Elizabeth Diaz (UT Health San Antonio): So today we’re going to discuss 4 widely used antibody–drug conjugates for breast cancer including: T-DM1, T-DXd, sacituzumab, and the new Dato-DXd. But first I’m going to start with a little background on HER2.

So HER2+ breast cancer represents approximately 15% to 20% of all invasive breast cancer cases. The subtype is characterized by the HER2 gene amplification, it’s not a mutation, and we know this drives very aggressive tumor growth. 30% to 50% of patients with HER2+ metastatic breast cancer will develop brain metastases. I think this really emphasizes the urgent need for better treatment options.

[00:04:50]

Evolution of HER2-Targeted Agents

So the landscape for HER2-targeted agents has really changed over the past few decades. First, we had the identification of the HER2 gene in 1984, and then in 1998, the approval for trastuzumab, which was really the first HER2-directed therapy available for these patients.

Subsequently, we’ve seen the approvals of lapatinib and pertuzumab, but again, today we’re focusing on the ADCs. And you’ll see the first one in 2013 that trastuzumab emtansine, which is T-DM1, followed by, in 2019, trastuzumab deruxtecan, which is T-DXd. And T-DXd has expanded its indication to now include HER2-low and recently HER2-ultralow.

This has dramatically broaden the treatment options as approximately 45% of breast cancer cases are classified as HER2-low.

[00:05:50]

HER2-Targeted ADCs in Breast Cancer

So the 2 HER2-targeted ADCs that first we’ll talk about is T-DM1. It combines trastuzumab, a monoclonal antibody that targets HER2 with a unique cytotoxic payload. And for T-DM1, it’s a microtubule inhibitor called emtansine. For T-DXd, you have the same monoclonal antibody, the trastuzumab combined with the payload, a topoisomerase I inhibitor called deruxtecan. This structure allows for precise delivery of chemotherapy to cancer cells while sparing normal tissues and thus reducing side effects.

[00:06:28]

Structure of ADCs

So how do these drugs work? So the ADCs consist of 4 key components: the antigen, antibody, linker, and payload. The tumor antigen is a target. It’s usually a protein, and for our discussion today, we’re really focusing on, again, HER2 and TROP-2, and it’s abundantly expressed on cancer cells, but ideally it’s minimally expressed in normal tissues.

The antibody binds to the antigen delivering the ADC to the tumor site. The linker ensures payload stability and circulation and enables efficient drug release inside the tumor cell.

Finally, the payload is a potent cytotoxic agent. It’s actually a nanoparticle that’s 100 to 1000 times more powerful than standard chemotherapy, and we can get that directly to the tumor cell.

[00:07:19]

ADC Mechanisms of Action and Toxicity

So these drugs bind to the tumor antigen on the cancer cell and then they’re followed by internalization via endocytosis. Once inside the cell, the cytotoxic payload is released inducing cell death.

Additionally, there’s something referred to as the bystander killing effect, where some of the payload is released from dying tumor cells and kills adjacent cells. As illustrated, some of the payload can also be released upon drug binding to the antigen before it gets internalized into the tumor cell.

So this bystander effect can result in off-target toxicity if the target antigen is expressed on normal tissue. And what this means, for example, is that HER2 is also expressed in the lungs, which may be part of the reason some of these drugs like T-DXd cause pneumonitis, a rare but serious toxicity that we see with this drug.

[00:08:20]

Poll 3

Beth Sandy: So we’re going to do another poll here. Patients need to be tested for TROP-2 expression before receiving sacituzumab govitecan. Is this:

1. True;
2. False; or
3. I don’t know.

All right. I’m not sure if we can close the poll. Since it’s a poll, I was thinking maybe we could get the answer. So 35% said true, 15% said false, and 50% said I don’t know. So Elizabeth, I’ll hand it back to you.

[00:09:07]

Biomarker Testing

Elizabeth Diaz: Perfect. So yeah, this is actually false and part of the reason is that we can’t track test for TROP-2 very well and also it—kind of expression varies within the tumor and it hasn’t actually been associated with a treatment response. But the HER2’s testing is what’s really critical to guide treatment. And that’s because we need to know their HER2 amplification, whether it’s HER2+, they’re HER2-low or ultralow. And we’ll go over the definitions of those in a minute.

I was kind of surprised to learn that actually 15% to 40% of breast cancer patients lose their expression of HER2 after their initial treatment with trastuzumab. So this is why it’s so important to obtain a new tissue biopsy at each progression to evaluate that HER2 amplification. So again, maybe someday we’re going to have the TROP-2 testing more standardized and be able to use it, but not currently.

[00:10:06]

Trastuzumab Deruxtecan: HER2-Targeted ADC

So T-DXd has a drug-to-antibody ratio of 8:1, which is significantly higher than other ADCs. It uses a cleavable linker to release its cytotoxic payload, which is an exatecan derivative. It also exhibits a potent bystander killer effect where highly potent chemo leaks out of the dead tumor cells and kills nearby tumor cells independent of HER2 expression. And you can see that box on the right. T-DXd is also approved in other cancers, including just kind of a tumor agnostic labeling for any patients with metastatic HER2+ disease.

[00:10:52]

T-DXd: FDA-Approved Indications in Breast Cancer

So there’s 3 approved indications for T-DXd in breast cancer. I’ll kind of try to run through this slide that has a lot of data on it. So the first column is for HER2 disease and it’s the DESTINY-03 trial which led to T-DXd’s initial approval showing a progression-free survival increase from 6.8 months with trastuzumab emtansine to 28.8 months with T-DXd.

