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As newer options become available for treating breast cancer, clinicians must recognize and manage associated adverse events (AEs).

Although the antibody-drug conjugate (ADC) trastuzumab emtansine (TDM-1; Kadcyla) has been FDA approved for more than a decade, the field is still adapting to two new ADC options: trastuzumab deruxtecan (T-DXd, Enhertu) and sacituzumab govitecan (Trodelvy). Checkpoint inhibitor pembrolizumab (Keytruda) has recently gained indications in triple-negative breast cancer (TNBC) as well.

T-DXd and Interstitial Lung Disease

"T-DXd is an ADC targeting the HER2 receptor with a cleavable link attached to a payload of topoisomerase I inhibitor," explained Mridula George, MD, of the Rutgers Cancer Institute of New Jersey in New Brunswick. "Because the cleaver is easily hydrolysable, it can cause a bystander effect responsible for killing of the tumor cells but also for some of the toxicities associated with the drug."

Many toxicities are familiar ones: nausea, fatigue, and neutropenia.

"Nausea may be one side effect that patients need help with," said Kelly E. McCann, MD, PhD, of UCLA Health in Los Angeles. "I have had patients describe a low-grade nausea that goes on for 2 weeks. We are having to learn that these chemotherapies, when attached to an antibody, are more slow releasing."

The AE of particular interest with T-DXd is interstitial lung disease (ILD) or pneumonitis. A 2022 of drug-related ILD and/or pneumonitis from nine trials of T-DXd across various cancer types showed an overall incidence of about 15%.

"The median onset of ILD is about the 5- to 6-month mark and the fatality rate is about 2.2%," George said. "This is a serious side effect and clinicians should be aware of it when using this drug," she stressed.

George detailed the five "S" rules to manage and mitigate ILD:

• Screen patients based on baseline risk for appropriate use of T-DXd, and continue screening during treatment
• Scans, and high-resolution CT in particular, are a fundamental diagnostic tool for ILD
• Synergy is needed among the treating team and should include multidisciplinary management, including a pulmonologist
• Suspend treatment if ILD is suspected
• Steroids are a mainstay treatment for T-DXd-induced ILD

McCann pointed out that ILD can prove "challenging because a lot of the patients we see may already be short of breath because they are anemic, have lung metastases, or other comorbidities."

"You do have to rule out other things but, for me, I have a low threshold for screening," she said.

Sacituzumab Govitecan

This Trop-2-directed antibody and topoisomerase inhibitor has a similar payload to T-DXd but has quite different AEs, said McCann, who noted that patients treated with sacituzumab govitecan are more likely to lose their hair and experience severe myelosuppression.

"The majority of patients will need filgrastim or peg-filgrastim for neutrophil support, and many will require dose-reductions to avoid blood transfusions, particularly for patients being treated in the later-line metastatic setting," she said.

George said that patients treated with sacituzumab govitecan can also experience serious hypersensitivity reactions, including life-threatening anaphylactic reactions.

"This can happen up to 24 hours after treatment and in up to 37% of patients, with 1% being grade 3 or 4 reactions," she explained. "Given that this can happen in up to one-third of patients, there is a need for premedication with antipyretics or antihistamine blockers."

Ocular Toxicities

Another unique set AEs linked with some of the newer ADCs in clinical trials are ocular toxicities including dry eye, conjunctivitis, or blurred vision.

McCann said that learning about these AEs was a challenge.

"For several of our clinical trials, patients were introduced to a regimen of three different eye drops and asked to place cold packs on their eyes during infusion. Ophthalmology was definitely outside of my oncology training," McCann said, adding that she feels lucky to have an ophthalmology clinic at her center where she can refer patients.

Pembrolizumab

Pembrolizumab is currently approved for early-stage high-risk TNBC for patients who require neoadjuvant therapy; in combination with chemotherapy for a subset of patients with metastatic TNBC; and for the treatment of any metastatic breast cancer that is microsatellite instability-high or that has a tumor mutation burden greater than 10 mutations per megabase.

"We are using checkpoint inhibitors more often now compared with 2 years ago, especially in patients with early-stage breast cancer," George said. "The side effects of pembrolizumab are more immune-mediated, and patients can develop side effects either while still receiving therapy or even after completion."

McCann recalled working with a patient who had visited her primary care physician with an odd constellation of symptoms.

"She had remarkably normal labs but was having severe fatigue, dizziness, nausea and vomiting, weight loss, abdominal pain, and urinary incontinence a couple of months after completion of chemotherapy with pembrolizumab. The patient requested antibiotics for frequent urinary tract infections, but her symptoms turned out to be secondary to adrenal insufficiency," McCann said.

She described another patient who experienced blurry vision, who was ultimately diagnosed with type 1 diabetes. "There can be life-threatening toxicities that clinicians might not be thinking about because traditionally immune checkpoint inhibitors have been relatively benign, but now they are being used in these younger women with stronger immune systems," she said.

Patients and their providers should be aware of the possibility of these immune-mediated side effects and should stay in close communication should any unexpected new-onset symptoms occur, George advised. She added that "thyroid hormones, liver function test, and cortisol levels should be closely monitored to pick up immune-mediated side effects. Adrenal insufficiency should be ruled out in any patients scheduled to undergo major surgery, as it can be life threatening."

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