Kevin Kalinsky, MD, MS, is a professor and director of the Division of Medical Oncology in the Department of Hematology and Medical Oncology at Emory University School of Medicine; and the Louisa and Rand Glenn Family Chair in Breast Cancer Research and director of the Glenn Family Breast Center at Winship Cancer Institute of Emory University in Atlanta, Georgia.

Komal Jhaveri, MD, FACP, is the section head of the Endocrine Therapy Research Program, clinical director of the Early Drug Development Service, and Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center

 In the remaining minutes, I want to go around the Zoom room and have everybody conclude with 1 clinical pearl or takeaway for those who’ve checked in [late]. I’m going to start with Allison, then go to Kandra, and then I’ll end with Komal.

 That’s a lot of pressure with 1 pearl. I was thinking sequencing and how the algorithm is going to fall into play is what’s interesting to me. These drugs keep moving earlier into the treatment algorithm, so we’ll see potentially targeted therapy be our first-line approach. Even in the neoadjuvant space, getting rid of chemotherapy as we know it and seeing where we go with more targeted agents.

 I’m excited about seeing some of the promising trials looking at triple-negative [breast cancer] and the impact with the target therapies. Also, the patients with hormone receptor–positive breast cancer with the 

 [human epidermal growth factor receptor 2] new and negative components and the impact of that. That’s exciting. There’s more room to grow and impact our patients.

 I second both comments from Allison and Kandra. This is a very active class of agents. They’re here to stay. We’re trying to get version 3 and 4 to improvise their use, to tackle their toxicities better—how can we improve outcomes by combining them better? With the DESTINY-Breast03 trial, for example, there were 16 complete responses in those patients. We’re beginning to cure some patients with this class of agents and these novel agents. In combination with, say, I/O [immuno-oncology], even in the first line or the utility up front they can help us achieve that, so I’m looking forward to a bright future. Hopefully we’ll see even better outcomes for our patients.

 I totally agree with these assessments. This question about the HER2-low population is a really interesting question. Going back to 1 of the things Allison said early on, we know that some of these targets are active targets, like

 and TROP2, and how the structure of the ADC [antibody-drug conjugate] can lead to different toxicities and adverse effects. This is an ever-evolving field, and where we are now is going to be different from where we’re going to be in 3 to 5 years. This is a moving target, and that’s exciting for us and our patients.

I want to thank Komal Jhaveri, Allison Butts, and Kandra Horne for joining us. This has been a great and active conversation. Thank you, everybody, for joining this panel discussion.

Videos

Clinical pearls regarding ways to integrate antibody-drug conjugates into treatment algorithms when managing patients with breast cancer.

Breast Cancer Treatment: Sequencing With Antibody-Drug Conjugates 

 Kandra, in clinic, how have patients tolerated the therapy? Talk us through some of the toxicities you’ve seen with some of these patients.

 For the most part, our patients have been tolerating this treatment pretty well. If you look at the ones who’ve been treated, they’ve been heavily pretreated. Some of those patients have neutropenia. You’ve probably seen the counts affected from previous treatments, fatigue, and what it looks like to be a patient with metastatic breast cancer. We see this sooner than later. Even though we initially start with day 1 and day 8, there are times where we’ve been able to switch the schedule to day 1 and day 15 to protect the counts. Sometimes we add something like Neulasta [pegfilgrastim] to support their counts. But that’s because these patients were heavily pretreated. There’s been fatigue and some nausea, but more commonly fatigue and neutropenia have been the adverse effects that we mostly see with these patients.

 In all the patients I’ve treated with this agent, everybody lost their hair. Have any of you treated somebody who’s not had alopecia with this?

 Allison, are there any other strategies for mitigating some of these toxicities? Kandra mentioned the fatigue, and certainly that’s something we see in clinic, and growth factor support is sometimes needed. Have you seen any other issues, such as significant gastrointestinal issues, where you needed to escalate beyond oral medications?

 Not escalating beyond oral medications, but it’s important to consider the pharmacology: the cytotoxic payload of sacituzumab is SN38. If you figure you’re giving the active metabolite of irinotecan, it’s not surprising that GI [gastrointestinal] toxicities will come into play. In my experience, it’s been cycle by cycle, honestly. We haven’t seen consistent diarrhea. It will flare up 1 cycle and not be too much of an issue the next. Fortunately, we’ve been able to manage that with oral medications.

