University of California San Francisco Helen Diller Family Comprehensive Cancer Center.
Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
JAMA Oncol. 2021 Apr 1;7(4):573-584. doi: 10.1001/jamaoncol.2020.7932.
ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation.
To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC.
DESIGN, SETTING, AND PARTICIPANTS: The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019.
Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice.
Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis.
A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). Margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable.
In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021.
ClinicalTrials.gov Identifier: NCT02492711.
重要性：在接受最佳治疗的情况下，晚期乳腺癌（ABC）中 ERBB2 阳性仍然通常无法治愈，而后续治疗线中尚无明确的定义。嵌合抗体 margetuximab 与 trastuzumab 具有相同的 ERBB2 特异性，但采用了工程化的 Fc 区域，以增加免疫激活。
目的：比较 margetuximab 与 trastuzumab 联合化疗在预处理过的 ERBB2 阳性 ABC 患者中的临床疗效。
设计、地点和参与者：SOPHIA 是一项 3 期、随机、开放标签试验，比较 margetuximab 联合化疗与 trastuzumab 联合化疗在 17 个国家的 166 个地点的 536 名患者中的疗效。纳入标准为在 2 种或以上抗 ERBB2 治疗后疾病进展，以及转移性疾病治疗线数为 1-3 线。数据分析于 2019 年 2 月至 2019 年 10 月进行。
干预措施：研究者在 1：1 随机分组前选择化疗，margetuximab 剂量为 15mg/kg，trastuzumab 剂量为 6mg/kg（负荷剂量为 8mg/kg），每 3 周为 1 个周期。分层因素包括转移性部位（≤2，>2）、治疗线数（≤2，>2）和化疗选择。
主要结局和测量：连续的主要终点为中心盲法分析的无进展生存期（PFS）和总生存期（OS）。所有 α 分配给 PFS，随后是 OS。次要终点为研究者评估的 PFS 和中心盲法分析的客观缓解率。
结果：共有 536 名患者随机接受 margetuximab（n=266）或 trastuzumab（n=270）治疗。中位年龄为 56 岁（27-86 岁）；margetuximab 组 266 名（100%）患者为女性，trastuzumab 组 267 名（98.9%）患者为女性。两组患者平衡。除 1 例患者外，所有患者均接受过 pertuzumab 治疗，489 例（91.2%）患者接受过 ado-trastuzumab emtansine 治疗。margetuximab 改善了原发性 PFS，与 trastuzumab 相比，相对风险降低了 24%（风险比[HR]，0.76；95%置信区间[CI]，0.59-0.98；P=0.03；中位，5.8[95%CI，5.5-7.0]个月 vs 4.9[95%CI，4.2-5.6]个月；2018 年 10 月 10 日）。在第二次计划的 270 例死亡的中期分析后，margetuximab 组的中位 OS 为 21.6 个月，trastuzumab 组为 19.8 个月（HR，0.89；95%CI，0.69-1.13；P=0.33；2019 年 9 月 10 日），研究者评估的 PFS 显示 margetuximab 组的相对风险降低了 29%（HR，0.71；95%CI，0.58-0.86；P<0.001；中位，5.7 vs 4.4 个月；2019 年 9 月 10 日）。margetuximab 提高了客观缓解率，与 trastuzumab 相比：22% vs 16%（P=0.06；2018 年 10 月 10 日）和 25% vs 14%（P<0.001；2019 年 9 月 10 日）。与 trastuzumab 相比，margetuximab 组更常见与输注相关的反应（35[13.3%]例 vs 9[3.4%]例），但安全性相当。
结论与意义：在这项 3 期随机临床试验中，与 trastuzumab 加化疗相比，在接受 2 种或以上抗 ERBB2 治疗后疾病进展的 ERBB2 阳性 ABC 患者中，margetuximab 加化疗在 PFS 方面具有可接受的安全性和统计学显著改善。预计在 2021 年进行最终的 OS 分析。
试验注册：ClinicalTrials.gov 标识符：NCT02492711。
