Fundamentals II: Identifying and Managing AEs of TROP-2, HER2, and HER3 ADCs

          T-DXd: FDA-Approved Indications

So Kim already addressed this area, which is just looking at the history of trastuzumab deruxtecan and how it came into its FDA approved indications. So I won't go through it in too much detail. But just as a reminder, we have it approved in multiple FDA indications, including HER2-positive metastatic breast cancer, HER2-low metastatic breast cancer, HER2-positive gastric and gastroesophageal junction adenocarcinoma, HER2-mutated non-small-cell lung cancer, and in HER2-positive solid tumors.

[00:41:42]

          DESTINY-Breast04: T-DXd-Related AEs

So in my practice, most commonly I'm using a trastuzumab deruxtecan in the hormone – hormone receptor positive HER2-low metastatic breast cancer setting. So I'm going to use DESTINY-Breast04 as my example to look at the most common adverse events that we are seeing with this therapy.

The – just for refresher, the DESTINY-Breast04 was a phase III trial that involved those patients with HER2-low metastatic breast cancer who had received one or – one or two previous lines of chemotherapy, and patients were randomly assigned to trastuzumab deruxtecan or investigator's choice, physician's choice chemotherapy.

So in looking at the T-DXd arm, as you can see, that nausea was the most common adverse event at 73% of patients. That was then also followed by fatigue, alopecia and vomiting, neutropenia, anemia, decreased appetite, thrombocytopenia, increase in transaminases, leukopenia, diarrhea, and constipation.

When looking at grade 3 events, most common were neutropenia and fatigue and nausea as well, and leukopenia.

So the most common treatment-emerging adverse events associated with dose reduction in the setting was nausea and fatigue. And most common reason for discontinuation of treatment actually on the trastuzumab deruxtecan was interstitial lung disease and pneumonitis in 8.2% of patients, which we'll discuss in a [inaudible].

[00:43:13]

          DESTINY-Breast04: Drug-Related TEAEs by Age

So in looking at the breakdown by age of the adverse events that we see with using trastuzumab deruxtecan, the treatment-emergent adverse events remained consistent among patients that were less than 65 years of age and greater than 65 years of age as well. Although there was a higher incidence of interstitial lung disease and treatment discontinuation for interstitial lung disease or any reason was seen in the patient population above the age of 65.

So this is important to note when looking at your patient population who's getting started on this treatment regimen, especially one when you're educating about adverse events, but also when monitoring for toxicity that might require drug discontinuation.

[00:43:56]

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

So in looking at the multiple – the pooled data across the DESTINY-Breast trials and looking at adverse events, it was relatively consistent in regards to the gastrointestinal side effects.

So as you can see, nausea continues to remain the most – most common side effect. And it's important to treat these patients with primary prophylaxis to prevent nausea. T-DXd is classified as a moderate emetic potential, although it appears to be on the high end of the moderate category, actually most closely resembling that of carboplatin.

Diarrhea is also observed in approximately one third of patients, but is rarely greater than grade 2. Grade 3 or higher neutropenia was relatively uncommon among these trials in the adverse event monitoring.

[00:44:47]

          ASCO Antiemetic Guidelines Update 2020

So in review of the antiemetic guideline update in 2020, you know, as we're looking at our patients who have this moderate to high emetic potential, we want to think of how we're prophylaxis these patients to make sure that they're able to tolerate safely and stay on therapy. Although that the – the drug is categorized as a moderate, but on the higher end of the moderate emetic risk, in my practice, we are actually offering patients a four drug combination regimen with an NK1 receptor antagonist and a 5-HT3 receptor antagonist, dexamethasone and olanzapine to make sure that we're giving proper nausea prophylaxis in these patients.

I will say that there has been an evolution of how I have prophylaxis, nausea in patients receiving T-DXd over my experience with the drug and therefore initially was treated more in the moderate category, and I found it's – I'm getting better control with my patients using the high emetic risk combination regimens to really prophylax them for nausea in this category.

[00:45:57]

          Assessing and Grading Nausea and Vomiting

And just as a reminder of ourselves, how do we assess our nausea and vomiting? Because we know most commonly we're seeing our patients with anywhere from grade 1 to grade 2 nausea in our practice when receiving treatment. But it's pretty difficult for patients when they are having consistently having grade 2 nausea, they're pretty uncomfortable. So we want to make sure that we're trying to be as proactive as we can to prophylax them and keep them comfortable and safe on this regimen.

