Maximizing Efficacy and Minimizing Toxicities With Antibody–Drug Conjugates in Breast Cancer

I am going to be presenting on maximizing efficacy and minimizing toxicities with antibody–drug conjugates in breast cancer.

[00:05:23]

Structure of ADCs

First of all, we are going to look at the structure of the antibody–drug conjugate. This is a familiar topic, I am sure, to several of you, as ADCs are being used in several different types of cancer now. The 3 main components are, first, starting off with our antibody. That is the large monoclonal antibody represented by our "Y" here. This targets tumor-specific or tumor-associated antigens. The antigen, of course, is abundant on the tumor tissues, and it is minimal on normal tissues. So our antibody is going to be the vehicle that allows the payload, or the chemotherapy attached to the antibody, to get directly to that tumor cell.

Now, some of the things that are going to determine toxicity or maybe how you manage symptoms or what to expect is really looking at these different parts of the ADC. So our linker is really key because our linker is attaching that chemotherapy payload to the monoclonal antibody. And so that linker has to be stable in plasma.

You want it getting to the specific site vs just releasing it into the plasma like chemotherapies do when we tend to refer to ADCs as more targeted therapy. So it is important that that linker is stable in plasma. And then once it is engulfed in the cell, you can have a cleavable or noncleavable linker.

And cleavable means it just releases more quickly or more easily off the monoclonal antibody. And that can then cause more activity, more of that bystander effect that we will talk about later. Whereas noncleavable means that that payload is really kind of held on to the monoclonal antibody, and there is less toxicity associated with noncleavable linkers.

And then, of course, you have your payload. And so this is a cytotoxic drug. It tends to be more potent than some of our small molecule chemotherapies, which is why we can use some of these again in this setting because it is being directly brought to the tumor cell vs a systemic release with a ton of toxicities.

[00:07:54]

ADC Mechanisms of Action and Toxicity

So here is another visual aid for you thinking about that mechanism of action and the potential for toxicity. Here we have that antibody–drug conjugate, our ADC, going for that targeted antigen that is on our tumor cell. Once it binds, that ADC is engulfed into that tumor cell.

And then at that point, depending on the linker, whether it is cleavable or noncleavable, if it is a cleavable linker, again, that payload is being released, there is membrane permeability, and then you have what is known as the bystander effect, where other tumor cells surrounding that area are also impacted and can be targeted and destroyed as well.

[00:08:42]

Factors Influencing the Toxicity of ADCs

So I like this as a visual aid. Again, there are many different ways of learning. So let me just walk us through this a little bit to really drive home the mechanism of action and the potential for toxicity depending on the components of that ADC.

At the top, when we are looking at that antibody, we have our on-target toxicities and we have our off-target toxicities that tend to be more immune-related. But for our on-target toxicities, there are some fairly stable things that we can expect.

For HER2, we are looking at cardiotoxicities. HER3, thrombocytopenia. And for our TROP-2, we are looking at rash, mucositis.

And again, our payloads. So on the bottom left, you can also see it is talking about the drugs, but it is also giving you this nice graph of toxicity. So on the far-left side of that, we are looking at the T-DM1 or DM1, which is one of the payloads that is very stable, tends to be less toxic, and is known as T-DM1. It is a HER2-targeted therapy.

But then, as we move to the right in that box, we can see now we are looking at some of our other drugs, DXd and SG, that is sacituzumab govitecan. We can call it SG. I probably should have told you that first, Amy. Sorry. And now these drugs are starting to have more toxicity. And we are also looking at a higher drug-to-antibody ratio. So that also makes a difference when we are thinking about toxicities.

Heading over to the linker box, again, talked about that cleavable and noncleavable. So the noncleavable ADC is that T-DM1. It is very stable. It has lower toxicities. But as we move into those linkers that are cleavable, where there is more of a release once it hits that cell, we are looking at increased toxicity. So our drug-to-antibody ratio makes a difference as far as toxicity, as well as that cleavable linker also can cause increased toxicity, creating that bystander effect.

[00:11:08]

ADC Indications in Breast Cancer

Of course, when we are thinking about what we are going to prescribe for our patient next, what sort of education we are going to need to provide, how can we prepare our patients, we too need to understand what the indication is. What can we give first? Sequencing is still the big question that is always a challenge. And we do not have a lot of head-to-head studies comparing ADC to ADC.

We have a lot of great options, and we have several indications. For instance, our T-DXd, when we are looking at breast cancer, is specifically approved for HER2+ breast cancer, as well as HR+/HER2-low or ultralow. And now those patients will need to have received endocrine therapy, at least one in the metastatic setting, in order to qualify.

I am not going to talk about trastuzumab emtansine. It is our T-DM1. It is still a very useful therapy and is still commonly used, but has taken a back burner some of these other ADCs.

