Managing Key TRAEs With ADCs

But let us talk about managing key side effects with ADCs.

[00:43:30]

Patient Case 2 Continued: Patient With TNBC

I think we touched on some of this in my answer to the last question, but I think we can dive a little bit deeper.

So going back to our patient with triple-negative breast cancer, the patient elected to receive sacituzumab govitecan, but unfortunately she struggled with grade 2 diarrhea. It resolved to grade 1 with 4-6 mg of loperamide daily. She unfortunately missed day 8 of treatment several cycles in a row and had pretty bad fatigue as well as persistent diarrhea that was now grade 3.

[00:44:04]

Pretest 3: In your current practice, which of the following would you recommend to manage the patient’s adverse events?

So in your current practice, which of the following would you recommend to manage this patient's adverse events?

1. Continue her SG, give supportive care and loperamide and monitor for worsening symptoms;
2. Hold the SG until resolution with supportive care and then resume at the same dosage;
3. Hold the SG until resolution with supportive care and then resume at a reduced dosage; or
4. Discontinue SG permanently.

Please vote.

Speaker: The poll is open. Five more seconds. All right, thank you. We will close the poll and share the results.

Dr Huppert: Great, so the most votes are for C, hold SG until resolution of supportive care and then resume at a reduced dosage, which, yes, I agree with that in this case. I think in this case, we have already tried appropriate management for her diarrhea. It is still grade 3. I would not want to treat through for grade 3 diarrhea. I would definitely want to hold to try to get that under better control. And then I think, given her severe diarrhea, despite appropriate management, and the ongoing fatigue, I think a dose reduction would be very appropriate in this patient. So, I would also do C here.

[00:45:34]

Common (in ≥30%) and Dose-Limiting/AESI Toxicities Associated With ADCs

Let us talk about the common and dose limiting side effects associated with each of these ADCs.

I think I touched on this in my last question, but I think just to emphasize one more time, it helps to see it here. I think the things I emphasize with T-DXd are the nausea, the fatigue, monitoring for the cardiac implications, and then the risk of pneumonitis, I think, are the big 4 I think about here. It is helpful to have the numbers, though.

I tend not to need growth factor in most patients for T-DXd, although the data shows that about 73% have some amount of white blood cell suppression. Sometimes you do need to add growth factor, either short- or long-acting. So I usually wait in the setting and do it as secondary prophylaxis and not do it off the bat.

Alopecia occurs in about a third. You do need to monitor. Increased AST and ALT can occur, not super common, but can definitely occur. And then the black box warnings are for ILD or pneumonitis, and then embryo-fetal toxicity with this agent.

Sacituzumab govitecan, the big 4, again, I think about are fatigue, diarrhea, neutropenia, and alopecia being, I think, things that I emphasize the most with patients, and using for the neutropenia growth factor off the bat with SG, just to emphasize that again. So either the short-acting, long-acting, or both, depending on what is approved with insurance and all of that. So that would be, I think, the biggest thing to know here. The diarrhea, using Imodium or other agents, and then dose reducing if needed.

Alopecia being more common and more severe than the others. So letting patients know about that. And I think for all of the ADCs, fatigue comes up for sure. We do not have any magic bullets, unfortunately, for fatigue. Some of our palliative colleagues try Ritalin or other agents like that, although the data is not so robust there. I think often a dose reduction is the most helpful.

So if a patient's really struggling with fatigue, I think that is a good reason to consider a dose reduction. Sometimes for SG, I will do a dose reduction off the bat for my elderly patients. You can always go up, but it is better not to make it too strong off the bat. So, sometimes I will start it rather than 10 mg, something like 8 mgs, and then see how it goes. And you can always go up, or you can just leave them at 8 mg.

The black box warnings here are for neutropenia and diarrhea.

And then Dato-DXd, just to emphasize again, I think stomatitis is definitely number 1, nausea, monitoring for the ocular adverse events. And then the ILD pneumonitis occurring at about 3-4%. We talked about the steroid mouthwash, as well as the preservative-free eye drops and seeing an ophthalmologist and then monitoring for the ILD here as well. Although about a third as often as with T-DXd. So, fortunately, a little bit lower rate of that.