The other adverse effect I want to mention that hasn’t been talked about is infusion reactions with this agent. With this drug, the first dose has to be given over a 3-hour period. Subsequently that could be 1 to 2 hours. It’s recommended that we premedicate with antihistamines, antipyretic, and corticosteroids to try to limit that effect. Fortunately with those premedications, I haven’t seen any infusion reaction. It seems to be doing well, but that’s a consideration in terms of scheduling, patient acceptance, etc.

 Kandra raises a good point: these are adverse effects that we see in a heavily pretreated population as this drug moves up. We’ll see whether the grade of fatigue is the same. Allison, when you were talking about premedications, for the antiemetics commonly utilized, do you find that most are using IV [intravenous] antiemetics and then de-escalating if patients aren’t having any nausea? Institutionally, how are things commonly practiced?

 Most institutions that I’m aware of are using oral antiemetics and treating it as a moderate medical potential drug, which is appropriate. Fortunately, we haven’t seen a lot of nausea. Our GI toxicities have been more diarrhea related, and the premedications we’ve been using have been successful.

 Komal, how do you start with antiemetics?

 My experience has been a little like Allison’s. Sometimes I’ve seen the hypersensitivity reactions. We obviously follow the 3 hours, but you’ll very rarely still see a patient struggle, and you’ll have to optimize the Benadryl [diphenhydramine] and the steroid as premedications during infusions. Diarrhea is something I’ve seen often, plus a lot of alopecia. For nausea, as I said, for patients who struggle more with nausea, we’ve been giving palonosetron during the infusion; otherwise, they’ve been getting ondansetron as needed every 8 hours. But for the diarrhea and the neutropenia…sometimes we’ll have to do dose reductions even if there’s struggle. But neutropenia, diarrhea, and alopecia are the top 3 adverse effects.

 Kandra, any other clinical pearls about this agent before we move on?

 No. Looking at the patient from where they are and the indication when they’re coming in, you’ve raised a great point in stating that as the indication has changed, where might this medication be at a further line, such as second line or later on with the heavily pretreated patients. That might make a difference in regard to some of the toxicities they’ve been experiencing.

 I agree. This agent is being evaluated in the operable setting, and we a have study that’s combining this with immunotherapy. Komal had mentioned that we’ll see whether the randomized phase 3 trial leads to an approval of patients with hormone receptor–positive vs negative disease, because the phase 1/2 basket studies show the same efficacy in that population compared with triple-negative [breast cancer]. Hopefully, we’ll see some of those data [soon].

Strategies that can be used to mitigate and manage adverse events associated with sacituzumab govitecan therapy for triple-negative breast cancer.

Sacituzumab Govitecan Safety Profile in TNBC 

 This patient returns to clinic for follow-up, and she’s experiencing nausea and fatigue. Kandra, do you have any thoughts about some of the adverse effects that Komal mentioned, or about some of them being easier to manage than others? Do you have any thoughts about nausea and a good antiemetic regimen for when we’re starting with this agent in patients? Maybe address some of the other adverse effects that Komal mentioned, just in terms of fatigue or hair loss or anything else you’re seeing in the clinic besides the pulmonary toxicity that we’ve highlighted.

 Komal did such an excellent job in describing that in great detail.There’s a patient who stands out clearly to me because she was doing great on her prior therapies. Then we placed her on T-DXd [trastuzumab deruxtecan], and she declined physically: severe fatigue, some nausea, and her counts dropped a little. She started experiencing alopecia, which was emotionally devastating for her. We dose reduced her, which was helpful as far as her being able to continue with therapy. It was so mentally and physically debilitating for the patient, she was just concerned she wasn’t going to be able to continue with the treatment. That’s 1 particular patient who stands out to me. For the most part, we need to know ahead of time that these symptoms can occur, make sure that there’s an antiemetic regimen available, talk to patients, and know how to manage adverse effects.

 As you were mentioning that case, it made me think of a case that we had in clinic. We had an older patient who had metastatic 

[human epidermal growth factor receptor 2]–positive disease who had large pleural effusions and was short of breath. It can be difficult if somebody has symptomatic lung issues to figure out if it is a result of the drug or the disease. Sometimes it can be a hard to distinguish. Kandra, any other clinical pearls that you have for management of T-DXd [trastuzumab deruxtecan] in clinic?

Just to make sure that we look at the patient holistically and see what their performance status is. For the most part, when we’re placing our patients on these drugs, we started at the standard dose of 5.4 mg/kg. Optimize the patient from the beginning of the treatment, and allow the patient to look for these symptoms and adverse effects, such as the ILD [interstitial lung disease], which can be symptomatic and severe to the point that they don’t minimize the cough. Be able to recognize that early on so it won’t develop into something more serious.

