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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,全身治疗主要依靠化疗。对于高风险早期或局部晚期三阴性乳腺癌,术前化疗可以缩小肿瘤,提高保乳手术可能性,并可观察肿瘤对抗癌药物的敏感性和预后。几十年来,高风险早期或局部晚期三阴性乳腺癌的标准化疗方案一直是紫杉类+蒽环类+环磷酰胺。最近,为提高术后病理完全缓解率,人们探索将铂类、免疫治疗加入术前标准化疗方案。另一方面,虽然每两周一次的蒽环类+环磷酰胺剂量密集化疗已被证实优于每三周一次,但是联合铂类和免疫治疗仍未得到充分探索。此外,传统紫杉类难溶于水,而助溶剂容易引起过敏反应,需要联合皮质激素;近年来问世的白蛋白结合型紫杉醇易溶于水,既不需要助溶剂,又不需要皮质激素,可进一步提高有效性和安全性。
2024年12月13日,国际四大医学期刊之一《美国医学会杂志》正刊以及全球最大的乳腺癌研究会议——第47届圣安东尼奥乳腺癌研讨会第三场全体大会同时公布复旦大学附属肿瘤医院陈力、吴松阳、曹朔文、王中华、范蕾✉️、邵志敏✉️以及四川省肿瘤医院李卉、南阳市中心医院张浩、广西医科大学附属肿瘤医院杨华伟、蚌埠医学院第一附属医院钱军、南昌市第三医院李志华、西安交通大学第一附属医院任予、北京大学人民医院王殊、浙江大学医学院附属第一医院傅佩芬、浙江省肿瘤医院杨红健、河北医科大学第四医院刘运江、安阳市肿瘤医院孙静、云南省肿瘤医院聂建云、粤北人民医院雷睿文、南京鼓楼医院姚永忠、广东省妇幼保健院张安秦、中南大学湘雅医院王守满、安徽省立医院马小鹏、厦门大学附属第一医院欧阳忠、遂宁市中心医院杨宏伟、广东省人民医院王坤、昆明医科大学第一附属医院蒋爱梅、湖南省肿瘤医院欧阳取长、哈尔滨医科大学附属肿瘤医院庞达、河南科技大学第一附属医院卫利民、江苏省人民医院查小明、江苏恒瑞医药朱晓宇等学者的CamRelief研究报告,首次对早期或局部晚期三阴性乳腺癌术前白蛋白紫杉醇+铂类+蒽环类+环磷酰胺联合中国原创免疫治疗新药卡瑞利珠单抗或者安慰剂的有效性和安全性进行双盲随机对照。这是《美国医学会杂志》创刊141年以来首次发表中国乳腺癌原创新药研究,也是继《英国医学杂志》之后国际四大医学期刊再次发表复旦大学附属肿瘤医院邵志敏教授团队乳腺癌研究成果。
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CamRelief (NCT04613674): A Study of Camrelizumab Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy in Participants With Triple Negative Breast Cancer (TNBC)
Official Title: A Multicentre, Randomized, Double-blind, Parallel-controlled Phase III Study to Evaluate Camrelizumab Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy in Patients With Early or Locally Advanced Triple Negative Breast Cancer (TNBC).
2024 SABCS GS3-06: Neoadjuvant camrelizumab plus chemotherapy (chemo) for early or locally advanced triple-negative breast cancer (TNBC): a randomized, double-blind, phase 3 trial.
