Background: Several classes of anti-cancer agents including certain immunotherapies, systemic chemotherapies, and targeted therapies including trastuzumab and T-DM1 increase the risk of interstitial lung disease (ILD) and fatal cases have been reported. For DS-8201a, interim efficacy and safety analyses of available data established a final recommended dose of 5.4 mg/kg IV q3wk in advanced HER2-positive breast cancer (BC). Based on preliminary clinical results, ILD was identified as an important risk for DS-8201a. A robust monitoring and management plan was established across all studies and an international, independent ILD adjudication committee (AC) reviews the cases reported as ILD on an ongoing basis.
Methods: All subjects (sbj) who received ≥1 dose of DS-8201a across 7 ongoing studies were included in this analysis. Reported ILD (standardized MedDRA Query terms) included the terms ILD, pneumonitis, and organizing pneumonia. ILD frequencies were calculated based on investigator's assessment and after adjudication. The analysis of potential risk factors associated with ILD is ongoing.
Results: As of 21 June 2018, 448 sbj received ≥1 dose of DS-8201a across multiple tumor types, including BC. Of the 321 sbj with BC, 173 (53.9%) were from Japan, 103 (32.1%) from the US, and 45 (14.0%) from 6 other countries (Spain, South Korea, Taiwan, Belgium, France, and Italy). These sbj received 1 of 7 doses of DS-8201a (0.8 mg/kg: 3 sbjs, 1.6 mg/kg: 1 sbj, 3.2 mg/kg: 3 sbjs, 5.4 mg/kg: 111 sbjs, 6.4 mg/kg: 178 sbj, 7.4 mg/kg: 20 sbj, 8.0 mg/kg: 5 sbj). Overall, 44 cases of potential ILD were reported by the investigators across all tumor types (44/448, 9.8%; Grade ≥3 10/448, 2.2%). In sbj with BC who received 5.4 mg/kg, any grade and Grade ≥3 investigator-reported ILD were 7.2% (8/111) and 0.9% (1/111), respectively. The ILD AC assessed 30 of 44 cases; 22 were considered drug-related ILD, 4 were ILD but not drug-related, and 4 were found not to be ILD. For adjudicated drug-related ILD cases, the median time to onset was 159 (range; 46-591) days from the time of first dose.
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 All Grades All tumors, All doses (N=448) Investigator-reported20 (4.5)14 (3.1)4 (0.9)1 (0.2)5 (1.1)44 (9.8)Cases adjudicated13840530Adjudicated as drug-related ILD9 (2.0)6 (1.3)3 (0.7)04 (0.9)22 (4.9) BC, All doses (N=321) Investigator-reported17 (5.3)11 (3.4)3 (0.9)1 (0.3)4 (1.2)36 (11.2)Cases adjudicated11830426Adjudicated as drug-related ILD8 (2.5)6 (1.9)3 (0.9)04 (1.2)21 (6.5) BC, 5.4 mg/kg (N=111) Investigator-reported4 (3.6)3 (2.7)001 (0.9)8 (7.2)Cases adjudicated120014Adjudicated as drug-related ILD00001 (0.9)1 (0.9)n (%), except where noted
Conclusions: These analyses confirm that ILD is an important identified risk for DS-8201a. Further analyses are ongoing to better understand the potential risk factors associated with the incidence of on-treatment ILD. When ILD is suspected, early diagnosis through appropriate imaging, laboratory tests, and pulmonary consultation as well as prompt management with steroids are recommended.
Citation Format: Powell CA, Camidge DR, Gemma A, Kusumoto M, Baba T, Kuwano K, Bankier A, Kiura K, Tamura K, Modi S, Tsurutani J, Doi T, Iwata H, Krop IE, Zhang L, Jasmeet S, Saito K, Shahidi J, Yver A, Takahashi S. Characterization, monitoring and management of interstitial lung disease in patients with metastatic breast cancer: Analysis of data available from multiple studies of DS-8201a, a HER2-targeted antibody drug conjugate with a topoisomerase I inhibitor payload [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-06.
