【原】曲妥珠单抗＋卡培他滨＋帕妥珠单抗能否改善生存？

　　对于曲妥珠单抗治疗失败后转移性乳腺癌患者，已知曲妥珠单抗＋卡培他滨优于卡培他滨、曲妥珠单抗＋帕妥珠单抗优于曲妥珠单抗、曲妥珠单抗＋紫杉类＋帕妥珠单抗优于曲妥珠单抗＋紫杉类，那么曲妥珠单抗＋卡培他滨＋帕妥珠单抗是否优于曲妥珠单抗＋卡培他滨？

　　2017年4月24日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表西班牙圣塞瓦斯蒂安肿瘤学基金会、加泰罗尼亚肿瘤学研究所、巴塞罗那大学实体肿瘤转化基因组学与靶向疗法研究中心、马德里自治大学普尔塔耶罗医院、英国西苏格兰比特森癌症中心、韩国首尔大学医院癌症研究所、首尔大学医学院、匈牙利国家肿瘤研究所、意大利克雷莫纳医院、瑞士罗氏、美国基因泰克的研究报告，对曲妥珠单抗＋卡培他滨±帕妥珠单抗用于曲妥珠单抗＋紫杉类治疗期间或之后疾病进展的人类表皮生长因子受体2（HER2）阳性转移性乳腺癌患者的有效性和安全性进行了评定。

　　该随机Ⅲ期研究（PHEREXA）于2010年1月30日～2013年8月12日从21个国家171个中心入组曲妥珠单抗＋紫杉类治疗期间或之后疾病进展的HER2阳性转移性乳腺癌女性患者452例，随机分入：

• 对照组：曲妥珠单抗（8mg/kg→每3周6mg/kg）＋卡培他滨（1250mg/m²，每天2次，用2周，休1周，每3周重复）；

• 帕妥珠单抗组：帕妥珠单抗（840mg→每3周420mg）＋曲妥珠单抗（用量用法同对照组）＋卡培他滨（1000mg/m²，用法同对照组）。

　　主要终点为独立评审机构评定的无进展生存。次要终点包括总生存和安全性。使用分层检验对无进展生存、总生存、客观缓解率的统计学检验进行Ⅰ类误差控制。

　　结果发现，对照组、帕妥珠单抗组随机分配的意向治疗人群分别为224、228例，中位随访分别为28.6、25.3个月

• 中位无进展生存分别为9.0、11.1个月（风险比：0.82，95%置信区间：0.65～1.02，P=0.0731）

• 中期分析时的中位总生存分别为28.1、36.1个月（风险比：0.68，95%置信区间：0.51～0.90）。

　　最常见的不良事件（所有等级，任何组的发生率≥10%，组间差异≥5%）对照组为手足综合征、恶心、中性粒细胞减少，帕妥珠单抗组为腹泻、皮疹、鼻咽炎。

　　因此，将帕妥珠单抗加入曲妥珠单抗＋卡培他滨并未显著改善无进展生存，帕妥珠单抗组的中位总生存增加8个月至36.1个月。对主要终点无进展生存进行分层检验后，总生存的差异无统计学意义；不过，总生存的差异大小与转移性乳腺癌既往研究结果相似。未发现新的安全问题。

J Clin Oncol. 2017 Apr 24. [Epub ahead of print]

Randomized Phase III Trial of Trastuzumab Plus Capecitabine With or Without Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Who Experienced Disease Progression During or After Trastuzumab-Based Therapy.

Ander Urruticoechea, Mohammed Rizwanullah, Seock-Ah Im, Antonio Carlos Sánchez Ruiz, István Láng, Gianluca Tomasello, Hannah Douthwaite, Tanja Badovinac Crnjevic, Sarah Heeson, Jennifer Eng-Wong, Montserrat Munoz.

Onkologikoa Foundation, San Sebastián; Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat; Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona; Hospital Universitario Puerta de Hierro, Madrid, Spain; Beatson West of Scotland Cancer Centre, Glasgow; Roche, Welwyn Garden City, United Kingdom; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; National Institute of Oncology, Budapest, Hungary; ASST di Cremona - Ospedale di Cremona, Cremona, Italy; F Hoffmann-La Roche, Basel, Switzerland; Genentech, South San Francisco, CA.

• Purpose: To assess the efficacy and safety of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy and received a prior taxane.

• Patients and Methods: Patients were randomly assigned to arm A: trastuzumab 8 mg/kg → 6 mg/kg once every 3 weeks plus capecitabine 1,250 mg/m² twice a day (2 weeks on, 1 week off, every 3 weeks); or arm B: pertuzumab 840 mg → 420 mg once every 3 weeks plus trastuzumab at the same dose and schedule as arm A plus capecitabine 1,000 mg/m² on the same schedule as arm A. The primary end point was independent review facility-assessed progression-free survival (IRF PFS). Secondary end points included overall survival (OS) and safety. Hierarchical testing procedures were used to control type I error for statistical testing of IRF PFS, OS, and objective response rate.

• Results: Randomly assigned (intent-to-treat) populations were 224 and 228 patients in arms A and B, respectively. Median IRF PFS at 28.6 and 25.3 months' median follow-up was 9.0 v 11.1 months (hazard ratio, 0.82; 95% CI, 0.65 to 1.02; P = .0731) and interim OS was 28.1 v 36.1 months (hazard ratio, 0.68; 95% CI, 0.51 to 0.90). The most common adverse events (all grades; incidence of ≥ 10% in either arm and ≥ 5% difference between arms) were hand-foot syndrome, nausea, and neutropenia in arm A, and diarrhea, rash, and nasopharyngitis in arm B.

• Conclusion: The addition of pertuzumab to trastuzumab and capecitabine did not significantly improve IRF PFS. An 8-month increase in median OS to 36.1 months with pertuzumab was observed. Statistical significance for OS cannot be claimed because of the hierarchical testing of OS after the primary PFS end point; however, the magnitude of OS difference is in keeping with prior experience of pertuzumab in metastatic breast cancer. No new safety signals were identified.

DOI: 10.1200/JCO.2016.70.6267