该全国多中心安慰剂双盲随机对照三期临床研究于2020年11月25日至2023年5月12日从中国40家医院入组高风险早期或局部晚期三阴性乳腺癌患者441例(中位年龄48岁)按1比1随机分为两组,其中222例给予卡瑞利珠单抗+化疗,其余219例给予安慰剂+化疗。化疗包括前16周每28天的第1、8和15天给予白蛋白紫杉醇+卡铂,随后8周每2周给予表柔比星+环磷酰胺。主要研究终点为病理完全缓解,即术后病理检查乳腺和淋巴结都找不到浸润癌。
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值得注意的是,该研究患者入组时III期占35.8%,高于阿替利珠单抗IMpassion031研究的21.2%和帕博利珠单抗KEYNOTE-522研究的24.9%;淋巴结阳性占70.5%,N3期占9.1%,也远高于IMpassion031研究和KEYNOTE-522研究。
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结果,截至2023年9月30日,中位随访14.4个月,范围0.0至31.8个月,卡瑞利珠单抗化疗组与安慰剂化疗组相比:
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亚组分析表明,无论患者年龄、体力状态、淋巴结状态、临床分期、免疫联合阳性评分,卡瑞利珠单抗化疗组的病理完全缓解率都高于安慰剂化疗组,尤其年龄≥40岁、体力状态评分0分、淋巴结阳性、免疫联合阳性评分较低的患者。
术前治疗期间,卡瑞利珠单抗化疗组与安慰剂化疗组相比:
≥3级不良事件发生率:89.2%比83.1%
严重不良事件发生率:34.7%比22.8%
致命不良事件发生率:0.9%比0
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因此,该研究结果表明,对于高风险早期或局部晚期三阴性乳腺癌患者,经过严格的安慰剂双盲对照,术前化疗加入卡瑞利珠单抗可显著提高病理完全缓解率,故有必要进一步随访患者长期生存。
对此,芬兰赫尔辛基大学医院发表同期编者评论:三阴性乳腺癌术前卡瑞利珠单抗。
JAMA. 2024 Dec 13. IF: 63.1Camrelizumab vs Placebo in Combination With Chemotherapy as Neoadjuvant Treatment in Patients With Early or Locally Advanced Triple-Negative Breast Cancer: The CamRelief Randomized Clinical Trial.Li Chen, Hui Li, Hao Zhang, Huawei Yang, Jun Qian, Zhihua Li, Yu Ren, Shu Wang, Peifen Fu, Hongjian Yang, Yunjiang Liu, Jing Sun, Jianyun Nie, Ruiwen Lei, Yongzhong Yao, Anqin Zhang, Shouman Wang, Xiaopeng Ma, Zhong Ouyang, Hongwei Yang, Song-Yang Wu, Shuo-Wen Cao, Kun Wang, Aimei Jiang, Quchang Ouyang, Da Pang, Limin Wei, Xiaoming Zha, Yu Shen, PhD; Xiangwen Qu, Fei Wu, Xiaoyu Zhu, PhD; Zhonghua Wang, Lei Fan, Zhi-Ming Shao.Fudan University Shanghai Cancer, Shanghai Medical College, Fudan University, Shanghai, China; Sichuan Provincial Cancer Hospital, Chengdu, China; Nanyang City Center Hospital, Nanyang, China; Guangxi Medical University Affiliated Cancer Hospital, Nanning, China; The First Affiliated Hospital of Bengbu Medical College, Bengbu, China; The Third Hospital of Nanchang, Nanchang, China; The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Peking University People's Hospital, Beijing, China; The First Affiliated Hospital of Zhejiang University, Hangzhou, China; Zhejiang Cancer Hospital, Hangzhou, China; The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; The Fifth Ward of Medical Oncology, Anyang Tumour Hospital, Anyang, China; Yunnan Cancer Hospital, Kunming, China; Yuebei People's Hospital, Shaoguan, China; Nanjing Drum Tower Hospital, Nanjing, China; Guangdong Women's and Children's Hospital, Guangzhou, China; Xiangya Hospital of Central South University, Changsha; Anhui Provincial Hospital, Hefei, China; The First Affiliated Hospital of Xiamen University, Xiamen, China; Suining Central Hospital, Suining, China; Guangdong General Hospital, Guangzhou, China; he First Affiliated Hospital of Kunming Medical University, Kunming, China; Hunan Cancer Hospital, Changsha, China; Affiliated Cancer Hospital of Harbin Medical University, Harbin, China; The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China; Jiangsu Provincial Hospital, Nanjing, China; Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China.This phase 3 randomized clinical trial examines the efficacy and adverse events of camrelizumab plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy for patients with triple-negative breast cancer.QUESTION: Does the addition of camrelizumab to chemotherapy increase the pathological complete response rate