 Allison, Komal, any other pearls you’d like to mention? The other thing that I wanted to highlight: Komal mentioned DESTINY-Breast03, as we saw updates on these data at San Antonio [Breast Cancer Symposium]. For the small population of patients who have CNS [central nervous system] metastasis, there seems to be some clinical activity in the CNS. Are there any other clinical data or pearls that you have for providers who are utilizing this agent?

 I was going to say 1 that Kandra brought up, hair loss, because for a lot of our patients, that’s a major issue. Unfortunately, for a lot of our patients, they’re well maintained on HP [trastuzumab, pertuzumab] for quite some time. For a lot of them, this will change, but they had been on T-DM1 [trastuzumab emtansine] for quite a while and had regained their hair at that point. It can’t be overlooked how important thinning hair is for these patients. It’s a little unpredictable, as Komal said. But it’s a delayed hair loss, and it’s something we certainly need to discuss with patients for whom this might come as a surprise.

 I was just going to say the same thing, that I’ve learned that overpreparing a patient for alopecia goes a long way compared with not mentioning or forgetting to mention that. Fortunately, most of my patients don’t end up having it. When they do have it, sometimes the hair starts growing back, which is also very weird. They stay on therapy, but the hair is growing back. I’m still trying to understand who develops it, why they develop it, and how it comes back—that happens, but it happens less often. I haven’t had grade 2 alopecia, and fortunately I haven’t had ILD clinically in my standard-of-care practice. Those 2 have been good for us. Kandra, I’m curious about your patient with nausea who you had to dose reduce. Did that come on quickly, or was it after awhile? Was it a chronic thing that needed dose reduction?

 I agree that nausea has been something that I felt like has been more predominant and accurately reported as 1 of the most common adverse effects. That’s the first thing that patients report—and fatigue. In terms of a clinical pearl, here’s a quick 1: I had a very young woman with gorgeous hair, an African American woman with great locks of hair. I had scared her about alopecia to be honest, because I didn’t want her to feel shocked if it came. Fortunately, she did not have hair loss, but she progressed through at least 6 lines of therapies, most recently with neratinib and capecitabine. Tucatinib wasn’t approved at that time, and she was on a clinical trial at our institution [Memorial Sloan Kettering Cancer Center]. She had this open wound in her breast, like a breast mass, which was the main issue. The rest of her disease was OK, but that mass was uncontrollable.

We started on T-DXd [trastuzumab deruxtecan], and after the first dose, it had completely healed. It remains healed, and she remains on T-DXd [trastuzumab deruxtecan] and still has her hair. It has been very gratifying to see that she’s got a good stretch. She recently did have a little progression again in the breast, but I was able to get palliative radiation therapy to the breast, and she remains on therapy. I think it’s an active drug. We have to be vigilant about certain toxicities. Some are common, and some are rare but could be fatal. If we’re vigilant about these and support them, then it’s a great therapy.

Strategies used to help monitor and manage T-DXd treatment-related adverse events.

Managing Patients With MBC on T-DXd Therapy 

 Let’s move along with this case. Her treatment course was complicated when she started to experience peripheral neuropathy, and she completed 9 of 14 cycles. Komal, how often do you feel like you see this in practice?

 About 20% to 25% of the time, I see this issue where some patients end up struggling with peripheral neuropathy more than others. It’s hard for patients to have a lot of treatment up front, whether it’s 6 cycles of TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] or AC-THP [doxorubicin hydrochloride, cyclophosphamide, docetaxel, trastuzumab, pertuzumab], plus whatever residual neuropathy they might have from the taxane-based therapy, and then 14 cycles thereafter. About 20% to 25% of the time, I end up seeing that. Many times I have either delayed a dose or done dose reduction to 3 mg/kg from the approved dose of 3.6 mg/kg to try and help them with this issue. Sometimes we resort to medications that might not have the best data supported by randomized trials. I’m sure Allison can speak more to that. We’ve tried gabapentin or, in some patients, duloxetine. There’s no great randomized sham control data for acupuncture either, but I see that as the least invasive approach to try to help a patient to get through this without issues. Sometimes I refer them for acupuncture as well, as long as they get that covered by insurance. Some patients do it out of pocket. Those are the things I see with neuropathy in T-DM1 [trastuzumab emtansine].

 Unfortunately, 6 months later, she’s found to have liver lesions and a biopsy-confirmed metastatic 

[human epidermal growth factor receptor 2]–positive disease. The patient goes on to receive T-DXd [trastuzumab deruxtecan] once every 3 weeks on a 21-day cycle. Komal, talk us through counseling points you have when talking with patients about T-DXd [trastuzumab deruxtecan].

