Real‐World Progression Patterns and Potential Prognostic Factors for Trastuzumab Deruxtecan‐Related Interstitial Lung Disease in Japanese Patients With Breast or Gastric Cancer

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Abstract
Background: Interstitial lung disease (ILD)/pneumonitis is a safety concern with trastuzumab deruxtecan (T‐DXd). We characterized post‐onset changes in ILD severity and imaging patterns, and explored potential prognostic factors for fatal T‐DXd‐related ILD in Japanese patients with breast or gastric cancer. Methods: This post hoc analysis included 381 independently adjudicated T‐DXd‐related ILD cases from two Japanese all‐patient post‐marketing surveillance studies. We described transitions from onset to worst Common Terminology Criteria for Adverse Events grade and imaging pattern changes. Exploratory tumor type‐stratified Cox proportional hazards models were used to assess factors associated with time to fatal (Grade 5) ILD. The variable with the highest hazard ratio (HR) and each of the remaining significant univariate factors ( p < 0.05 or a 95% confidence interval excluding 1) meeting the criteria were included in two‐covariate multivariable models. Results: At ILD onset, 60.1% of patients had Grade 1 ILD. Overall, 30 of the 381 adjudicated ILD cases (7.9%) progressed to fatal Grade 5, initially presenting with Grade 1 ( n = 9), 2 ( n = 5), or 3 ( n = 16); time to death was 3–173 days. Of 24 cases with imaging pattern changes, 14 transitioned from nondiffuse alveolar damage (non‐DAD) to DAD (10 were fatal). Abnormal C‐reactive protein (CRP) at onset had the highest HR in univariate analyses. In separate CRP‐adjusted two‐covariate multivariable models, preexisting ILD and several onset factors (dyspnea; abnormal SpO 2 /lactate dehydrogenase/Krebs von den Lungen‐6; pleural/cardiac effusion; DAD pattern; traction bronchiectasis) were associated with fatal ILD. An organizing pneumonia pattern was associated with a lower hazard. Conclusions: T‐DXd‐related ILD may progress rapidly to fatal outcomes, even from low‐grade or non‐DAD presentations, and several onset factors (e.g., elevated CRP, decreased SpO 2 , and DAD pattern) were associated with fatal ILD outcomes. These findings are exploratory and should not be used to determine whether to initiate or withhold corticosteroids. Guideline‐concordant ILD management remains essential regardless of these factors, while their potential role in identifying patients requiring closer monitoring warrants further validation. Trial Registration: The breast cancer and the gastric cancer surveys were registered at the Japan Registry of Clinical Trials ( https://jrct.mhlw.go.jp/en‐top ) under the identifiers jRCT1080225197 and jRCT2001200001, respectively
Funding Information
  • Daiichi Sankyo Company

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