罗氏新药能否减轻乳腺癌治疗负担 / 开普饭

　　大约15%～20%的乳腺癌患者HER2过表达，CLEOPATRA、NeoSphere、APHINITY研究已经分别证实帕妥珠单抗＋曲妥珠单抗可以显著提高HER2阳性晚期乳腺癌患者的总生存率、HER2阳性早期乳腺癌患者术前新辅助化疗的病理完全缓解率、HER2阳性早期乳腺癌高复发风险患者术后辅助化疗的无浸润病变生存率。不过，静脉注射帕妥珠单抗、曲妥珠单抗，每次分别需要30～60、30～90分钟。加入透明质酸酶的皮下注射制剂可将注射时间减少至几分钟。2020年6月29日，美国食品药品监督管理局根据2019年12月圣安东尼奥乳腺癌大会公布的FeDeriCa研究初步结果，批准了罗氏旗下基因泰克的固定剂量帕妥珠单抗＋曲妥珠单抗＋透明质酸酶三合一皮下注射制剂（商品名：PHESGO）用于HER2阳性乳腺癌早期术前新辅助和术后辅助治疗、晚期转移治疗，首次帕妥珠单抗1200毫克＋曲妥珠单抗600毫克＋透明质酸酶3万单位，皮下注射8分钟；随后每3周帕妥珠单抗600毫克＋曲妥珠单抗600毫克＋透明质酸酶2万单位，皮下注射5分钟。

　　2020年12月21日，英国《柳叶刀》肿瘤学分册在线发表美国基因泰克、北卡罗来纳医疗中心列文癌症研究所、韩国首尔大学医院癌症研究所、蔚山大学首尔峨山医院、巴西圣保罗佩罗拉·白灵顿医院、西班牙马德里自治大学公主医院、俄罗斯莫斯科市立临床肿瘤医院、波兰华沙肿瘤研究中心、意大利那不勒斯国家癌症研究所、法国巴黎居里学院、德国汉堡乳腺中心、奥芬巴赫萨纳医院、英国罗氏、瑞士罗氏的FeDeriCa研究术前新辅助治疗初步结果全文，对固定剂量帕妥珠单抗＋曲妥珠单抗＋透明质酸酶三合一皮下注射制剂与帕妥珠单抗＋曲妥珠单抗静脉注射制剂用于HER2阳性早期乳腺癌术前新辅助化疗的药物代谢动力学、有效性和安全性进行了比较。

FeDeriCa (NCT03493854): A Phase III, Randomized, Multicenter, Open-Label, Two-Arm Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Patients With HER2-Positive Early Breast Cancer

　　该国际多中心非盲随机对照非劣效三期临床研究于2018年6月14日～2018年12月24日从19个国家或地区106家医院入组年龄≥18岁、美国东部肿瘤学协作组体力状态评分0或1、左心室射血分数≥55%的II～IIIC期HER2阳性局部晚期或炎性乳腺癌可手术患者500例，按1∶1的比例通过语音或网络反馈系统随机分为两组：

静脉注射组252例：首次静脉注射帕妥珠单抗840毫克＋曲妥珠单抗每公斤体重8毫克，随后每3周静脉注射帕妥珠单抗420毫克＋曲妥珠单抗每公斤体重6毫克
皮下注射组248例：首次皮下注射15毫升帕妥珠单抗1200毫克＋曲妥珠单抗600毫克，随后每3周皮下注射10毫升帕妥珠单抗600毫克＋曲妥珠单抗600毫克

　　随机分组前，研究者从研究方案批准的两种标准方案（每2周多柔比星＋环磷酰胺×4个周期→每周紫杉醇×12周，每3周多柔比星＋环磷酰胺×4个周期→每3周多西他赛×4个周期）选择其一进行术前新辅助化疗，紫杉醇或多西他赛化疗期间给予HER2靶向治疗4个周期。术后，患者继续HER2靶向治疗14个周期，合计18个周期。

