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三阴性乳腺癌的雌激素受体、孕激素受体、人类表皮生长因子受体HER2均为阴性，对内分泌治疗和HER2靶向治疗通常无效，晚期患者主要依靠化疗。近年来，免疫治疗对三阴性乳腺癌获得巨大成功。其中，免疫细胞程序性死亡蛋白PD-1是重要的免疫抑制分子和免疫检查点，高表达于三阴性乳腺癌等恶性肿瘤，可以阻断人体免疫系统对肿瘤细胞的攻击，PD-1或其配体PD-L1抑制剂可以激活人体免疫系统的抗肿瘤活性。2018年，美国麻省医学会《新英格兰医学杂志》发表IMpassion130研究首次中期分析，证实PD-L1抑制剂阿替利珠单抗与安慰剂相比，联合白蛋白紫杉醇一线治疗晚期三阴性乳腺癌，可显著改善全部患者和PD-L1阳性患者的无进展生存，但是仅改善PD-L1阳性患者的总生存。随后，IMpassion131研究向三阴性乳腺癌发起第二次挑战，但是阿替利珠单抗与安慰剂相比，联合紫杉醇一线治疗晚期三阴性乳腺癌，无论全部患者还是PD-L1阳性患者，无进展生存和总生存均未显著改善。 2024年5月15日，欧洲肿瘤内科学会（ESMO）官方期刊《肿瘤学年鉴》与在德国柏林召开的ESMO乳腺癌年会同步发表新加坡、法国、西班牙、英国、德国、美国、土耳其、墨西哥、韩国、意大利、中国、瑞士、葡萄牙、加拿大联合开展的IMpassion132研究报告，对早期复发无法切除的局部晚期或远处转移三阴性乳腺癌一线化疗±阿替利珠单抗的有效性和安全性进行了比较。 
IMpassion132 (NCT03371017): A Study of the Efficacy and Safety of Atezolizumab Plus Chemotherapy for Patients With Early Relapsing Recurrent Triple-Negative Breast Cancer: A Phase III, Randomised, Double-Blind, Placebo-Controlled, Multicentre Study Of The Efficacy And Safety Of Atezolizumab Plus Chemotherapy For Patients With Early Relapsing Recurrent (Inoperable Locally Advanced Or Metastatic) Triple-Negative Breast Cancer 该国际多中心双盲安慰剂随机对照三期临床研究于2018年1月11日至2023年8月4日从欧洲、美洲、亚洲和非洲28个国家126家医院入组末次化疗（蒽环类和紫杉类）或早期三阴性乳腺癌手术后12个月内复发的局部晚期或远处转移三阴性乳腺癌尚未治疗患者595例，随机分组前用SP142抗体集中检测PD-L1。最初，无论PD-L1阳性还是阴性都入组。自2019年8月起，仅入组PD-L1阳性（肿瘤免疫细胞≥1%）患者。按1∶1的比例将患者随机分为两组，其中298例给予安慰剂＋研究者选择化疗方案，其余297例每21天给予阿替利珠单抗1200毫克＋研究者选择化疗方案，直至疾病进展或出现无法耐受的毒性反应。分层因素包括化疗方案（卡铂＋吉西他滨或卡培他滨单药）、内脏（肺和/或肝）转移和（初始）PD-L1状态。主要终点为总生存，对PD-L1阳性肿瘤患者进行分层检验，如果阳性，那么对改良意向治疗人群（2019年8月前随机入组的全部患者）进行检验。次要终点包括无进展生存、客观缓解率和安全性。 
结果，PD-L1阳性患者354例，两组各177例，无病间隔少于6个月占68%，卡铂＋吉西他滨化疗占73%。截至2023年9月15日，中位随访9.8个月（范围0.0～63.7），阿替利珠单抗组与安慰剂组相比： 
化疗期间，两组相比，阿特珠单抗＋卡铂＋吉西他滨或卡培他滨的不良事件（主要为血液学）相似。 因此，该研究结果表明，对于12个月内复发的三阴性乳腺癌患者，总生存极差，将阿替利珠单抗加入一线化疗并未改善总生存，迫切需要对局部晚期或远处转移患者免疫治疗耐药进行生物学定义，以便下一次临床试验为这些患者开发新疗法。 相关链接 Ann Oncol. 2024 May 15. IF: 50.5IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer.Dent R, André F, Goncalves A, Martin M, Schmid P, Schütz F, Kümmel S, Swain SM, Bilici A, Loirat D, Villalobos Valencia R, Im SA, Park YH, De Laurentis M, Colleoni M, Guarneri V, Bianchini G, Li H, Kirchmayer Machackova Z, Mouta J, Deurloo R, Gan X, Fan M, Mani A, Swat A, Cortés J.National Cancer Center, Singapore; Duke-NUS Medical School, Singapore, Singapore; Gustave Roussy, Université Paris Saclay, Villejuif; Aix Marseille University, Institut Paoli-Calmettes, CRCM, Marseille, France; Hospital General Universitario Gregorio Maranón, Universidad Complutense, Madrid, Spain; Barts Cancer Institute, Centre for Experimental Cancer Medicine, London, UK; University Breast Unit, National Center for Tumor Diseases, Heidelberg; Kliniken Essen-Mitte, Essen; Charité—Universitatsmedizin Berlin, Berlin, Germany; Georgetown University Medical Center and MedStar Health, Washington, USA; Istanbul Medipol University Medical Faculty, Istanbul, Turkey; Institut Curie, Paris, France; Centro Medico Dalinde, Mexico City, Mexico; Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul National University, Seoul; Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; IRCCS Istituto Nazionale Tumori Fondazione Giovanni Pascale, Napoli; European Institute of Oncology, IRCCS, Milan; University of Padova, Padova; Veneto Institute of Oncology IOV—IRCCS, Padova; IRCCS Ospedale San Raffaele, Milan; Università Vita-Salute San Raffaele, Milan, Italy; Peking University Cancer Hospital and Institute, Beijing, China; F. Hoffmann-La Roche Ltd, Basel, Switzerland; Roche Farmacêutica Química Lda, Amadora, Portugal; Roche (China) Holding Ltd, Shanghai, China; Hoffmann-La Roche Limited, Mississauga, Canada; Genentech/Roche, South San Francisco, USA; International Breast Cancer Center (IBCC), Pangaea Oncology, Quironsalud Group, Barcelona; Universidad Europea de Madrid, Madrid; IOB Madrid, Hospital Beata Maria Ana, Madrid, Spain.- Data on outcomes in patients with rapidly relapsing TNBC are scarce.
- The phase III IMpassion132 trial enrolled patients with TNBC relapse <12 months after chemotherapy/surgery for early TNBC.
- OS was not improved by adding atezolizumab to chemotherapy for rapidly relapsing PD-L1-positive TNBC.
- Patients with rapidly relapsing TNBC have a dismal prognosis and represent a population with huge unmet need.
BACKGROUND: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce.PATIENTS AND METHODS: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety.RESULTS: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure.CONCLUSIONS: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.KEYWORDS: disease-free interval, immune checkpoint, PD-L1, prognosis, rapid relapse, triple-negative breast cancerDOI: 10.1016/j.annonc.2024.04.001
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