Rugo H S, Tokunaga E, Iwata H, Petry V, Smit E F, Goto Y, Kim D-W, Shitara K, Gruden J F, Modi S, Cortés J, Krop I, Jänne P A, Cheng Y, Taitt C, Cheng F-C, Powell C A
Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, USA.
Department of Breast Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
Ann Oncol. 2025 Aug 5. doi: 10.1016/j.annonc.2025.07.015.
Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate treatment for multiple solid tumors, carries risk of interstitial lung disease/pneumonitis (ILD). Management guidelines generally mandate interrupting T-DXd treatment for grade 1 ILD, with possible retreatment following resolution of imaging findings. This pooled analysis examined T-DXd retreatment duration and ILD recurrence following recovery from grade 1 ILD.
Data were pooled from nine clinical trials of patients with various human epidermal growth factor receptor 2 (HER2)-positive, HER2-low, or HER2 (ERBB2)-mutant solid tumors treated with T-DXd (5.4-8.0 mg/kg). ILD events were reported and graded by investigators and confirmed as drug related by an independent ILD adjudication committee. Patients who recovered from a first investigator-assessed grade 1 and adjudication committee-confirmed drug-related ILD event (ILD1) could receive T-DXd retreatment. Patients were evaluated until disease progression or data cut-off.
Among 2145 pooled patients, 9% (193/2145) had grade 1 ILD1, of which 23.3% (45/193) were retreated with T-DXd. Median retreatment duration was 85 days (range 1-848 days); 17.8% (8/45) of patients received T-DXd retreatment for ≥1 year. ILD recurrence (ILD2) occurred in 33.3% (15/45) of retreated patients; median time to ILD2 from T-DXd retreatment was 64 days (range, 22-391 days) and were low-grade events (grade 1, n = 6; grade 2, n = 9; no grade ≥3 or fatal events). Reasons for T-DXd retreatment discontinuation were disease progression [33.3% (15/45)]; ILD recurrence [20% (9/45)]; non-ILD adverse events [17.8% (8/45)]; and physician's decision [4.4% (2/45)]. At the analysis cut-off, 24.4% (11/45) of retreated patients were still receiving treatment, and most patients with ILD2 [60% (9/15)] had recovered with/without sequelae.
This first large-scale pooled analysis demonstrates the safety of T-DXd retreatment after recovery from grade 1 ILD. ILD recurred in one-third of patients; all recurrence events were grade 1/2 and manageable using existing treatment guidelines. T-DXd retreatment following resolution of grade 1 drug-related ILD has potential to maximize therapeutic benefit.
曲妥珠单抗德瓦鲁单抗（T-DXd）是一种用于多种实体瘤的抗体药物偶联物治疗药物，存在间质性肺病/肺炎（ILD）风险。管理指南通常要求对1级ILD中断T-DXd治疗，影像学检查结果恢复后可能重新治疗。这项汇总分析研究了1级ILD恢复后T-DXd重新治疗的持续时间和ILD复发情况。
汇总了9项临床试验的数据，这些试验的患者患有各种人表皮生长因子受体2（HER2）阳性、HER2低表达或HER2（ERBB2）突变的实体瘤，接受T-DXd（5.4-8.0mg/kg）治疗。ILD事件由研究者报告并分级，并由独立的ILD判定委员会确认为与药物相关。从首次研究者评估为1级且判定委员会确认的药物相关ILD事件（ILD1）中恢复的患者可以接受T-DXd重新治疗。对患者进行评估直至疾病进展或数据截止。
在2145例汇总患者中，9%（193/2145）发生1级ILD1，其中23.3%（45/193）接受了T-DXd重新治疗。重新治疗的中位持续时间为85天（范围1-848天）；17.8%（8/45）的患者接受T-DXd重新治疗≥1年。重新治疗的患者中有33.3%（15/45）发生ILD复发（ILD2）；从T-DXd重新治疗到ILD2的中位时间为64天（范围22-391天），均为低级别事件（1级，n=6；2级，n=9；无≥3级或致命事件）。T-DXd重新治疗中断的原因是疾病进展[33.3%（15/45）]；ILD复发[20%（9/45）]；非ILD不良事件[17.8%（8/45）]；以及医生决定[4.4%（2/45）]。在分析截止时，24.4%（11/45）的重新治疗患者仍在接受治疗，大多数ILD2患者[60%（9/15）]已康复，有/无后遗症。
这项首次大规模汇总分析证明了1级ILD恢复后T-DXd重新治疗的安全性。三分之一的患者发生ILD复发；所有复发事件均为1/2级，可根据现有治疗指南进行管理。1级药物相关ILD缓解后进行T-DXd重新治疗有可能使治疗获益最大化。
