers here but more general principles of oncology nursing.

And more than anything we’re just here to hear our faculty speak. I always loved going to rounds and just listening to people, and that’s really what we do when we do our programs. We have 44 faculty members here, 4 in each one of these programs. We’re really thrilled to be able to share and hear about their experiences, and again, particularly the issue of new drugs. There are so many. It’s really an incredible time to be in oncology, but it’s also very challenging.

We’ve viewed this over the years as kind of making rounds. This is the new way of making rounds here today technologically.

And one of our focuses here is the key triad of the oncologist, oncology nurse and the patient and their loved ones, and we’ll get into that as we hear about some real patients.

Some of the themes that are going to go through this entire meeting are the concept of personalized oncology: individualizing treatment for the patient. Today we’re going to talk about 4 specific clinical scenarios in lung cancer and breast cancer, but throughout these programs we’ll be focusing on very specific situations, based on what the stage of the cancer is, the type of cancer, and also what’s going on with the patient. Why is it different to take care of this patient than another patient in the same oncology situation? And we’ll get into that with some of the cases we talk about.

A big factor now, one that we really are going to talk a lot about, we talk about all the time, is the issue of biomarkers. This is the way oncology is. We look at the tumor, the genetics of the tumor, to try to figure out how best to treat the patient, and there are many assays that contribute to that. We’re going to talk about that as we go along.

And another theme that is always underlying our work is the concept of what we call “the bond that heals." The fact that the relationship that we have with our patients is of tremendous benefit to them that goes beyond any specific therapy that we’re giving, and it’s something that the patients value and obviously we here in the field value. And so we’ll look at this and how we individualize this to specific patients.

Overview of Antibody-Drug Conjugates (ADCs)

DR LOVE: So we’re going to start out now, and we’re going to focus on the issue of antibody-drug conjugates. I feel like we’re talking about this almost every time we do an education program. It’s become a part of so many different pieces of oncology. We’re going to spend a couple minutes just talking about what antibody-drug conjugates are, and then we’ll get into 4 clinical situations, 2 in breast cancer and 2 in non-small cell lung cancer, where these agents are used and give you more granularity about how they’re used and some of the things you might want to be discussing with your patient.

But first, Tiffany, I wanted to get into the issue of what an antibody-drug conjugate is, and thanks to Marianne, this is a slide she put together. I thought it was really a great description. And in particular, Tiffany, we talked about the 3 components. I’ve heard you people talk about the Lego thing and the different components. Can you talk about what an antibody-drug conjugate is?

DR TRAINA: Yeah, sure, happy to. So I think of this as a really engineered way to deliver cytotoxic chemotherapy right where it needs to be to the cancer cell. So you’ve got an antibody that is engineered against the target that ideally the cancer cell expresses more so than any other normal cells do. There is a linker that then attaches to what we call a payload, which is essentially a metabolite of some of our really active chemotherapy drugs, and you can have a high concentration of those molecules attached to the tail of the antibody, bringing that drug right to the cancer cell that expresses that target.

DR LOVE: So many antibody-drug conjugates are currently approved in the treatment of cancer. We’re going to talk about several of the important ones here today.

But Eddie, just in breast cancer, for example, we have trastuzumab emtansine that’s been out there since 2013, first in metastatic disease, this is in HER2-positive breast cancer, and also later on in 2019 for patients who got neoadjuvant treatment for the primary tumor and had residual disease at surgery, a really great benefit seen with this antibody-drug conjugate.

Sacituzumab govitecan is another antibody-drug conjugate used in the metastatic setting. It’s been out there since 2020, triple-negative disease, as well as HER2-positive.

Dato-DXd, or datopotamab deruxtecan, just approved a couple months ago in breast cancer in metastatic disease.

And one of the most exciting agents in all of oncology, and now it is going throughout all of oncology, because it’s approved in many different cancer types, trastuzumab deruxtecan, where you can see it started out in 2019 in breast cancer, metastatic disease, and just more and more approvals. Now it’s used in HER2-positive solid tumors — many solid tumors, including lung cancer.

But just to give you — some of these we’re going to be talking about in other programs. We’re doing a program in ovarian cancer here. Mirvetuximab is an antibody-drug conjugate. In cervical cancer tisotumab, interesting ophthalmic toxicity. In bladder cancer enfortumab vedotin used first line now, first-line treatment combined with immunotherapy beat out cisplatin-based chemotherapy, really amazing. And then also in hematologic cancers, gemtuzumab used in AML. Saturday night we’ll be talking about lymphomas, brentuximab vedotin is used there, including Hodgkin lymphoma, diffuse large B-cell. ALL. Polatuzumab used in diffuse large B-cell, now part of first-line therapy. And loncastuximab, another ADC.

There’s a bunch more coming along targeting different types of targets, different types of payloads, as Tiffany was just talking about.

Eddie, any comments on how you’ve seen this integration of ADCs into clinical practice and where you see that heading?

DR GARON: Yeah. So antibody-drug conjugates in lung cancer, which is what I mainly manage, has mainly been — at least approved approaches have been based on HER2. I think some of the really interesting things moving forward are, and we’ll talk about it a little bit, in selected populations. For instance, patients with EGFR mutations we have a few additional antibody-drug conjugates that are coming, but also some of these selective agents beyond HER2. The compound that was noted just previously that’s looking, for instance, at MET, which is a similar oncogene, one that we know. In some circumstances we’ve been able to drug, and I think that people are developing antibody-drug conjugates against a whole host of different targets, some just because they’re expressed on cells, but some because we think they’re also very relevant for the biology of the cancer.

DR LOVE: So Marissa, I’m kind of curious. Actually, now usually the “payload,” as Eddie was saying, is chemotherapy, so this is a targeted way to hopefully deliver chemotherapy specifically to the cancer cell, except, as always, nothing is perfect in oncology and often we can see normal cells being involved, and you do see some chemotherapy side effects. There are other agents in development bringing in immune payloads, but right now we’re mainly functioning with chemotherapy.

So Marissa, I’m kind of curious. We’ll get into this when we talk about your patients, but how do you explain to a patient what an antibody-drug conjugate is? Are they interested in it? What’s a good way to explain it?

MS MARTI-SMITH: Yeah. So I actually had a patient last week that I’ll tell about when I speak later, but she was totally confused, thought she was on “full chemotherapy,” and I explained to her that truly she is on an ADC, and she looked at me like I had 3 heads, and so then I followed up with my usual analogy that I’ll tell you guys. But anyways, I just explained to her the payload and the specification and how we treat targeted cells, and she looked amazed. But it’s interesting to educate patients so that they’re more aware of what they’re getting, and they’re aware of why they do better, I think, with these therapies because they’re less toxic.

DR LOVE: And Marianne, another thing we see in oncology, a lot of variation of what people want to know. Some patients don’t want to hear anything, others — maybe you’ve had nurses as your patient or physicians who want to know more. Any clinical pearls? Do you ever use the — I’ve heard the Trojan horse one, they’re bringing in the chemo. How do you explain it?

MS DAVIES: Well, I think the first thing is to find out what everybody’s level of experience is. Some of these drugs are being used in the secondary setting now, so patients may have had prior experience with other chemotherapy, and so they try to just relate to their past experience or trying to explain the difference, if it’s now going to be used in the second line how the toxicities can be a little bit less.

For those that haven’t had prior experience we all know people that have been treated with some kind of therapy, probably, in our life, and so just trying to kind of align these different treatment regimens into different buckets. This is not immune therapy. This is not chemotherapy. It’s sort of a targeted therapy, but not like our EGFR inhibitors, et cetera. So really trying to help explain all of the different pillars of how we treat our patients can be challenging.

But meeting our patients is really finding out what their baseline understanding is and how much, really, they want to know about the mechanism of action, actually.

DR LOVE: Yeah. That EGFR scenario, we’ll talk about that later on today. That’s the last scenario we’re going to talk about. There are many different targets in non-small cell lung cancer where really you can see terrific benefit without usually as much side effects as with chemotherapy. We’ll get into 1 example of that later on with EGFR.

Trastuzumab Deruxtecan (T-DXd) in Patients with HER2-Positive Metastatic Breast Cancer (mBC) with and without Brain Metastases

DR LOVE: So this is a scenario we’re going to start talking about, Tiffany, an unfortunate scenario of a patient with HER2-positive metastatic breast cancer. This patient had prior treatment at initiation, usually, for HER2-positive disease, that means chemotherapy and anti-HER therapy initially, followed by surgery, and then if there’s disease left, followed by trastuzumab deruxtecan, an antibody-drug conjugate. Or if they’ve had a complete response maybe just pertuzumab and trastuzumab.

But then, Tiffany, the issue of the patient recurring, which occurs, and some of these patients never recur and are cured, but others come back. And we’re going to talk about a situation that’s not uncommon at all, which is the patient not only recurring but something you see more in HER2-positive breast cancer, which is brain metastases.