[00:46:27]

          ADCs: Interstitial Lung Disease

So important thing to talk about when referring to treating patients with T-DXd is the concept of interstitial lung disease. So lung toxicity is a – is frequent with oncology drugs including taxanes and anthracyclines.

Interstitial lung disease is characterized by ineffective gas exchange due to alveolitis, disrupted alveolar structures, and fibrosis. The specific mechanism with ADCs is unknown, but theories include target independent uptake of payload in the immune cells, bystander effect of the release payload, damage from circulating payload after release, and early diagnosis and intervention are important to prevent – are important to averting a serious outcome. In

looking at the comparison to other ADCs, you can see that there is a higher incidence of ILD with T-DXd compared to the other HER2 ADCs looking in the range of about 10% to 15% of all grade ILD, and in the range of 0% to 2% for fatal ILD events, depending on the trial that we are evaluating.

[00:47:36]

          T-DXd: Occurrence of Treatment-Related ILD/Pneumonitis in Phase III Trials  

So in looking at the treatment-related ILD and pneumonitis in all – in the phase III trials using T-DXd across tumor type, including the DESTINY-Breast, Lung and Gastric trials, you can see that across the trials, ILD incidence of any grade was in the range of 10% to 15% when T-DXd was specifically dosed at 5.4 mg per kg.

There was a higher rate noted in the DESTINY-Lung02, when the T-DXd was just at a higher dose of the 6.4 mgs per kg. So again, important to be aware when your patients are on T-DXd to educate and monitor for this serious potential adverse event.

[00:48:18]

          Strategies to Manage ILD Associated With T-DXd

Strategies to manage ILD associated with T-DXd is, first, we want to monitor these patients very closely. So first we want to suspect. You know, we want to urge our patients to immediately report cough, dyspnea, fever and/or new worsening pulmonary symptoms to us. We want to monitor them closely and promptly investigate and evaluate for any evidence of ILD.

We want to evaluate them with radiographic imaging and assess very closely. We want to assess including imaging such as high resolution CT scan. We potentially will refer for pulmonary consult, if indicated. Infectious disease consult, if concerned that we also have an infectious process going on. Rule out other infectious possibilities with blood cultures, blood counts and other blood tests as needed. If indicated, consider bronchoscopy and BAL, if feasible.

We can also evaluate by looking at pulmonary function tests and pulse oximetry. Arterial blood gases have indicated. And as soon as ILD is suspected, can consider doing pharmacokinetic assessments, if feasible, but also ruling out other causes of ILD.

We know our patients may have had radiation in the past due to history of breast cancer or other cancers that might be in the lung field area. Are they on any other drugs that could also be causing ILD that we need to consider. And all ILD events should be followed until resolution and after drug discontinuation. Pardon me.

For grade 1 ILD, we want to hold until resolved to grade zero and consider corticosteroid treatment if indicated. If a patient resolves in less than or equal to 28 days from the onset, we can maintain that dose. But if resolves in greater than 28 days after onset, we will need to reduce the dose by one level.

But for any grade or 2 – grade 2 to 4 ILD, we do need a permanently discontinued treatment and promptly initiate systemic corticosteroid treatment, such as greater than 1 mg per kg per day of prednisone, or equivalent for greater than or equal to 14 days, and then followed by a taper. In this setting, we're generally having a pulmonary medicine also monitor and assessed.

[00:50:30]

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

So a way to detect and manage is to really think of the five S rule. We want to screen our patients with careful patient selection prior to even starting T-DXd, optimize monitoring strategies according to baseline – according to their baseline risk. Ongoing screening is continued throughout treatment, with regular clinical evaluations to detect signs and symptoms of ILD.

We want to scan our patients, so particularly with that high resolution CT scan as the primary diagnostic method for ILD. A baseline scan is recommended and followed by imaging every 6 to 12 weeks. Commonly this does correlate with disease status assessments, but sometimes it doesn't depending on clinical practice. So we do need to remember that although a patient might not be due for disease staging with imaging to remember to screen them for ILD, with imaging.

Synergy. We want to reduce the risk of ILD. It requires teamwork, it involves patient education on the front end, training the entire care team to recognize signs or symptoms of ILD. And then multidisciplinary management once ILD is suspected, such as involving the pulmonary medicine team.

We want to suspend treatment with the T-DXd should be stopped immediately, if ILD is suspected and only resumed once asymptomatic ILD has completely resolved. And again, corticosteroids remains the primary treatment of choice for T-DXd-induced ILD, with the dosage being according to the severity of the toxicity.