 With T-DXd [trastuzumab deruxtecan], the first thing we talk about in terms of expected adverse effects with patients is nausea. At our institution [Memorial Sloan Kettering Cancer Center], we do standing palonosetron at the time of the infusion along with dexamethasone as a premedication. We also offer ondansetron as needed for nausea, because nausea is something we see with this agent. Fatigue is another thing I warn them about. And I talk to them about the possibility of alopecia. We had seen a lot more alopecia in DESTINY-Breast01, but we’re not necessarily seeing a lot of that in practice. It probably [depends on] prior therapies and preexisting alopecia these patients had. I’ve been counseling them because we’re not able to predict which patient will have it vs which patient won’t. It’s better to discuss that with the patient.

Most important, after these 3, I educate them about the risk of interstitial lung disease or pneumonitis. With that, I want them to report any dry cough that’s lingering around more than usual, any extreme fatigue that some patients present with, and any worsening shortness of breath that’s limiting their daily activities of living. I keep a close eye on the radiological findings as well to see if there are any ground-glass opacities that sometimes imaging can point toward pneumonitis. We do that with our nurses as well, who are the first line of defense and who take these phone calls from these patients when patients call in to report their symptoms. These are a few things that I discus with our patients when we start them on T-DXd [trastuzumab deruxtecan].

 Komal, are there any known predictors for ILD [interstitial lung disease] as an adverse effect? Do you do anything preventively? Do you check PFTs [pulmonary function tests] or anything like that in these patients?

 Excellent questions. We’ve tried to see a lot of retrospective analyses to answer that question. Can we identify who might be at more risk? There were some indicators that a decline in renal function or GFR [glomerular filtration rate] might be able to predict which patients get this. Surprisingly, we didn’t see patients who had baseline lung metastases, who might be at higher risk for pneumonitis. We didn’t see that in the retrospective evaluation of patients who’ve received T-DXd [trastuzumab deruxtecan]. Patients with lung cancer who get the therapy might be at higher risk; we just don’t know. For breast cancer, with lung metastases in the retrospective evaluation, we did not see that as a big risk factor.

We did see that with a higher dose. Fortunately, the 5.4 mg/kg was better off than the 6.4 mg/kg. Maybe higher dose or multiple prior lines of therapies can potentially put a patient at higher risk. But now that we have data for DESTINY-Breast03, we’re trying to utilize our good agents early on. I’m hoping that’s what is translating into less events. Certainly the vigilance that we as a community of oncologists, patients, and nurses have together—and knowing to intervene and look for this trouble sign sooner—has helped reduce the grade 4 and 5 events in DESTINY-Breast03. It’s a combination of all those. There are no data necessarily to support that you should be looking for diffuse lung capacity or PFTs to identify which patient might be at a higher risk.

Having said that, I do that for all my patients who start T-DXd [trastuzumab deruxtecan] as a way of having a baseline. If a patient did end up having interstitial lung disease or pneumonitis, and we do a PFT at that particular time, we don’t have a baseline to compare. What if they had interstitial disease at baseline? This is an area of active research, and hopefully with more efforts we might be able to come up with something that might help us identify this risk better. But my practice has been to do it.

 Allison, at your institution [University of Kentucky HealthCare], do you have other strategies for monitoring interstitial lung disease being implemented or instituted in the clinic?

 Komal laid it out nicely. At our institution, we are not monitoring PFTs at baseline or at any point during treatment. It’s an interesting area of research to understand more about how we might implement that. It’s interesting to hear that your practice is doing that. But yes, educating the patient is extremely important to explain the signs and symptoms and how important it is that they report those so we can promptly initiate steroids and begin a work-up to get them on treatment.

 Kandra, at your institution [Winship Cancer Institute], have you seen providers checking baseline PFTs?

 No, I haven’t. We haven’t been doing it.

 That reiterates the point that this is something to be very mindful of. We’ve learned with experience to be careful and to express to patients the importance of looking for shortness of breath and to let us know if they’re having a cough or anything like that, because if patients are having grade 2 or higher events, we should be stopping the agent.

Recommendations for starting a patient with HER2+ metastatic breast cancer on T-DXd after prior T-DM1 therapy.

Allison Butts, PharmD, BCOP

Articles

Breast Cancer Treatment: Sequencing With Antibody-Drug Conjugates

Sacituzumab Govitecan Safety Profile in TNBC

Managing Patients With MBC on T-DXd Therapy

T-DXd for HER2+ Metastatic Breast Cancer