The second column highlights really the groundbreaking DESTINY-04 trial in 2022, which compared T-DXd to chemotherapy and resulted in the first approval of a drug for HER2-low disease. So before this, we didn’t have anything to target patients that had an IHC score of 1+ or 2+. It wasn’t really actionable. We kind of lumped them into this, you know, HER2- category, but now we have these targeted therapies.

And so the third column, DESTINY-06, was the recent approval in January for HER2-ultralow. So these are patients that have an IHC score of zero but still have some membrane staining. So it’s like less than 10%. And these patients with hormone receptor-positive disease only right now are candidates to receive T-DXd after at least 1 line of prior endocrine therapy.

[00:12:12]

TROP-2 Overexpression in Solid Tumors

I’ll switch now to talk a little bit about TROP-2. The other ADCs approved in breast cancer target TROP-2, and this stands for the Trophoblast Cell Surface Antigen 2. It’s a glycoprotein that’s overexpressed across many solid tumors, especially breast cancer. In fact, 78% of triple-negative breast cancer cases exhibit TROP-2 overexpression, which makes it a very viable target. We have 2 ADCs that target TROP-2 including sacituzumab govitecan and the new Dato-DXd.

[00:12:51]

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

So sacituzumab govitecan was the first FDA-approved TROP-2 directed ADC. It features a humanized anti-TROP-2 antibody linked to SN-38, and this is a potent topoisomerase I inhibitor whose parent compound is irinotecan. And sometimes as high—try to remember some of the side effects for these drugs. I know there’s a lot of drugs for breast cancer, but we know irinotecan causes neutropenia and diarrhea and the same is true for sacituzumab.

So this ADC uses a pH-sensitive linker that facilitates a rapid payload release into the tumor microenvironment. Again, here we have this bystander effect which results in more tumor cell death because the payload diffuses into neighboring TROP-2-negative cells, where the drug couldn’t bind. So you get the chemotherapy leaking out and still killing those cells by other mechanisms.

[00:13:42]

Sacituzumab Govitecan: 2 FDA-Approved Indications

So the first approval for sacituzumab came in the triple-negative breast cancer setting as the ASCENT trial, where sacituzumab improved median overall survival from 6.9 months with chemotherapy to 11.8 months. It is approved for locally advanced triple-negative breast cancer after 2 prior therapies. And in the metastatic setting it’s approved for triple-negative breast cancer after just 1 prior therapy.

The other side of this slide is the hormone receptor-positive disease. It’s showing you the TROPiCS-02 trial where, again, sacituzumab went against chemotherapy and an overall survival increased from 11.2 to 14.5 months in the sacituzumab arm. In this setting, it’s indicated after endocrine therapy and 2 lines of chemotherapy. But remember, for triple-negative, it only requires 1 line of prior therapy in the metastatic setting.

[00:14:46]

Posttest 1

Beth Sandy: All right. So let’s go back to our posttest question now. Which of the following patients would be eligible for sacituzumab govitecan therapy?

A. Newly diagnosed patient with resectable locally advanced triple-negative breast cancer;

B. Patient with metastatic triple-negative breast cancer after 1 additional systemic therapy;

C. Patient with metastatic hormone receptor-positive/HER2- breast cancer after 1 additional systemic therapy in the metastatic setting; or

D. Newly diagnosed patient with resectable locally advanced hormone receptor-positive/HER2- breast cancer in combination with endocrine therapy.

So go ahead and put your vote in and then we’ll find out what the correct answer is.

[00:15:45]

Posttest 1: Rationale

Okay. The correct answer is B, patient with metastatic triple-negative breast cancer after 1 additional systemic therapy. So initially, 28% of people guessed that and now 37% did. But I will tell you, Elizabeth, 35% said C. So I don’t know if you want to comment at all on that?

Elizabeth Diaz: Absolutely. This was a—I mean, almost a trick question. I haven’t looked at the other questions since I don’t know if this is the hardest one we put in this slide deck. But, well, first of all, A and D were incorrect and it was kind of tricky because it’s only approved for unresectable locally advanced disease. And then the C for patients with hormone receptor-positive breast cancer, they have to have had 2 additional lines of systemic therapy, whereas the reason B was correct is with triple-negative disease, you only have to have 1 prior systemic therapy.

Beth Sandy: Great.

[00:16:39]

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

Elizabeth Diaz: So lastly, the ADC for breast cancer which was just approved in January is called datopotamab deruxtecan. It’s another TROP-2-directed ADC with a drug-to-antibody ratio of approximately 4:1. It contains an exatecan derived payload, and yes, this is the same payload used with T-DXd and that’s because these drugs are actually made by the same company. But they do have a different monoclonal antibody and 2 different targets. So don’t get confused. Trastuzumab, the T-DXd is Herceptin, HER2, and then this one is called datopotamab, that’s the monoclonal antibody and it’s targeting TROP-2.

[00:17:23]

TROPION-Breast01: Dato-DXd

And it was approved based on the TROPION-Breast01 trial that showed 37% reduction in disease progression with Dato-DXd vs chemotherapy. This led to its FDA approval for patients with unresectable or metastatic hormone receptor-positive/HER2- metastatic breast cancer after prior endocrine therapy and prior chemotherapy.

So now while the trial met the primary endpoint for progression-free survival, it did not show a significant overall survival benefit. There are several reasons for this. This was a heavily pretreated group of patients, but it is still a good option for hormone receptor-positive/HER2- metastatic disease, especially for patients that don’t have another actionable mutation. Okay.