So sacituzumab govitecan is a TROP-2–directed ADC, and it is given by infusion on Day 1 and Day 8 of a 21-day cycle. And it has been indicated for triple-negative breast cancer metastatic. It has also now been indicated for our HR+/HER2- as well, who have previously received endocrine therapy in the metastatic setting, as well as some other additional therapies in the metastatic setting.

And Dato-DXd is also a TROP-2–directed antibody–drug conjugate, and it is given IV every 3 weeks. In this situation, it has now been approved for HR+/HER2- metastatic breast cancer, who have received prior endocrine therapy and chemotherapy in the metastatic setting.

So you can see there are a couple of therapies here that have all been indicated for second-line or beyond in the metastatic setting. And like I said, that sequencing is always something to consider and discuss with your patient as well when we are talking about the toxicities and what to help prepare them for.

[00:13:31]

Treatment Algorithm for mBC

This is another algorithm to, again, drive this point home of how we think about therapies. And this is not complete because the Dato-DXd, the datopotamab deruxtecan information has not been added to this slide yet.

But again, it gives you just kind of a nice visual algorithm. If you are HR+, your first-line therapy is at the top, doing a lot of your endocrine therapies or your targeted therapies for other mutations. Then moving into, well, are they HER2-low? Are they HER2-ultralow? Do they qualify for T-DXd? And then again, in that setting, HR+/HER2-, sacituzumab govitecan is also appropriate.

Several treatment options for our HER2+ breast cancer patients metastatic setting are Herceptin's Perjeta, moving on to T-DXd, and several other lines of therapy that we can choose from.

In our HR-, typically we are looking at, do they have a BRCA mutation? Pembrolizumab is now being used commonly in that first-line setting. And then looking into assessing whether they are HER2-low or ultralow and can get T-DXd or SG or Dato, depending on the indication.

[00:15:00]

Trastuzumab Deruxtecan: HER2-Targeted ADC

So let us look at trastuzumab deruxtecan quickly. I just want to point out a few things here about this ADC.

So here we are looking at an 8:1 drug-to-antibody ratio. So quite an abundant amount of that payload on a single antibody. It also has a cleavable linker. So based on some of the things that we have learned here, we can anticipate some higher toxicities, some needing to really manage and minimize some of the toxicities due to this high drug-to-antibody ratio, as well as the cleavable linker that is causing some potential bystander effect as well.

And you can see here how many other settings, cancer settings it has been approved in.

[00:15:50]

TROP-2 Overexpression in Solid Tumors

For our TROP-2 overexpression, this shows you how many different types of cancer actually have TROP-2 overexpressed. We are going to be focusing on breast today, and you can see several patients with breast cancer and triple-negative breast cancer have TROP-2 overexpression.

[00:16:12]

Sacituzumab Govitecan: First-in-Class TROP-2–Targeted ADC

So our first-in-class TROP-2–targeted ADC is sacituzumab govitecan or SG. Again, just kind of looking at some of the key components of this ADC. The payload is similar to irinotecan. So thinking of that, if you have used that before in the past, we know that we are looking at some diarrhea, some neutropenia, maybe some skin issues as well. And again, because it is that monoclonal antibody and being delivered directly to the cell, that does make it more tolerable, I would say, than just someone receiving irinotecan. But we still are going to have some side effects that we need to educate our patient about and be prepared to manage.

We are also looking at another high drug-to-antibody ratio of 7.6:1 and, as well as, that cleavable linker.

So down at the bottom of the slide, you can see here that that bystander effect is something to educate our patients about as well. And just for our own edification, to be aware of this and know we are going to have to manage side effects.

[00:17:24]

Datopotamab Deruxtecan (DS-1062; Dato-DXd): TROP-2‒Directed ADC

Now, the newest member of the ADCs is datopotamab deruxtecan. It also is a TROP-2–directed antibody–drug conjugate.

Looking over onto the right side of the slide at that box about the Dato-DXd, we are seeing here that it has a deruxtecan payload, that there is a cleavable linker. So we are looking at some of that bystander effect. But the drug-to-antibody ratio for Dato-DXd is 4:1. So a slightly lower drug-to-antibody ratio than the other ADCs. We have seen that this can be more tolerable as far as toxicity goes, but it has some unique side effects that we will review. But definitely, when we are looking at all the ADCs, even though we have not done head-to-head studies, I would say that this has the potential to be less toxic than the other ADCs.

[00:18:24]

Administration Considerations for Approved ADCs

Again, thinking about the considerations for prescribing this medication to our patient. We need to know these things in advance. We need to inform our patients about these things as well.

So some of the unique things about sacituzumab govitecan is we pay attention to our premeds. We are seeing here a lot of antiemetics. So we know we are going to have to deal with nausea. We are also looking at atropine if it is not contraindicated. There is a potential for severe diarrhea and severe neutropenia on SG. That should start you thinking about how am I going to manage diarrhea? How am I going to educate my patient? What about neutropenia? What about risk for infection?