So this patient had previously received 4 — the first treatment for metastatic disease, the common treatment is chemotherapy, usually a taxane with the antibodies trastuzumab/pertuzumab, and then you see progression.

And Tiffany, a couple years ago we saw an interesting tyrosine kinase inhibitor, tucatinib, that was thought to penetrate the brain very well and was often used in this situation with chemotherapy. More recently another — an antibody-drug conjugate, trastuzumab deruxtecan, has been used. And we asked you to review some of the research data that underlies the fact that a patient like that today is very likely to be treated with an antibody-drug conjugate, specifically trastuzumab deruxtecan.

So we’re going to think about this clinical situation, have Tiffany talk a little bit what the oncologist is thinking and particularly tapping into the available clinical research out there. You have lots of patients on clinical trials, and the reason they’re on clinical trials is some of them, a lot of them, end up really affecting patient care. The trials of this antibody-drug conjugate were dramatically positive. As soon as people saw it, they were ready to go and ready to use it. Very quick FDA approval.

But I want you to kind of go through, Tiffany, what are some of the key trials that have been done that would lead you to figure out how to treat a patient like this.

DR TRAINA: Absolutely, happy to. So this is an all-too-common circumstance, and I thought it would be helpful to put this into context of what our patient experience has been and what their expectations might be. So I’ll pause just for a moment on first-line HER2-positive metastatic breast cancer standard of care is a taxane with trastuzumab and pertuzumab. And this works beautifully. So you can see 16-month improvement here in median progression-free survival, 16% difference, absolute difference in overall survival. And median overall survival is measuring out to almost 5 years.

So often what ends up happening, chronic chemo exposure is hard. Neuropathy develops on the taxane. And so in practice we usually will give a few months of the taxane but then drop it, and our patients are able to just stay on dual antibody therapy for years on average, right? So imagine what that quality of life experience is. It’s pretty terrific, showing up every 3 weeks just for an antibody. You’re feeling well, and it’s keeping disease under control.

Ultimately, when there’s progression of disease, we’re fortunate that we have many options, but we have to keep that context in mind of what the patient experience has been to that point.

So many guidelines now really established the antibody-drug conjugate trastuzumab deruxtecan as a preferred option in the second-line setting. Both NCCN Guidelines and ASCO Guidelines say this. But we do have some other options, like oral TKIs, and so we’ll step through some of the data and then some of the pros and cons of how I try to do some shared decision making with my patients.

You heard a little bit about the construct of ADCs already. Trastuzumab deruxtecan targets HER2, and so we do need to know there’s HER2 expression when we’re using this agent. The payload is a topoisomerase I inhibitor, something highly active in breast cancer. And that linker is one that is cleavable, so the drug actually can diffuse out of the HER2-positive cell and get into some of the neighboring cells, and this bystander effect probably contributes, as well, to really great responses.

So some of the early studies of T-DXd — trastuzumab deruxtecan — showed amazing responses, even in heavily pretreated women. You can see that waterfall plot on the left, the lower the bar the better the benefit there, and almost every patient was deriving some degree of benefit by using this ADC. And median overall survival for this heavily pretreated patient population was now pushing out about 2 and a half years. So this was really a spectacular presentation of the data for a single-agent ADC.

That led to this big, randomized Phase III study putting T-DXd up ahead — up against the standard-of-care ADC at the time, which was T-DM1. So these are patients who had previously seen trastuzumab, most had seen pertuzumab before, and they get randomized to T-DXd or T-DM1.

And when you look at these curves even from the back of the room you can see lots of separation between the lines. The line on the top is showing the benefit of T-DXd in terms of progression-free survival, so how long are women staying with their disease quiet and under control, including a survival endpoint in there, and there was a dramatic benefit to T-DXd over the old standard of care of T-DM1. Overall survival was also significantly improved. So median overall survival, again, out to about 4 and a half years now, compared to what T-DM1 was offering. So this really quickly became an option as a standard of care in the second-line setting.

But what’s the tradeoff, right? What’s the downside? What are the toxicities we have to be aware of for our patients? So in terms of Grade toxicity, nausea, upper GI symptoms can be relatively common for all grade. About 77% of patients experienced some GI tox, and about 7% of that was nausea. Alopecia is a concern, and with this antibody-drug conjugate 30 to 40% of women will have some degree of alopecia. We’re not sure how well scalp cooling works with these ADCs. It’s a HER2-targeted agent, so we have to keep in mind cardiac function and LVEF monitoring.

And then a unique and fortunately rare toxicity, but one we need to acknowledge, is the risk of pneumonitis or ILD. So all-grade ILD, this was occurring about 16% of the time. In early studies some women died as a result of pneumonitis, and so we need to be very cautious. The forest plot here on the bottom right is showing some of the clinical features that might indicate a higher risk of ILD, and that can include multiple lines of prior chemotherapy. For some reason there seems to be an increased prevalence in the Japanese population as opposed to non-Japanese population. Folks who had underlying lung comorbidity seemed to have higher risk of ILD. So it’s something I certainly keep in the back of my mind when I’m thinking about drug choice in that second-line or later setting.

So I wanted to touch on the brain metastases issue, a big issue for patients with HER2-positive disease. Some series have said 30 to 50% of women with HER2-positive breast cancer can develop brain mets, and that has a significant impact on potential survival, loss of function, quality of life; really important to be talking about what social supports these patients have and proxy designation.

The TKI tucatinib showed significant benefit in overall survival when combined with capecitabine and trastuzumab, and about 50% of women in this randomized study had brain metastases, both treated and untreated. So significant benefit in overall survival, yet there’s a downside to an oral regimen with a big pill burden, and that was diarrhea with the TKI, significant Grade 3 diarrhea. So we need to be educating around prophylaxing and making sure our patients are staying really well hydrated.

There’s been pooled analysis to see how T-DXd works in patients who have breast cancer brain mets, and there’s suggestion of activity here. So this is across the DESTINY portfolio. You can see CNS advantage in terms of responses. We’re seeing that in terms of CNS progression-free survival, as well, for treated or untreated brain metastases.

And now we’ve got a trial, a prospective trial, DESTINY-Breast12, that looked at T-DXd in patients with HER2-positive brain mets. And also in this population you’re seeing a really nice response in the brain with T-DXd. So this is encouraging, and I don’t know that brain mets alone is a deciding factor for choosing a TKI over ADC when we have these sorts of data.

So in the last moment, how do I choose in the second-line setting? I think there’s some real pragmatic pros and cons to each of these regimens. For T-DXd there’s superiority there in PFS and OS in a randomized trial up against a typical standard of care, and we’ve got some suggestion of brain met benefit, and it has a really convenient once-every-3-week schedule. Downside is that ILD risk, the high alopecia concern, it’s intravenous therapy, and we really don’t know with prospective data how to sequence these agents. For the tucatinib, HER2CLIMB regimen, there’s impressive OS data there, whether you’re talking about a brain met population or all-comer population, but in terms of cons it is a large pill burden for patients to manage. There’s overlapping toxicity with both the tucatinib, as well as capecitabine, so when you think about polypharmacy and managing all of that it’s a bit challenging there, and the diarrhea is a real issue.

DR LOVE: I think you’ve got your case next.

DR TRAINA: Yeah.

DR LOVE: I was going to — before you get to the case, actually, I was going to ask Eddie, I just want to pick up on a couple of the slides that you showed, because you’re going to see slides like this, I’m sure you’ve seen them before, but just to clarify. Eddie, we see a lot of curves like the one up there right now, where you see 2 lines, and you can see one is the patient gets one treatment, and the other gets the other treatment. In this case it’s T-DXd versus the control arm.

And if you look at the side there, the higher it is the more the chance is the patient has not had progression. So the bigger the space between the 2 lines the greater the benefit. And you can see over on the right there there’s a huge difference, this is in patients with brain metastases, in the patients that got T-DXd versus — and these kind of lines are used to look at progression-free survival, overall survival.

And then the other slide — type of slide that you’re going to see a lot of is the so-called waterfall plot. If we can go to the last one there, that waterfall plot. And again, you’re going to see these all throughout this. Each one of these little sticks is a patient, and if it goes down, you can see there’s a zero going through the middle, if it goes down it means the tumor diameters, the tumor volume, is going down, and the farther it goes down you can see there’s a percent. If there’s no evidence of tumor it’s 100%, all the way on the right. Those individual patients, the tumor was not detectable. Others still had tumor but not as much.

And Eddie, when you see — regardless of the type of cancer, a lot of them, you don’t see necessarily every patient decreasing. This is a very favorable waterfall plot. Any comment about how oncologists look at these kinds of curves?

DR GARON: Sure. So the one thing I think that’s always a little hard is when laypeople look at the curves, they see those 100%, and they say the cancer is gone. The cancer radiographically is gone, but of course we know that these are not curative approaches. On the other hand, as you can imagine, these patients who have substantial reductions in the tumor are generally doing extremely well clinically.