[00:48:48]

ADC-Related ILD/Pneumonitis

So for ADC-related ILD or pneumonitis, this can happen with chemotherapy as you all know as well.

But we think about it a lot, in particular T-DXd and then, to a lesser degree, Dato-DXd here. We actually do not totally understand the risk factors and mechanisms. I think, in general, it is thought to be target-independent uptake of the payload in immune cells with some bystander effect of the release payload and damage from circulating payload after release.

But there is a lot of ongoing translational work to try to understand this better, how to prevent it, who is at highest risk. We know that there are some data about patients being at higher risk if they had a history of smoking, if they are older, if they have renal dysfunction. So there are some risk factors that we can pull out from large cohort studies, but there is not a biomarker or anything to predict who is at highest risk there.

I think in general, I would avoid T-DXd in patients who have severe lung injury at baseline, a history of ILD that was severe if they are on oxygen. I think sometimes then it is considered too risky, and you might avoid it. I do feel comfortable giving T-DXd to patients with a history of more mild COPD or lung issues after, especially, I talk with our pulmonologist if they have one so that we are just monitoring a bit more closely. But I think generally avoiding it in patients that have very severe baseline lung comorbidities.

SG does not have a risk of ILD. So it is a great option for patients that do have those severe lung comorbidities. And then Dato-DXd, like I said, is about a third as much as with T-DXd. We do not have any data on if someone had T-DXd pneumonitis. Presumably the risk is slightly higher with Dato. We do not know for sure.

So I think, you know, again, if you are choosing between SG and Dato, prior ILD could be one of the factors that leads you one way or the other.

[00:50:48]

Managing ILD/Pneumonitis With T-DXd

Managing symptoms of ILD with T-DXd. I think the monitoring and counseling patients to immediately report cough, dyspnea, fever, worsening respiratory symptoms. I tell patients, "Do not wait till your next visit. I want to know about it right away. This can be very serious."

So I do really emphasize that. And then if they do report a new cough or new shortness of breath, getting a CT scan right away to look for ILD by radiographic imaging. And then, obviously, especially in the winter, do they have COVID? Do they have a virus? I am often sending those tests as well because if it is not ILD, I want to know what it is if I can figure that out so that I feel more confident, you know, re-challenging and proving that it is not pneumonitis. So I do that workup as well.

So, sending those studies, you are going to confirm with a high-resolution CT. Sometimes we are involving pulm, especially if it is more severe, you know, not always getting bronchoscopy, and most of these patients, again, in less severe or PFTs, but I do rule out other causes. And then for grade 1, if they are asymptomatic, but just, you know, imaging, you do need to hold the drug until resolved to grade 0. And so, basically, what that means is you are going to hold that dose of T-DXd. It is controversial whether you need steroids with grade 1. I do tend to give 0.5 mg/kg of prednisone there for a 3-4 week taper. I re-scan after 3 to 4 weeks. And if it does not have to be completely gone, but if it looks improved on imaging, then you are able to re-challenge. And the first re-challenge you can do at the same dose.

If I am seeing this happen multiple times with grade 1, then I often do a dose reduction subsequently. But for grades 2-4 symptomatic, you do have to permanently discontinue T-DXd. And so, like I said, for grade 1, you can consider steroid treatment, 0.5 mg/kg prednisone or prednisolone. I usually do go ahead and give it if I do think it is related to pneumonitis and not a virus or something else. For grade 2 or higher, you definitely need steroids, 1 mg/kg. You have got a prolonged taper here typically.

And then for grade 1, usually you can maintain the dose, if it is less than 28 days. If it takes a really long time, that is when you are dose reducing, or if it is a second dose reduction. And then here is just a reminder of the doses for breast over here on the left, 5.4 mg to 4.4 mg to 3.2 mg.

[00:53:08]

Managing Clinically Significant Nausea and Vomiting With T-DXd

And then managing clinically significant nausea and vomiting. Like I mentioned before, a 3-drug regimen, that is IV, and it is typically built into most of our protocols. Take-home antiemetics, like I said, in addition to Zofran and Compazine and Ativan, we usually do Olanzapine 2.5 mg. I do not usually do dex off the bat, but I will usually add it if needed. And then dose reductions are also an option.

