Clinical and imaging features of interstitial lung disease in cancer patients treated with trastuzumab deruxtecan

Abstract

Background: Interstitial lung disease/pneumonitis (ILD/pneumonitis) has been identified as a drug-related adverse event of special interest of trastuzumab deruxtecan (T-DXd), but there were a few reports of T-DXd-related ILD/pneumonitis in clinical practice.

Methods: Between May 25, 2020 (the launch of T-DXd in Japan) and February 24, 2022, there were 287 physician-reported potential ILD/pneumonitis cases from the Japanese post-marketing all-case surveillance. By February 27, 2022, an independent adjudication committee assessed 138 cases and adjudicated 130 cases as T-DXd-related ILD/pneumonitis. The clinical features and imaging characteristics of these cases were evaluated.

Results: The majority of adjudicated T-DXd-related ILD/pneumonitis cases were grade 1 or 2 (100/130, 76.9%). The most common radiological pattern types observed were organizing pneumonia patterns (63.1%), hypersensitivity pneumonitis patterns (16.9%), and diffuse alveolar damage (DAD) patterns (14.6%). Eleven cases (8.5%) from 130 resulted in death; the majority of these (8/11, 72.7%) had DAD patterns. The overall proportion of recovery (including the outcomes of recovered, recovered with sequelae, and recovering) was 76.9%, and the median time to recovery was 83.5 days (interquartile range: 42.25-143.75 days). Most cases (59/71, 83.1%) that were treated with corticosteroids were considered responsive to treatment.

Conclusions: This is the first report to evaluate T-DXd-related ILD/pneumonitis cases in clinical practice. Our findings are consistent with previous reports and suggest that patients with DAD patterns have poor outcomes. Evaluation of a larger real-world dataset may further identify predictors of clinical outcome.

Keywords: Adverse event; Computed tomography; Drug-related pneumonitis; Interstitial lung disease; Post-marketing; Trastuzumab deruxtecan.

Fig. 1

Flow diagram of ILD/pneumonitis cases. Approximately 3000 patients (1830 patients with breast cancer and 1170 patients with gastric cancer) were estimated to have initiated T-DXd treatment in Japan between May 25, 2020 and February 24, 2022. ^aReported terms coded by preferred terms (PTs) using MedDRA/J version 25.0: pneumonitis, interstitial lung disease, organizing pneumonia, radiation pneumonitis, and lung disorder. ARDS acute respiratory distress syndrome, BC breast cancer, DIC disseminated intravascular coagulation, ILD/pneumonitis interstitial lung disease or pneumonitis, GC gastric cancer, PPFE pleuroparenchymal fibroelastosis, T-DXd trastuzumab deruxtecan

Fig. 2

Representative images of DAD, OP, HP, and NSIP patterns of T-DXd-related ILD/pneumonitis. CT computed tomography, DAD diffused alveolar damage, HP hypersensitivity pneumonitis, ILD/pneumonitis interstitial lung disease or pneumonitis, NSIP non-specific interstitial pneumonia, OP organizing pneumonia, T-DXd trastuzumab deruxtecan

Fig. 3

The overall proportion of ILD/pneumonitis outcomes. The proportion of recovery is the percentage of patients with the outcomes recovered/resolved, recovered/resolved with sequelae, or recovering/resolving. ILD/pneumonitis interstitial lung disease or pneumonitis, IQR interquartile range, T-DXd trastuzumab deruxtecan

Fig. 4

The proportion of ILD/pneumonitis outcomes by a worst Common Terminology Criteria for Adverse Events grade and b imaging pattern. The proportion of recovery is the percentage of patients with the outcomes recovered/resolved, recovered/resolved with sequelae, or recovering/resolving. In panel a, among the nine cases of grade 1 ILD/pneumonitis who did not recover, four cases were lost to follow-up. The eight cases of grade 2 ILD/pneumonitis with no recovery remained in follow-up, and the two cases of grade 3 ILD/pneumonitis who had not recovered were lost to follow-up. In panel b, the two cases with a DAD pattern and who had not recovered were lost to follow-up. Among the 12 cases with an OP pattern and who had not recovered, four were lost to follow-up. Those who had not recovered and had an HP pattern or an NSIP pattern remain in follow-up. DAD diffused alveolar damage, HP hypersensitivity pneumonitis, ILD/pneumonitis interstitial lung disease or pneumonitis, IQR interquartile range, NSIP non-specific interstitial pneumonia, OP organizing pneumonia, T-DXd trastuzumab deruxtecan

Fig. 5

Clinical course of grade 5 ILD/pneumonitis cases. Black triangles indicate the time of onset for adjudicated ILD/pneumonitis cases. Black boxes indicate times of death. White bars indicate periods without corticosteroid therapy. Dark gray bars indicate periods of high-dose intravenous corticosteroid therapy. Light gray bars indicate periods of lower-dose corticosteroid therapy. Black bars indicate periods of oxygen therapy. The adjudicated severity grade of ILD at onset is shown below the time of onset for adjudicated cases (black triangle). The daily corticosteroid doses (milligrams) are shown after the abbreviations of corticosteroids inside of dark gray and light gray bars. ^aThe detailed periods of high-dose intravenous corticosteroid therapy of Case #3 were not provided. ^bThe initial grade 2 ILD/pneumonitis of Case #10 was improved after conventional corticosteroid therapy. However, the breathing symptoms deteriorated on Day 88, the patient died on Day 96 despite receiving high-dose corticosteroid therapy. The ILD adjudication committee determined that the cause of breathing difficulties and death was because of both worsening of ILD and Pneumocystis pneumonia. CPA cyclophosphamide, DAD diffused alveolar damage, G Common Terminology Criteria for Adverse Events grade, HOT home oxygen therapy, ILD/pneumonitis interstitial lung disease or pneumonitis, mPSL methyl prednisolone, O₂ oxygen therapy, OP organizing pneumonia, PSL prednisolone, T-DXd trastuzumab deruxtecan