So these are some of the things that come to my mind when I am thinking about someone starting on SG, as well as some infusion-related reactions. Occasionally there is while they are getting treatment, an immediate reaction, or a post reaction as well, which we will review.

And for our Dato-DXd, again here when we are looking at premeds, we will talk a little bit more about the dexamethasone mouthwash, as well as the lubricating eye drops. But these are 2 of the more interesting, more specific for Dato, as are the dose-limiting toxicities of the stomatitis or ocular toxicity. So we have been in our practice, when we have our premeds that we are releasing for the patient, not only do we have our antiemetics for the day of infusion, but we also send people home with a steroid-based mouth rinse, as well as lubricating eye drops. And we will talk a little bit more about that.

Here we are looking at a risk of ILD. Again, we are looking at that payload as being the deruxtecan. So in that situation, we are seeing some ILD or some pneumonitis issues, but the infusion-related reactions here are low. And as I had mentioned before, there are some interesting toxicities to manage with Dato, but they tend to be manageable.

And for our T-DXd, again, several indications. Antiemetics, really key. This has a high hematogenic potential, so lots of nausea to really help our patients manage upfront. What is nice about this is that the nausea tends to decrease over time. So that is a benefit, but more immediately, within the first few months, we need to help our patients manage nausea. And again, that risk for ILD, constantly doing pulmonary checks on patients and screening for ILD as well.

Patient Case Workshop

[00:21:22]

So let us move on to our first patient case discussion for T-DXd.

[00:21:29]

Case Discussion 1: T-DXd Patient Case

We have a 58-year-old woman who was diagnosed with early-stage ER+/PgR+/HER2+ breast cancer in 2019.

She completed her neoadjuvant TCHP standard of care followed by mastectomy, sentinel lymph node biopsy, radiation, adjuvant HP, and an aromatase inhibitor. Two years after completing surgery, she was hospitalized for headaches and found to have HER2+ left cerebral metastases. She proceeded with resection and radiation and started T-DM1.

Repeat staging scans revealed systemic and brain disease progression, and she completed SRS and started T-DXd in January of 2024. Nausea was managed with triple antiemetic with olanzapine being added, and fatigue became severe, limiting ADLs, and the T-DXd dose was reduced.

[00:22:30]

Case Discussion 1: Routine staging scan revealed increasing small patchy densities mostly in the upper lungs suspicious for pneumonitis. What is your initial management based on this finding?

Amy Goodrich: So case discussion one. So routine staging scan revealed increasing small patchy densities, mostly in the upper lung, suspicious for pneumonitis. So what is your initial management based on this finding?

1. Are you going to prescribe oxygen and an inhaler?
2. Are you going to call the patient to assess symptoms and hold their T-DXd?
3. Are you going to proceed with her scheduled T-DXd?
4. Are you going to prescribe a steroid taper?
5. Both B and C?

Which are you thinking here?

And B seems to be the winning answer, so we will see if that is the correct answer.

And Kim, take it away.

Kimberly Podsada: Thank you. So for that, we can discuss that, but let me just kind of move into maybe some of the AEs that we are looking at, but that was the correct answer.

[00:23:44]

Common AEs Associated With ADCs

So when we are looking at T-DXd, some of the key AEs here are the ILD and the pneumonitis, and we will talk about how to manage that. But again, the nausea is really significant, so we have to stay on top of that, as well as abnormal labs.

Now, just kind of briefly reviewing SG and Dato, it is important to point out that the majority of these ADCs do have some amount of nausea that we are going to have to help our patients manage, as well as have a lot of premeds upfront and PRN meds at home for our patients.

Some of the things with the SG that stand out to me is that neutropenia. So most significant is the neutropenia for SG, as well as diarrhea. And then for the Dato-DXd, we are looking at that stomatitis and ocular events.

[00:24:38]

Management of ILD/Pneumonitis by Severity

So for managing ILD or pneumonitis, it is important to understand grading. And I am sure many of us have learned grading, looking at our PI, trying to figure out, okay, this grade means I need to do this or that.

So for ILD, it is really straightforward. If they are asymptomatic, which is grade 1, you basically have just caught it on imaging. You are holding T-DXd, and you are going to wait until it resolves and they recover with no signs of ILD or pneumonitis. You can consider starting steroids, really depends on the situation and the individual, but you are basically just going to hold T-DXd. If it resolves less than 28 days, you can start at the same dose. If it takes longer than 28 days, then you are going to dose reduce. And that is for grade 1.

Any symptomatic, grade 2 and beyond, the ILD is permanently discontinuing, not rechallenging and immediately starting steroids to help resolve the ILD. Again, that is symptomatic, cough, shortness of breath, dyspnea on exertion, they are having a grade 2 or higher reaction, and T‑DXd is discontinued.

