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Professor of Medicine
University of Pittsburgh School of Medicine
Associate Chief, Hematology-Oncology
University of Pittsburgh Cancer Institute
Adam M. Brufsky, MD, PhD, has disclosed that he has received consulting fees from AstraZeneca, Puma, Roche, and Seattle Genetics.
Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate recently approved in the United States and Japan and currently under accelerated assessment by the European Medicines Agency for patients with previously treated advanced HER2-positive breast cancer. These regulatory approvals were based on findings from the phase II DESTINY-Breast01 trial, which showed a 61% ORR in heavily pretreated patients with a median response duration of 14.8 months and a median PFS of 16.4 months.
The T-DXd adverse event profile from DESTINY-Breast01 was generally safe and mirrored our expectations for an exatecan derivative with predominantly grade 1/2 nausea, fatigue, alopecia, vomiting, constipation, and diarrhea. Interstitial lung disease (ILD) was an unusual and potentially serious side effect.
ILD Associated With T-DXd
Among the 184 patients receiving T-DXd 5.4 mg/kg in the DESTINY-Breast01 trial, 25 ILD events occurred. The median time to investigator-reported onset was anywhere from 42 to 535 days. For the subset with grade ≥ 2 ILD, glucocorticoids were administered in 17 of 20 cases. In terms of overall outcomes, 7 patients recovered, 2 were recovering at the time of analysis, 12 had an unknown status or were not followed for ILD resolution, and 4 (2.2%) died. These deaths from ILD occurred between 9 and 60 days after ILD diagnosis.
In the DESTINY-Lung01 trial of T-DXd for HER2-mutated NSCLC recently reported at ASCO 2020 by Smit and colleagues, grade 2 ILD occurred in 11.9% of patients with no higher grade ILD events reported. While 7.6% of patients discontinued treatment, there were no toxic deaths.
Clinical Management of ILD
It is important to educate patients about ILD symptoms and closely monitor for ILD symptoms such as shortness of breath, cough, and fever. Radiographic findings could indicate lymphangitic spread but it is important to rule out ILD. As clinicians who treat HER2-positive metastatic breast cancer, we tend to see many patients with fatigue and dyspnea. In the past, we may have discounted this presentation. Similarly, if a radiologist had told us that “there’s some haziness on the CT,” we might have considered it nonspecific and moved on. Going forward, we need to be aware of these findings in patients treated with T-DXd, and consider ILD in the differential diagnosis.
When symptoms do arise, clinicians should obtain a high‑resolution CT, pulmonologist consultation, blood cultures, and pulse oximetry. If indicated and feasible, additional diagnostics may include bronchoscopy, bronchoalveolar lavage, and arterial blood gasses.
If ILD is suspected, hold T-DXd and initiate steroids. Every ILD event should be followed to resolution, but the length of drug discontinuation depends on ILD severity. If grade 1 ILD resolves within 28 days, T-DXd may be restarted at the same dose; if resolution occurs beyond 28 days, reduce the T-DXd dose by one level. If grade 1 ILD occurs beyond cycle Day 22 and has not resolved completely within 49 days of the last infusion, discontinue T-DXd. For patients with grade 1/2 ILD and worsening symptoms despite initiation of steroids, consider increasing the dose of steroids and/or switching to IV administration with methylprednisolone. ILD severity above grade 1 requires permanent discontinuation of T-DXd.
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