[00:53:36]

Managing Neutropenia With T-DXd

Neutropenia, you can educate patients on the potential for neutropenia, but I would say for most patients, I do not end up needing growth factor. I do not add it off the bat. I wait and see if I need it. If you do need to add it, you obviously need to hold if their ANC is less than 1,000. And then typically once you add the GCSF, you do not run into any further problems.

You sometimes need to titrate the dose of their GCSF accordingly, but that is more straightforward to manage in most patients on T-DXd.

[00:54:07]

Managing Diarrhea With Sacituzumab Govitecan

Managing the diarrhea with SG. Typically, it is considered grade 1 if it is less than 4 stools per day. Grade 2 is 4 to 6. Grade 3 is 7 or more. Grade 4 is life-threatening.

Typically, if it is shortly after the infusion, there are some patients that get this immediate diarrhea. You can use atropine. I have not had as much of that recently, but I have used that in the past on several patients, so knowing that that is an option. It is often built into our protocols here as well. More commonly, we are seeing a delayed onset diarrhea. We are using a little loperamide, dietary management, and sometimes you need to add other agents there as well.

And then hopefully the use of the antidiarrheal medications helps. If not, sometimes you can consider the use of octreotide, fluid electrolyte replacement, dose reduction, ruling out infectious causes of diarrhea. And then definitely, if it is grade 3 or grade 4, you take it very seriously. Often consider a hospital admission if it is ongoing, fluids, octreotide, antibiotics if there is concern for something else going on. And then definitely making sure that you dose-reduce in the future. For a grade 4, you would probably even consider a permanent discontinuation there.

[00:55:24]

Managing Neutropenia With Sacituzumab Govitecan

For SG, like I mentioned before, the neutropenia we manage with growth factor off the bat. So this is important. And definitely either the short-acting or long-acting or both.

You can check for the UGT1A1*28 genotype, especially if they have prolonged neutropenia. At UCSF, we have actually started checking that off the bat for patients, just to be aware. We can send a pharmacogenomics panel to see if they have that. And so, you go into it often with a dose reduction if they do. But if you do not check it off the bat at your center, if they have prolonged diarrhea or neutropenia, that is something to consider checking.

[00:56:08]

Management of Additional Toxicities Associated With SG

And then, hypersensitivity reaction, typically within the first 24 hours, can occur in some patients. So pre-medicating them with H1 and H2 blockers and corticosteroids. The first infusion is longer just to monitor for this, and then subsequently a little bit shorter, and then having emergency equipment available.

Nausea and vomiting, this is also a high medic risk agent. So a 3-drug regimen. I typically see less nausea than with T-DXd, but it definitely can be bad, and some patients can have delayed nausea. So, some of the same tips that we went over before.

[00:56:44]

Management of Stomatitis/Mucositis Associated With Datopotamab Deruxtecan

And then stomatitis, like I mentioned, good oral care, but then the steroid-containing mouthwash 4 times a day is definitely really helpful. And I emphasize that a lot to patients.

I say it is way better to prevent it than to have it bother you and come up in the future. So I really do emphasize that one for sure. There is mixed data about whether ice chips or ice water helps. The half-life of these agents is really long. Some people do try that, although we have not seen definitive evidence that that helps.

I think what to look for, I think the biggest takeaway, I have given a lot of Dato-DXd on trial, and one thing I will say is that you do not always see the mouth sores like with other chemotherapy agents. Often it is like the patients report pain or difficulty eating, and that is more prominent than sometimes what to see visibly, I will say for many of my patients. So just keep that in mind. Although sometimes you do see actual changes.

And then supportive care, using more mouthwashes. Sometimes if they are having more pain, adding a magic mouthwash or something with some lidocaine in it as well to help with the symptoms and discomfort. And then I have involved our oral care team or dermatology if this is a severe case to consider sort of other options as well. But typically the dose hold and dose reductions do work well here if needed.