[00:18:13]

Current ADC Indications and Data From Clinical Trials and Real-World Cohorts

So now I’ll turn this over to Kim. She’s going to tell us more about the indications for the ADCs and how they’re utilized in clinic.

Kimberly Podsada: (UCSD Comprehensive Breast Health Center): Thanks, Elizabeth. And welcome to everyone. I’m glad you were able to make it today. I’m going to be discussing Current ADC Indications and Data From Clinical Trials and Real-World Cohorts.

[00:18:39]

Case Discussion 2: De novo mBC

Our first patient case, a 59-year-old postmenopausal woman was diagnosed with de novo metastatic breast cancer to bones and lymph nodes, ER 30%, PR 10%, HER2 1+ by IHC. No molecular or germline testing was performed. She was started on first-line therapy with a CDK4/6 inhibitor and anastrozole. Repeat staging scans at 3 months showed progression.

[00:19:15]

Poll 4

What therapy should you consider next?

Here are your 4 options. Please choose what you think is most appropriate and I’ll give you a couple more seconds to choose. This is for second-line setting. Polling is now closed.

[00:19:39]

Understanding HER2-Low/Ultralow

So first of all, when we’re thinking about what to choose for our patient in sequencing and next-line therapy, it’s always important to look at those biomarkers and the classification of HER2+—or HER2 breast cancer has evolved beyond the traditional positive and negative. And although that is still common terminology and is still appropriately used, we need to take into consideration this expanded spectrum of HER2 positivity.

If you do look to the right of the slide here, I’m pointing out that HER2 1+ and HER2 2+, those are now considered HER2+ and some patients who have not been eligible for HER2-directed therapy may now be eligible based on this actionable level of HER2 expression, including patients who were initially seen as HER2 0, IHC 0.

Now if we see incomplete staining or faint staining less than 10%, these patients may be eligible for a targeted ADC therapy now, and that’s considered ultralow.

[00:20:47]

ADC Indications in Breast Cancer

We also need to think about the indications and how certain medications or ADCs were approved and in what line of therapy as well. So we’re looking at our patient, we’re thinking about what next line of treatment for her, we’re looking at her HER2 status and now we’re going to look at also the indications.

So initially, right here, I have some bolded points I want to point out. For T-DXd, you can see that it’s been indicated for hormone-positive/HER2-low or ultralow progression after 1 or more lines of endocrine therapy in the metastatic setting.

I also want to point out sacituzumab govitecan, or SG, is now also indicated for metastatic hormone-positive/HER2- breast cancer who have received endocrine-based therapy or 2 or more additional lines of systemic therapy in the metastatic setting. I can also point out here the Dato-DXd as well, but this is more indicated for further lines of treatment and right now we’re thinking about that second-line of treatment.

[00:21:53]

Common AEs Associated With ADCs

We also have to think about common AEs associated with our ADCs. Now Julia’s going to do a much more thorough and beautiful job in the next session, reviewing AEs and managing those AEs. But just thinking about our patient right now and what we might need to educate her about when we’re looking at kind of this broad ADC potential AEs, you can see that nausea is fairly common, fatigue, lab abnormalities, and hair thinning. So these are things we’re going to be discussing with our patient.

[00:22:30]

Newer Approved ADCs in Breast Cancer: Final PFS and ORR

We also need to consider why we are choosing ADCs over maybe a standard of care single-line chemotherapy. So in this slide, what I’m trying to draw your attention to is the ORR and the median progression-free survival of the ADCs in clinical trials compared to the standard of care arm, typically, which has been a single-agent chemotherapy.

So if you just look at that ORR response, you’ll see that more patients are having a partial or complete response to the ADC vs the comparator arm. Also looking at the median progression-free survival as well, you’re seeing that patients have a—there’s a larger number of months that patients are staying on therapy vs the comparator arm.

So for our ADCs, we’re looking at patients having more complete responses, more partial responses, and they’re able to stay on therapy longer before they progress.

[00:23:28]

Patient Case Continued: Discussion, Assessment, and Goals

So we’ve decided that we’re going to start her on T-DXd and we’ve talked with her about her goals and we also need to know a few things about her. She denies a history of ILD or pneumonitis or cardiac instability. She had manageable pregnancy-induced nausea for her first trimester only.

She continues to have a grade 1 neutropenia and anemia from her last therapy, and she has tolerable fatigue with no signs or symptoms of infection. Her chemistry panel is normal but of clinical interest, patients started on T-DXd, it’s important to note that there was a higher incident of grade 1 and grade 2 ILD pneumonitis has been associated and observed with patients with moderate renal impairment.

So labs, of course, are going to be checked every 3 weeks or is clinically indicated. She continues to work part-time and prefers minimal amount of time in the infusion clinic and she’d really like to keep her hair, and so she requests any support for hair loss.

[00:24:35]

Case Discussion 3: De Novo mBC

So again, looking at our patient, she did first-line therapy with CDK4/6 inhibitor and anastrozole. Her second-line treatment was T-DXd. And after 14 months of therapy, metastasis was discovered in her liver and her liver biopsy now revealed ER-, PR-, HER2 0 metastatic breast cancer.

[00:24:59]

Poll 5

So what therapy should we consider for her next?

Please look at the options below. Make your choice. I’m going to give you a few seconds. And so now we’re talking about third-line therapy and she’s now triple-negative. Okay. Polling is closed.