[00:51:55]

          Assessing and Grading ILD

And as a reminder, what is grade 1 pneumonitis? So that's asymptomatic. So that's only with clinical or diagnostic observations. So commonly that's where we're seeing a change on imaging before the patient is presented with any symptoms.

It is only in this setting that it is considered appropriate to resume T-DXd after resolution. Because grade 2 to 3 or 4 ILD we would permanently discontinue. And that's once anybody is presenting with symptoms and then is confirmed ILD based on the further evaluation.

[00:52:33]

          Managing Neutropenia With T-DXd

Neutropenia, also a common adverse event with T-DXd. So we want to educate our patients on the potential for neutropenia. Usually it is low grade, but we want to monitor CBC with differential before starting T-DXd and before each dose – before each dose and as clinically indicated.

The median time to first onset of neutropenia is 16 to 21 days. And we have to manage this with dose holds, reductions and potential use of growth factor. We want to hold, if the ANC is less than 1000 or a patient develops febrile neutropenia, dose reduce for grade 4 neutropenia or grade 3 febrile neutropenia.

We want to discontinue if there is a third dose reduction needed, and consider managing with G-CSF or consider G-CSF prophylaxis if there is a history of prior neutropenic complications.

[00:53:18]

          Monitoring Left Ventricular Dysfunction With T-DXd

We know that left ventricular dysfunction can occur with T-DXd with HER2 – anti-HER2 therapies, and it has been seen with T-DXd, including this medication here. So we want to assess the ejection fraction prior to initiation of T-DXd and at regular intervals during treatment, as clinically indicated.

In our higher risk patients, we may need to assess troponin and BNP at baseline or assessing every couple cycles to monitor that people are not having cardiotoxicity with this drug.

[00:53:54]

          T-DXd: Dosage and Administration Strategies

And looking at our dosage and administration strategies, here we have listed how the dosages are started depending on tumor type. So for breast cancer, non-small cell lung cancer and solid – and HER2 positive solid tumors, we are starting dosing at 5.4 mg per kgs every 3 weeks.

And then in the gastric cancer at 6.4 mg per kg every 3 weeks. All dosing strategies would have prophylactic antiemetics recommended. And then dose reductions are listed here for reference for toxicities and management.

[00:54:31]

          Sacituzumab Govitecan: 3 FDA-Approved Indications

So now moving to sacituzumab govitecan. As Kim had mentioned earlier, there are 3 FDA-approved indications, though now the third urothelial cancer – cancer being withdrawn. So we're really focusing on those patients in the triple negative breast cancer metastatic setting and the hormone positive HER2-negative breast cancer metastatic setting.

[00:54:58]

          TROPiCS-02 Trial of SG vs Chemotherapy in HR+/HER2- MBC: Safety Summary

So in looking at the TROPiCS-02 trial, which was a trial that looked at sacituzumab govitecan versus chemotherapy in the HR-positive, HER2-negative metastatic breast cancer setting, here's the safety summary listed.

So there were 74% of patients who received um sacituzumab govitecan had treatment-related adverse events that were greater than or equal to grade 3. So that was a reasonable amount where we're seeing that we need to monitor and educate these patients for, which we'll discuss in just a moment the particular AEs we need to monitor.

There were, excuse me, 6% of patients that actually had to have discontinuation of drug related to adverse events. 66% of patients requiring dose delays, 34% of patients requiring dose reductions. Also 28% of patients having serious adverse events and 2% of patients with adverse events that led to death.

[00:56:02]

          TROPiCS-02 Trial of SG vs Chemotherapy in HR+/HER2- MBC: Most Common TEAE

Looking at the most frequent adverse events of any grade with sacituzumab govitecan versus chemotherapy, 71% of patients who received the sacituzumab govitecan drug had neutropenia, compared to only 55% of patients on the chemotherapy.

We also saw a rate of 62% of patients having diarrhea, 59% of patients having nausea, 48% of patients having alopecia, and 37% of patients having anemia. The most common grade 3 or worse treatment-emergent adverse events were neutropenia at 51% vs 39% in the chemotherapy alone –vs sacituzumab vs chemotherapy. And diarrhea in 10% vs 1%.

[00:56:48]

          TROPiCS-02 Trial of SG vs CT in HR+/HER2- MBC: Treatment-Related Adverse Events  

Treatment-related all-grade neuropathy was observed in 9% of patients on sacituzumab in the – vs 16% in the chemotherapy group. And there were no cases of pneumonitis in the sacituzumab group.

Febrile neutropenia at greater than grade 3, however, was at a slightly increased rate at 5% in the sacituzumab govitecan group.

