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

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.

 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.

Videos

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.

T-DXd for HER2+ Metastatic Breast Cancer

Komal Jhaveri, MD, FACP, attending physician, Memorial Sloan Kettering Cancer Center, clinical director of the Early Drug Development Service, assistant professor of medicine, Weill Cornell Medical College, discusses the importance of outlining the first-line treatment course for patients with HER2-positive breast cancer.

 metastatic HER2-positive breast cancer, outlining the potential plan for their entire course of treatment can be overwhelming, says Jhaveri. As such, it may be beneficial to focus on first-line therapy. The same can be true for patients who develop advanced-stage disease where treatment options are more palliative than curative, Jhaveri explains. 

One standard frontline option for patients with advanced-stage disease is the combination of paclitaxel or docetaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta), Jhaveri says. 

Typically, patients receive the chemotherapy backbone until maximal response, Jhaveri explains. This occurs after about 6 months of weekly paclitaxel or 6 to 8 cycles of docetaxel. Then, patients receive maintenance trastuzumab/pertuzumab, Jhaveri concludes.

Komal Jhaveri, MD, FACP, discusses the importance of outlining the first-line treatment course for patients with HER2-positive breast cancer.  



Dr. Jhaveri on Outlining First-Line Treatment in HER2+ Breast Cancer 

Komal Jhaveri, MD, FACP, a section head within the breast medicine service at Memorial Sloan Kettering Cancer Center, discusses the use of trastuzumab (Herceptin) biosimilars in breast cancer.

The trastuzumab biosimilar data, presented by Hope Rugo, MD, showed that the biosimilar trial designs for bioequivalence were met when compared with reference trastuzumab, explains Jhaveri.

The purpose of biosimilars in breast cancer is to have similar efficacy of original trastuzumab for patients, without the financial toxicity many approved agents cause, says Jhaveri. The financial toxicity can be very difficult for certain patient populations, especially in countries outside of the United States, concludes Jhaveri.

Komal Jhaveri, MD, FACP, discusses the use of trastuzumab biosimilars in breast cancer.

Komal Jhaveri, MD, FACP

Articles

Managing Patients With MBC on T-DXd Therapy

T-DXd for HER2+ Metastatic Breast Cancer

Dr. Jhaveri on Outlining First-Line Treatment in HER2+ Breast Cancer

Dr. Jhaveri on the Use of Trastuzumab Biosimilars in Breast Cancer