Dana-Farber Cancer Institute, Boston, MA.
Stanford Comprehensive Cancer Institute, Palo Alto, CA.
J Clin Oncol. 2021 Aug 20;39(24):2667-2675. doi: 10.1200/JCO.20.02822. Epub 2021 May 4.
Effective therapies are needed for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) with brain metastases. A trastuzumab radioisotope has been shown to localize in brain metastases of patients with HER2-positive MBC, and intracranial xenograft models have demonstrated a dose-dependent response to trastuzumab.
In the phase II PATRICIA study (ClinicalTrials.gov identifier: NCT02536339), patients with HER2-positive MBC with CNS metastases and CNS progression despite prior radiotherapy received pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. The primary end point was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary end points included duration of response, clinical benefit rate (complete response plus partial response plus stable disease ≥ 4 or ≥ 6 months) in the CNS, and safety.
Thirty-nine patients were treated for a median (range) of 4.5 (0.3-37.3) months at clinical cutoff. Thirty-seven patients discontinued treatment, most commonly because of CNS progression (n = 27); two remained on treatment. CNS ORR was 11% (95% CI, 3 to 25), with four partial responses (median duration of response, 4.6 months). Clinical benefit rate at 4 months and 6 months was 68% and 51%, respectively. Two patients permanently discontinued study treatment because of adverse events (left ventricular dysfunction [treatment-related] and seizure, both grade 3). No grade 5 adverse events were reported. No new safety signals emerged with either agent.
Although the CNS ORR was modest, 68% of patients experienced clinical benefit, and two patients had ongoing stable intracranial and extracranial disease for > 2 years. High-dose trastuzumab for HER2-positive CNS metastases may warrant further study.
对于人表皮生长因子受体 2（HER2）阳性转移性乳腺癌（MBC）伴脑转移的患者，需要有效的治疗方法。曲妥珠单抗放射性同位素已被证明可定位于 HER2 阳性 MBC 的脑转移灶，颅内异种移植模型已证明曲妥珠单抗具有剂量依赖性反应。
在 II 期 PATRICIA 研究（ClinicalTrials.gov 标识符：NCT02536339）中，HER2 阳性 MBC 伴 CNS 转移且既往放疗后 CNS 进展的患者接受帕妥珠单抗联合高剂量曲妥珠单抗（每周 6mg/kg）治疗，直至 CNS 或全身疾病进展或出现不可接受的毒性。主要终点是根据神经肿瘤学脑转移反应评估标准（Response Assessment in Neuro-Oncology Brain Metastases criteria）确认 CNS 中的客观缓解率（ORR）。次要终点包括 CNS 中的反应持续时间、临床获益率（完全缓解+部分缓解+稳定疾病≥4 或≥6 个月）和安全性。
截至临床截止日期，39 例患者中位（范围）接受治疗 4.5（0.3-37.3）个月。37 例患者停止治疗，最常见的原因是 CNS 进展（n=27）；2 例患者仍在接受治疗。CNS ORR 为 11%（95%CI，3 至 25），有 4 例部分缓解（缓解持续时间中位数为 4.6 个月）。4 个月和 6 个月的临床获益率分别为 68%和 51%。有 2 例患者因不良事件（左心室功能障碍[与治疗相关]和癫痫，均为 3 级）永久停止研究治疗。无 5 级不良事件报告。两种药物均未出现新的安全性信号。
尽管 CNS ORR 较低，但 68%的患者有临床获益，有 2 例患者颅内和颅外疾病稳定持续>2 年。高剂量曲妥珠单抗治疗 HER2 阳性 CNS 转移可能需要进一步研究。
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