[00:25:56]

Detecting and Managing T-DXd–Related Interstitial Lung Disease: The 5 “S” Rules

So they have come up with this 5 "S" rule to kind of help us think about how to manage the ILD for someone. Now, these are all kind of happening at the same time.

Screening our patients, asking about their respiratory symptoms, doing our baseline scan and repeat scans. If we are ever concerned about symptoms, getting scans immediately, really using our multidisciplinary approach to help manage this, call our radiologists, make sure our radiologists know what we are looking for. So a thing to remember also when you are ordering scans is monitoring for ILD, they are on T-DXd or Dato-DXd, to help our radiologists know what we are looking for. Do we need to call our pulmonologists to get their help as well? So that synergy of that multidisciplinary approach is really important. And of course, holding treatment.

If it is a grade 2 or beyond, they are symptomatic, you are holding treatment, and then promptly initiating steroids. So all of this is happening at the same time.

[00:27:05]

Summary of AEs of Interest With T-DXd From Key Phase III Breast Cancer Trials

And then looking at some of the Phase III breast cancer clinical trials with T-DXd, we have 3 main ones here.

And what I really want to point out is that there was no new safety signal seen with all different trials here. We understand that nausea is going to be something we need to manage. And so it is very common. We need to do our primary prophylaxis. It is classified as a high emetic potential. And we see that throughout all 3 of these trials.

Diarrhea was observed approximately in one-third of patients, but it was really rarely grade 2 or more. And that grade 3 neutropenia, again, not significant compared to maybe other ADCs, but still something we need to pay attention to and be prepared for intervention. And febrile neutropenia was very rare.

[00:28:02]

ASCO Antiemetic Guidelines Update 2020

So looking at our ASCO guidelines for managing nausea, I think most are now pretty familiar with the 3-drug regimen. We often now are adding in olanzapine as well to send home for patients to start that night of chemo and then to do pretty much nightly for 4-7 nights, depending on the provider. So that seems to have helped with a lot of the nausea, especially with our chemotherapies, our ADCs that have that high emetic risk.

Down below, you can see what some of the 5-HT3 receptor agonist recommendations are, as well as our NK1 receptor antagonist too. And then for our moderate emetic risk, I think many of you probably are familiar with this, and now it is already embedded in our treatment plans, but you do want to make sure that your patients have as-needed antiemetics at home with them and that you are giving them a plan and a description on how to use what and when to use it as well.

[00:29:10]

Case Discussion 2: Dato-DXd Patient Case

So looking at our next patient case for Dato-DXd, a 72-year-old woman was diagnosed with recurrent metastatic ER+/HER2- (IHC 2+) breast cancer with disease in the right axilla in May of 2018.

She received multiple lines of therapy, fulvestrant + ribociclib, paclitaxel, eribulin, everolimus, capecitabine, T-DXd, fulvestrant and capivasertib, but discontinued due to severe skin SJS-like reactions and stomatitis. So carboplatin/gemcitabine was started, but eventually dropped the carboplatin, added in pembrolizumab.

So she is currently on sacituzumab govitecan with disease progression.

Patient reports baseline significant fatigue, neuropathy, diarrhea, and a history of stomatitis. Amy.

[00:30:10]

Case Discussion 2: What prophylactic patient education is essential to help mitigate common and severe side effects of Dato-DXd?

Amy Goodrich: Okay, so what prophylactic patient education is essential to help mitigate common and severe side effects of Dato-DXd?

1. Managing neuropathy;
2. Managing oral and ocular toxicity;
3. Managing nausea;
4. Managing headaches;
5. Both B and C; and
6. Both A and D.

And I am going to give you a minute to wrap your head around that one because there are multiple answers here.

Okay, great.

[00:30:50]

Case Discussion 3: The patient starts Dato-DXd and reports SOB and DOE. What do you do?

And then number 3, so the patient starts Dato-DX, and reports shortness of breath and dyspnea on exertion. So what do you do?

1. Tell her to rest and relax;
2. Order a stat chest CT;
3. Prescribe an inhaler;
4. Hold the Dato-DXd;
5. Both C and D; or
6. Both B and D.

And again, I am going to give you a second to look at these. And so far, the last one is our winner, both B and D.

[00:31:33]

Stomatitis/Mucositis With Dato-DXd

Kimberly Podsada: Let us see. So that would definitely be correct. When we are looking at now managing some of the toxicities for Dato-DXd, a couple of the unique ones are the stomatitis and then the ocular toxicity.

So fortunately, the stomatitis or mucositis were mostly low grades. So 55.6% of any-grade, that grade 1 was about 25%, and that grade 2 was about 23%. And so we also know we have our charts, and we can look at our grades, but it is also what the patient is saying, if something is really bothersome vs not being that bothersome. I become comfortable with just prophylactic mouthwash. It is a steroid-based containing, when available, to use about 4 times a day. It is highly recommended. It is not required. Patients can always wait and see, but I would make sure your patient has this at home just in case. So if they want to wait and see, as soon as they start to feel anything, they can start using it immediately.