[00:25:25]

Patient Case 3 Continued: Discussion, Assessment, and Goals

So we’ve decided that we’re going to start her on sacituzumab govitecan. And again, we need to talk about her goals. We have to assess how she’s doing, and also discuss side effects that she needs to be prepared for.

So her fatigue level is mild but she has reduced her hours even more to just barely part-time. She’s experienced neutropenia on T-DXd, which was managed with dose interruptions. She did have hair thinning on T-DXd but it was managed with a short haircut. It was considered a grade 1 alopecia so it was not really observable from outside observers, but she did notice hair thinning.

And she now reports increased GI sensitivities which she’s been managing mostly with nutrition choices and as needed medications. But now we need to let her know, after starting sacituzumab, that she should expect grade 2 alopecia, diarrhea, neutropenia. But she wants to extend her life and remain on next-line therapy as long as possible. She feels confident in her ability to manage her symptoms and communicate with her care team, which we know is very important.

[00:26:38]

Treatment Algorithm for mBC

So one of the things to consider when we are looking at that sequencing, which can be challenged as we get into later lines of therapy. Here, it’s kind of doing a really nice visual of showing you let’s lurk at those biomarkers first, hormone positivity, HER2 positivity, or hormone receptor-negative.

For HER2 positives, we really want to think about exhausting all of our endocrine therapies as well as some other targetable therapies, oral therapies. If there are other mutations like an ESR1 mutation or an AKT mutation, then we also need to consider their HER2 testing.

If they’ve been considered HER2-, are there low levels of HER2 expression and she may be available for an ADC? Her HER2 positives have a little bit of better sequencing for us. We know our first-line or second-line. And once we get into third-line, it gets a little more convoluted, but we have several options to choose from.

And then our hormone receptor-negative, consider pembrolizumab, are they BRCA positive? Is there a role for olaparib? And then looking at the HER2 testing as well.

[00:27:59]

Case Discussion 4: Early TNBC

So onto our next patient case. A 35-year-old woman was diagnosed with early triple-negative breast cancer and she received neoadjuvant chemotherapy followed by bilateral mastectomy and BSO due to her BRCA2 mutation. After radiation, she was started on adjuvant olaparib, and after 13 months from completion of adjuvant treatment, she presented with new symptoms and was diagnosed with lung and lymph node metastases. So she was started on first-line therapy with pembrolizumab and chemotherapy. Three months after starting treatment, she reported new and worsening headaches and she was diagnosed with multiple brain metastases by MRI.

[00:28:49]

Poll 6

So next polling question. What therapy would you consider next after whole brain radiation?

Your 4 options are below. Please take a look and consider what you think is the most appropriate therapy now. Polling is now closed.

[00:29:11]

Case 4 Continued: Early TNBC

So we’ve decided to start her on SG as second-line therapy and she reported symptomatic relief after the first cycle. Subsequent brain MRI showed a near-to-complete intracranial response. SG was dose reduced to persistent grade 2 asthenia. And 10 months after starting SG, a systemic disease progression was documented, while intracranial response was maintained.

What’s important also here for our own knowledge as well as to educate the patient about is that SG is not indicated for the treatment of brain metastases.

[00:29:55]

ADCs in Breast Cancer

However, if you look at the bottom line here, it is showing CNS activity is we’re seeing some preliminary activity and penetration to the brain, the CNS with SG, and there is a real-world study also that confirms some of this activity, but again, it’s not indicated at this time to treat brain mets. However, we are seeing on T-DXd that there is CNS activity.

[00:30:28]

Case Discussion 5: HR+/HER2+ BC

So for our final case, a 47-year-old perimenopausal female is diagnosed with locally advanced stage III, strongly hormone-positive, HER2 2+ by IHC, an ISH-negative breast cancer. No genetic mutation, however an AKT mutation was identified. And she started on a CDK4/6 inhibitor and AI with ovarian ablation as her adjuvant treatment.

She struggled with menopause symptoms, diarrhea, neutropenia. And after she progressed on this therapy, so she’s now considered metastatic, she started on capivasertib and fulvestrant and continued on ovarian ablation. After disease progression, she was started on T-DXd.

[00:31:25]

Poll 7

So here’s your next polling question. What would you give as third-line therapy for this patient who is hormone receptor-positive/HER2- metastatic breast cancer?

See your 4 options below. Pick what you think is most appropriate. I’ll give you a few more seconds. Polling is now closed. Thank you.

[00:31:56]

Discussion, Assessment, and Goals

So after each progression, we’re having lengthy discussions with our patients about treatment options and goals and we’ve decided to start her on Dato-DXd. And one of the things we really need to know about her, because we know some of the possible side effects of Dato-DXd, which Julia will be presenting shortly, she lets us know that she already has allergies and uses eye drops and ophthalmic ointment for dry eyes.

She sees an optometrist about every 6 months and she tends to have a seasonal dry irritating cough and uses inhalers as needed but currently doesn’t have any pulmonary symptoms. She denies a history of mouth sores but reports she’s willing to use rinses several times a day in order to reduce the risk of ulcers. She has a good performance status and maintains an active lifestyle and has no other comorbidities.

[00:32:54]

Where ADCs Fit Into HR+ mBC Treatment

So where do all of these ADCs fit into metastatic breast cancer? For our hormone positives, we really want to think about exhausting all the endocrine therapies first as well as any other targetable mutations. Then we need to consider about the HER2 status and whether they were HER2 0 but are technically HER2-low or ultralow and then they may be able to go on to T-DXd.