[00:57:19]

          Treatment-Related AEs With SG

The safety data was consistent and also the ASCENT trial, which looked at metastatic triple negative breast cancer, where we saw also biggest most common side effects being neutropenia, as well as seeing diarrhea also with our highest rate of grade 3 and grade 4 events again being in neutropenia and diabetes – neutropenia and diarrhea in this trial as well.

[00:57:46]

          Management of Common and Potentially Severe Toxicities Associated With SG

So how do we manage these common and potentially severe toxicities associated with sacituzumab govitecan?

So first of all, neutropenia. We do want to suspect that there is UGT1A1 28 genotype if there is prolonged neutropenia or unresponsive to treatment. So if you recall this was also a genotype that we saw in patients receiving irinotecan therapies, which we know is – has the SN-28.

The SN-38 was a payload in the sacituzumab govitecan, which is similar. So therefore we can see that similar toxicity kind of come across here. So we want to monitor regularly and withhold if the ANC is less than 1500 on Day 1 or less than 1000 on Day 8 or for neutropenic fever.

We want to manage with G-CSF and dose reductions for grade 4 neutropenia lasting greater than or equal to seven days, or grade 3 febrile neutropenia. And we want to use anti-infective treatment and prophylaxis in patients with febrile neutropenia.

For diarrhea, prophylaxis is not recommended unless there is a prior history of diarrhea. But it's really important to educate our patients about taking loperamide prior to first dose. And – and that is an option but also to early treat. So for any – for earlier diarrhea of any severity though, you do want to administer atropine as a potential cholinergic response.

For late diarrhea, we want to rule out infectious etiologies and administer loperamide. We also want to manage with fluids electrolyte substitution, dose reductions and withhold for greater than or equal to grade 3 diarrhea until resolution.

For nausea or vomiting, we do want to premedicate with 2 to 3 drug regimen, including steroid 5-HT3 receptor antagonist or NK1 receptor antagonist. Onset may be delayed, so it's important to – that patients are educated on this and are provided with a prescription for antiemetics to have at home.

And you can manage their nausea, potentially with dose reductions, and withhold if there is a high grade. Hypersensitivity to the drug, can occur within 24 hours of dosing. All grade – 37% occurred of all grades in reactions of hypersensitivity, with only 1% occurring as a grade 3 or 4 hypersensitivity reaction.

We want to premedicate patients receiving sacituzumab govitecan with antipyretics, histamine 1 and histamine 2 blockers and corticosteroids for patients with a history of prior infusion reactions. We want to observe patients for at least 30 minutes after each infusion, and have emergency equipment available for immediate use during and after infusion.

[01:00:32]

          Assessing and Grading Diarrhea

So, as a reminder, you know there is a risk for severe diarrhea while on sacituzumab govitecan. So it's important to educate your patients and to be aware when dose interruptions and reductions are necessary, and to educate our patients of taking antidiarrheals to help support them while on this therapy.

[01:00:56]

          Counselling Patients Receiving SG

We want to educate patients on this treatment about hair loss often complete, and we do want to offer prescription for a wig. We want to educate patients to recognize adverse events that require also urgent intervention. So as discussed hypersensitivity can occur. So we want patients to call immediately if they're having any symptoms of anaphylaxis such as facial lip or tongue swelling or difficulty breathing.

We want them to call if they're having urticaria, pruritus or rash, lightheadedness, dizziness, chills, wheezing, hypotension – hypotension, flushing, or fever onset within 24 hours. We also want to educate them on the severity of diarrhea that if they develop any black or bloody stools, if they were concerned that they're developing symptoms of dehydration, their inability to take fluids by mouth due to nausea, or if they're having onset of vomiting or diarrhea within 24 hours of prophylaxis, to make sure we're having close observation and immediate intervention.

[01:01:52]

          SG: Dosage and Administration Strategies

Here I'm showing the starting dose of the sacituzumab is at the 10 mg per kg dosing on Day 1 and Day 8 of a 21-day cycle, and monitoring for 30 minutes after infusion for hypersensitivity reactions. And then the dose reductions are listed. And again, this is in the setting of metastatic breast cancer previously treated for advanced – for triple negative breast cancer or hormone receptor positive HER2-negative disease.

[01:02:19]

          Sacituzumab Govitecan and the UGT1A1*28 Genotype

So as discussed before, so the UGT1A1 is the enzyme that metabolizes the SN-38 payload of the sacituzumab govitecan. And gene polymorphisms can result in reduced enzyme activity and increased toxicity.