　　根据激素受体状态、临床分期和化疗方案对患者进行分层。主要终点为两组患者按研究方案用药并评定药物代谢动力学的第7个周期帕妥珠单抗血清谷浓度（即第8个周期用药前帕妥珠单抗浓度）非劣效性。非劣效性定义为几何平均比的90%置信区间下限≥0.8。对按研究方案用药（包括化疗或HER2靶向治疗）至少一次的全部患者进行安全性分析。入组、术前新辅助治疗和手术已经完成，术后辅助治疗和随访正在进行。

　　结果，皮下注射组与静脉注射组相比，帕妥珠单抗血清谷浓度的几何平均比为1.22（90%置信区间：1.14～1.31），达到主要终点。

　　静脉注射组与皮下注射组相比，病理完全缓解率为60%比60%，术前HER2靶向治疗＋新辅助化疗期间发生率≥5%的3～4级不良事件：

中性粒细胞减少症：13%比14%
中性粒细胞计数减少：12%比11%
中性粒细胞减少症伴发热：6%比6%
腹泻：5%比7%
白细胞计数减少：7%比4%
治疗相关严重不良事件：10%比10%

　　两组各有1例致死不良事件（静脉注射组尿毒症1例，皮下注射组急性心肌梗死1例）；死亡都与HER2靶向治疗无关。

　　因此，该研究结果表明，对于HER2阳性早期乳腺癌术前新辅助化疗患者，皮下注射固定剂量帕妥珠单抗＋曲妥珠单抗与静脉注射帕妥珠单抗＋曲妥珠单抗相比，第7个周期帕妥珠单抗血清谷浓度非劣效，病理学完全缓解率相似。两组安全性相似，并且与帕妥珠单抗、曲妥珠单抗和化疗的其他研究结果一致。正在随访长期结局，包括疗效和长期安全性。

　　对此，奥地利维也纳医科大学、德国埃森大学医院发表同期评论：FeDeriCa研究结果能否减轻乳腺癌治疗负担？

皮下注射五分钟视频演示

帕妥珠单抗＋曲妥珠单抗皮下注射制剂价格

帕妥珠单抗静脉注射制剂（帕捷特）价格

曲妥珠单抗静脉注射制剂（赫赛汀）价格

相关链接

Lancet Oncol. 2020 Dec 21. Online ahead of print.

Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection plus chemotherapy in HER2-positive early breast cancer (FeDeriCa): a randomised, open-label, multicentre, non-inferiority, phase 3 study.

Antoinette R Tan, Seock-Ah Im, André Mattar, Ramon Colomer, Daniil Stroyakovskii, Zbigniew Nowecki, Michelino De Laurentiis, Jean-Yves Pierga, Kyung Hae Jung, Christian Schem, Alexandra Hogea, Tanja Badovinac Crnjevic, Sarah Heeson, Mahesh Shivhare, Whitney P Kirschbrown, Eleonora Restuccia, Christian Jackischon; FeDeriCa study group.

Levine Cancer Institute, Atrium Health, Charlotte, NC, USA; Genentech, South San Francisco, CA, USA; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Hospital Pérola Byington, Sao Paulo, Brazil; Hospital Universitario La Princesa, Madrid, Spain; City Clinical Oncology Hospital 62, Moscow, Russia; Centrum Onkologii-Instytut, Warsaw, Poland; Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy; Institut Curie and Université de Paris, Paris, France; Mammazentrum Hamburg, Hamburg, Germany; Sana Klinikum Offenbach, Offenbach, Germany; Roche Products, Welwyn Garden City, UK; F Hoffmann-La Roche, Basel, Switzerland.