If they are truly HER2-, then SG or Dato-DXd are also options for them. And then we also need to consider for some of our patients, that may be revisiting a single-agent chemotherapy or an endocrine therapy are reasonable options for symptomatic patients or stable patients wanting a chemotherapy holiday.

Clinical trials are also very good options if they are available and they are eligible. And we also need to keep in mind to continue to check ctDNA for any acquired actionable mutations.

And I want to hand it off to Julia who will review Optimizing Safety and Quality of Life in Patients Receiving ADCs. Thank you.

[00:34:20]

Optimizing Safety and Quality of Life in Patients Receiving ADCs for Breast Cancer

Beth Sandy: Thanks. Actually, Julia, I’m going to take over for a minute and just do your case study and polling question in the beginning and then I’ll hand it off to Julia. So Julia’s going to cover safety and quality of life in breast cancer patients receiving ADCs.

[00:34:34]

Case Discussion 6

We’re going to start off with a case discussion. This is Jane, who is a 48-year-old woman with a history of metastatic triple-negative breast cancer to the lung and thoracic lymph nodes. Her cancer recently progressed on first-line pembrolizumab, gemcitabine, and carboplatin. Her physician recommends second-line sacituzumab govitecan per the ASCENT trial.

You educate Jane about the risks of neutropenia and diarrhea associated with sacituzumab govitecan and she tolerates the first 2 cycles without significant events. While she is receiving her infusion on cycle 3, Day 1, she reports abdominal cramping and diarrhea.

[00:35:13]

Pretest 2

So everybody get ready to vote. This is the pretest question. What is the next most appropriate step for Jane’s abdominal cramping and diarrhea during sacituzumab govitecan administration? Is it:

1. Continue the infusion at its current rate; this is an expected transient side effect;
2. Stop the infusion and notify the MD or NP of possible hypersensitivity reaction;
3. Slow the infusion rate;
4. Administer atropine IV.

So go ahead and vote.

[00:35:44]

Pretest 3

Okay. And then another pretest question. When educating a patient who is about to start therapy with Dato-DXd, which of the following adverse events should you monitor or assess score? Is it:

1. Ocular adverse reactions;
2. Diarrhea;
3. QTc prolongation; or
4. Congestive heart failure.

[Inaudible] Julia, I’m going to hand it off to you now.

[00:36:41]

Similarities and Differences in Safety Profiles of Newer Approved ADCs

Julia LaBarbera (UCLA Hematology Oncology): All right. Sorry about that. Thank you, Beth, and thank you, Elizabeth and Kimberly, for such an interesting discussion. All right. So first, we’re going to talk about key similarities and differences between the newer ADCs used for breast cancer.

[00:37:08]

Administration Considerations for Newer Approved ADCs

The indications for these agents have already been reviewed and are included here for reference. One of the main considerations for treatment selection may be the dosing schedule. Both Dato-DXd and T-DXd are given once every 3 weeks, whereas SG is given on Days 1 and 8 on a 21-day cycle. So this is pertinent for any patient who may have indications for both SG or T-DXd, and may have some limitations in terms of getting to the treatment facility.

T-DXd and SG have similar recommendations for pre-medications which include strong antiemetic coverage, histamine blockers, and antipyretics, if indicated. Dato-DXd premedication include these as well plus prophylaxis for stomatitis and ophthalmic toxicity, which we will explore more shortly.

Unlike Dato-DXd and T-DXd, SG does not carry a risk for interstitial lung disease or ILD. However, all 3 agents carry a risk for hypersensitivity reaction with about a third of patients experiencing infusion reaction with SG. Both T-DXd and SG are given over a longer duration for the first infusion, which can be shortened with subsequent administrations if the patient tolerates the infusion well.

Post-infusion monitoring is recommended for all 3 of these agents, which can also be shortened in duration over time if the patient continues to do well.

[00:38:36]

Sacituzumab Govitecan: Key Adverse Events

I just want to highlight a few key adverse effects to be mindful of each of these ADCs. SG has a black box warning for severe neutropenia and diarrhea, so definitely educate your patients about these effects. Nausea, vomiting, fatigue, and anemia are also very common as well as alopecia.

[00:39:10]

Dato-DXd: Key Adverse Events

Dato-DXd has black box warnings for ILD or pneumonitis, ocular toxicities, mucositis and embryo-fetal toxicity. Nausea, vomiting, constipation, and fatigue, and alopecia are common. And you may also notice changes in liver enzymes and some anemia and mild neutropenia.

[00:39:31

T-DXd: Key Adverse Events

And lastly, for T-DXd, this carries a black box warning for severe ILD, which can lead to death, neutropenia, and left ventricular dysfunction. Common AEs include anemia, nausea, vomiting, bowel changes, and fatigue and alopecia as well.

[00:39:46]

Monitoring and Managing Key AEs

All right. Now we’re going to explore some strategies for managing key side effects for these ADCs starting with neutropenia.

[00:40:00]

Neutropenia With Sacituzumab Govitecan

For SG, we want to be sure to check a CBC prior to each treatment. We want that ANC to be greater than 1500 on Day 1 and at least 1000 on Day 8, and treatment should be deferred until these parameters are met. We’re going to hold the dose with any neutropenic fever and promptly start antibiotics per your institutional policy.

You should also suspect a UGT1A1 mutation in any patient with prolonged neutropenia that is not responding to standard treatment and consider formal testing for this in these cases. Dose modifications are indicated for severe neutropenia lasting a week or more or with any febrile neutropenia.

