本文由小咖机器人翻译整理

期刊来源：Lancet

原文链接：https://doi.org/10.1016/S0140-6736(24)00054-0

摘要内容如下：

背景

PherGain旨在评估基于曲妥珠单抗和帕妥珠单抗双重阻断人表皮生长因子受体2（HER2）的无化疗治疗在HER2阳性早期乳腺癌（EBC）患者中的可行性、安全性和有效性。它使用了一种基于18氟-氟脱氧葡萄糖-PET的病理完全反应（PCR）适应策略。

方法

PHERGAIN是一项随机、开放标签的2期临床试验，在7个欧洲国家的45家医院进行。它以1:4的比例将中心确诊的、HER2阳性的、I-IIIa期侵袭性、可手术的乳腺癌患者（至少有一个PET可评价的病变）随机分配到A组，其中患者接受多西他赛（75mg/m2，静脉注射）、卡铂（曲线下面积6mg/ml/min，静脉注射）、曲妥珠单抗（600mg固定剂量，皮下注射）、和帕妥珠单抗（840mg负荷剂量，随后420mg维持剂量，静脉内；TCHP），或B组，其中患者每3周接受曲妥珠单抗和帕妥珠单抗联合或不联合内分泌治疗。随机分配根据激素受体状态进行分层。在基线和两个治疗周期后进行集中回顾PET。B组患者根据治疗中PET结果进行治疗。B组中对PET有反应的患者继续接受曲妥珠单抗和帕妥珠单抗联合或不联合内分泌治疗6个周期，而对PET无反应的患者则改为接受6个周期的TCHP。手术后，B组中未达到PCR的PET应答者接受了6个周期的TCHP治疗，所有患者均完成了18个周期的曲妥珠单抗和帕妥珠单抗治疗。主要终点是两个治疗周期后B组PET应答者的PCR（先前已报道其结果）和B组患者的3年侵袭性无病生存率（IDF）。该研究已在ClinicalTrials.gov（NCT03161353）上注册，目前正在进行中。

调查结果

在2017年6月26日至2019年4月24日期间，共有356名患者被随机分配（A组71名患者，B组285名患者），A组和B组分别有63名（89%）和267名（94%）患者接受手术。在第二次分析中（数据截止日期:2022年11月4日），中位随访时间为43.3个月（范围0.0-63.0）。B组3年IDFS发生率为94.8%（95%CI 91.4~97.1；P=0.001），达到主要终点。未发现新的安全信号。A组治疗相关不良事件和严重不良事件（SAE）发生率高于B组（≥3级62%vs 33%；严重不良事件分别为28%和14%）。具有PCR的B组PET应答者表现出最低的治疗相关3级或更高不良事件发生率（1%），无任何严重不良事件。

解释

在HER2阳性的EBC患者中，基于PET的PCR适应策略与良好的3年IDFS相关。这一策略确定了大约三分之一的HER2阳性EBC患者可以安全地省略化疗。

英文原文如下：

Abstracts

BACKGROUND  PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an 18fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy.

METHODS  PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries. It randomly allocated patients in a 1:4 ratio with centrally confirmed, HER2-positive, stage I-IIIA invasive, operable breast cancer with at least one PET-evaluable lesion to either group A, where patients received docetaxel (75 mg/m2, intravenous), carboplatin (area under the curve 6 mg/mL per min, intravenous), trastuzumab (600 mg fixed dose, subcutaneous), and pertuzumab (840 mg loading dose followed by 420 mg maintenance doses, intravenous; TCHP), or group B, where patients received trastuzumab and pertuzumab with or without endocrine therapy, every 3 weeks. Random allocation was stratified by hormone receptor status. Centrally reviewed PET was conducted at baseline and after two treatment cycles. Patients in group B were treated according to on-treatment PET results. Patients in group B who were PET-responders continued with trastuzumab and pertuzumab with or without endocrine therapy for six cycles, while PET-non-responders were switched to receive six cycles of TCHP. After surgery, patients in group B who were PET-responders who did not achieve a pCR received six cycles of TCHP, and all patients completed up to 18 cycles of trastuzumab and pertuzumab. The primary endpoints were pCR in patients who were group B PET-responders after two treatment cycles (the results for which have been reported previously) and 3-year invasive disease-free survival (iDFS) in patients in group B. The study is registered with ClinicalTrials.gov (NCT03161353) and is ongoing.

FINDINGS  Between June 26, 2017, and April 24, 2019, a total of 356 patients were randomly allocated (71 patients in group A and 285 patients in group B), and 63 (89%) and 267 (94%) patients proceeded to surgery in groups A and B, respectively. At this second analysis (data cutoff: Nov 4, 2022), the median duration of follow-up was 43·3 months (range 0·0-63·0). In group B, the 3-year iDFS rate was 94·8% (95% CI 91·4-97·1; p=0·001), meeting the primary endpoint. No new safety signals were identified. Treatment-related adverse events and serious adverse events (SAEs) were numerically higher in patients allocated to group A than to group B (grade ≥3 62% vs 33%; SAEs 28% vs 14%). Group B PET-responders with pCR presented the lowest incidence of treatment-related grade 3 or higher adverse events (1%) without any SAEs.

INTERPRETATION  Among HER2-positive EBC patients, a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. This strategy identified about a third of patients who had HER2-positive EBC who could safely omit chemotherapy.

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