Also, I would recommend maybe using some ice chips or ice water throughout the treatment. That also helps as well. And again, looking at our grades, grade 1 is asymptotic or mild. And so you are going to maintain the dose. You are not going to change it.

For grade 2, now you are starting to have a little more discomfort and pain. Hopefully they are using their mouth rinse at this point, but you might want to consider a dose delay and waiting until it resolves to a grade 1 or less.

When we move into our grade 3 and grade 4s, we are talking about them having some pain, and it may at this point be interfering with how they are eating and drinking and their nutrition. So obviously our goal is to not let it get that bad, which is why we will have things at home for the patient to use. And we will tell them, again, it is important to let them know the potential consequences. They can wait and see, but this is what we have been experiencing, and this is what we recommend. And so making sure they have the tools at home is of the most importance, of course.

[00:33:44]

Ocular Toxicity With Dato-DXd

And the ocular toxicity with Dato-DXd, about 51% of the patients experience some ocular adverse reactions, very low grade 3 events. So only 1.9%. And again, as we have learned more about how to manage these things because of the clinical trials, I think we are going to get a lot better at preventing these things from even happening. Most common adverse event was dry eye at about 27%, keratitis, blepharitis, increased lacrimation, meibomian gland dysfunction. So making sure that the patient is using a preservative-free lubricant eye drop several times a day is what is strongly recommended. And we also ask them not to use contacts too. Again, something to talk with your patient about if they are a contact user, are they comfortable using glasses throughout this?

Getting an eye exam as a baseline, routine follow-up visits as needed, and then definitely at the end of treatment. But having your eye doctor, a part of your care team for this medication is really important. And again, very minimal grade 3 events. These things can be prevented and managed. It is just something new to have on your radar to make sure you are talking with your patient about.

[00:35:10]

Sacituzumab Govitecan Patient Case

So looking at our sacituzumab govitecan patient case, we have a 75-year-old woman who was diagnosed with an early-stage triple-negative breast cancer in 2016. She completed neoadjuvant chemotherapy, lumpectomy, lymph node dissection, and radiation.

In 2020, an incidentally discovered lung nodule suspicious for metastatic recurrence was confirmed as metastatic triple-negative breast cancer, status post-lobectomy. And she started on atezolizumab and nab-paclitaxel. Pembrolizumab was not approved at that time, but she reported significant fatigue and developed endocrinopathies due to the immune therapy.

Baseline and chronic comorbidities included osteoarthritis, back pain, diabetic neuropathy, cervical stenosis with a history of C-spine fusions, obstructive sleep apnea, BMI of 40, and history of migraine. So a very common patient I am sure we have all encountered.

She uses an electric wheelchair for difficulty with ambulating and has a long history of back pain and other joint pains.

After 6 months of therapy, staging scans show disease progression, and she started SG in December of 2020.

[00:36:29]

Common AEs Associated With ADCs

Looking at some of our side effects for SG, nausea is something we are going to have to be thinking of managing. Neutropenia again is key with managing for SG as well as some of the GI issues, especially that diarrhea.

[00:36:48]

Sacituzumab Govitecan Patient Case

So she starts on SG with increased fatigue as well as new nausea and diarrhea. Additional antiemetic was added to infusion premeds which reduced her nausea. And diarrhea management can be challenging if an adverse effect management plan is not developed to help support our patients.

[00:37:06]

Recommendations for Treating Patients

So when we think about again minimizing toxicity and maximizing efficacy, we need to make sure that these symptoms that the patient is aware of possible side effects. A lot of education upfront, it will save you a lot of time if you give your patient time and attention upfront with how to manage side effects and give them a plan and have everything written out and let them know that they are getting IV meds and that they will have as-needed meds to take at home, who to call if there is a problem, whether we need to get nutrition involved as well.

So having this plan upfront for the patient I have noticed has really made patients feel more confident and have some sense of control over a time, where they do not feel like they are in control.

And then what is your monitoring plan afterward? Does someone call and check on the patient? Do you have a nurse navigator or someone that will call and check on symptoms? Does the patient know who to call as well? And letting the patient also know that there are management options as far as additional medications or dose reductions if needed.

[00:38:25]

Managing Diarrhea With Sacituzumab Govitecan

So for the diarrhea with sacituzumab, govitecan, again, knowing our grades is important.

So for our grade 1 and grade 2 diarrhea, we are looking at less than 4 stools over their baseline. And for grade 2, that is 4-6 stools a day over their baseline. So some of this can be pretty challenging for patients.

One of the interesting things about SG is that there is a potential for an onset during or shortly after the infusion. So you may need to give atropine. You may need to give atropine prophylactically if you see that they are having issues with infusion-related diarrhea.

And then you are going to continue SG at the same dose for this grade 1 or grade 2. You really just need to have interventions. For that grade 2, making sure that they know how to take their loperamide when they are at home, that loading dose, and then subsequent doses, as well as maybe dietary management issues.