BACKGROUND: A subcutaneous formulation of pertuzumab and trastuzumab with recombinant human hyaluronidase in one ready-to-use, fixed-dose combination vial (pertuzumab, trastuzumab, and hyaluronidase-zzxf) was approved by the US Food and Drug Administration (FDA) on June 29, 2020. We report the primary analysis of the FeDeriCa study, which was designed to assess the pharmacokinetics, efficacy, and safety of the fixed-dose subcutaneous formulation compared to intravenous pertuzumab plus trastuzumab in patients with HER2-positive early breast cancer in the neoadjuvant-adjuvant setting.

METHODS: FeDeriCa, a randomised, open-label, international, multicentre, non-inferiority, phase 3 study, was done across 106 sites in 19 countries. Patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1, HER2-positive, operable, locally advanced, or inflammatory stage II-IIIC breast cancer, and a left ventricular ejection fraction of 55% or more were randomly assigned (1:1), using a voice-based or web-based response system, to receive intravenous pertuzumab (840 mg loading dose, followed by 420 mg maintenance doses) plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg maintenance doses) or the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (1200 mg pertuzumab plus 600 mg trastuzumab loading dose in 15 mL, followed by 600 mg pertuzumab plus 600 mg trastuzumab maintenance doses in 10 mL), both administered every 3 weeks with neoadjuvant chemotherapy. Patients were stratified by hormone receptor status, clinical stage, and chemotherapy regimen. The investigator selected one of the two protocol-approved standard chemotherapy regimens before randomisation. Four cycles of HER2-targeted therapy were administered concurrently with the taxane. After surgery, patients continued the HER2-targeted therapy to receive an additional 14 cycles (total of 18). The primary endpoint was non-inferiority of the cycle 7 pertuzumab serum trough concentration ( C trough; ie, cycle 8 predose pertuzumab concentration) within the fixed-dose combination for subcutaneous injection versus intravenous pertuzumab plus trastuzumab in the per-protocol pharmacokinetic population (all enrolled patients who adhered to prespecified criteria for pharmacokinetic assessment). Non-inferiority was concluded if the lower bound of the 90% CI of the geometric mean ratio was 0.8 or higher. The safety population included all patients who received at least one dose of study medication, including chemotherapy or HER2-targeted therapy. Enrolment, neoadjuvant therapy, and surgery have been completed; adjuvant treatment and follow-up are ongoing. The trial is registered with ClinicalTrials.gov, NCT03493854.

FINDINGS: Between June 14, 2018, and Dec 24, 2018, 252 patients were randomly assigned to the intravenous infusion group and 248 to the fixed-dose combination group. The geometric mean ratio of pertuzumab serum C trough subcutaneous to serum C trough intravenous was 1.22 (90% CI 1.14-1.31). The most common grade 3-4 adverse events occurring during neoadjuvant treatment with HER2-targeted therapy plus chemotherapy in 5% or more of patients were neutropenia (34 [13%] of 252 patients in the intravenous infusion group vs 35 [14%] of 248 patients in the fixed-dose combination group), decreased neutrophil count (31 [12%] vs 27 [11%]), febrile neutropenia (14 [6%] vs 16 [6%]), diarrhoea (12 [5%] vs 17 [7%]), and decreased white blood cell count (18 [7%] vs nine [4%]). At least one treatment-related serious adverse event was reported in 25 (10%) patients in the intravenous infusion group and 26 (10%) patients in the fixed-dose combination group. One patient in each treatment group had an adverse event that led to death (urosepsis in the intravenous infusion group and acute myocardial infarction in the fixed-dose combination group); neither death was related to HER2-targeted therapy.

INTERPRETATION: The study met its primary endpoint: the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection provides non-inferior cycle 7 pertuzumab serum C trough concentrations to intravenous pertuzumab plus trastuzumab in the neoadjuvant setting with comparable total pathological complete response rates, supporting the FDA approval. Safety was similar between treatment groups, and in line with other pertuzumab, trastuzumab, and chemotherapy trials. Follow-up is ongoing for long-term outcomes, including efficacy and long-term safety.

FUNDING: F Hoffmann-La Roche and Genentech

DOI: 10.1016/S1470-2045(20)30536-2