And so I think the way we tend to look at this are (1) we look at how many people have a decrease overall, assuming that’s meaningful. You can see the bar listed that’s there, the dotted line at 30%. That’s a somewhat artificial line we use but one we use that defines whether we call in a clinical trial that someone has had a response or not. But in addition to looking at how many people go down we look at the depth of the response, and this is a very impressive depth of response.

Going back to the question with what we call the Kaplan-Meier curves, these curves that track how people do over time, we tend to view curves very differently. For instance, in the brain metastases example, when you have, for instance, a slight increase of all of the points to the right, where there’s a — it looks like perhaps — and if we can maybe go back to that slide, there’s — that maybe there’s a couple months difference throughout. But then there are times when you see a very large separation of the curves, and in those examples we really tend to think of the benefit as being particularly profound, and we get even more enthusiastic. Obviously, doing better and living longer and progressing at a longer timepoint is always helpful, but particularly if you’re having very substantial improvements overall amongst the patients participating in the trial.

DR LOVE: So we’re going to move on in a second. Marissa’s going to pick up on this situation, this theme in how we think through it and what we say to patients. But just curious, Tiffany. This is a very good example of what we just talked about. 69-year-old woman presents with metastatic disease, including to the brain, and is HER2-positive, you can see 3+, gets what Tiffany was talking about, chemo plus antibodies, but then has new brain lesions and eventually has actually lower extremity weakness, concerns in the spine. What happened when she got T-DXd?

DR TRAINA: She responded beautifully and actually cleared her cytology for leptomeningeal disease, which is really, I mean, I think above and beyond parenchymal brain metastases, a real area of unmet need. So we were able to continue therapy, dose reduce to manage some of the fatigue, and she continues to do beautifully.

And I want you to just note that date of diagnosis is 2015.

DR LOVE: Wow.

DR TRAINA: We’re talking about 10 years now having presented with de novo HER2-positive metastatic breast cancer.

DR LOVE: This is something we didn’t talk about a few years ago. We were talking about EGFR. We first started seeing it in targeted therapy in lung cancer, and people used to think brain mets, not good, and here you have a patient who’s gone 9 years. So it’s a different discussion with the patient now.

And we’ll get into this next with Marissa. I’m also curious what it’s like. One of the docs she works with I guess mainly is Dr Joyce O’Shaughnessy, like a 4'10", she’s been at this meeting before, a dynamo. I call her the encyclopedia of breast cancer. I can’t imagine what it’s like to work with her every day.

But anyhow, Marissa, I’m sure you’re going to share a lot of pearls about the use of antibody-drug conjugates in this situation, HER2-positive disease.

MS MARTI-SMITH: Yeah. So antibody-drug conjugates. So we’ll start first with T-DXd. So I’m a visual person. I love seeing pictures. So this, again, just kind of shows you how the antibody attaches, enters the cell. You’ll hear us say all of the keywords with the linker and the payload. It’s essentially a really cool way of saying that it enters the cell, kills the cell, and then there’s that bystander effect, where it’s doing cell kill-off around it. And I love explaining this to patients because it’s just so interesting on a cellular level how it works in comparison to our usual cytotoxic chemotherapy that I always say is just killing all the good and the bad cells.

So I use the analogy of a guided missile. I know the Trojan horse, I’ve heard that many a time, but to me a guided missile is easy to understand also. But essentially these cells are being targeted by a specific missile delivering that toxic payload to the cells directly, and then thankfully doing even that bystander kill-off around it. And like we had said with T-DXd, it’s that HER2-positive target, and the data on progression-free survival is wonderful. And I’ve seen this in my practice, patients really do so well and for the most part tolerate therapy extremely well.

So the downside is a little bit of the ILD monitoring, which we’ll talk about toxicities quite a bit today just so that everyone’s aware and well educated for both you and your patients. But in terms of ILD, I’ll cover that. So ILD essentially refers to the umbrella of inflammation and/or fibrosis in the lungs. For these patients you want to look at their baseline O2 sats, check their O2 sats when they’re coming in for their usual every 3-week visits. You should be doing a high-resolution CT chest every 12 weeks. In the research I read over the last week it says really for higher-risk patients you can do every 6 to 9 weeks. In our clinic we do 9 weeks on everyone. And you could consider ordering baseline pulmonary function tests.

And as Dr Traina said, with our higher-risk patients you should be super mindful if they have, for example, poor renal function. I saw a patient just yesterday that’s on dialysis 3 days a week. She’s on a lower dose of T-DXd, and it didn’t really hit me until later when I was re-reviewing all of this, that I should have been way more sensitive to how poor her renal function is. But we should always be aware of these really high-risk patients, especially those with decreased lung function at baseline.

This might be hard for you guys to see, but it is a great table as you’re looking at management of ILD. In the grand scheme of things Grade 1 is asymptomatic pneumonitis. It’s very clear how you manage these patients. You really hold therapy, you ideally treat them with oral steroids, 0.5 mg/kg of prednisone or equivalent, as soon as you suspect ILD or pneumonitis. And then you hold really until they resolve, and we always reimage them after about 3 to 4 weeks, before restarting, and depending on where they’re at you do dose reduce per the schedule.

If they are symptomatic, meaning they’re Grade 2 or higher, you permanently discontinue T-DXd. So that makes it pretty easy if you’re managing these patients. If they have any cough, shortness of breath, we always say a sniff of a cough, we hold therapy, and we scan them to make sure they don’t have ILD because there’s, in our clinic especially, a really low threshold for these patients, so we educate them a lot at the beginning to let them know the seriousness of ILD.

This is another table, again, that’s just helpful as you’re kind of learning the different grades. Corticosteroid treatment, imaging, and worsening if they are or are not improving with the therapy. It goes through grades 1 and 2, which, again, Grade 1 is when they’re asymptomatic. Grade 2 is when they have some symptoms, and you’re doing a little bit of a higher dose of prednisone. Grades 3 and 4, if you are in a hospital, those are the people that you’re seeing. If you’re in the outpatient setting those are the patients that you say you can head to the hospital. So for the most part I’m only really seeing Grade 1 and 2 that we’re managing in the clinic.

So this was my T-DXd patient case study that I thought of when we were reviewing all of this data. It’s a 74-year-old female. She’s on her fourth line, metastatic breast cancer to the bone. She does have a history of renal insufficiency. She got all the way to cycle 4, and we did her routine CT chest, and we happened to find ground-glass changes in the upper lobes. She was not having any symptoms. She was really tolerating it very well, with just a little bit of fatigue, some nausea. We put her on a prednisone taper, held her treatment for 3 to 4 weeks, reimaged her, and she totally resolved, so we restarted her at a little bit of a — the first dose reduction, the 4.4 mg/kg, and she stayed on it until cycle 21. So she got, to me, a good amount of time on T-DXd and really tolerated it very well.

DR LOVE: So we’re going to move on now and talk about another scenario, but just a comment. This algorithm, we’re going to go back through it because it’s so critical, because for example, T-DXd generally is very well tolerated, but it does have this unusual — or rare or uncommon complication that potentially can be even life threatening, so it’s really critical to implement the algorithm that Marissa just talked about.

And the thing that’s been interesting is now there’s an approval for T-DXd in any cancer that’s HER2-positive, so bladder cancer, lung cancer. Any time you see a patient in the clinic who has metastatic disease, particularly if they’re running out of options of standard therapy, should have a test for HER2. And if you don’t see it in the chart ask the physician about it because these people respond to HER2 — T-DXd specifically. And a lot of times a general oncologist who treats breast cancer, they know this algorithm, but now that it’s coming into GU and other tumors, they’re not as familiar with it, and so it’s always helpful to kind of bring this up.

Role of ADCs for Patients with ER-Positive mBC

DR LOVE: Okay. Let’s talk about another scenario in breast cancer where ADCs are used. Breast cancer, we think about HER2-positive disease, we talk about ER-positive disease, and then we talk about triple negative that doesn’t have HER2 or ER. We’re going to focus on a scenario — ER-positive disease, the most common type of breast cancer, tonight. We’re going to spend 2 hours just talking about ER-positive disease, mainly hormonal therapy, which has gotten incredibly interesting, but also a little bit complicated, but we’ll explain it tonight.

But after hormonal therapy is when people start thinking about chemotherapy and now ADCs. And so this is a scenario that’s pretty common in metastatic ER-positive, HER2-negative. HER2-positive is another subset. But we also talk about so-called HER2-low. This is a new thing since T-DXd came out.

