Hamilton Erika, Galsky Matthew D, Ochsenreither Sebastian, Del Conte Gianluca, Martín Miguel, De Miguel Maria José, Yu Evan Y, Williams Anja, Gion Maria, Tan Antoinette R, Agrawal Laila, Rutten Annemie, Machiels Jean-Pascal, Cresta Sara, Debruyne Philip R, Hennequin Audrey, Moreno Victor, Minchom Anna, Valdes-Albini Frances, Petrylak Daniel, Li Li, Tsuchihashi Zenta, Suto Fumitaka, Cheng Fu-Chih, Kandil Maha, Barrios Daniel, Hurvitz Sara
Department of Medical Oncology, Sarah Cannon Research Institute, Nashville, Tennessee.
Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
Clin Cancer Res. 2024 Dec 16;30(24):5548-5558. doi: 10.1158/1078-0432.CCR-24-1513.
This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC).
Part 1 determined the recommended dose for expansion of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate by independent central review.
In part 1, seven patients with mBC were enrolled and received T-DXd 3.2 mg/kg (four patients) or 5.4 mg/kg (three patients) plus nivolumab. The recommended dose for expansion for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously every 3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of three administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and four with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the confirmed objective response rates (95% confidence interval) for cohorts 1 to 4 were 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. The median treatment duration (range) with T-DXd in cohorts 1 to 4 was 8.9 (1-23) months, 6.9 (1-21) months, 3.9 (1-21) months, and not assessed, respectively; the most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, and 75.0%, respectively). Adjudicated drug-related interstitial lung disease/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0%, respectively (one grade 5 each, cohorts 1 and 3).
T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T-DXd. Interstitial lung disease/pneumonitis is an important risk and requires careful monitoring and prompt intervention.
本多中心Ib期研究调查了曲妥珠单抗德鲁昔单抗（T-DXd）联合纳武利尤单抗用于HER2表达的转移性乳腺癌（mBC）和转移性尿路上皮癌（mUC）患者的疗效。
第1部分确定T-DXd联合纳武利尤单抗扩大剂量的推荐剂量。第2部分评估疗效和安全性；主要终点是经独立中央审查确认的客观缓解率。
在第1部分，7例mBC患者入组，接受T-DXd 3.2 mg/kg（4例患者）或5.4 mg/kg（3例患者）联合纳武利尤单抗治疗。T-DXd扩大剂量的推荐剂量为5.4 mg/kg联合纳武利尤单抗360 mg，每3周静脉注射一次。在第2部分，32例HER2阳性mBC患者（队列1；包括第1部分中3例接受5.4 mg/kg治疗的患者）、16例HER2低表达mBC患者（队列2）、30例HER2高表达mUC患者（队列3）和4例HER2低表达mUC患者（队列4）入组。在数据截止时（2021年7月22日），队列1至4经确认的客观缓解率（95%置信区间）分别为65.6%（46.8%-81.4%）、50.0%（24.7%-75.3%）、36.7%（19.9%-56.1%），队列4因样本量小未进行评估。队列1至4中接受T-DXd治疗的中位持续时间（范围）分别为8.9（1-23）个月、6.9（1-21）个月、3.9（1-21）个月，队列4未进行评估；最常见的治疗中出现的不良事件为恶心（分别为55.2%、62.5%、73.3%和75.0%）。经判定的药物相关间质性肺疾病/肺炎发生率（队列1-3）分别为20.7%、0%和20.0%（队列1和3各有1例5级事件）。
T-DXd联合纳武利尤单抗在HER2表达的mBC或mUC中显示出有前景的抗肿瘤活性，且安全性与T-DXd已知特征一致。间质性肺疾病/肺炎是一个重要风险，需要仔细监测和及时干预。