The Diplotype 28/28 is a poor metabolizer and associated with an increased risk of discontinuation of the drug due to toxicity without a correlation to disease progression based on the mutation status.

So early UGT1A1 may identify patients at risk for excess toxicity, and therefore we can initiate early dose reductions that may prevent early drug discontinuation. In the TROPiCS-02 trial, they did find that the patients treated with the sacituzumab govitecan, 38% of patients had wild type, 44% to 44% of patients had the heterozygous type, and 9% of patients had that homozygous type, which was associated with being a poor metabolizer. So 9% of those patients were associated with having the increased risk of excess toxicity.

[01:03:31]

          Investigational ADC-Based Strategies in Late-Stage Clinical Development

Now we'll shift into discussing some of the investigational ADC-based strategies in the late – and those in late-stage clinical development. So Kim had spoken about a couple of these new agents with their same target but different structure or a novel target.

So we're mostly going to focus on 2 ADCs here. So we'll discuss the TROP-2 ADC datopotamab deruxtecan and the novel target HER3 ADC with the patritumab deruxtecan. ADCs with currently FDA approved indications are also under investigation in other malignancies, both in the first-line and early-stage settings in metastatic settings and in combination with immune checkpoint inhibitor therapies.

[01:04:17]

          Common (in ≥30%) and Dose-Limiting/AESI Toxicities Associated With Sacituzumab Govitecan vs Dato-DXd

So in first looking at the datopotamab deruxtecan, this image here kind of shows the differences of what types of adverse events that we can see in terms of common dose-limiting toxicities and adverse events of special interest for us to kind of discuss.

So we have already gone through the adverse events commonly seen with sacituzumab govitecan. So I did want to point out that with the Dato-DXd that we are also seeing alopecia in 30% of patients – 32% of patients. Nausea is also common, as well as neutropenia is also common in the Dato-DXd treatment.

But special interest adverse events that we are seeing also is ocular events, stomatitis and mucositis, and also seeing interstitial lung disease in this drug category as well.

[01:05:12]

          Assessing and Grading Mucositis

So as a reminder of how we assess and grade mucositis is, we're looking really at that spectrum of the patient who is asymptomatic or having mild symptoms, but doesn't really require intervention to moving through that spectrum of those who have pain and limitations to the oral intake.

So we want to familiarize ourselves with mucositis, how to manage and how we can help treat our patients to help keep them on therapy and – and help manage those adverse events.

[01:05:40]

          Management of Stomatitis/Mucositis Associated With Datopotamab Deruxtecan

So what we're looking for is, you know, looking at their lips and their mucosa, are they appearing redder than normal? Are we seeing visible sores on the oral mucosa? Are they just having pain which then can affect chewing and swallowing. And are they having issues with their taste?

So in our ability to grade mucositis, we then can approach are we capable of maintaining the dose? Do we need to consider dose delays or reductions? And do we need to delay until we're seeing resolution to less than or equal to grade 1 or baseline, and also making sure that we are instituting supportive medications and that they're already optimized before we're hopefully not getting to the point where we're having grade 4 toxicity, where we're having to discontinue the drug.

[01:06:30]

          Supportive Care and Management of Stomatitis/Mucositis

So supportive care management of stomatitis and mucositis, you know, is we want to tell our patients to avoid spicy or highly acidic foods, soft or liquid diets, artificial salivas, topical anesthetics such as viscous lidocaine, mouth rinses, and oral liquid dexamethasone to, you know, help decrease that inflammation.

[01:06:57]

          Management of Ocular Surface Toxicities Associated With Datopotamab Deruxtecan

Another unique adverse event that we were seeing with the Dato-DXd was the ocular surface toxicity. So we're looking for dry eyes and keratitis. So assessing our patients for eye redness, stinging, burning or scratchy sensation, that feeling of having something in your eye changes to their tearing or discharge from the eye, or inability to open their eyelid due to pain and issues with decreased vision.

So it's really important that we'll have to, you know, have a multidisciplinary team to assess these patients and potentially have a good collaboration with ophthalmology for assessments and helping manage side effects and understanding our dose reductions and how to really keep these patients safe and on appropriate treatment.

[01:07:45]

          HERTHENA-Lung01 Trial of Patritumab Deruxtecan (HER3-DXd): Safety Summary

Shifting over to the HER3 ADC with the patritumab deruxtecan. Just in using the HERTHENA-Lung01 trial to look at the safety summary.