For our grade 3, now we are looking at something where we have greater than 7 stools over their baseline a day. They are not feeling well. Maybe they have bloodier black stools. They are feeling dizzy and dehydrated. This is critical. Grade 4, of course, can be life-threatening.

So in this situation, when we are looking at grade 3 diarrhea, we really want to consider whether we need to bring them into the hospital, whether we need to bring them into the same-day cancer services to get them hydrated, check electrolytes. And now we are going to intervene with the octreotide 100-150 micrograms sub-q 3 times a day. And also consider antibiotic therapy. Is there a potential infectious cause for this diarrhea as well? And if everything resolves, then we have a plan here of how to continue to manage. If it does not resolve, then we are moving on to the next level of intervention.

But for that grade 3 diarrhea, that is when we are going to start our octreotide. Grade 1 and grade 2, we are using atropine. We are using loperamide. And we may be doing some dose changes if needed, but it is not typically recommended at this point. Depends on what your patient is saying. Do not forget.

[00:40:56]

Management of Common and Potentially Severe Toxicities Associated With SG

So some of the SG toxicity again here, we will talk a little bit about neutropenia, so I am not going to go into that. But I will point out here that if your patient has prolonged neutropenia and they are just not responding to treatment intervention, they may have this rare genotype. We do not check for this genotype up front because it is rare.

But for those individuals who just do not seem to be recovering from neutropenia with all interventions, they may have this genotype, and you may need to consider a different therapy or dose reductions.

We just reviewed how to manage diarrhea. And then, of course, hypersensitivities, need to be aware of that after treatment and during treatment as well.

[00:41:43]

Case Discussion 4: SG Patient Case

So for our SG patient case, a 43-year-old woman was diagnosed with de novo metastatic triple-negative breast cancer to her bones, confirmed by biopsy. BRCA was negative for mutation. She was given her first-line therapy with paclitaxel and pembrolizumab. And after subsequent infusion, she reported neuropathy and hypothyroidism and an immune-mediated adverse reaction. And she was started on long-term thyroid hormone replacement and paclitaxel dose was reduced.

At the time of disease progression, she started on carboplatin and gemcitabine. Dose was reduced and discontinued on Day 8 due to cytopenias and fatigue. She started on sacituzumab govitecan at the time of progression.

[00:42:32]

Case Discussion 4: When educating a patient who is about to start therapy with sacituzumab govitecan, which of the following adverse events should you monitor/assess for?

Amy Goodrich: When educating a patient who is about to start therapy with SG, which of the following adverse events should you monitor or assess for?

1. Stomatitis/mucositis;
2. Neutropenia;
3. Neuropathy;
4. ILD/pneumonitis; or
5. Decreased ejection fraction.

And we are sort of all over here a little bit.

[00:43:12]

Posttest 1: When addressing sacituzumab-related diarrhea, what are the first appropriate steps to safely manage diarrhea of different grades?

Okay. So posttest. When addressing SG-related diarrhea, what are the first appropriate steps to safely manage diarrhea of different grades?

1. Grade 1, are you using octreotide;
2. Grade 2, are you dose reducing until recovery?
3. Grade 3, are you administering octreotide?
4. Grade 4, are you giving aggressive loperamide to max out at 8 tablets or 16 mg a day?

And let us see what folks are saying here.

B is the top answer with 48%, and we have 27% at C.

[00:44:14]

Kimberly Podsada: So when I was reviewing the slide about sacituzumab-related diarrhea, we did talk about how grade 1 and grade 2, you really wanted to use more of your atropine if you needed to, or using loperamide. Dose reductions were not recommended for grade 1 and grade 2. However, again, depending on what the patient says, you will manage appropriately. But for this situation, grade 3 is where you need to be more aggressive with managing diarrhea, and you will be starting octreotide. Very important when someone has grade 3 to get them in, assess them, rehydrate them, check for infectious-related issues, hydrate them, potentially hospitalization, if needed.

But the correct answer is C here, giving them octreotide.

[00:45:16]

Managing Neutropenia

So looking at managing the neutropenia here, of course, we need to take into consideration, especially for SG, that it occurs in 64% of the patients, and grade 3/4neutropenia is 49%. That median onset is about 16-20 days, and it can last for up to 7-8 days.

So can we have G-CSF ordered in advance? Will insurance allow that? Are they going to wait and see if someone has neutropenia? With this high percentage of it happening, we do try to get some G-CSF approved in advance, depending on the insurance, whether we can or not. So here, if we cannot have it in advance, we really need to let the patients let us know if they are having any signs of infection, let us know immediately if there is any fever, burning with urination, etc. And plus, for SG, it is being given on Day 1 and Day 8, so we are looking at CBCs on a regular basis.