[00:58:08]

Patient Counseling on Stomatitis/Mucositis

I think we talked about the steroid mouthwash probably being the most important thing. I have not used as much artificial saliva, but that is an option. You can continue doing the same mouth rinses that you do with chemotherapy. I mentioned the viscous lidocaine if they are having symptoms that are really bothersome. And then patients often modify their diet if needed. I have definitely had patients that have needed to do a more bland or soft diet if they are having more mouth sores or more pain.

[00:58:38]

Management of Ocular Toxicities Associated With Datopotamab Deruxtecan

And then the ocular toxicity, we talked about an ophthalmologic exam at baseline or around the time of study start is how it is worded. You can do it even right after baseline. And then at least 4 times a day, up to 8 times a day, preservative-free lubricant eye drops. I will say some of my patients do less than that, but I do try to get them to do the 4 times a day off the bat to start.

It is important to mention patients should avoid contact lenses. That is a big deal. Definitely mentioning that for your patients.

And then what you are looking for, I think many of us as oncologists are not as comfortable with the eye, but I am definitely asking about ocular symptoms. I am not doing an eye exam myself in clinic, but if they have any ocular symptoms, I am sending them back. That is why it is helpful to have them see an ophthalmologist or optometrist off the bat because you can send them back to that person if anything else comes up. Of course, if you do notice any eye symptoms on your exam, sending them as well. But most often it is patient-driven symptoms that are driving me to send them back.

Median onset's about 2 months. Most events, fortunately, are grade 1 and grade 2, and then sending them back to an ophthalmologist if they are having bothersome symptoms.

[00:59:50]

Management of Additional Toxicities Associated With Datopotamab Deruxtecan

And then additional symptoms here, there is a risk of hypersensitivity as well with Dato-DXd. So again, a slower infusion to start and speeding up after that. And nausea and vomiting, again, sort of similar. Usually I am using a 2-drug regimen here as well as take-home antiemetics.

And then the ILD, 3-4%, monitoring for new or worsening symptoms. And then I manage it basically the same way I do for T-DXd. We do not actually have specific data about this yet, but if they are asymptomatic, again, holding, considering steroids. And then I would re-challenge just based on what we know about T-DXd, whereas for grade 2 or higher, permanently discontinuing and using steroids is important.

[01:00:32]

Let’s Revisit a Question

So we are a couple of minutes over, but let us finish quickly.

[01:00:34]

Patient Case 2 Revisited: Patient With TNBC

So revisiting our patient with TNBC. So the patient elects to receive sacituzumab govitecan. She struggles with grade 2 diarrhea, but resolves to grade 1, but then unfortunately has ongoing grade 3 with fatigue.

[01:00:48]

Posttest 3: Now, which of the following would you recommend to manage the patient’s adverse events?

Now our posttest, which of the following would you recommend to manage this grade 3 diarrhea and fatigue? Please vote.

Speaker: Poll is open. Five more seconds. All right, thank you. We will close the poll and share the results.

Dr Huppert: Great. So yes, I would agree with C, which more of you responded to this time. Fabulous. So, holding the SG until resolution with supportive care and then resuming at a dose reduction here would be the best response.

[01:01:52]

Maximizing Patient Support and Outcomes

So I think strategies for patient support and outcomes, you know, definitely good patient counseling, using culturally sensitive education and supportive care, identifying common barriers, working with your multidisciplinary team, your nurses, your pharmacists to all help with this.

[01:02:06]

Patient and Caregiver Education for ADCs

There is a lot of different educational information for patients about these signs and symptoms. Some of them are shown here.

[01:02:16]

Navigating the Healthcare Ecosystem: Addressing Potential Healthcare Disparities

Obviously, as Mary Jane highlighted, cost can be an issue. So highlighting that there are manufacturer grants and assistance programs if needed. Communication is key. And then there are gaps in our outcomes research. So, we need more clinical trials in underrepresented groups. And then working with a multidisciplinary team.

[01:02:39]

Shared Decision-making

Shared decision-making is key with anything in oncology, but again, counseling patients about the options, understanding their priorities, and choosing the option that is best for each patient.