The first dose reduction is 75% of the original dose, then 50%. Then treatment is discontinued if neutropenia persists despite this. Definitely consider filgrastim or pegfilgrastim as indicated and per your institutional policy to prevent neutropenia and keep patients on track with their treatment schedule.

[00:41:00]

Neutropenia With T-DXd

For T-DXd, neutropenia is not as severe as with SG, but it can still occur. Monitor CBC prior to each infusion. Treatment hold is indicated for any grade 3 neutropenia on Day 1, which is an ANC of less than 1000. Wait to resume treatment until the counts recover to at least a grade 2, which is ANC of 1000 or higher.

Dose hold is indicated for any grade 4 neutropenia, which should actually read as ANC less than 500 here. Again, you want to wait until the ANC recovers to 1000 or greater but then reduce the dose by 1 level once treatment is resumed. Dose hold and reduction is also indicated for febrile neutropenia and the guidelines for dose modifications are included here for your reference.

[00:41:53]

ILD/Pneumonitis With T-DXd and Dato-DXd

So for ILD or pneumonitis, remember, this is associated with both T-DXd and Dato-DXd, but we really don’t see it with SG. The median time to onset is about 4 months after treatment starts. So definitely be suspicious of this with any new respiratory symptom your patient experiences in this timeframe.

As far as monitoring, we want to make sure it’s appropriate to give these agents in the first place. These are not drugs I would choose for someone with a history of pneumonitis from another agent or severe underlying pulmonary disease like advanced COPD. Know your patient’s baseline prior to starting treatment. Monitor oxygen saturation regularly. Get a baseline CT chest and repeat imaging every 6 to 12 weeks on therapy.

If you suspect ILD, don’t delay getting imaging. Promptly start steroids and consider treatment hold to workup the patient. Also consider pulmonology referral for co-management and assistance with the workup and rule out any other potential causes of the patient’s symptoms like progressive disease or infection.

Most importantly, teach your patients about this toxicity and what to look for. I advise all my patients to report any new cough or changing respiratory symptoms like shortness of breath, wheezing, or fever.

[00:43:20]

Management of ILD/Pneumonitis by Severity

Once ILD is confirmed by imaging, treatment depends on the severity. Remember, this applies to both Dato-DXd and T-DXd. For grade 1 or asymptomatic cases, we want to continue corticosteroids of at least 0.5 milligrams per kilogram per day until this resolves to grade 0. If it resolves within 28 days from onset, you can continue the ADC at the same dose, but if it takes longer than that to improve, the dose should be reduced by 1 level.

For any cases grade 2 or above, which is pulmonary changes and symptoms, start steroids of at least 1 milligram per kilogram per day for at least 2 weeks and then taper slowly. The respective ADC treatment should be permanently discontinued with any grade 2 ILD or higher.

[00:44:18]

Management of Acute Diarrhea With Sacituzumab Govitecan

Okay. So for management of diarrhea with SG, strategies depend on the time-to-symptom onset. For any diarrhea that occurs within the first 24 hours of the infusion, this is likely due to the anticholinergic effect and should be managed with IV atropine.

Start with 0.2 milligrams IV every 15 minutes times 2, then continue to give 0.2 milligram doses as needed for a total of 1 milligram. Any diarrhea that starts more than a day after the infusion is likely due to the SN-38 payload itself. Management with loperamide is indicated as directed here, and counsel patients on dietary modifications and increased fluid intake as needed.

For more severe cases, consider high dose loperamide, which is 4 milligrams initially, followed by 2 milligrams every 2 hours. Octreotide may be indicated for cases unresponsive to oral therapy. And, of course, replace fluids and electrolytes as needed.

[00:45:26]

Posttest 2

Beth Sandy: All right, let’s do a voting on our posttest second question. What is the next most appropriate step for abdominal cramping and diarrhea during a sacituzumab administration? Is it:

1. Continue the infusion of its current rate; this is an expected transient side effect;
2. Stop the infusion and notify the MD/NP of possible hypersensitivity reaction;
3. Slow the infusion rate; or
4. Administer atropine IV.

So go ahead and place your votes and then we’ll see how we did in a pre and posttest setting.

[00:46:14]

Posttest 2: Rationale

Okay, the correct answer is D, administer atropine IV. And we can see that 27% of people said that in the pretest and 68% of people said that in the posttest. So very good.

[00:46:31]

Management of Severe Diarrhea With Sacituzumab Govitecan

And then—sorry, I will get to the next question when we get there. Back to you.

Julia LaBarbera: All right. So this is any case of grade 3 diarrhea or higher or grade 1 or 2 diarrhea that’s quickly progressing to grade 3 or 4, we do want to consider a hospital admission for these patients. We want to give IV fluids and octreotide would be indicated 3 times a day subcutaneous or through the IV.

And then consider antibiotics as appropriate, and if there’s an underlying infectious cause for diarrhea. We’re going to hold treatment until symptoms resolve until at least a grade 1 and then we will resume SG with a 1 level dose reduction.

[00:47:20]

Nausea and Vomiting With Sacituzumab Govitecan and T-DXd

All right, for nausea/vomiting management, SG is moderately emetogenic and T-DXd is highly emetogenic. So you definitely want good prophylaxis with a 2 to 3 drug regimen, as outlined here and per our NCCN guidelines. This includes dexamethasone plus an NK1 antagonist and a 5-HT3 receptor antagonist. And you can also consider olanzapine for acute or delayed nausea at any point during the treatment cycle.