What they found was that typically HER2-positive is on the test they do 3+. Then they started looking at patients who had 1+ and 2+. They had some HER2 but not as much, and the responses weren’t quite as frequent but still significant and very beneficial to patients. So now in ER-positive disease all of a sudden we had another consideration, where again, for patients who are already gone through usually a couple lines of hormonal therapy, they might have had the oral chemotherapy capecitabine. Typically, after that, if they’re so-called HER2-low, like this scenario, they often will get T-DXd. If they have progression beyond that they’ll get another ADC, sacituzumab govitecan, with a different target, TROP2. And now they’re about to start therapy with another ADC that was just approved in the last few months, datopotamab deruxtecan.

So we’re going to focus on this situation, really second line or third line, depending on how you look at it, let’s just say post endocrine therapy, and what the data are that a physician might think about and how they would integrate that into the treatment of this kind of patient. So Tiffany, take it away.

DR TRAINA: Great. Thank you. So it’s becoming increasingly complicated in the hormone receptor-positive space, and this is a good thing. We have multiple ADCs now. So you’ve heard a lot about T-DXd. As you look at the other two, we’ll talk about sacituzumab and Dato-DXd, they share features in that they’re target is something called TROP2. TROP2 is highly expressed in breast cancer cells, so we don’t need to test for it as a biomarker, in contrast to HER2, what you heard Dr Love describing, where you need to know the level of HER2 expression to know whether T-DXd is appropriate for your patient. These have different payloads, slightly different chemistry, but we’ll take a look.

I’ll let you refer to this slide when you have access to the deck because it tries to compare these side by side with their FDA label whether you need to test for the target, what their main tox is. And the punchline is we do not have sequencing data in prospective randomized trials, so this is a place where art of medicine is coming in, opinion is coming in, we have some retrospective data I’ll share with you, but it’s something we really look to ongoing studies to help answer for us.

A reminder that you heard in that particular case, that patient went through multiple lines of therapy before we even got to this discussion of ADCs, so please remember that is the standard of care for hormone receptor-positive breast cancer. We’re going to leverage all the other targets we find, all the other molecular opportunities here with new drugs that have been developed, but eventually endocrine resistance develops, and we need to move on to cytotoxic therapies, and that’s the story we’re going to be talking about in the next couple of minutes.

The HER2 definition has really been evolving. So it used to be 3+ is what we called positive, and then we had this shade of gray, the 1+, 2+, which we now define as HER2-low. There’s still some expression there, and it’s enough for T-DXd to bind to that target and have great benefit, and we’ll show you those data.

And there’s now even yet another lower bar in something called HER2-ultralow, where these are the tumors that used to be called zero because they didn’t meet the benchmark for the pathologist to call it 1+. But there was actually a little bit of HER2 staining there, and we now have trial data to say that that group can derive benefit, as well, from T-DXd.

So first we had DESTINY-Breast04. This is looking at T-DXd up against standard of care chemotherapies, and this was really remarkable. In this patient population that had HER2-low expression, 1+ or 2+, we saw a significant benefit here not just in PFS but in overall survival as well. But note that these were women who had seen at least 1 line of prior chemotherapy and at least a line of endocrine therapy for metastatic disease, so a great, powerful option that we have in our pocket to think about second line and later.

Safety is a concern, and I would ask you is the risk/benefit balance different as you’re thinking about these discussions with our patients, knowing they’ve been through years of simple endocrine therapies for the most part. Often they would have had capecitabine as an oral agent that kept them out living their lives with really an easily managed toxicity profile, to now take on an ADC, intravenous therapy, that potential risk of ILD, and some of the other toxicity we discussed already.

In DESTINY-Breast04 treatment discontinuation related to toxicity from T-DXd was upwards of 17%. There may be a learning curve here in us to learn how to manage those adverse events to make this sustainable for our patients.

So DESTINY-Breast06 now moved T-DXd up into testing it in the first-line setting, so that is a difference, first line, but it also included that ultralow population, right, and it was compared to standard of care chemotherapy, capecitabine or taxanes. And what you can see, the separation on those curves is looking pretty impressive. So PFS was prolonged over standard of care chemotherapy and even in that ultralow population, what we’re calling the 0+ tumor population, they also derived benefit from T-DXd over standard chemo.

So I would say how do we weigh safety and efficacy? We start to think about things like burden of disease, sites of disease. What’s that patient’s underlying risk of ILD? How frail are they? What’s their performance status? And then psychosocial and patient preference factors, like oral versus IV therapy, alopecia, the burdens of traveling to an infusion center for q3-week therapy. All of that comes into play when I think about am I going to use this in the first-line setting when I know I still have benefit there based on DESTINY-Breast04 in the second line or later.

We have other ADCs to talk about. So sacituzumab, the anti-TROP2 ADC, was compared to standard of care chemotherapy in patients who had seen a prior line of endocrine therapy and between 2 and 4 prior chemos. And sacituzumab was associated, as well, with significant progression-free survival benefit and also an overall survival benefit.

It's unique safety characteristics tend to be neutropenia and also diarrhea, so something quite different that we need to be aware of and manage.

And now we have Dato-DXd. So Dato-DXd is targeting TROP2, but it’s got that same payload that T-DXd has. And this randomized trial was up against standard of care chemotherapy. It was in patients that were no longer suitable for endocrine therapy, and they had seen 1 to 2 prior lines of chemo. And the efficacy data was compelling as well. So significant benefit here in progression-free survival. Dato-DXd is given intravenously once every 3 weeks. The OS data is immature. It’s a little too soon to know, but PFS was a win here.

And the safety profile is actually different than what we see with T-DXd. So much less reports of ILD. Here what we’re seeing more to manage is stomatitis, and so this can be mitigated with prophylactic steroid oral mouthwashes that have been recommended for our patients. And there needs to be an awareness of some ocular toxicity, and in the studies patients had ophthalmology monitoring. And if it’s going to manifest tends mostly to be dry eye.

So what about sequencing the ADCs? As I said, no randomized prospective data. We do have this retrospective look at sequencing saci then T-DXd or T-DXd then saci. And some of the takeaways is that whichever one you used first performed better. Some folks have debated whether there should be a sandwich approach, like putting chemo, plain old chemotherapy in between before you use the second ADC, and I don’t know that that’s necessarily any better or worse.

We really need to know what’s the mechanism of resistance to the first ADC because if it’s the payload then we would think about following up with a compound that’s got a different payload. But if it’s the target, and we’re lowering expression of that target, then maybe our second one should switch out a different target and can continue to use the same payload.

DR LOVE: I’ll just mention — maybe we can kind of just get onto your cases.

DR TRAINA: Yeah.

DR LOVE: But just to mention. This issue of sequencing, again, is going to come up in almost every meeting we do, particularly in metastatic disease of many different types, where patients will get sequential therapies. A lot of times it’s difficult to decide what’s going to be next? There’s often not a clinical trial that gives you that answer.

This is a theme you’re going to hear a lot about in patients with multiple prior therapies. ER-positive disease, like this 72-year-old lady, again, who got endocrine therapy, did well, then shows up with a seizure, has CNS mets and goes on T-DXd. We were just talking about brain mets in HER2-positive disease.

DR TRAINA: Right.

DR LOVE: Now we’re talking about ER-positive but HER2-low. So a little bit — but you see it’s HER2 2+ not 3+, so technically not HER2-positive but HER2-low. What happened on the T-DXd, Tiffany?

DR TRAINA: Yeah. So this is in collaboration with our neuro-oncologists knowing T-DXd has activity, including a population with leptomeningeal disease. Here it was the choice to use for her, and she has done quite well. We’re about 3 months in, and she’s tolerating it well and regaining function and strength, fortunately.

DR LOVE: I wanted to point out before, your other patient, I didn’t realize when I saw the slide, not only had brain mets but had leptomeningeal mets. Did she have cranial nerve issues? Because a lot of times these patients have cranial nerve palsies.

DR TRAINA: Yeah. Fortunately she didn’t. It was more —

DR LOVE: That’s incredible that she had a response.

And again, we’re going to talk more about T-DXd when we get to lung cancer. I want to let Marissa go through some of the issues related to what Tiffany was just talking about, particularly the issue of this new ADC, Dato-DXd, just approved. I make this joke that oncologists wake up in the morning and they check their phone to see what’s been approved, and then they start figuring out what to do about it. It happens so often. So Dato shows up, they’ve never used it, now you’ve got to look at the trials and figure out what to do. Marissa, tell us about it.

MS MARTI-SMITH: Yeah. So with Dato-DXd, as I’m thinking about it, as I explain to patients, I try to simplify everything unless they’re nurses or physicians or people that are scientists that are all about hearing all the things. But it is TROP2 directed. It is an antibody-drug conjugate. So this, again, explains the whole system of the derivative that’s the exatecan, and then the linker and how we, again, target these cells and ultimately we’re able to save these patients from having super systemic side effects because we’re targeting TROP2 directed.

