T-DXd for HER2-Low BC: Analysis Confirms Adverse Effects

A safety analysis following a landmark randomized phase 3 trial confirms that vomiting and nausea are quite common in patients who take the drug trastuzumab deruxtecan (T-DXd; Enhertu) to treat HER2-low metastatic breast cancer. Interstitial lung disease (ILD) also remains a concern, and it’s not clear if retreatment after resolution is warranted.

In general, however, “T-DXd demonstrates a manageable safety profile consistent with prior reports. Results from this safety analysis continued to support its use as a new standard of care in patients with HER2-low metastatic breast cancer,” said report lead author Hope Rugo, MD, of the University of California, San Francisco, during a presentation at the European Society for Medical Oncology Breast Cancer 2023.

T-DXd, an antibody-drug conjugate, received FDA approval in August 2022 for patients with HER2-low disease. The drug has been touted as “practice changing” and a “new standard of care.”

However, physicians have noted that the benefits of the drug come at the cost of significant adverse effects, including some that can cause hospitalization. There’s special concern about high-grade interstitial lung disease/pneumonitis, and an FDA boxed warning cautions clinicians about this possible side effect.

For the new analysis, researchers presented additional safety data from the industry-funded DESTINY-Breast04 trial, whose results was published in July 2022 in the New England Journal of Medicine. That study randomized 373 patients to T-DXd and 184 to physician’s choice of treatment. It found that, “among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (hazard ratio for disease progression or death, 0.50; P < .001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = .001).”

Exposure-adjusted incidence rates for any-grade treatment-emergent adverse events were lower for T-DXd versus physician’s choice of treatment (1.30 vs. 2.66). However, nausea and vomiting events were more than twice as common in patients who took T-DXd versus the physician’s choice (79.5% vs. 35.5%).

A total of 50.9% of patients in the T-DXd arm received antiemetic prophylaxis versus 37.2% in the physician’s choice arm. A single patient discontinued T-DXd treatment because of vomiting, and a single patient discontinued treatment because of nausea. No patients in the physician choice group discontinued treatment because of nausea or vomiting.

Neutropenia and febrile neutropenia were less frequent in the T-DXd arm versus physician’s choice (12.9% vs. 18.0% and 0.3% vs. 2.9%, respectively.)

ILD occurred in 45 patients (12.1%) of those in the T-DXd arm versus 1 (0.6%) in the physician choice arm. Ten patients of the patients in the T-DXd arm had not recovered by the data cutoff point.

Six patients with ILD were retreated following resolution; one discontinued because of an adverse event, two discontinued because of progressive disease, and three remained on the drug. “Given that there was only a small number of patients who were retreated with T-DXd, it’s difficult to make clinically meaningful conclusions on the effect of retreatment following grade IDL events that have resolved,” Dr. Rugo said.

In the big picture, “ILD pneumonitis remains an important identified risk and an adverse event of interest associated with T-DXd,” Dr. Rugo said. “It’s important that we adhere to management guidelines and updated toxicity management guidelines.”

In a discussion, Dr. Rugo said she prescribes three antiemetic drugs to help patients tolerate T-DXd therapy: “It makes a big difference. Anecdotally, it really has improved management of nausea. Start more and back down [as symptoms fade].”

Gustavo Werutsky, MD, PhD, of Moinhos de Vento Hospital, Porto Alegre, Brazil, the discussant for the presentation, also emphasized the importance of prevention and said he prescribes two or three prophylactic drugs. “In the beginning, we didn’t know these events were so important. A big part of the message is that patients from the beginning need to have a good prophylaxis for the nausea and vomiting.”

The researchers also presented a related report at the conference, an analysis of patient-reported outcomes from DESTINY-Breast02, a randomized phase 3 study of T-DXd (n = 406) versus physician’s choice of treatment (n = 202) in patients with HER2-positive metastatic breast cancer who were resistant/refractory to trastuzumab emtansine.

The analysis, led by Tanja Fehm, MD, of University Hospital Düsseldorf (Germany), found that the median time to definitive deterioration was longer with T-DXd versus the other arm per the EORTC QLQ-C30 global health status/quality of life score (14.1 vs. 5.9 months; HR, 0.56; 95% confidence interval, 0.44-0.71).

The studies were funded by Daiichi Sankyo and AstraZeneca, which make T-DXd. Dr. Hugo discloses relationships with Puma, NAPO, Blueprint, Scorpion Therapeutics, Merck, AstraZeneca, Gilead, Astellas, Daiichi Sankyo, F. Hoffmann–La Roche/Genentech, GlaxoSmithKline, Lilly, Novartis, OBI, Pfizer, Pionyr, Sermonix, Taiho Oncology, and Veru. Multiple other authors of both studies have various disclosures.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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