早期乳腺癌术前免疫＋双靶＋化疗

　　对于HER2阳性早期乳腺癌高风险患者，卡铂＋多西他赛＋曲妥珠单抗＋帕妥珠单抗被指南推荐为新辅助治疗首选方案之一，可显著提高术后病理完全缓解率，但是卡铂毒性反应较大，难以用于老年患者和合并症较多患者。临床前研究表明，抗HER2治疗＋免疫检查点抑制剂具有协同作用，可最大限度提高疗效并最大限度减少毒性反应。那么，用免疫检查点抑制剂取代顺铂，能否提高HER2阳性早期乳腺癌高风险患者术前多西他赛＋曲妥珠单抗＋帕妥珠单抗新辅助治疗的有效性和安全性？

　　2022年7月7日，《美国医学会杂志》肿瘤学分册在线发表韩国嘉泉大学吉医院、高阳国家癌症中心、首尔大学盆唐医院、延世大学医学院、蔚山大学首尔峨山医院、成均馆大学三星首尔医院、首尔大学医院的韩国癌症研究协作组（KCSG）BR18-23（Neo-PATH）研究报告，探讨了HER2阳性II或III期乳腺癌患者术前阿替利珠单抗＋多西他赛＋曲妥珠单抗＋帕妥珠单抗新辅助治疗的缓解率和安全性。

Neo-PATH (NCT03881878): TAHP for Patients With HER2-positive Early Breast Cancer and Subsequent AHP Adjuvant tHerapy After Surgery: Docetaxel Plus Atezolizumab Plus Herceptin SC and Pertuzumab (TAHP) for Patients With HER2-positive Early Breast Cancer and Subsequent Atezolizumab Plus Herceptin SC and Pertuzumab (AHP) Adjuvant tHerapy After Surgery

　　该非随机非盲多中心二期临床研究于2019年5月～2020年5月由韩国癌症研究协作组从6家医院入组临床II或III期HER2阳性乳腺癌原发肿瘤大小＞2厘米或经病理证实淋巴结阳性尚未远处转移患者67例（年龄33～74岁，中位52岁）其中32例（48%）患者激素受体表达阳性，术前每3周接受阿替利珠单抗（1200mg）多西他赛（75mg/m2）曲妥珠单抗（皮下注射600mg）帕妥珠单抗（首次840mg，随后420mg）新辅助治疗6个周期，随后手术。术后病理完全缓解患者每3周接受阿替利珠单抗＋曲妥珠单抗＋帕妥珠单抗辅助治疗12个周期。术后未病理完全缓解患者每3周接受阿替利珠单抗1200mg＋恩美曲妥珠单抗3.6mg/kg辅助治疗14个周期。主要终点为病理完全缓解率，定义为原发肿瘤和区域淋巴结未浸润癌细胞（ypT0/is ypN0）。次要终点包括临床客观缓解率、根据病理完全缓解实现的3年无事件生存率、无病生存、总生存、毒性反应和生活质量结局。

　　结果，其中65例患者完成治愈手术，其余2例患者由于新辅助治疗期间出现疾病进展且其肿瘤成为无法切除。

　　全部患者病理完全缓解率为61%

• 激素受体阴性与阳性患者相比：病理完全缓解率显著较高（77%比44%）
• PD-1阳性与阴性患者相比：病理完全缓解率显著较高（100%比53%）

　　3～4级中性粒细胞减少和发热性中性粒细胞减少发生率分别为12%和8%。仅4例患者发生3～4级免疫相关不良事件（3级皮疹、脑炎、肝炎和发热）。术前新辅助阶段未发生治疗相关死亡。

　　因此，该小样本非随机二期临床研究结果表明，对于II或III期HER2阳性乳腺癌术前患者，阿替利珠单抗＋多西他赛＋曲妥珠单抗＋帕妥珠单抗新辅助治疗方案的病理完全缓解率和毒性反应似乎均可接受，故有必要进一步开展随机对照三期临床研究，验证该免疫联合方案对HER2阳性早期乳腺癌的效果。

JAMA Oncol. 2022 Jul 7. Online ahead of print.

Response Rate and Safety of a Neoadjuvant Pertuzumab, Atezolizumab, Docetaxel, and Trastuzumab Regimen for Patients With ERBB2-Positive Stage II/III Breast Cancer: The Neo-PATH Phase 2 Nonrandomized Clinical Trial.

