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曲妥珠单抗静脉注射每次通常需要30～90分钟，加入透明质酸酶（玻尿酸溶解酶）的曲妥珠单抗皮下注射制剂可以将每次时间缩短至5分钟。2012年《柳叶刀》肿瘤学分册公布的3期非盲随机对照研究HannaH初步分析结果表明，曲妥珠单抗皮下注射与静脉注射相比，对于HER2阳性早期乳腺癌患者的短期安全性和有效性相似。 2019年4月18日，《美国医学会杂志》肿瘤学分册在线发表德国奥芬巴赫萨纳医院、俄罗斯莫斯科市肿瘤医院、法国斯特拉斯堡保罗施特劳斯癌症治疗中心、韩国成均馆大学三星首尔医院、捷克帕拉茨基大学医学院教学医院、中国台湾桃园长庚纪念医院、瑞士巴塞尔罗氏、巴西圣保罗佩罗拉拜因顿医院的3期非盲随机对照研究HannaH最终分析结果报告，比较了曲妥珠单抗皮下或静脉注射治疗HER2阳性早期乳腺癌患者随访6年的长期有效性和安全性。 HannaH: A Study to Compare Subcutaneous (SC) Versus Intravenous (IV) Administration of Herceptin (Trastuzumab) in Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Early Breast Cancer (NCT00950300) 该国际多中心新辅助＋辅助治疗非劣效非盲随机对照3期前瞻临床研究于2009年10月19日～2010年12月1日从24个国家或地区81个中心入组HER2阳性早期乳腺癌女性患者596例，随机分入皮下注射组、静脉注射组，接受术前新辅助治疗、手术、术后辅助治疗。术前新辅助治疗包括8个周期化疗（前4个周期为每3个星期多西他赛75mg/m²，后4个周期为每3个星期氟尿嘧啶500mg/m²＋表柔比星75mg/m²＋环磷酰胺500mg/m²）和曲妥珠单抗（皮下注射组每3个星期600mg，静脉注射组第1个星期8mg/kg随后每3个星期6mg/kg）。术后辅助治疗包括10个周期曲妥珠单抗，直至完成1年抗HER2治疗。初步分析主要终点为：病理完全缓解、术前给药第8个周期时的药物血清谷浓度。最终分析主要结局：根据生存曲线计算无事件生存和总生存，通过多因素比例风险回归推算风险比，根据研究方案标准对不良事件和严重不良事件进行分级。 结果，截至2017年1月24日，皮下注射组、静脉注射组相比：
获得全部（乳房＋腋窝）病理完全缓解的患者，与残留病变的患者相比，无事件生存时间更长，6年总生存率更高。 因此，该研究最终分析结果进一步证实了皮下与静脉注射曲妥珠单抗的长期有效性和安全性相似，并且强调了曲妥珠单抗皮下注射适合作为HER2阳性早期乳腺癌患者的替代给药途径。 相关阅读 JAMA Oncol. 2019 Apr 18. [Epub ahead of print] Subcutaneous vs Intravenous Trastuzumab for Patients With ERBB2-Positive Early Breast Cancer: Final Analysis of the HannaH Phase 3 Randomized Clinical Trial. Christian Jackisch, Daniil Stroyakovskiy, Xavier Pivot, Jin Seok Ahn, Bohuslav Melichar, Shin-Cheh Chen, Christoph Meyenberg, Nedal Al-Sakaff, Dominik Heinzmann, Roberto Hegg. Sana Klinikum Offenbach GmbH, Offenbach, Germany; City Clinical Oncology Hospital 62, Moscow, Russian Federation; Centre de Lutte contre le Cancer Paul Strauss de Strasbourg, Strasbourg, France; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic; Chang Gung Memorial Hospital, Taoyuan City, Taiwan; F. Hoffmann-La Roche Ltd, Basel, Switzerland; Hospital Pérola Byington, Sao Paulo, Brazil. This final analysis of the phase 3 randomized clinical trial HannaH evaluates the efficacy and safety of subcutaneous trastuzumab compared with that of intravenous trastuzumab for patients with ERBB2-positive early breast cancer after 6 years' follow-up. QUESTION: Do subcutaneous trastuzumab and intravenous trastuzumab have comparable long-term efficacy and safety for patients with ERBB2 (HER2)-positive early breast cancer? FINDINGS: In this final analysis of a randomized clinical trial of 596 patients, 6-year event-free survival rates were 65% with subcutaneous and intravenous trastuzumab, and 6-year overall survival rates were 84% in both study groups. Safety was comparable between subcutaneous and intravenous treatment. MEANING: Subcutaneous trastuzumab has long-term efficacy and safety comparable to that of intravenous trastuzumab, thus confirming the suitability of subcutaneous trastuzumab treatment for patients with ERBB2-positive early breast cancer. IMPORTANCE: Confirmation of long-term comparability between subcutaneous and