Expert Discusses Navigating Toxicities, Understanding Antibody-Drug Conjugate Adverse Events

In an interview at the 2023 San Antonio Breast Cancer Symposium, Heather McArthur, MD, clinical director of breast oncology at UT Southwestern Medical Center, discusses the toxicities associated with antibody-drug conjugates (ADCs) used in breast cancer treatment. Each ADC comes with its own set of challenges, ranging from neutropenia to interstitial lung disease. McArthur emphasizes the importance of individualized patient assessments, early identification of toxicities, and proactive interventions to support patient adherence and quality of life.

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Q: What are the common toxicities associated with antibody-drug conjugates used in breast cancer treatment, and how do they differ from toxicities associated with traditional chemotherapy?

Heather McArthur: Each of the antibody drug conjugates has a unique toxicity profile. They often mimic, actually, the payload that they're derived from. So for example, sacituzumab govitecan, which has an SN-38 payload is derived from a derivative govitecan and neutropenia is the biggest issue with that antibody drug conjugate which has, trastuzumab deruxtecan. Nausea and vomiting is a major clinical issue and requires for drug prophylaxis with one of these novel agents like dato dxd, which is also a trope to directed antibody drug conjugate. Stomatitis or mucositis is a side effect of clinical concern and requires prophylactic mouthwash so they each have individual issues.

There's a misconception that interstitial lung disease is a class effect; it’s really not, so that hasn't been an issue with sacituzumab govitecan. For example, it has been an issue with trastuzumab deruxtecan, but with more frequent conservative monitoring, we've been able to identify early issues early on, and it's less common with drugs like [datopotamab deruxtecan] (dato dxd), for example.

Q: In the context of ADCs, what are the key considerations in assessing a patient's baseline health and comorbidities to anticipate and manage potential toxicities effectively?

Heather McArthur: It really depends on the drug that's under consideration and the individual patient characteristics and their comorbid conditions. Someone who has a lot of lung metastasis burden or who has a background of severe [chronic obstructive pulmonary disease], I might be more reluctant to use an antibody drug conjugate that has a interstitial lung disease side effect, for example. Some of these drugs have significant liver toxicity as well, and so it really depends on the individual patient and the set of metastases and their underlying comorbid conditions. It's often a discussion. I mean, it's wonderful that we have so many options now for these patients that we have the opportunity to have these discussions. Patient preferences is obviously critically important as well.

Q: What should health care providers be looking for to recognize and report early signs of potential toxicities associated with ADCs for breast cancer?

Heather McArthur: trastuzumab deruxtecan, for example, which has the interstitial lung disease potential toxicity issue, if you have grade 2 or higher interstitial lung disease on that drug, you have to permanently discontinue. So early identification of grade 1 toxicity is critically important. That is asymptomatic radiographic interstitial lung disease. If you can treat that disease at the grade 1 level with steroids and bring it back down to grade 0, then you can effectively rechallenge, they’ve shown that in the DESTINY Breast trials that you can do that. Early identification and early intervention is really critically important.

Q: What strategies can pharmacists and other health care providers implement to monitor and manage infusion-related reactions associated with ADCs in breast cancer treatment?

Heather McArthur: Most of these treatments come with specific recommendations for prevention of infusion reactions. I think our pharmacist infusion nurses are very familiar with infusion reactions that are not specific, of course, to this class of drugs, so I think just adherence with the prescribed recommendations for prevention are critically important.

Q: How can the toxicity profile of ADCs impact patient adherence to treatment, and what interventions can pharmacists and health care providers implement to support patients in managing and coping with treatment-related side effects?

Heather McArthur: Because these drugs are infusion drugs, they're all [intravenous] medications. There is some degree of control over adherence because patients have to, obviously, come to clinic and receive the infusions. Prophylaxis, I think is critically important. So for example, with trastuzumab deruxtecan, the 4 drug prophylactic regimen to prevent nausea is critically important and has a big impact on patients desire to continue therapy with some of the novel agents like the Trop-2 directed antibody drug conjugate dato dxd, dexamethasone, or steroid mouthwashes are critically important to prevent stomatitis or mucositis from occurring. [These] need to be continued throughout the duration of exposure to treatment. So just being really proactive about intervening early on to prevent those potentially devastating events from occurring so that patients can continue on comfortably, because of course, quality of life is our primary concern together with extending survival.

Q: How can a multidisciplinary care team collaborate to ensure a comprehensive approach to toxicity management in patients receiving ADCs for breast cancer treatment?

Heather McArthur: I think that everything that we do now is really multidisciplinary. It's really not me functioning in isolation. It's collaboration with pharmacist, with nurses, our nurse practitioners, and everyone outside of our immediate clinical environment. There has to be awareness in the emergency room, for example, about some of these common side effects, and we've learned that with immunotherapy, for example, so there's still that education that's ongoing. Communication is obviously critically important.

Q: How can health care providers approach dose modifications and manage interruptions to manage toxicities while maintaining the efficacy of ADC treatment in breast cancer?

Heather McArthur: There is very specific guidance for essentially every drug that is available for administration. For example, trastuzumab deruxtecan, the 5.4 milligrams per kilogram is the starting dose. If you have a grade 1 interstitial lung disease event that's treated and resolved, so comes down to grade 0, then you can rechallenge at the lower dose level 4.4 milligrams per kilogram. If you need to do that, again, there's a second dose reduction to 3.2 milligrams per kilogram. There are very clear specific guidelines around dose reductions for very specific clinical situations.