This showed that the most common side effects was nausea seen in this particular ADC. And then going down, you can see also a lot of thrombocytopenia and neutropenia, those of which having the most frequent greater than grade 3 – grade – greater than or equal to grade 3 toxicity in that category, really seeing those cytopenias. But also still seeing, you know, patients having issues with GI toxicity, including decreased appetite, diarrhea, vomiting, also seeing changes to their labs as well as fatigue on this ADC.

Also of note, there was an increased incidence of ILD on this ADC compared to others that we've looked at as well. So it's important to know that the majority of ILD events on in the HERTHENA-01 one and also seen in the 02 trials were grade 1 and grade 2, but there were two grade 5 ILD events in the HERTHENA-Lung02 and one grade 5 event in the HERTHENA-Lung01 trial. So that's important to know that on this ADC, also needing to monitor for that ILD as well.

[01:09:11]

          Assessing and Grading Alopecia

Alopecia can be common with ADCs, and it's important to discuss that with your patients up front because although in – when we're grading alopecia, we really only have 2 grades, grade 1 and grade 2. And it's really hard to explain to somebody that, oh, grade 1 alopecia, hair’s thinning, but greater than 50 – less than 50% hair loss. But if someone has, you know, 45% hair loss on an ADC, that can be particularly devastating. So it is really important to educate our patients on these ADCs about the risk of alopecia, even when it is grade 1, just so they can be prepared. And you can offer them a prescription for wig as well.

[01:09:50]

          Alopecia in HER2, HER3, and TROP-2 ADCs

And looking at the pooled data across all of these ADCs that we've discussed, there is an overall risk of alopecia of any grade on all of them, as you can see in the T-DXd of 34%, the Sacituzumab govitecan of 45%. And then in looking at the TROPION-Breast01 data, we saw 36% of alopecia in the Dato-DXd and in the HERTHENA-Lung01, 25% of alopecia in the patritumab deruxtecan.

[01:10:20]

Let's Revisit a Couple Questions

So let's go back and revisit our pretest questions and see how we've done.

[01:10:27]

          Posttest 2

So again a patient on T-DXd presents with new moderate shortness of breath, dry cough and a pulse oximetry reading of 89% on room air. An updated CT scan of the chest shows new diffuse ground glass opacities suspicious for ILD. How would you proceed? Would you:

1. Continue treatment, but start prednisone at greater than or equal to 1 mg per kg per day and refer to pulmonary for further management;
2. Interrupt treatment and start prednisone at greater than or equal to 1 mg per kg per day and resume once symptoms resolved;
3. Interrupt treatment and start prednisone at greater than 1 mg per kg per day and resume once symptoms resolved and imaging is normalized;
4. Permanently discontinue treatment and start prednisone at 1 mg per kg per day.

Please answer now. So looks like it's still across the board, but the – with the T-DXd, it is important to note that grade 2 to grade 2. So grade 2, grade 3 or grade 4 pneumonitis. It is recommended to permanently discontinue treatment. So this patient has a low pulse oximetry – pulse oximetry reading at 89%. And they are symptomatic. So it is important that you would permanently discontinue treatment and start high dose corticosteroids and work with your pulmonary team to make sure they're treated appropriately and tapered over a slow taper to ensure recovery.

[01:12:12]

          Posttest 3

So for our posttest question here. A patient is started on sacituzumab govitecan for HR-positive HER2-negative metastatic breast cancer. What serious events should you discuss with your patient prior to initiation?

1. Mucositis and ocular toxicities;
2. Neuropathy and interstitial lung disease;
3. Neutropenia and diarrhea; or
4. Ocular toxicities and skin rash.

Please answer now. Excellent. Everyone is – is learning about neutropenia and diarrhea with sacituzumab govitecan.

[01:13:00]

          Posttest 3: Rationale

So we do know that severe or life-threatening neutropenia and diarrhea has been observed in treatment and Sacituzumab govitecan actually does have a black box warning discussing this.

[01:13:15]

          Skill Building and Feedback II: AE Recognition and Management

Kristi Kay Orbaugh: Before you start, just so you can answer this, I saw a question pop up in the questions and answer that wanted your opinion on ordering MUGAs or echos.

Sara Cooper: I don't have a strong opinion. It's usually based on what you have access to. I mean, the most important thing is we want to see that ejection fraction we're worried about, you know, that challenge on that – on that ventricular wall. So the ejection fraction is the – the – the – the toxicity that we're looking out for.

