Turner Nicholas, Saura Cristina, Aftimos Philippe, van den Tweel Evelyn, Oesterholt Mayke, Koper Norbert, Colleoni Marco, Kaczmarek Emilie, Punie Kevin, Song Xinni, Armstrong Anne, Bianchi Giulia, Stradella Agostina, Ladoire Sylvain, Lim Joline Si Jing, Quenel-Tueux Nathalie, Tan Tira J, Escrivá-de-Romaní Santiago, O'Shaughnessy Joyce
Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom.
Medical Oncology Department, Vall d'Hebron University Hospital, and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
J Clin Oncol. 2025 Feb 10;43(5):513-523. doi: 10.1200/JCO.24.00529. Epub 2024 Oct 23.
Human epidermal growth factor receptor 2 (HER2)-targeted therapy is standard of care for HER2-positive (HER2+) breast cancer, but most patients develop progressive disease with persistent HER2 expression. No definitive treatment guidance currently exists beyond second line. Trastuzumab duocarmazine (T-Duo) is a third-generation, HER2-targeted antibody-drug conjugate that demonstrated efficacy and acceptable safety in phase I studies of heavily pretreated patients with HER2+/HER2-low breast cancer.
In this open-label, randomized, phase III trial, T-Duo was compared with physician's choice (PC) in patients with unresectable locally advanced/metastatic HER2+ breast cancer with progression during/after ≥2 HER2-targeted therapies or after trastuzumab emtansine (T-DM1). The primary endpoint was progression-free survival (PFS) by blinded independent central review.
In total, 437 patients were randomly assigned 2:1 to T-Duo (n = 291) or PC (n = 146). The median age was 56.0 years (range, 24-86); most patients (93.6%) had metastatic disease. The median time from diagnosis of metastatic disease to trial entry was 3.5 years; the median number of prior HER2-targeted therapies in metastatic setting was three. The median PFS was 7.0 months (95% CI, 5.4 to 7.2) with T-Duo versus 4.9 months (95% CI, 4.0 to 5.5; hazard ratio [HR], 0.64 [95% CI, 0.49 to 0.84]; = .002) with PC. PFS benefit was maintained across most predefined subgroups. The median overall survival (first analysis) was 20.4 (T-Duo) versus 16.3 months (PC; HR, 0.83 [95% CI, 0.62 to 1.09]; = .153). Objective response rate was 27.8% (T-Duo) versus 29.5% (PC); other efficacy end points-clinical benefit rate, duration of response, and reduction in target lesion measurement-tended to favor T-Duo. Grade ≥3 treatment-emergent adverse events occurred in 52.8% (T-Duo) versus 48.2% (PC).
Treatment with T-Duo was manageable, but tolerability was affected by prevalent ocular toxicity, leading to a higher discontinuation rate in the T-Duo arm. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who have progressed during/after ≥2 HER2-targeted therapies or after T-DM1.
人表皮生长因子受体2（HER2）靶向治疗是HER2阳性（HER2+）乳腺癌的标准治疗方案，但大多数患者会出现疾病进展且HER2持续表达。目前，二线治疗以外尚无明确的治疗指导。曲妥珠单抗多卡霉素（T-Duo）是一种第三代HER2靶向抗体药物偶联物，在HER2+/HER2低表达乳腺癌的I期研究中，对经过大量预处理的患者显示出疗效且安全性可接受。
在这项开放标签、随机、III期试验中，将T-Duo与医生选择（PC）的治疗方案进行比较，纳入的患者为不可切除的局部晚期/转移性HER2+乳腺癌，且在≥2种HER2靶向治疗期间或之后或曲妥珠单抗恩美曲妥珠单抗（T-DM1）治疗后出现疾病进展。主要终点是由盲态独立中央审查评估的无进展生存期（PFS）。
总共437例患者按2:1随机分配至T-Duo组（n = 291）或PC组（n = 146）。中位年龄为56.0岁（范围24 - 86岁）；大多数患者（93.6%）有转移性疾病。从转移性疾病诊断到试验入组的中位时间为3.5年；转移性疾病中既往HER2靶向治疗的中位次数为3次。T-Duo组的中位PFS为7.0个月（95%CI，5.4至7.2），而PC组为4.9个月（95%CI，4.0至5.5；风险比[HR]，0.64[95%CI，0.49至0.84]；P = 0.002）。在大多数预定义亚组中均维持了PFS获益。中位总生存期（首次分析）为20.4（T-Duo）对16.3个月（PC；HR，0.83[95%CI，0.62至1.09]；P = 0.153）。客观缓解率为27.8%（T-Duo）对29.5%（PC）；其他疗效终点——临床获益率、缓解持续时间和靶病灶测量值的降低——倾向于T-Duo组。≥3级治疗中出现的不良事件发生率在T-Duo组为52.8%，而PC组为48.2%。
T-Duo治疗可控，但耐受性受常见眼部毒性影响，导致T-Duo组停药率较高。T-Duo显著降低了在≥2种HER2靶向治疗期间或之后或T-DM1治疗后出现进展的晚期HER2+乳腺癌患者的疾病进展风险。