Make sure to also provide the patient to have antiemetics at home for any acute or delayed nausea they may experience after the infusion.

[00:48:08]

Stomatitis/Mucositis With Dato-DXd

Stomatitis or mucositis is more prevalent with a Dato-DXd than the other ADCs. About half of participants on the TROPION-Breast01 study developed mucositis and most cases were low grade. In the trial, prophylactic steroid-based mouthwash 4 times daily was recommended but not required. Eating ice chips or holding ice water in the mouth during the infusion can also be used prophylactically.

Criteria for grading severity of mucositis is listed here. Dose holds or reductions may be indicated for severe cases with a lot of mouth pain or impaired oral intake.

[00:48:59]

Ocular Toxicity With Dato-DXd

Ocular toxicity is really specific to Dato-DXd with about half of the patients experiencing some eye-related event in a TROPION-Breast01. The most common events were dry eye and keratitis, but also included blepharitis and increased lacrimation. The median time to onset was 2 months and most cases resolved. Advise patients to use preservative-free eye drops several times a day and avoid contact lenses. Baseline eye exam with ophthalmology is recommended and should be repeated annually while on treatment, at the end of treatment, or as clinically indicated.

[00:49:36]

Management of Ocular Surface Events With Dato-DXd

When evaluating patients for eye toxicity on Dato-DXd, you want to look for any signs or symptoms related to the eyes: redness, increased lacrimation, reports of eye pain, form body sensation, or vision changes. Grading and suggested management strategies are listed here. Dose holds are recommended for symptomatic cases with moderate change in visual acuity. Dose reductions would be needed for significant decline in visual acuity or symptoms that interfere with self-care. And you should discontinue treatment for severe cases of vision loss or corneal perforation.

[00:50:24]

Absolute Decrease in LVEF With T-DXd: Assessment and Management

Like any other HER2-targeted agent, we have to be mindful of decreases in left ventricular ejection fraction with T-DXd. Incidence was low in clinical trials, but there were some grade 3 events in DESTINY-Breast04. So you want to obtain baseline Echo or MUGA scans and repeat every 3 to 4 months or as clinically indicated. I’ve also included guidelines for management based on severity here with dose hold and treatment discontinuation recommended for severe cases such as a decline in ejection fraction of 10 to 20% from baseline or an LVEF 40% or less.

[00:51:03]

Quality of Life Considerations With Sacituzumab Govitecan, T-DXd, and Dato-DXd

Lastly, I just want to touch on a few things related to overall quality of life with these newer ADCs. Remember that fatigue and alopecia were common for all 3 of these agents. For fatigue, I want to encourage adequate nutrition, hydration, and exercise where feasible.

For alopecia, cold caps hasn’t been studied with these agents and is likely not effective given the long half-life these drugs have. Provide your patients with emotional support and validation. Discuss wig resources if desired, and refer to dermatology where applicable.

Remember that our treatment goals with metastatic breast cancer are to balance quality of life with disease control. So it’s really important to understand the impact these side effects have on the patient’s wellbeing and day-to-day life.

[00:51:58]

Posttest 3

Beth Sandy: So let’s take our last posttest question, I believe it’s our last one. When educating a patient who is about to start therapy with Dato-DXd, which of the following adverse events should you monitor and assess for?

1. Ocular adverse reactions;
2. Diarrhea;
3. QTc prolongation; or
4. Congestive heart failure?

Go ahead and put your votes there.

[00:52:41]

Posttest 3

Okay, the correct answer is A, ocular adverse reactions. It’s pretty known for Dato-DXd, of course. We’ll see what our polling results show. So pre-test, 35% of people had said it, and posttest, 52%. Though 25% still said diarrhea, 20% still said CHF. I feel like that was, you know, more of the sacituzumab govitecan that we were talking about earlier. But the ocular stuff is definitely, you know, with the Dato-DXd. So if you want to bring us home?

[00:53:17]

Maximizing Patient Support and Outcomes

Julia LaBarbera: All right. All right, so other ways we can support our patients through long-term treatment is really maximizing supportive care efforts to manage optimal dosing schedule and achieve the best response to therapy. Educate and reeducate patients and caregivers about side effects and management as needed. Provide culturally sensitive care to the best of your ability and identify any potential barriers to treatment adherence, including cost.

[00:53:57]

Patient and Caregiver Education for ADCs

This slide just kind of provides a summary of the signs and symptoms we should be teaching our patients to report when on these ADCs. Also, consider providing your patients with a wallet card, indicating the type of treatment they’re on and your office contact information in case of emergency.

[00:54:14]

Shared Decision-making

It’s important to involve the patient in the decision-making process when determining the most appropriate therapy. Encourage patients to voice their priorities when it comes to the next treatment, whether it’s to achieve disease control or the reduction of disease burden or avoid AEs or the number of supportive measures needed to manage quality of life.

Remember, each person has their own limit on what they’re willing to tolerate or accept from systemic therapy to achieve disease control. And we have to remain cognizant of that to meet the individual’s needs.

[00:55:02]

Navigating the Healthcare Ecosystem: Addressing Potential Healthcare Disparities

A lot more can be said about addressing healthcare disparities than we really have time to address in this talk, but it’s important to be mindful of our own beliefs and implicit biases when interacting with patients. Remember that people of color and women have historically been underrepresented in clinical research, and we need to work together to improve this.

Utilize members of the healthcare team whenever possible to provide education and access to resources to empower patients to take charge of their health.