So I think if you are able to keep your patients on treatment by readily getting access to MUGAs to get that ejection fraction, I think that's reasonable. And if you have access to an echocardiogram where you can evaluate a little closer, especially if someone does develop any shortness of breath or other toxicity, you have a little more data to look for other causes. I think that's also helpful.

And then I saw there was another question in here. If you use olanzapine, do you absolutely avoid using compazine as well? I've heard conflicting info.

I'm not commonly using compazine as a premedication. I'm using the 5-HT3 antagonist. So I'm not commonly having to run into that challenge, but we do worry about, you know, combination of antiemetics in the QT prolongation issues that we're seeing across the board with all of our antiemetics and treatments. Some of the compazine for breakthrough.

I'll use compazine for breakthrough, but usually not at the same time.

Kimberly Podsada: Right. And as far as the – the – because of the, you know, T-DXd being highly emetogenic, I – we also at our facility use the four-drug regimen. But we also have found, and I don't know about you that – that nausea tends to decrease over – over time maybe either just with the – getting used to the medication or maybe that's something that's just normal for – for that drug.

And definitely baseline echo, and then the indication doesn't actually say to do it every three months like a trastuzumab does. But we tend to do it fairly frequently for the every three to four months for the first year or two. And then we go out to every six months.

Sara Cooper: Yeah. Especially for our patients who have had prior anthracycline as well, you know, increase their risk. So it's really important to kind of individualize your plan per patient. And it's really interesting that you brought up the four-drug regimen. I have seen an evolution in treating our patients. I think we all originally started treating them with a two-drug regimen or a three-drug regimen. And it just – I think we started two drug regimen. And it was very clear from the beginning it was not enough.

And so I would rather overtreat and scale back because of the challenges that we were seeing patients have.

Kimberly Podsada: Yeah, absolutely.

Kristi Kay Orbaugh: I'm like you, Kim. We tend to use more of a four-drug regimen. And for the question about using olanzapine and compazine, I think my big concern would be I wouldn't mix those. I'd worry about extrapyramidal effects. We do use a lot of olanzapine and have really good success with it. But we don't – we don't use it in combination with compazine.

Sara Cooper: I find I use a little more lorazepam sometimes for nausea when I start, but then I also worry about, you know, how sedating are we? I'm typically only giving olanzapine for a couple days after T-DXd. So therefore, when patients are having breakthrough, it's usually when they're not on the olanzapine anymore.

Kimberly Podsada: Right. And there's a question then about what we use for breakthrough nausea and vomiting. And so I – I too use – I think we – we use olanzapine five to seven days. And then for breakthrough nausea, I send them home with compazine and zofran. So, you know many patients prefer the ondansetron. But then you have to monitor for the constipation.

And I do have more patients that use compazine that have the extrapyramidal side effects. So again, there's always something to – to treat or balance.

Sara Cooper: Yeah. So let's go to our skill building and feedback, because maybe this will also bring in some questions. Because I did see across the board some differences on all – the ILD response as well of how patients – how people are treating their patients who may have developed either asymptomatic or mild ILD.

You know, we talked about nausea and vomiting on this patient as – well, let's read the case first. I apologize.

So Ms. Thomas is a 62-year-old woman with a diagnosis of HR-positive, HER2-low metastatic breast cancer. She's starting treatment with T-DXd for progression in her liver. Her medical history includes type 2 diabetes on metformin and high blood pressure on HCTZ. She has a history of severe nausea during pregnancy and has never been on chemotherapy.

So first let's – we've talked about nausea. Would you counsel this patient in any specific way about nausea on T-DXd?

Kimberly Podsada: Well, I do find that women that have had nausea with pregnancy, that tends to be something that they are more prone to. So definitely going to educate her a lot about nausea and prevention and being proactive and taking prescribed medications and taking as needed medications as well. And to just again, stay in really good communication with us because what if we need to bring her in for hydration and checking electrolytes?

Sara Cooper: No, I. Agree with the history of the pregnancy-related nausea. I find that always to be that little red flag and making sure there's that extra education and extra touch points. How – how would you screen her for ILD? Do you find that we – that you’re scanning every six weeks or just at disease intervals? How would you be screening for that?

Kristi Kay Orbaugh: We're scanning every 12 weeks unless clinically indicated sooner.

Kimberly Podsada: Yeah, same here.

Kristi Kay Orbaugh: We are consistent with every 12 weeks.

Kristi Kay Orbaugh: Just to kind of circle back to the nausea and vomiting, I really appreciate that. We were talking about pregnancy and how, you know, being nauseated during pregnancy really increases your risk. But also remember, motion sickness is another little red flag that we need to be aware of.