So again I use the guided missile analogy. I’m explaining to patients more recently about ADCs because I feel like they need to understand that, again, just because there’s so many different therapies these days. Patients get overloaded and overwhelmed, and so I explain it to them as we had said before, where we’re really targeting those TROP2 cells. I don’t really explain TROP2 to patients, but again, if they are interested I will. But it does really help them to understand what we’re doing, and understanding that TROP2 is expressed at a lower level in normal epithelial cells helps you kind of understand why the side effect profile is a little bit more, which we’ll go into.

So the Dato-DXd side effects, like Dr Traina was saying, we do see a fair amount of stomatitis, but we try to prevent the most that we can. We see some dry eyes, keratitis. They can still have some low blood counts, definitely fatigue, which I feel like is always at the top of our list with therapies, so it’s not necessarily new, some GI toxicities, especially with nausea. They can get decreased calcium levels, some alopecia, of course rash, and some pneumonitis, some ILD risk, and some elevation in their LFTs.

So my patient case is pretty interesting for Dato-DXd. So I have a 68-year-old female. She actually got on this therapy first line in the metastatic breast cancer. She’s triple negative. She had 4 lesions on her liver, pretty extensive lymphatic spread and disease in her breast as well.

She got put on the BEGONIA trial. It’s been, I think, almost, yeah, almost 3 years ago. She started the trial with durvalumab plus Dato-DXd IV every 3 weeks. Overall she really had pretty manageable side effects. She had fatigue. She had mouth sores and some dry mouth, poor appetite, and she did have some watery eyes.

At cycle 7 we did have to dose reduce her Dato-DXd because her mucositis was pretty bothersome, and she was losing quite a bit of weight. So we did dose reduce her to 4 mg/kg. She actually started the full dose of 6 mg/kg. And then at cycle 18 we actually had to start holding her durvalumab because she had worsening inflammatory arthritis symptoms. I didn’t realize until I started looking at this case that actually back in the day, 2009, she had had, not rheumatoid arthritis diagnosis, but pretty significant arthritis in her hands and was on methotrexate.

So anyways, long story short, she’s had durvalumab held since then. She did about a year of it, and so she’s just continued on the Dato-DXd for the last really 3 years, and she just recently got her cycle 50. So she’s had stability, really NED for the last 3 years. And when she was diagnosed really thought this is a death sentence. There’s no way I’m ever going to live to see a year or 2 years and actually had a really close loved one get diagnosed with metastatic renal cancer in the middle of her treatment and pass away just recently. So it’s been such a hard time celebrating her success on this trial when she lost someone that was so sick to cancer kind of in the middle of it. But she’s done really amazingly well on this therapy.

DR LOVE: And another point I think this case makes is the potential benefit to patients participating in clinical trials. We always think about the new generations of patients who will benefit when these patients participate, but the patients themselves in the trial can benefit as well. This woman got a therapy using immunotherapy plus Dato and really had a much better response than you would typically see in just the Dato alone. Don’t think that Dato does this in all patients, this is an incredible response, but this patient benefited by actually being part of the trial.

I want to just bring up — we talked a little bit about this other antibody-drug conjugate very commonly used in metastatic breast cancer, again ER-positive, also triple negative. Tiffany, just a word about the common toxicity of sacituzumab, diarrhea and also neutropenia. How often do you see these problems, and what do you do about it?

DR TRAINA: Yeah. I think diarrhea is one that we educate our patients about right out of the gate because that is relatively common. And so I’ll usually be prescribing and recommending loperamide in the house right at the get-go. Folks sometimes will modify their diet, they’ll have some insensitivities, but that can be managed.

The neutropenia is the other real clinically relevant issue that we’ve had, where sometimes we’ll use long-acting growth factor on day 8 so that it helps carry them through the cycle, it’s a 2 week on, 1 week off cycle, as opposed to having to use the short-acting growth factor. And dose reductions is always a potential strategy. Oftentimes I’ll make sure I’m maximizing my supportive care before then just reducing the dose, and that can help mitigate both of these issues.

T-DXd in Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC) with HER2 Alterations

DR LOVE: So we’re going to move on now and talk about lung cancer. I was just flashing on the fact a couple years ago ONS was at Anaheim, Eddie, and it was the week after Coachella, and I was saying this is our version of Coachella. You’re going to see 44 speakers and hear 88 songs here today — in the next few days, so we’re going to flip over to our next 2 speakers talking about lung cancer and maybe compare and contrast what you hear to what you just heard about breast cancer.

So we’re going to start out with a patient who presents with metastatic non-small cell lung cancer, a huge topic in and of itself, but often guided by what I talked about earlier, genetic analysis of the tumor. We take the tumor, we send it for special testing, and then we’ll say oh, there’s a mutation in EGFR, and they’ll get, we’ll talk about that in a second, a drug like osimertinib.

But we’ve been talking about HER2-positive cancer, but there’s also HER2-mutant. HER2-positive is overexpression. The receptor’s not mutated, but it’s overexpressed. But there’s also HER2-mutant cancer, and to me, weirdly for some reason, that’s very common in lung cancer. Maybe it has something to do with smoking, I don’t know, but you see HER2-mutant disease. You also can see HER2-overexpressing disease, which we just talked about, and there’s already an approval for T-DXd, but also T-DXd is used with HER2-mutant disease and seems to be just as effective.

So again, Eddie, you have a patient with non-small cell lung cancer, typically a nonsquamous cancer, and they have a HER2 mutation with metastatic disease. Can you talk a little bit about what the trial showed that leads you to consider an antibody-drug conjugate?

DR GARON: Sure. Well, thank you. So again, I’ll be addressing the role of antibody-drug conjugates in lung cancer for HER2, and really this is trastuzumab deruxtecan as this is the only approved issue here.

This is a patient case. This is a woman in her early 60s, no smoking history. That is typical of patients who present with HER2 mutations. The patient presented when chest x-ray, which was obtained for work, ended up showing masses. So the patient was feeling clinically quite well, but the scans demonstrated bilateral lung lesions, including actually 3 large masses over 4 cm apiece.

Biopsy was obtained, as is also typically the case, the histology was adenocarcinoma, and this patient had a mutation in exon 20 of ERBB2, also known as HER2/neu, and this was a duplication mutation. That is, again, fairly typical of what is seen in HER2-mutant lung cancer.

So I always think that for people who don’t do this a lot this can be very confusing. So in breast cancer, as we talked about, mainly what is looked at is the HER2 amplification that is seen. But in lung cancer we have typically looked at HER2 mutations. Amplification just means there are more copies of the DNA, whereas a mutation means that there’s an abnormality in the DNA. I guess one can rarely see the mutation in breast cancer, but what we typically see in breast cancer is amplification. In lung cancer it tends to be mutations, and it is seen in about 2% of cases.

HER2 amplification, this is the bottom bullet point here, which are common in breast cancer, are relatively uncommon in lung cancer, making up nearly 1% of non-small cell lung cancer. And this is a little bit hard to see, but this goes through HER2 staining across a bunch of different malignancies, and what you can see is that somewhere around — maybe around 3% of lung cancer has 3+ HER2 staining, and as we’ll talk about, that is also an indication for trastuzumab deruxtecan.

One thing that I also think for a group of people who has a general oncology practice, they may say well, these are pretty small percentages, why is this of interest at all? And the answer is even a lot percentage of a large number can be a large number. And so when we have lung cancer, which unfortunately is a very common disease, somewhere on the order of 200,000 cases per year in the United States, when you add up all of these things it ends up being a number that is similar to some of the fairly common malignancies we treat in terms of HER2-driven non-small cell lung cancer.

So the original approval for trastuzumab deruxtecan, which is still the only approved antibody-drug conjugate in non-small cell lung cancer, was in this HER2 mutation-positive disease. Again, this is the only drug approved now. There are the 2 indications. We’ll talk about the other in a moment. But again, these waterfall plots, where you see very substantial reduction in tumor burden, this was in patients who were previously treated, and this is the current indication for trastuzumab deruxtecan, previously treated patients with HER2 mutant-positive disease.

And I’m not going to belabor it, but at the bottom you see all of these small boxes. What that’s referring to are different molecular abnormalities that are seen in HER2 mutation-positive tumors. And what you can see is that really there was effectiveness that was seen across different observations with relation to the pathology.

One thing that was a little unique in that study, the dose that was used for trastuzumab deruxtecan was higher than what is used in breast cancer. DESTINY-Lung02 is really a bridging study to show that if you looked at the more typically used drug, the 5.4 mg/kg, versus the 6.4 mg/kg, the results were essentially identical, and the 5.4 mg toxicity profile was considerably better. So the approved dose of the two, of both lung cancer and breast cancer, is the same.

As I mentioned, there’s also an approval based on patients who are 3+ for HER2. You can see this, again, is a waterfall plot. There are a lot less lines on this because the number of patients is relatively low. This is 36 patients, and they were testing HER2 3+ and 2+. You can see the approval is actually in the 3+, which is the dark blue lines, and you can see that the results looked impressive. They were also impressive for how long patients did well. However, of note, this is in a very small number of patients, and this was part of an approval across the board for patients with solid tumors who have HER2 expression of 3+ or greater.