Ahn HK, Sim SH, Suh KJ, Kim MH, Jeong JH, Kim JY, Lee DW, Ahn JH, Chae H, Lee KH, Kim JH, Lee KS, Sohn JH, Choi YL, Im SA, Jung KH, Park YH.

Gachon University Gil Medical Center, Incheon, Korea; National Cancer Center, Goyang, Korea; Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea; Yonsei University College of Medicine, Seoul, Korea; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

This nonrandomized clinical trial aims to determine whether neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab therapy for ERBB2-positive early breast cancer warrants continuation to the next phase.

QUESTION: What are the outcomes of neoadjuvant atezolizumab with docetaxel, trastuzumab, and pertuzumab (PATH) for the treatment of ERBB2-positive early breast cancer?

FINDINGS: In this single-arm, phase 2, nonrandomized clinical trial of 67 patients with ERBB2-positive early breast cancer, the overall pathologic complete response rate of 6 cycles of neoadjuvant PATH regimen was 61%. During the neoadjuvant phase, the incidence rate of febrile neutropenia was 8% and grade 3 or 4 immune-related adverse events occurred in 4 patients.

MEANING: Use of the neoadjuvant PATH regimen for ERBB2-positive EBC warrants further investigation.

IMPORTANCE: Addition of immune checkpoint inhibitors to anti-ERBB2 treatment has shown synergistic efficacy in preclinical studies and is thus worth investigating as a neoadjuvant treatment to maximize efficacy and to minimize toxic effects.

OBJECTIVE: To determine if neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab therapy for ERBB2-positive early breast cancer warrants continuation to the next phase.

DESIGN, SETTING, AND PARTICIPANTS: This nonrandomized, open label, multicenter, phase 2 trial was conducted by the Korean Cancer Study Group and enrolled patients across 6 institutions in Korea from May 2019 to May 2020. Eligible patients were diagnosed with ERBB2-positive breast cancer (primary tumor size >2 cm or pathologically confirmed lymph node-positive cancer, without distant metastases) with a clinical stage of II or III.

INTERVENTIONS: Patients received 6 cycles of neoadjuvant pertuzumab (840 mg at first cycle, 420 mg during subsequent cycles), atezolizumab (1200 mg), docetaxel (75 mg/m2), and trastuzumab (600 mg via subcutaneous injection) every 3 weeks, followed by surgery. Patients with pathologic complete response (pCR) received 12 cycles of adjuvant atezolizumab, trastuzumab, and pertuzumab every 3 weeks after surgery. Patients without pCR were treated with 14 cycles of atezolizumab, 1200 mg, plus trastuzumab emtansine, 3.6 mg/kg, every 3 weeks.

MAIN OUTCOMES AND MEASURES: The primary end point was pCR rate, which was defined as the absence of invasive cancer cells in the primary tumor and regional lymph nodes (ypT0/isN0). Secondary end points included clinical objective response rate, 3-year event-free survival rate according to pCR achievement, disease-free survival, overall survival, toxic effects, and quality-of-life outcomes.

RESULTS: A total of 67 women (median [range] age, 52 [33-74] years) were enrolled. Hormone receptor expression was positive in 32 (48%) patients. Curative surgery was performed in 65 patients because 2 patients showed disease progression during neoadjuvant treatment and their tumors became unresectable. The overall pCR rate was 61% (41 of 67 patients). The pCR rate was higher in hormone receptor-negative disease vs hormone receptor-positive disease (27 of 35 [77%] patients vs 14 of 32 [44%] patients) and in programmed cell death 1-positive expression vs programmed cell death 1-negative expression (13 of 13 [100%] patients vs 28 of 53 [53%] patients). Grade 3 and 4 neutropenia and febrile neutropenia occurred in 8 (12%) patients and 5 (8%) patients, respectively. Grade 3 and 4 immune-related adverse events occurred in only 4 patients (grade 3 skin rash, encephalitis, hepatitis, and fever). No treatment-related death occurred during the neoadjuvant phase.

CONCLUSIONS AND RELEVANCE: In this nonrandomized clinical trial, treatment with the neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab regimen in patients with stage II or III ERBB2-positive breast cancer appears to have had an acceptable pCR rate and modest toxic effects. Further investigation of this immunotherapy combination in ERBB2-positive early breast cancer is warranted.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03881878

PMID: 35797012

DOI: 10.1001/jamaoncol.2022.2310

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