If patients say – you know, I'll ask my patients, can you ride in the back of a car and read and not get sick? Or can you – you know, can you ride on a roller coaster? Although I guess that's extreme, but that will also kind of give you some indication as to whether the patient's going to have some nausea. And I think there's data that supports the – the motion sickness as well.

Sara Cooper: And then alopecia. So the reason I wanted to bring this one up is I feel that when T-DXd first came on the market, there was almost this education of, oh, it's just hair thinning that we weren't – that you weren't expecting this significant alopecia. And I've had a fair number of patients with devastating alopecia and devastating hair loss while on treatment, which really did shift how I educate patients while starting this drug, that it is variable, that not everybody loses their hair.

But it's important that I prepare patients. What about – what about you, Kim and Kristi? How are – how are you approaching this subject with your patients?

Kristi Kay Orbaugh: Well, just to kind of give it a more personal feel. I have a very good friend on this drug, and she's doing great. She has no evidence of disease, but she's also a little bummed that she's spending all of her time vault. I mean, that's – that's difficult for her. So I do think that this discussion, before you start, you know, make sure you've got your scarves, make sure you've got your hats, make sure you've got your wigs in case you need them.

Kimberly Podsada: Yeah. And like you were saying, you did a good job of, you know, describing the grade 1 and grade 2. A grade 1 for us is, you know, that textbook, oh, it's just hair thinning, I can't see it. You know, no one from the outside can really see it, but it's really what the patient is saying and what the patient is feeling and what they're noticing and – and their comfort level. And so, yes, I always educate my patients about the risk of alopecia.

And – and then we'll give them a list of – of local shops if they want to go and look at some things or – or just a prescription for a wig, you know, just – just to get, like you said, prepare them.

Sara Cooper: Yeah. I want to move on to the next page – next slide. But I did get an interesting question. Cold capping. So someone asked, do you tell your patients to cold cap? So I did a literature search on this recently, and I could not find any data supporting that there's evidence that there's a benefit of cold capping. So I do educate patients and say you can try, but in terms of asking them to put forth the cost and the time, I don't encourage patients to cold cap.

Kimberly Podsada: I think in the metastatic setting, it is more challenging because they are on this therapy indefinitely for as long as it's working. It - it does become very expensive. And – but at some point with cold caps, you meet the deductible and you've paid all this money, and then it's really just a matter of – of patients preference, whether they want to keep – keep doing it or not.

Sara Cooper: Yeah.

Kristi Kay Orbaugh: It also requires that they bring people with them, or at least at our clinic. We – we don't care if people cold cap per se. We don't encourage or discourage, but we also can't allow the nurses, our infusion nurses to be – you know, to be utilized in applying the caps and such. They have to have a support person with them.

Kimberly Podsada: We – we actually have the chairs in our clinic. So they –

Kristi Kay Orbaugh: How cool.

Kimberly Podsada: It's really cool. It's – it's really nice. Again, not covered by insurance yet, but it makes – it makes it much more streamlined for the patient. And no other person is involved.

Sara Cooper: Well, I want to move on to our next patient, because that way we can get on to Kristi's fabulous presentation.

But this is looking at Ms. Johnson, a 55-year-old woman with a diagnosis of HR positive, HER2-negative metastatic breast cancer starting treatment with sacituzumab govitecan, has a serious adverse event of diarrhea during cycle one on day nine of her regimen. She calls with seven diarrhea episodes per day feeling weak. How are you managing this patient? Would you suggest dose adjustments? And how would you have responded if she had had diarrhea at the time of infusion versus on day nine?

Kristi Kay Orbaugh: Well, if she had diarrhea at the time of infusion, and she's on – she's on saci, then we're going to definitely give her atropine because you're having a cholinergic reaction. So that's totally different than I guess I'll call the delayed diarrhea or the run of the mill diarrhea.

Kimberly Podsada: I'd be interested to ask either of you too. Do you always prophylax with atropine, or do you wait for them, the patient, and see if they have an anti – or have a cholinergic reaction?

Kristi Kay Orbaugh: At our particular clinic, we don't start people out pre-treating them with atropine. But if they have that reaction. But I do hear a fair amount of clinics, that's just part of their pre-treatment for that drug.

Kimberly Podsada: I do not prophylax.

Sara Cooper: I mostly – I mostly educate and respond and then I know some prophylax even just Imodium – excuse me, loperamide, you know for any diarrhea but I don't prophylax, I educate and say at the first sign, go ahead and start that loperamide. And then, you know, follow closely.