Division of Medical Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea.
Center for Breast Cancer, National Cancer Center, Goyang, Korea.
JAMA Oncol. 2022 Sep 1;8(9):1271-1277. doi: 10.1001/jamaoncol.2022.2310.
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.
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.
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.
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.
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.
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.
ClinicalTrials.gov Identifier: NCT03881878.
在临床前研究中，加入免疫检查点抑制剂的抗 ERBB2 治疗显示出协同疗效，因此值得研究作为新辅助治疗，以最大限度地提高疗效，最大限度地减少毒性作用。
确定 ERBB2 阳性早期乳腺癌的新辅助阿特珠单抗、多西他赛、曲妥珠单抗和帕妥珠单抗治疗是否需要继续进入下一阶段。
设计、地点和参与者：这项非随机、开放性标签、多中心、2 期试验由韩国癌症研究组进行，在韩国的 6 个机构招募了 2019 年 5 月至 2020 年 5 月期间的患者。符合条件的患者被诊断为 ERBB2 阳性乳腺癌（原发性肿瘤大小>2cm 或病理证实淋巴结阳性癌症，无远处转移），临床分期为 II 期或 III 期。
患者每 3 周接受 6 个周期的新辅助培妥珠单抗（第 1 个周期 840mg，随后的周期 420mg）、阿特珠单抗（1200mg）、多西他赛（75mg/m2）和曲妥珠单抗（通过皮下注射 600mg），随后进行手术。病理完全缓解（pCR）的患者在手术后每 3 周接受 12 个周期的辅助阿特珠单抗、曲妥珠单抗和培妥珠单抗治疗。无 pCR 的患者接受阿特珠单抗、1200mg 和曲妥珠单抗-美坦新偶联物（T-DM1）、3.6mg/kg 的 14 个周期治疗，每 3 周一次。
主要终点是 pCR 率，定义为原发性肿瘤和区域淋巴结（ypT0/isN0）中无浸润性癌细胞。次要终点包括临床客观缓解率、根据 pCR 达到的 3 年无事件生存率、无病生存率、总生存率、毒性作用和生活质量结果。
共有 67 名女性（中位[范围]年龄，52[33-74]岁）入组。32 名（48%）患者的激素受体表达为阳性。由于 2 名患者在新辅助治疗期间出现疾病进展且肿瘤不可切除，65 名患者进行了根治性手术。总的 pCR 率为 61%（67 名患者中有 41 名）。激素受体阴性疾病的 pCR 率高于激素受体阳性疾病（35 名患者中有 27 名[77%] vs 32 名患者中有 14 名[44%]），程序性死亡 1 阳性表达的 pCR 率高于程序性死亡 1 阴性表达的 pCR 率（13 名患者中有 13 名[100%] vs 53 名患者中有 28 名[53%]）。8 名（12%）患者和 5 名（8%）患者分别发生 3 级和 4 级中性粒细胞减少和发热性中性粒细胞减少。只有 4 名患者发生 3 级和 4 级免疫相关不良事件（3 级皮疹、脑炎、肝炎和发热）。在新辅助阶段没有与治疗相关的死亡。
在这项非随机临床试验中，在 II 期或 III 期 ERBB2 阳性乳腺癌患者中使用新辅助阿特珠单抗、多西他赛、曲妥珠单抗和培妥珠单抗方案似乎具有可接受的 pCR 率和适度的毒性作用。需要进一步研究这种免疫疗法联合在 ERBB2 阳性早期乳腺癌中的应用。
ClinicalTrials.gov 标识符：NCT03881878。