And as I mentioned, approximately a year ago there was an approval granted for this group of patients who had HER2-positive IHC 3+.

So again, the objective response rate was very high, over 50%, duration of response exceeded a year, with the caveat that the number of patients is quite low.

So just to sum up what happened in the case that I presented. As is standard, the patient was initially presented with chemoimmunotherapy. She did well, progressed after approximately a year and a half, then was switched to trastuzumab deruxtecan and tolerated it quite well. Again progressed after a year and a half and then actually went on a clinical trial of a tyrosine kinase inhibitor, a pill, and there are now pills that are being developed particularly for these HER2-mutant cases.

So the conclusions, and I’ll sum up there, are that although there’s no molecular abnormality with high prevalence, when you combine them it is of reasonable prevalence, HER2-driven non-small cell lung cancer. Trastuzumab deruxtecan is the only approved agent for these, although there are oral inhibitors in development, and the molecular findings in lung cancer do differ quite significantly from what’s seen in breast cancer.

Thank you.

DR LOVE: So just to emphasize a point that Eddie made, again, I think that really goes across all of oncology, is the importance of identifying small subsets of patients, often based on biomarkers.

We were doing a program on breast cancer, Tiffany, and talking about the new data that came out on ER-positive, HER2-positive disease with CDK inhibitors. And people were saying well, HER2-positive, ER, that’s only 10% of breast cancer, and we were saying that’s more than all the patients who present with CLL that we talk about all the time. So these subsets of patients with common tumors are important to identify, and again, important to look at the chart. If they have lung cancer, have they had pan genetic testing, NGS testing that you see in all your patients? Every patient with metastatic lung cancer needs that in order to identify these abnormalities.

So Marianne, let’s talk a little bit about antibody-drug conjugates in lung cancer.

MS DAVIES: Great. Thank you.

So I’m going to introduce you to my patient, Joe. He’s a 62-year-old gentleman who has adult children, works in sales. He is pizza aficionado, and he came to New Haven for treatment, which New Haven is the pizza capital of the world, in case anybody wants to know. So he’s scoring Pepe’s Pizza here.

Anyway, the other interesting thing about him that we found out in his chart review is that — or in his family history was that he was a domestic bird owner and breeder.

So he was diagnosed incidentally with a HER2-mutant non-small cell lung cancer, and he was — again, it was incidental. He was getting worked up for his hypertension and for coronary artery disease.

So as has been pointed out, HER2-mutant non-small cell lung cancer is more common in females and never smokers and younger age. So he was a little bit older, he had a minor previous smoking history, and obviously male. But we still have to screen all of our patients, and I think that’s the most important thing. It does make up 2 to 4% of non-small cell lung cancer. And as Dr Garon said, you can have amplifications or overexpression, but he actually had the mutant HER2, which threw him for a loop because he just assumed hearing HER2 that this was a female disease, so that was a little confusing, and we had to really help explain that we see this across all different kinds of diseases.

I know that Marissa covered ILD, but one of the things I wanted to point out is that there’s a lot of different pillars for how we’re managing ILD. A lot of us have experience with managing ILD/pneumonitis with IO therapies, et cetera, but it’s important that we take into consideration all aspects of the management, and one key thing is really ruling out other potential causes of ILD. And that certainly came into play when it had to do with this patient being a previous bird owner — or not previous, he is a current bird owner, because there is actually a component of hypersensitivity reaction that people can get from being exposed to domesticated birds. And so that came into play when we were working him up for an early-stage Grade 1 pneumonitis later on his treatment.

So as Dr Garon said, trastuzumab deruxtecan is the only approved ADC in non-small cell lung cancer right now, and it is approved in the second-line setting after somebody’s had a prior line of treatment. However, this patient elected to go on — was offered and elected to go on a clinical trial with this.

So the side effects are very similar that you can see in breast cancer: diarrhea, neutropenia, thrombocytopenia, rash, interstitial lung disease. There’s also cardiac complications, such as myocarditis, that can occur, so it’s important that we are assessing patients’ left ventricular ejection fraction while they’re on the course of this therapy. We have obviously our younger patients, so reproductive considerations are something that we have to always keep in mind. In lung cancer I’m used to seeing most of my patients being older, but there are many that could still be of reproductive age.

So as far as cardiac toxicity, the overall incidence with trastuzumab is about 4.6%. A much smaller percent actually have more significant toxicities. But we do have to assess their LVEF prior to therapy and at least every 3 months while they’re on the treatment. And then there are certain treatment considerations, if there is a drop in their LVEF, based on the degree of the percentage drop. So there oftentimes can be dose reductions if we see that we’re tracking a reduction in that.

Nausea and vomiting, because of the chemotherapy component, is fairly significant. This drug has been classified as a very highly emetogenic regimen by NCCN and ONS, and so we’re very aggressive with our antiemetic regimen. So at least — not just in the acute setting, but also in the delayed onset of nausea/vomiting, so we’re very aggressive days 1 through 4, also with the addition of NK1 inhibitors, 5-HT3 antagonists.

Olanzapine has become something that we’ve introduced. And I can just say as a teaching point for our patients, it is approved as an antipsychotic drug for schizophrenia, and so I’m really careful when I write my prescription that I write for nausea/vomiting because patients might get that prescription or look it up and get all freaked out thinking what the heck are you giving me. So that can be really stressful. And the other part is that it has significant complications as far as somnolence and fatigue. And so if I’m looking at what’s causing the fatigue from the treatment, that’s one of the first things that I try to eliminate so that I can potentially keep the patient on their regimen. So other nonpharmacologic interventions, so that we’re all familiar, as far as dietary changes can be helpful for the nausea and vomiting as well.

Neutropenia management. We monitor blood counts very frequently, prior to each infusion. We do incorporate dose delays or dose reductions for patients that have Grade 3/4 toxicity, and then certainly consider growth factor initiation, especially for patients that have high-risk factors. This patient was on a clinical trial, but had they received prior chemotherapy they may have already kind of demonstrated that they’re at high risk for treatment-related neutropenia, so those might be a patient that I’m going to recommend that to.

In terms of patient education, remember, he’s a bird owner, and they carry a lot of parasites and bacteria, so we really had to instruct him to like alter his lifestyle in terms of that management on this treatment. Fatigue management. We’re very familiar with how we manage fatigue. But again, I mention that other drug interaction that could potentially contribute to the fatigue, which would be something that we would certainly pay attention to.

And then the alopecia. So it typically manifests as thinning. We could consider scalp cooling. We don’t traditionally use this in non-small cell lung cancer just because of the logistics of being able to offer it, but that is an option, but we want to rule out other causes, as well, as potential contributors, particularly thyroid dysfunction. And so really counseling patients on the fact that this can occur is really beneficial.

DR LOVE: I was just flashing on the fact that we view our programs to some extent also as a diversion for you. You’ve got lots of things on your mind, personal and professional. One thing we hope is we capture your attention. I was thinking about how I like to binge-watch on Netflix. Can you imagine watching all 11 of these at one time? Because they’re all going to be like this, the same thing.

Anyhow, just a couple quick questions before we go on to the next scenario. Eddie, this issue of being a nonsmoker that you mentioned. It’s more common with these mutations. I don’t know if we understand why. Any thoughts about why you see it in people who don’t smoke, and you see it earlier?

DR GARON: Yeah. So in general we think that it is going to be independent of whether or not one smokes, whereas obviously smoking is associated as a major causative factor of lung cancer.

And so in fact, some of these mutations that present at later ages, for instance there’s a mutation, MET exon 14 skipping, that tends to be seen in older patients. The smoking rates are significantly higher amongst that group of patients. But part of that is simply that the smoking rate in the United States peaked at around 40%, so there was a time when about 40% of all adults were active smokers. And so certainly if you are treating older patients the likelihood that they have been smokers in the past is higher.

But I think that you have to remember that you would miss a significant percentage of people if you only screened, for instance, your adenocarcinoma cases who are nonsmokers, because again, we don’t think that a nonsmoker necessarily any — we don’t think that a smoker is at less risk of developing HER2-mutant or EGFR-mutant non-small cell lung cancer, we just think that if you are taking a group of people who have already been diagnosed with lung cancer, those who have not been smokers are more likely to need some alternative explanation rather than the carcinogens of the cigarette smoke.

DR LOVE: Yeah. That was a really great point. Actually, it helped me understand it better right now. But you can see these mutations in smokers. There are just less smokers nowadays.