[00:46:27]

Looking at our grades here, again, for that grade 2, we will be holding SG during Day 1, if the ANC is less than 1500, and on Day 8, if it is less than 1000.

[00:46:45]

Managing Neutropenia With Sacituzumab Govitecan

Another visual here to think about managing neutropenia with sacituzumab govitecan. Patient education is key, letting them know you are aware of this potential, educating them about the signs to report, telling them about labs will be checked even before giving them an infusion on Day 1 and Day 8, holding if necessary based on the PI, managing with G-CSF, and dose reducing if necessary.

[00:47:17]

ADC AEs: Summary

So for our ADC/AEs summary, before we move on to our final polling questions, our ADCs have nausea to varying degrees, most of them do. It is important to know that risk, anticipate intervention, and educate patients in advance about this potential, reassuring them that there is a plan in place, write it down for them, give them reading information, let them know there is a plan, make them feel confident in the care that they are getting and that they have tools at home so they know what to do as far as how to manage their nausea. Abnormal labs, including neutropenia, can be severe and an increased risk of infection, so anticipate it, have a plan in place instead of waiting till it happens last minute, and educate patients about reporting symptoms.

Again, the SG does have a higher risk for neutropenia than the other ADCs, but Dato-DXd also may need G-CSF intervention as well, so all abnormal labs on most of the ADCs do occur. That Dato-DXd, the AE of special interest, we are looking at that ocular and oral toxicity, and we are going to encourage prophylaxis intervention, the mouthwash in advance, the lubricating eye drops in advance, and using it on a regular basis.

For our T-DXd and our Dato-DXd, again, that DXd payload, we are looking at the potential for ILD, whether it is asymptomatic or symptomatic. Asymptomatic, we hold. Symptomatic, we hold and do not resume.

That common SG AEs, as I mentioned, the diarrhea and neutropenia. and understand the AEs in advance to provide specific education to mitigate and reduce severe AEs for your patient.

That education you give up front will really make a difference in the future. There is a lot of hand-holding that really will benefit you if you let the patient know about the plans and give them the tools.

Let’s go back to our questions

[00:49:34]

Posttest 2: A 36-yr-old woman was diagnosed with stage III locally advanced HR+/HER2- (IHC 0) right breast cancer. She proceeded with neoadjuvant ddAC-T. Repeat imaging, prior to surgery and post chemotherapy, showed partial response in her breast but suspicious lung nodules. Biopsy confirmed HR+/HER2- mBC. She started endocrine therapy with ovarian ablation, anastrozole, and CDK4/6 inhibitor. At the time of progression, genomic testing revealed a PIK3CA mutation. After progressing on PI3K inhibitor, what therapy should she start next?

Amy Goodrich: So our 36-year-old, diagnosed with stage III locally advanced HR+/HER2- right breast cancer. She got her neoadjuvant ddAC-T repeat imaging. Prior to surgery, post-chemo showed partial response, suspicious lung nodules that end up being metastatic disease. She starts endocrine therapy with ovarian ablation, anastrozole. She does her CDK4/6 inhibitor, and at the time of progression, she is noted to have a PI3K3CA mutation. So after progressing on a PI3 kinase inhibitor, what therapy should she start next?

1. T-DXd;
2. Eribulin;
3. SG; or
4. Dato-DXd.

So which one do you think the right answer is?

So SG is 53%.

Kimberly Podsada: Excellent. Okay.

Amy Goodrich: So there we go.

Kimberly Podsada: Yes. Outstanding. Good job. So this patient does meet criteria based on the indication approval. She has locally advanced, unrespectable, metastatic breast cancer. She has received chemotherapy, and endocrine therapy, and a targeted therapy.

The sequencing question, again, can be very challenging. And this was not supposed to be a trick question because Dato-DXd, that could have been an option as well. But the reason in this situation that I would choose SG over Dato is that SG has a statistically meaningful median progression-free survival, as well as an overall survival compared to the other treatment options. So that is why SG is the right answer here.

[00:51:42]

Posttest 3: A 63-yr-old woman with HR+/HER2- (IHC 1+, ISH not amplified) mBC previously received 2 lines of endocrine therapy, capecitabine, T-DXd for HER2-ultralow disease. She has no genetic mutations. For her next line of therapy, things to consider include multiple holds and dose reductions due to neutropenia. Based on the adverse effect profiles of the ADCs below, what would you pick for her next line of therapy?

Amy Goodrich: Now back to our 63-year-old. With metastatic breast cancer, HR+/HER-. She has had 2 lines of endocrine therapy, capecitabine, T-DXd, HER2-ultralow disease, no genetic mutations. For her next line of therapy, things to consider include multiple holds and dose reductions due to neutropenia. Based on the adverse event profiles of the ADCs below, which would you pick for her next line of therapy?

1. SG;
2. Dato-DXd;
3. T-DM1; or
4. T-DXd.

Okay. And Dato-DXd is our winner at 51%. And yay, that is the correct answer.