[00:55:38]

Panel Discussion: Questions from the Community

All right, so we have some questions for the panel that we are going to address as a group. I’ll just start with the first one. Why does the risk of ILD vary so much between ADCs? Kimberly or Elizabeth, do either of you want to take a stab at this?

Elizabeth Diaz: Yeah, I can answer that. So I don’t think we are really sure why exactly, but mainly it’s due to, I think, the drug structure. We see a much higher rate of ILD, like you said with T-DXd, it’s about 12% and Dato-DXd, it’s 4% vs, like you said, SG, we don’t really see it.

And with TDM-1, even though it’s HER2 directed, I think it was very minimal, like 1 or 2%. So, the main reason is we think that probably that exatecan payload that’s used with T-DXd and it has to do with it having a cleavable linker. So a little bit more chemo leaks out, it’s a very potent drug. And then there’s some other factors such as, you know, there’s always patient risk factors to watch out for: prior respiratory disease, COPD, smokers. But I don’t know, Kimberly, if you have any other thoughts on that.

Kimberly Podsada: I completely agree with you.

Julia LaBarbera: Yeah, I think to our best understanding, this seems to be somewhat related to like an off-target effect of these agents because it’s not just something we see with the HER2-directed ADCs, we’re also seeing it with Dato-DXd and TROP-2 directed therapies. So probably something we’ll be learning about the longer these drugs are out.

All right. Do you test for UGT1A1 polymorphisms in patients starting sacituzumab govitecan?

Kimberly Podsada: We don’t actually do that. Patients can declare themselves without having that information of being very highly sensitive. And because it is a low polymorphism, we don’t tend to test everyone in advance.

Julia LaBarbera: Agree. That’s the policy of my institution as well. And I do think patients declare themselves usually pretty quickly that neutropenia really does not recover with your standard efforts. Should atropine be given as a premedication for all patients starting sacituzumab govitecan?

Elizabeth Diaz: We don’t do that at our institution. Of course, if they’re having abdominal cramping or diarrhea during the infusion, or if you see them back in clinic and it was really severe, you know, probably within 48 hours of that, then we’ll add atropine to the next infusion.

Kimberly Podsada: Absolutely. I agree as well.

Julia LaBarbera: Yeah, the atropine was not given prophylactically in the clinical trials, so it’s not something that we typically do at our institution either. I am seeing some providers start to do it prophylactically, more and more, with the assumption it kind of can’t hurt the patient, but clinically speaking, it was not used that way in clinical trials.

[00:59:20]

Poll 8

Beth, do you want to move on to the last polling questions?

Beth Sandy: So let’s do the last polling question. Do you plan to make a practice change in patient care based on what you learned today?

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

[00:59:43]

Poll 9

And then please take a moment to enter one key change that you plan to make in your clinical practice based on this education.

[00:59:48]

Question and Answer Session

Beth Sandy: And then while we do that, I’ll take a couple questions here and then we’ll wrap up. There’s a question from Debbie, who I’ve known for 20 years. Hi, Debbie. She sent this question in during the Dato-DXd discussion. So I think that’s the drug she’s referring to. If dose reduction, if symptoms resolve, would an increase back to the previous dose level be appropriate?

Julia LaBarbera: So typically with any dose reduction, you don’t typically go back to the starting level that you were at just because of concerns for safety. But that’s really a discussion between the patient and their provider. You know, because I think it’s more of an individualized case by case basis where you might consider, you know, administering more drug with the potential to cause that toxicity again or any newer toxicity. So that is an individualized choice, but not the typical recommendation to re-escalate the drug once it’s been dose-reduced.

Beth Sandy: Kimberly or Julia, do you have any comments?

Kimberly Podsada: Yeah, I was going to say that I agree with that in that, you know, again, we’re doing that balancing act of effective treatment, quality of life. And so if someone’s symptoms have actually improved and at a lower dose, I think we have pretty good data now and most of these and many of these studies and that they will come out in later updates about how dose reductions also were effective and that we really need to balance that cancer destruction as well as quality of life. So at our practice, we don’t currently go back up.

Elizabeth Diaz: And I agree. At our practice, we usually wouldn’t dose escalate either, just because of the risk for a more severe toxicity and cumulative toxicity. I’m trying to think of maybe drugs that we—that I—we ever do that with would be more maybe like oral TKIs—not for breast cancer, for other cancers. You know, maybe you’d play around with something oral that you could quickly lower the dose back. But yeah, we wouldn’t typically re-escalate most of the IV therapies that I can think of.

Beth Sandy: Yeah, I agree with you guys. I don’t treat breast cancer, I treat lung cancer, but the only time we ever dose escalate is if we started someone low because we were worried about toxicity and then they did really well, we might, but if I dose-reduced due to toxicity, it would be rare that I would go back up.

One last question with Dato-DXd. Does your institution utilize steroid eye drops as prophylaxis for ocular toxicities?

Julia LaBarbera: So we don’t, we use the preservative-free eye drops really, like as much as the patient needs it, and only unless we’re starting to see some, you know, keratitis or eye pain or discomfort do we start steroid eye drops. So we’ll see how this evolves, but it wasn’t indicated as prophylaxis in the clinical trials.

Julia LaBarbera: Right. We will do the oral rinse, though. We do strongly recommend even though it was not something that they recommended you must do. We tend to really strongly encourage that for our patients.

Elizabeth Diaz: Us as well, we would recommend the lubricant eye drops and not use the steroid eye drops unless they had, you know, keratitis or developed the toxicity.