One other question, back to you, Marianne, whenever we talk about T-DXd, and we talk about it — we were talking about it a couple weeks ago at the Society of Gynecologic Oncology meeting. We did an entire program on that. When we get into this issues of interstitial lung disease, and we talk about all of the different cancers that it’s used for, everybody goes well, what about the smoker who gets T-DXd, which of course is much more common in lung cancer. Smokers have heart disease. They have chronic lung disease. They may already have abnormal chest x-rays. How do you deal with a patient who already has some kind of underlying problem, Marianne, in terms of picking up ILD from T-DXd.

MS DAVIES: So we try to make sure that we get really frequent and go back retrospectively to look at what their CT scans looked like, to look at the historical kind of trajectory of what their ILD was if they had it in the past so that we can have a better assessment if they do develop it in the future, because you look at those patterns of distribution, and absolutely collaborate with our pulmonologists to make sure that they’re doing an assessment so that when we do run — if we run into trouble with these drugs that we get them right into that pulmonologist so that we can help make that assessment.

Some of them might need a bronchoscopy, also, to kind of help weed out — I mean, in this patient that did develop a low-grade — again, low grade meaning that you didn’t have any symptoms, but we saw it on a CT scan — did have some ground-glass opacities. We needed to rule out — and we wound up just being a little cautious and holding off on steroid start, and he wound up clearing up by the next scan, so we were able to restart therapy on him. But if it did progress, then we would have had to stop the treatment.

DR LOVE: I mean, the lesson we learned from breast cancer is if the ILD is going to be diagnosed you want to pick it up when it’s asymptomatic. You don’t want to wait for the patient to come in and say I’m short of breath, or I’m coughing or whatever, and that’s why we’re very aggressive about imaging of the lungs.

Emerging Role of ADCs for Patients with Progressive EGFR-Mutant NSCLC

DR LOVE: Alright. So our final scenario. We’ve been talking about this issue, a very common type of treatment used in non-small cell lung cancer, targeted therapy. You mentioned EGFR, which we’re going to talk about right now, currently osimertinib is one drug. Amivantamab combined with lazertinib, another combination used in these patients in lung cancer.

But we’re going to say that this is a patient who has metastatic disease who has already gotten targeted therapy, and we know that once you get progression — and these people, a lot of times, Eddie, I guess the typical patient who gets osimertinib for metastatic disease might go, what, a year or 2 before they have progression?

DR GARON: Yeah. The median’s a year and a half.

DR LOVE: And then they have progressive disease. Whether or not targeted therapy works that well is kind of debatable. A lot of these patients in the past have gone on to chemotherapy second line, and now we’re starting to see the emergence of antibody-drug conjugates, and specifically what we’re going to talk about here is this new agent that was just approved in breast cancer, Dato-DXd.

Eddie, before we kind of get started, anything you want to say in general about what happens when these patients during first-line therapy, while they’re getting what commonly might be osimertinib, osimertinib with chemo or ami/lazer?

DR GARON: Yeah. So EGFR mutation-positive disease is going to be about 10% of lung cancer in the United States. In East Asia it can be up to 30 to 50%. I’d say that still predominantly most patients are receiving single-agent osimertinib, which is in most cases a very well-tolerated oral pill. And as you say, the middle person is on for approximately a year and a half.

There are a couple of intensification regimens that have been approved recently. One basically adds our standard front-line chemotherapy to osimertinib. The other takes a drug very similar to osimertinib called lazertinib and adds a monoclonal antibody against EGFR and MET. These have definitely improved the length that people are on therapy. This has caused some debate in the field.

The question becomes is it a good thing to have a less well-tolerated therapy for a longer period of time or not. And I think that there is some suggestion, and now some data indicating survival advantage of these alternate regimens. But also there are some caveats to that as to whether or not this is based on whether these agents would otherwise be available at later timepoints. So this ends up being a very long discussion that we end up having with our patients.

DR LOVE: So Marianne, I’m curious. What do you typically see during that year and a half or whatever period of time it’s going to be? A patient maybe, as Eddie said, commonly able to get osimertinib as a single agent. What do you see in terms of quality of life and toxicity?

MS DAVIES: Typically the patients that are on the single-agent osimertinib do quite well as far as quality of life. They have some epidermal kind of cutaneous side effects, such as rash, paronychia. Some have diarrhea, although it’s less than our first-line TKI for that EGFR inhibitor. So mostly a very good quality of life. It’s well tolerated. Maybe a little bit of nausea, occasionally a little bit of stomatitis, and maybe a little bit of fatigue. But these people just carry on their lives.

But most of them are educated enough to know, they’re kind of waiting for the ball to drop at that 1-year mark. They’re like alright, when am I going to see this? Because they’ve read the data or they’ve heard about it. And they’re like alright, when am I going to progress and what are my options? So we’re already beginning to look at that when we start to get to that point.

DR LOVE: So as I mentioned, here this week we’re really focusing on clinical scenarios. Here’s a scenario, a patient comes in, and they’re diagnosed with metastatic lung cancer. Terrible news for a patient. And yet they learn, well, you’re kind of in the fortunate subset. You don’t need chemotherapy. You’re going to be able to get this targeted therapy, but it’s much better tolerated, but it’s not likely to cure you, and it’s likely that you’re going to need more therapy in 1 or 2 years. Now they do have progression, are coming in.

Eddie, can you talk about how you kind of think through what to do next, what the clinical research is that you think about, and then how you individualize it to the patient.

DR GARON: Yeah. So in the first-line setting certainly we talked a little bit about what the options are. One of the things, even though, in the patients who do go into front-line single-agent osimertinib after initial — our initial enthusiasm about the targeted agents, I work very hard now not to disparage chemotherapy in the sense that chemotherapy does end up playing a role in these patients’ care. And so it’s not something I want them to ideally be terrified of.

I think that most of our patients currently, when they are progressing, are progressing on front-line single-agent osimertinib. And it’s also a bit of a complication because the patients have done quite well clinically.

And in fact, the case that I’m going to describe is a patient who’s in their mid to late 70s, and when I’m seeing her, she’s actually relocated to be closer to family because they’re worried. This is someone who actually has had a long history of EGFR mutation-positive non-small cell lung cancer, actually had been on gefitinib, which is one of our first-generation EGFR inhibitors, for several years, then progressed and went onto another oral therapy.

And that it’s really 8 years into her disease course, but now the easy stuff isn’t working anymore, so we need to make a decision, and our standard approach would have been platinum-based chemotherapy, but the patient is looking for other options. And we’ll talk about it later. She did end up going on datopotamab deruxtecan.

Just to preface the things I’m going to talk about, there are really 2 agents that we’re talking about here, that we’ll be talking about, datopotamab deruxtecan and patritumab deruxtecan. They have the same payload, so the chemotherapy portion is the same, they just have different antibodies. And so this is, again, we can go on to the — first the data on datopotamab deruxtecan.

So datopotamab deruxtecan is currently not approved in lung cancer, although it is being evaluated, and the data really comes largely from a couple of datasets. One is a study that I would argue overall was a somewhat disappointing study. Our standard second-line agent is docetaxel, and you can see that this was a second-line study that randomized people to datopotamab deruxtecan or docetaxel. But as part of this study they also allowed patients who had received prior chemotherapy to — if they had an EGFR mutation, to undergo the same randomization.

This is a little bit of an unusual study. We’ve shown you a lot of these Kaplan-Meier curves, where we show outcome over time. And what you see here is something that you haven’t really seen in a lot of these curves. In non-small cell lung cancer the 2 major histologies are squamous cell carcinoma or adenocarcinoma. Adenocarcinoma makes up the great majority of the nonsquamous subtype.

And what you can see here is you can see the docetaxel, which is listed in a bluish color, or more of a purplish, for the datopotamab deruxtecan. And you can see that how the 2 agents perform relatively to each other differs between the 2 histologies. So in squamous, if anything, it looks like the docetaxel was a better arm, whereas in the nonsquamous this was — it was better to receive datopotamab deruxtecan. And this is even more true in patients who had what we describe as actionable genomic alterations, which a large percentage of those are patients with EGFR mutations.

The overall survival from the study, this pooled squamous and nonsquamous patients, looked not particularly impressive. But as you can see, there certainly is a suggestion, on the boxed area on the bottom of this figure, of better outcomes in the patients who had actionable genomic alterations, again the most common of those being EGFR mutations.

There was also a study specifically evaluating patients with actionable genomic alterations. As you can see, again, over half of these patients had EGFR mutations, and that group did particularly well, with a response rate over 40%, and the median patient being on for nearly 6 months.

Here you can see the waterfall plot, I know we’ve discussed waterfall plots in the past, but showing that the great majority of people with actionable genomic alterations are deriving some shrinkage of their tumor from datopotamab deruxtecan. And maybe in the interest of time I’ll skip this, what we call the spider plot below, which just shows how things look radiographically on each set of scans.