[01:02:52]

Overcoming Healthcare Disparities

And then, lots of different ways that we as healthcare providers can help overcome healthcare disparities. For the sake of time, I will not go through all of these, but I think a lot of things that we really need to be thinking about to help our patients successfully complete their therapy without having severe financial toxicity.

[01:03:13]

InterACT Discussion

Please send your comments

So finally, I think we do not have time for this one today.

[01:03:14]

Poll 4: Which of the following topics related to toxicity management and adherence would you like the faculty speaker and patient advocate to discuss?

I think we went through it already, though.

[01:03:18]

Breast Cancer Support Groups

So here is some information on breast cancer support groups. Mary Jane highlighted she likes breastcancer.org support groups, but here are a whole bunch of others as well. Good resources for your patients. They can be really helpful to build confidence and improve treatment adherence.

[01:03:36]

Let’s Revisit a Few Final Questions

And I think let us do the final post-test.

[01:03:39]

Posttest 1: Now, how confident are you in your ability to incorporate a patient’s treatment goals and preferences into decisions related to ADC therapy selection and supportive care?

How confident are you in your ability to incorporate a patient's treatment goals and preferences into their ADC therapy selection and support based on the lecture today?

Please vote.

Speaker: The poll is open. Five more seconds. All right, thank you. We will close the poll and share the results.

Dr Huppert: Great. So we moved the needle a little bit. So, more of you are confident now. Wonderful. And I think this is a really good slide deck, actually, to have on hand to go over the side effects and such. So keep that in your back pocket.

[01:04:21]

Poll 5: Do you plan to make any changes in your clinical practice based on what you learned in today’s program?

And then, 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.

Speaker: The poll is open. Five more seconds. All right, thank you. We will close the poll and share the results.

Dr Huppert: Great. So most of you are thinking of making changes based on what you learned today. Fabulous.

[01:05:02]

Poll 6: Please take a moment to text in one key change that you plan to make in your clinical practice based on this education.

And then please take a moment to text in one key change that you plan to make. So use this QR code.

Speaker: As Dr Huppert said, you can use the QR code on the screen to text in a response, or also, we have a polling box open if you would like to simply just type in your response. We \appreciate all input. So with that, Dr Huppert, you can move on.

[01:05:40]

Thank You for Attending Our Program!

Dr Huppert: Okay, great. And then I think that is it. So thank you so much for attending our program.

Here is the QR code to access the online evaluation and claim your credit. And the additional program resources are provided there.

So thank you all so much for your attention today. And happy to take any final questions if there are any, although I know we are a few minutes over. So I want to get you back to your rest of your day. But thanks for joining.

Wendy: Hi, thank you so much, Dr Huppert and Mary Jane for your teaching today. I just want to draw your attention to the QR codes on the screen. In addition, you will find these links located in the chat.

Q&A

And then, Dr Huppert, I did see 2 questions that came in to the Q&A. I am not sure if you can see those on your side.

Dr Huppert: Oh, yes, let me check.

Wendy: All right, great.

Dr Huppert: Where is the Q&A? Sorry, I am seeing the chat.

Speaker: If it will help you find it, you can stop sharing. I will put up the QR codes.

Dr Huppert: Thanks. Where do ADCs fit relative to double SERDs? Yes, so the first question is a great one. I do definitely utilize all of my endocrine therapy before I move on to ADCs.

So if I think a patient is still endocrine therapy-sensitive, I will use the oral SERDs or PIK3CA agents. And then, once I feel like they are no longer as endocrine-sensitive and I am thinking about moving on to chemo, that is when I am sort of making a decision about should I use chemo or ADC? So that is a great question.

And then, is there a role for prophylactic growth factor support in patients with borderline ANC? Yes, I think depending on how borderline it is, I will consider adding just a single dose of filgrastim or short-acting growth factor. Often when their ANC is, you know, 1.5 or less is when I will think about adding it just so that in the future I do not have to delay things. It also depends on their trends. Like if it was just one time that it was 1.5, but every other time it has been high, I often just wait and see if I need to, just to avoid adding something that I do not need to for T‑DXd, for example. But if it is consistently borderline, then yes, I would add some growth factor to avoid delaying future doses.

And then, as I mentioned for SG, definitely, I do it off the bat for everyone.