when used as neoadjuvant therapy for patients with early or locally advanced triple-negative breast cancer?FINDINGS: In this randomized clinical trial that included 441 patients with early or locally advanced triple-negative breast cancer, camrelizumab plus chemotherapy, compared with placebo plus chemotherapy, significantly improved the rate of pathological complete response (56.8% vs 44.7%).MEANING: Among patients with early or locally advanced triple-negative breast cancer, a neoadjuvant treatment strategy of adding camrelizumab, compared with placebo, to chemotherapy resulted in improved pathological complete response rate.IMPORTANCE: Preferred neoadjuvant strategies for early or locally advanced triple-negative breast cancer include a 4-drug chemotherapy regimen containing anthracyclines, cyclophosphamide, taxanes, and platinum. Blockade of the programmed death receptor 1/ligand-1 (PD-1/PD-L1) pathway may improve efficacy of classic neoadjuvant chemotherapy. Camrelizumab, an anti–PD-1 antibody, has showed antitumor activity in advanced triple-negative breast cancer.OBJECTIVE: To evaluate the efficacy and adverse events of camrelizumab plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy for patients with early or locally advanced triple-negative breast cancer.DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, phase 3 trial enrolled patients from 40 hospitals in China between November 25, 2020, and May 12, 2023 (data cutoff: September 30, 2023). A total of 441 eligible patients were enrolled.INTERVENTIONS: Patients were randomized in a 1:1 ratio to receive either camrelizumab 200 mg (n = 222) or placebo (n = 219) combined with chemotherapy every 2 weeks. The chemotherapy included nab-paclitaxel (100 mg/m2) and carboplatin (area under the curve, 1.5) on days 1, 8, and 15 in 28-day cycles for the first 16 weeks followed by epirubicin (90 mg/m2) and cyclophosphamide (500 mg/m2) every 2 weeks for 8 weeks.MAIN OUTCOMES AND MEASURES: The primary end point was pathological complete response (defined as no invasive tumor in breast and lymph nodes [ypT0/Tis ypN0]).RESULTS: Among 441 females randomized (median age, 48 years), the median (range) follow-up duration from randomization was 14.4 (0.0-31.8) months. Pathological complete response was achieved in 126 patients (56.8% [95% CI, 50.0%-63.4%]) in the camrelizumab-chemotherapy group and 98 patients (44.7% [95% CI, 38.0%-51.6%]) in the placebo-chemotherapy group (rate difference, 12.2% [95% CI, 3.3%-21.2%]; 1-sided P = .004). In the neoadjuvant phase, adverse events of grade 3 or higher occurred in 198 patients (89.2%) in the camrelizumab-chemotherapy group and 182 (83.1%) in the placebo-chemotherapy group; serious adverse events occurred in 77 patients (34.7%) in the camrelizumab-chemotherapy group and 50 (22.8%) in the placebo-chemotherapy group, with fatal adverse events occurring in 2 patients (0.9%) in the camrelizumab-chemotherapy group.CONCLUSIONS AND RELEVANCE: Among patients with early or locally advanced triple-negative breast cancer, the addition of camrelizumab to neoadjuvant chemotherapy significantly improved pathological complete response.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04613674DOI: 10.1001/jama.2024.23560JAMA. 2024 Dec 13. IF: 63.1Neoadjuvant Camrelizumab for Triple-Negative Breast Cancer.Helsinki University Hospital and University of Helsinki, Helsinki, Finland.DOI: 10.1001/jama.2024.25927