Datopotamab deruxtecan, as I mentioned, is not currently approved but was granted priority review in the United States for patients with previously treated advanced EGFR-mutated non-small cell lung cancer. Priority review can be particularly helpful for a drug like datopotamab deruxtecan in that, as was mentioned, it is now an approved drug in breast cancer, so it is a drug that is available, and now the FDA will be able to presumably quickly determine whether or not to approve it specifically in EGFR-mutant non-small cell lung cancer.

As I mentioned, patritumab deruxtecan has the exact same payload, but rather than an antibody directed against TROP2, which we talked about earlier in this program, here there’s an antibody directed against HER3. So EGFR is HER1. It’s just another name for it. So these are basically all part of the HER family, where one sees dimerization and then signaling into the cell. And so for years there has been evaluation of the rule of HER3 in EGFR-mutant non-small cell lung cancer.

You can see here is the HERTHENA-Lung01 study. This was just treating patients with patritumab deruxtecan who had EGFR mutations. And again, you can see the impressive waterfall plots in this previously treated patient population, with most of the patients having some degree of shrinkage. Again, not to belabor the point, but you see a lot of different resistance mechanisms and clinical characteristics, noted in the small boxes at the bottom of this chart. And what you can see is there’s no clear pattern. Patients with all sorts of different features do appear to be deriving benefit from patritumab deruxtecan.

We haven’t gotten too much into this. Everyone has mentioned already that TROP2 is widely expressed in non-small cell lung cancer, breast cancer and other malignancies. But both TROP2 and HER2, people have tried to look at the levels as a predictor of response, and those have not worked.

Here you’re looking at these box plots, which again, not to get too detailed on it, but basically you’re showing here the amount of staining for HER3, and you’re tracking it. On the left you see the people with complete response or partial response — CR/PR — stable disease as D, progressive disease — PD — or nonevaluable. And you can see that the amount of HER3 staining doesn’t appear to be particularly relevant. And like Dr Traina mentioned in her case, where there was a patient with one of these antibody-drug conjugates who derived benefit for central nervous system disease, the same thing has been seen with patritumab deruxtecan.

And patritumab deruxtecan, we have a press release that now states that it demonstrated a statistically significant improvement in progression-free survival as compared to standard chemotherapy in patients with advanced EGFR-mutant non-small cell lung cancer. And of course we look forward to seeing that data.

So the conclusions for this section. The greater efficacy of datopotamab deruxtecan has really been particularly seen among patients whose tumors harbor EGFR mutation. Patritumab deruxtecan has also demonstrated efficacy among patients with EGFR mutations. Neither are currently approved, but we are enthusiastic about the potential that both of these will be approved in the near future. The toxicity profile, which I haven’t gotten much into, but there is a little bit of difference between the 2. You tend to get a little more mouth sores, for instance, with datopotamab deruxtecan, a little more cytopenias with patritumab deruxtecan. And as I mentioned, to date we really haven’t seen a clear association of the target of the antibody along with the effectiveness of the drug, but evaluation is ongoing.

DR LOVE: So just to clarify, in terms of looking for the target, with HER2 we need to look for it and see it. Many times we just use a drug because we know it works in most patients. It doesn’t seem to correlate with levels. TROP2 is an example. HER2 is a little bit different. So more to say on that, and we’ll get into this also as we get into other programs.

Just a reminder, tonight at 6 PM on the fourth floor Capital Ballroom we’ll talk about ER-positive breast cancer.

Marianne, let’s talk about the patient with progressive disease on targeted therapy for EGFR-mutant non-small cell lung cancer and where ADCs might fit in.

MS DAVIES: Okay, great. So this is Rose. She’s a 55-year-old, never smoker, married, adult children. Interestingly enough, her husband is an ophthalmologist, and this comes into play in terms of her treatment decision later on.

She does a lot of volunteer work. Here’s she’s made a ton of blankets for the newborn intensive care unit at the hospital.

Anyway, she was diagnosed a couple of years ago with EGFR-mutant non-small cell lung cancer, a very common point mutation that she had in exon 21. She was treated with 18 months of an EGFR inhibitor therapy and then had progression on her recent scans, and she was about to start treatment on Dato-DXd. This was on the clinical trial because, as Dr Garon said, this is not approved at this particular time.

So some of the unique side effects. We do see the nausea. We do see an increase in stomatitis and mucositis, inflammation of all grades, and the reason for that is because of the target, on TROP2, there’s a lot of expression on mucosal tissue, and so that’s why you see it more commonly than versus some of the other targeted therapies that we see.

It also has a unique ocular toxicity with keratitis, dry eyes, increased lacrimation, and also the ILD, as we’ve already talked about, and then the hematologic toxicities with neutropenia, pancytopenia and fever.

So we haven’t talked about ocular toxicities before, but we have to be mindful of this. It’s not something that we’re used to seeing in our patients, so we should be asking patients about their vision. They should have an ophthalmology assessment prior to starting treatment. And we need to be asking them about any eye irritation, any change in vision. When we look at our grading criteria, besides just symptomatic moderate decrease in visual acuity we specifically look at if they have a defect of 3-line loss.

And so basically you remember the old-fashioned Snellen charts that you all look at when you go to the eye doctor, and 20/20 is perfect, and as you move the line — so it would be basically 20/40 would be the level of change that you would see, that’s a 3-line loss of visual acuity. So patients should be assessed for that intermittently when they’re on the therapy, especially if they do report any particularly eye irritations.

Other things that we can do is tell them to avoid contact lens use, use lubricating eyedrops. For some of the other ADCs that have been in use across some of the other diagnoses, there is recommendations for prophylactic steroid use or lubricants or vasoconstrictive drugs. Those are not incorporated into the Dato recommendations at this time, but that may be in the future, so that’s something we keep in the back of our minds. Also things like cooling packs during infusions may decrease some irritation, so kind of eye icepacks.

The stomatitis/mucositis. If we’re making decisions about whether we’re going to continue treatment on the Dato our guidelines are that we maintain our current dosing if they have a Grade 1 toxicity, consider dose delay or dose reduction at Grade 2, and definitely dose delay if they’re Grade 3 until they resolve to a Grade 1 or completely resolved. And then with Grade 4 toxicity for the stomatitis/mucositis we permanently discontinue. Some strategies that we can incorporate for patients is really educating them on the importance of oral hygiene, hydration, lubrication of the oral mucosa, in some cases recommending a steroid-containing mouthwash, so 4 times a day, swish and swallow. Some examples of that are a dexamethasone mouth rinse.

For pain some strategies we can use if they do develop it are things like doxepin or viscous lidocaine rinses. Some people are using cryotherapy, a fancy word for using ice chips during their infusions to see if that helps to minimize it. So those are just some of the management strategies.

For ILD, we’ve talked about this a bit. So some of the risk factors that we assess for are do they have prior ILD exposure? Is their ECOG performance status poor? Do they have a smoking history? Pre-existing lung disease? We do know that our patients with non-small cell lung cancer are at higher risk due to underlying pre-existing lung pathology and higher rates of smoking. And the thing we have to keep in mind is for patients that have received a prior EGFR TKI some of those TKI-EGFR inhibitors do also have an association of ILD with that. So we want to make sure we’re screening for that prior to moving on to this therapy.

So a very standard management strategy that Marissa’s already gone over. We’re monitoring our patients. We’re going to hold therapy if they are at a Grade 1; consider the length of time it takes them to resolve on their scans. Again, Grade 1 is asymptomatic. So once it is resolved, it it’s within a certain period of time we can reintroduce the treatment at the same dosing, but if it takes longer to resolve, then we would do it — introduce the drug at a dose reduction.

I just want to take a second just to point out that this chart is different than how we manage pneumonitis from immune checkpoint inhibitor therapy, because we’re hearing so much about ILD with all of our treatment regimens now, that there are very different kind of grading algorithms that we’re using. In IO therapy, as I’m sure you’re familiar, we do not do dose reductions. And so there’s just a different strategy, so you just have to really know the drug category your patients being treated with to help guide the management strategy.

DR LOVE: Just a couple quick follow-up questions. Tiffany, it was interesting, when Dato-DXd came out it was interesting to see the reaction of the lung cancer community to mucositis, because that was something they really hadn’t dealt with. They’re like what do we do? Because at the same time it was coming out in breast cancer. They’re like, oh yeah, we’ve dealt with this before, everolimus, et cetera. What’s your experience with mucositis with Dato-DXd? And is it able to be prevented as effectively, as it is with these other situations, with prophylactic mouthwash?

DR TRAINA: Absolutely. Prophylactic mouthwash is super, super helpful, and in my patients on study who started to experience more of the stomatitis we just had to confirm are you really using that mouthwash as frequently as was prescribed. And if they kind of upped that again it really could mitigate that. Also some cryotherapy, sucking on ice pops during infusion. That also seemed to help mitigate it.

DR LOVE: Cryotherapy. I like that.

DR TRAINA: Yup.

DR LOVE: Ice chips. Cool. Alright. We’re coming back tonight at 6. Thanks so much to the faculty.