【原】HER2阳性早期乳腺癌免疫治疗结果

　　对于高风险HER2阳性早期乳腺癌，目前术前新辅助治疗标准方案为曲妥珠单抗＋帕妥珠单抗＋化疗。免疫细胞程序性死亡配体PD-L1抑制剂阿替利珠单抗已被证实可能改善三阴性晚期乳腺癌的抗肿瘤免疫、细胞毒性化疗药物活性和患者结局。那么，阿替利珠单抗对高风险HER2阳性早期乳腺癌是否有效？

　　2022年6月28日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表瑞士圣加仑州立医院、巴塞尔罗氏、德国乌尔姆大学医院、巴西南大河天主教大学圣卢卡斯医院、圣母玛利亚医院、日本东海大学医学院、波兰玛丽·居里国家肿瘤研究所、中国台北马偕纪念医院、美国匹兹堡大学希尔曼癌症中心、纽约纪念医院斯隆凯特林癌症中心、俄罗斯莫斯科临床科学与实践中心、英国罗氏的IMpassion050研究报告，首次比较了阿替利珠单抗或安慰剂联合曲妥珠单抗＋帕妥珠单抗＋术前新辅助化疗对高风险HER2阳性早期乳腺癌患者的有效性和安全性。

IMpassion050 (NCT03726879): A Study To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer (A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial To Evaluate the Efficacy and Safety Of Atezolizumab or Placebo in Combination With Neoadjuvant Doxorubicin + Cyclophosphamide Followed By Paclitaxel + Trastuzumab + Pertuzumab In Early Her2-Positive Breast Cancer)

　　该国际多中心双盲安慰剂随机对照三期临床研究于2019年1月～2020年8月从全球12个国家73个地点入组原发肿瘤＞2厘米（T2-4）且组织学证实为淋巴结阳性（N1-3）早期（M0）HER2阳性乳腺癌术前患者454例，按1∶1的比例随机分配给予阿替利珠单抗（226例）或安慰剂（228例）联合剂量密集多柔比星＋环磷酰胺→紫杉醇＋帕妥珠单抗＋曲妥珠单抗新辅助治疗。术后，患者继续阿特珠单抗或安慰剂＋帕妥珠单抗＋曲妥珠单抗总计1年HER2靶向治疗；对于残癌患者，可以改用恩美曲妥珠单抗＋阿替利珠单抗或安慰剂。共同主要疗效终点为意向治疗人群和PD-L1阳性人群的病理完全缓解率（ypT0/is ypN0）。

　　结果，截至2021年2月5日，中位随访15.9和15.7个月，安慰剂组与阿特珠单抗组相比，病理完全缓解率：

• 意向治疗人群：62.7%比62.4%（相差-0.33%，95%置信区间：-9.2～8.6，P=0.9551）
• PD-L1阳性人群：72.5%比64.2%（相差-8.26%，95%置信区间：-20.6～4.0，P=0.1846）

　　阿替利珠单抗组与安慰剂组相比，3～4级和严重不良事件发生率较高。5级不良事件5例（术前治疗阶段4例、术后治疗阶段1例，其中治疗相关2例）都发生于阿替利珠单抗组。总体而言，与阿替利珠单抗其他联合研究相比，安全性一致。

　　因此，该研究初步分析结果表明，对于高风险HER2阳性早期乳腺癌意向治疗患者或PD-L1阳性患者，阿特珠单抗与安慰剂相比，联合剂量密集多柔比星＋环磷酰胺→紫杉醇＋帕妥珠单抗＋曲妥珠单抗新辅助治疗，并未提高病理完全缓解率。帕妥珠单抗＋曲妥珠单抗＋化疗仍为标准治疗方案；延长随访可能有助于确定阿替利珠单抗免疫治疗的长期影响。

J Clin Oncol. 2022 Jun 28. Online ahead of print.

Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial.

Huober J, Barrios CH, Niikura N, Jarzab M, Chang YC, Huggins-Puhalla SL, Pedrini J, Zhukova L, Graupner V, Eiger D, Henschel V, Gochitashvili N, Lambertini C, Restuccia E, Zhang H.

Cantonal Hospital, Breast Center St Gallen, St Gallen, Switzerland; F. Hoffmann-La Roche Ltd, Basel, Switzerland; University Hospital, Ulm, Germany; Centro de Pesquisa em Oncologia, Hospital Sao Lucas, PUCRS, Porto Alegre, Brazil; Hospital Nossa Senhora da Conceicao, Porto Alegre, Brazil; Tokai University School of Medicine, Isehara, Japan; Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland; Mackay Memorial Hospital, Taipei, Taiwan; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA; Memorial Sloan Kettering Cancer Center, New York, NY; SBIH Moscow Clinical Scientific and Practical Center named after A.S. Loginov of DHM, Moscow, Russia; Roche Products Limited, Welwyn Garden City, United Kingdom.

PURPOSE: Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients.

METHODS: Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)-positive populations.

RESULTS: At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference -0.33%; 95% CI, -9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1-positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference -8.26%; 95% CI, -20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies.

CONCLUSION: Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide-paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1-positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.

KEY OBJECTIVE: Can addition of atezolizumab to neoadjuvant standard of care (pertuzumab and trastuzumab [PH], and chemotherapy) improve outcomes in high-risk, human epidermal growth factor receptor 2-positive early breast cancer? To our knowledge, IMpassion050 was the first study to assess this question.

KNOWLEDGE GENERATED: Compared with placebo plus PH and chemotherapy, atezolizumab plus PH and chemotherapy was not superior with regards to pathologic complete response rate, both in the intention-to-treat and programmed cell death-ligand 1-positive population. The overall safety profile was consistent with that observed in other combination studies of atezolizumab.

RELEVANCE: These findings highlight the validity of PH and chemotherapy in human epidermal growth factor receptor 2-positive early breast cancer, but longer follow-up of IMpassion050 is required to inform the long-term role of cancer immunotherapy, such as atezolizumab, in this setting.

PMID: 35763704

DOI: 10.1200/JCO.21.02772