Drug-related interstitial lung disease occurred in less than 16% of patients with HER2-positive metastatic breast cancer following treatment with trastuzumab deruxtecan-nxki (T-DXd) at the approved dose of 5.4 mg/kg. In addition, the majority of these cases were classified as grade 1 or 2, according to findings presented by lead author Charles A. Powell, MD, and colleagues at the ESMO Breast Cancer Virtual Congress 2021 (Abstract 920).

Charles A. Powell, MD

DESTINY-Breast01

Dr. Powell, of the Pulmonary Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, said that the phase II DESTINY-Breast01 study demonstrated the strong efficacy of T-DXd in patients with pretreated HER2-positive metastatic breast cancer. The study demonstrated an objective response rate of 61.4%, and median progression-free survival of 19.4 months. In addition, a manageable safety profile was shown, which supported approval in the United States, Japan, European Union, and United Kingdom for the treatment of patients with HER2-positive metastatic breast cancer that has progressed on two or more anti-HER2 therapies.

Interstitial Lung Disease With T-DXd

However, interstitial lung disease remains an important identified risk with T-DXd. Dr. Powell and his co-investigators set out to determine the occurrence of interstitial lung disease in this patient population.

They used data from patients with HER2-positive metastatic breast cancer treated with T-DXd monotherapy at 5.4 mg/kg every 3 weeks from August 2015 to June 2020; of these, 61 patients participated in two phase I studies (DS8201-A-J101 and DS8201-A-A104), and 184 patients were in the phase II DESTINY-Breast01 study.

Imaging and clinical data from baseline through the time of potential interstitial lung disease case were retrospectively reviewed by an independent adjudication committee.

This analysis included data from 245 patients with heavily pretreated HER2-positive metastatic breast cancer who received T-DXd for a median of 9.7 months (range = 0.7–40.3 months).

Results

During treatment, 38 patients (15.5%) experienced an interstitial lung disease event that was adjudicated as drug-related. Thirty (12.2%) were grade 1 or 2 events; grade 3 and 4 interstitial lung disease events were reported in one (0.4%) patient each. Six (2.4%) patients died due to a grade 5 interstitial lung disease event. Of patients with interstitial lung disease, most (79%) experienced grade 1 or 2 events.

Most of the interstitial lung disease events occurred within the first 12 months of treatment. The median time to first event was 5.6 months (range = 1.1–20.8), with 97% of patients experiencing the first onset of interstitial lung disease prior to 12 months. Forty-two percent of patients were treated for ≥ 12 months.

The risk of patients having a new any-grade interstitial lung disease event beyond 12 months after treatment initiation was low, with a conditional probability of 1.8%.

In 27 of 44 (61.4%) events, the adjudication committee assessed the onset of interstitial lung disease as being earlier than that reported by investigators (median difference = 52 days; range = 1–288 days). A summary on the use of steroids to manage interstitial lung disease was also reported.

The investigators concluded that when T-DXd was administered at the approved dose (5.4 mg/kg), most interstitial lung disease events were of a low grade and occurred in the first 12 months. They added that the risk decreased after 12 months from the start of treatment, suggesting no cumulative toxicity.

They researchers also noted that the adjudication committee assessed the onset of interstitial lung disease as being earlier than the investigators in the majority of cases, which highlights the need for close monitoring that allows for earlier identification and effective management of interstitial lung disease using updated guidelines. Finally, they stated that additional follow-up is needed to confirm these findings.

Commentary

Harold J. Burstein, MD, PhD, FASCO

Harold J. Burstein, MD, PhD, FASCO, of Dana-Farber Cancer Institute and Harvard Medical School, further discussed the study findings. He said that interstitial lung disease and pneumonitis are uncommon, but potentially serious, side effects of many breast cancer treatments, including emerging therapies such as trastuzumab deruxtecan. Clinicians and patients need to be very aware of this risk, he noted, since risk factors are not well characterized; prospective studies are needed to better define risks and screening. He also noted that it will be particularly important to assess safety in early-stage, curative treatment.

Disclosure: Funding from AstraZeneca Pharmaceuticals LP was disclosed for this analysis. In March 2019, AstraZeneca and Daiichi Sankyo entered into a global development and commercialization collaboration agreement for trastuzumab deruxtecan. For full disclosures of the study authors, visit oncologypro.esmo.org.