intravenous trastuzumab is essential. OBJECTIVE: To evaluate efficacy and safety of subcutaneous trastuzumab compared with that of intravenous trastuzumab for patients with ERBB2 (HER2)-positive early breast cancer after 6 years' follow-up in the HannaH (Enhanced Treatment With Neoadjuvant Herceptin) trial. DESIGN, SETTING, AND PARTICIPANTS: Open-label, prospective, multicenter, international, neoadjuvant-adjuvant, randomized, phase 3 noninferiority clinical trial (primary end points: pathologic complete response and serum trough concentration predose cycle 8) conducted for 596 patients with ERBB2-positive early breast cancer enrolled from October 19, 2009, to December 1, 2010. INTERVENTIONS: Eligible patients received 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m², followed by 4 cycles of fluorouracil, 500 mg/m², epirubicin, 75 mg/m², and cyclophosphamide, 500 mg/m²) with either fixed-dose subcutaneous trastuzumab, 600 mg, or intravenous trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in the neoadjuvant setting. Patients received an additional 10 cycles of subcutaneous trastuzumab or intravenous trastuzumab (according to their initial randomization) after surgery in the adjuvant setting to complete 1 year of anti-ERBB2 therapy. MAIN OUTCOMES AND MEASURES: Event-free and overall survival rates were calculated using the Kaplan-Meier method. Hazard ratios were estimated by Cox proportional hazards regression. Adverse events and serious adverse events were graded per standard criteria. RESULTS: In total, 294 women (mean [SD] age, 50.3 [11.1] years) treated with subcutaneous trastuzumab and 297 women (mean [SD] age, 49.5 [10.8] years) treated with intravenous trastuzumab were included in respective intention-to-treat populations. Six-year event-free survival rates (65% in both study groups; hazard ratio, 0.98; 95% CI, 0.74-1.29) and overall survival rates (84% in both study groups; hazard ratio, 0.94; 95% CI, 0.61-1.45) were similar between the subcutaneous and intravenous trastuzumab groups. Patients achieving a total pathologic complete response had longer event-free survival and higher 6-year overall survival rates than those with residual disease. Incidence of adverse events (290 of 297 [97.6%] vs 282 of 298 [94.6%]), grade 3 or higher adverse events (158 of 297 [53.2%] vs 160 of 298 [53.7%]), cardiac events (44 of 297 [14.8%] vs 42 of 298 [14.1%]), and serious adverse events (65 of 297 [21.9%] vs 45 of 298 [15.1%]) was comparable between the subcutaneous and intravenous trastuzumab treatment groups. CONCLUSIONS AND RELEVANCE: This final analysis of the HannaH trial further confirms the comparable efficacy and safety of subcutaneous and intravenous trastuzumab and highlights the suitability of subcutaneous trastuzumab as an alternative route of administration for patients with ERBB2-positive early breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00950300 DOI: 10.1001/jamaoncol.2019.0339 |
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