[00:52:40]

Kimberly Podsada: Great. Thank you. This is super.

So again, not supposed to be a trick question here, but the SG did have a lot of neutropenia. And so if our patient is already struggling with neutropenia, we could save SG for potentially later. The Dato-DXd is the correct answer.

Patient had already received T-DXd, and T-DM1 is for HER2+ only. So the correct answer is Dato-DXd. And although it was not formally compared, Dato-DXd did show the lowest hematologic toxicity compared to SG and T-DXd.

And so the rate of treatment-related adverse events was lower in the intervention arm compared to the control arm, which is a chemotherapy. So the Dato-DXd, 30% all grades of neutropenia, and 1.6% had grade 3/4. So again, very tolerable compared to the chemo, 61% all grades and 35% grade 3/4.

So Dato-DXd is the correct answer.

[00:53:52]

Posttest 4: When discussing the unique characteristics of ADCs with patients, which of the following would you tell them about potential for a “bystander effect”?

Amy Goodrich: And let us see what we can do with this one. When discussing the unique characteristics of ADCs with patients, which of the following would you tell them about a potential for "bystander effect"?

1. ADCs with a cleavable linker and high drug-to-antibody ratio may allow membrane-permeable payloads to also affect adjacent cells;
2. The cytotoxic payload on ADCs only affect target cancer cells, preventing bystander effects on the surrounding healthy cells;
3. ADCs with a noncleavable linker and low drug-to-antibody ratio are more likely to result in increased systemic exposure to the payload; or
4. Lower specificity of the ADC target to the target antigen on cancer cells can prevent potential bystander effects.

So A, 60% of people voted A.

[00:55:13]

Kimberly Podsada: You are making me so proud. Thank you. So yes, when we first started off the slide deck, I was reviewing the mechanism of action, potential toxicity. And so for our ADCs that have that cleavable linker where the drug is released more quickly once it is engulfed into that tumor cell and the high drug-to-antibody ratio, you have more of a local event happening. There is permeability.

So it is because of that cleavable linker and the high drug-to-antibody ratio that does contribute and cause that bystander effect. So that is absolutely correct.

Great job, everyone. Thank you.

[00:56:02]

Poll 2: Do you plan to make any changes in your clinical practice based on what you learned in today’s program?

Amy Goodrich: So do you plan to make any changes in your clinical practice based on what you learned in today's program?

1. Yes;
2. No; or
3. Uncertain.

[00:56:12]

Poll 3: Please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education.

And then if you can take a moment to click in one change that you plan to make in your clinical practice based on this education, that is super helpful.

Q&A

Amy Goodrich: We do have some questions before we wrap this up. And so I actually have a question because I work in the lymphoma space, and we use ADCs with very stable linkers that are very stable for a long time. And so all of the toxicity we see is from the payload. So what is the benefit of having these sort of loosey-goosey linkers that cause all of this toxicity, and are new generations being worked on to minimize that?

Kimberly Podsada: Well, the interesting thing is we are also seeing really good outcomes, though, too, on the clinical trials. The ADCs are actually allowing us to use certain payloads that are very effective but were more toxic before when they were just kind of given on their own. So the ability to really bring a very effective chemotherapy specifically to the tumor cell is having a tremendous effect on getting a great response in getting patients' cancers under control and destroyed.

And that bystander effect also allows other cells surrounding that area to be destroyed as well. And for whatever reason, are those cells maybe in a different phase of development and not readily destroyed by the ADC, but this bystander effect is really destroying them better? Do not know a lot of that. A lot of this, again, is just theoretical, but we are seeing tremendous progression-free survival and overall survival by the introduction of these ADCs. Managing toxicities is always going to be an issue.

Amy Goodrich: Right. So what I hear you saying is the toxicity is worth the efficacy.

Kimberly Podsada: Absolutely.

Amy Goodrich: And so for those of you who see lots of diseases like that, you do not want bystander effect in the heme malignancy space where you are targeting circulating cells, right? So that would be just devastating. So this has really been super interesting.

And so I am going to ask you one more question that has come in. So as new ADCs come to the space, are there key triggers that people can understand? Are they named? Is there a certain name to the linker or the payload or something that can spark people to expect or not expect significant toxicity? Hmm. I see what you are saying.

Kimberly Podsada: Yes. Some of that is really just the familiarity with the ADC. But again, if it says that it has a cleavable linker, you can expect more toxicity.

Amy Goodrich: Because of the bystander.

Kimberly Podsada: Because of the bystander effect. Exactly. The drug-to-antibody ratio, if an antibody is carrying more drug on it, there is potential for more toxicity.

So for that Dato-DXd, when it had 4 drug-to-antibody ratio, that has more tolerability because it is less drug on the antibody compared to Dato-DXd or T-DXd. So really the key things when understanding potential toxicities for ADCs is that linker cleavable or noncleavable and the drug-to-antibody ratio.