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初步研究表明,，免疫療法聯合化療對于許多不同類型腫瘤的療效令人鼓舞,。2018年美國麻省醫(yī)學會《新英格蘭醫(yī)學雜志》發(fā)表的IMpassion130研究中位隨訪12.9個月第一次中期分析報告證實，免疫檢查點PD-L1靶向抑制劑阿特珠單抗＋白蛋白納米紫杉醇一線治療晚期三陰性乳腺癌患者,，無進展生存顯著較長，總生存相似,。 IMpassion130: A Phase III, Multicenter, Randomized, Placebo-Controlled Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Nab-Paclitaxel Compared With Placebo With Nab-Paclitaxel for Patients With Previously Untreated Metastatic Triple-Negative Breast Cancer (NCT02425891) 2019年11月27日,，英國《柳葉刀》腫瘤學分冊在線發(fā)表英國倫敦大學瑪麗王后學院、美國舊金山加利福尼亞大學（俗稱加州大學舊金山分校）,、紐約大學,、基因泰克、哈佛大學達納法伯癌癥研究院,、匹茲堡大學、德國癌癥研究中心,、海德堡大學,、巴西南里奧格蘭德天主教大學、拉丁美洲腫瘤學協作組,、日本愛知癌癥中心醫(yī)院,、法國巴黎居里研究院、歐仁馬奎斯癌癥中心,、瑞士霍夫曼羅氏,、澳大利亞墨爾本大學彼得麥卡倫癌癥中心的IMpassion130研究中位隨訪18.5個月預設第二次中期分析報告，更新了阿特珠單抗＋白蛋白納米紫杉醇一線治療晚期三陰性乳腺癌患者的有效性和安全性數據,。 該國際多中心隨機雙盲安慰劑對照三期臨床研究于2015年6月23日～2017年5月24日從41個國家或地區(qū)246個學術型和社區(qū)型腫瘤醫(yī)院入組年齡≥18歲,、尚未治療、有組織學檢查記錄,、美國東部腫瘤學協作組（ECOG）體力狀態(tài)評分0～1分,、局部晚期或遠處轉移的三陰性乳腺癌患者902例，按1∶1隨機分入兩組,，其中阿特珠單抗組451例,、安慰劑組451例。并按是否用過紫杉類,、是否肝轉移,、腫瘤浸潤免疫細胞PD-L1表達對隨機分組進行分層。每28天的第1,、15天靜脈注射840毫克阿特珠單抗或安慰劑,，第1、8,、15天靜脈注射每平方米體表面積100毫克白蛋白納米紫杉醇,，直至疾病進展或毒性反應無法耐受。研究者、患者,、資助者均不知治療分組,。共同主要研究終點為研究者根據實體腫瘤療效評價標準1.1版，對意向治療患者和PD-L1免疫細胞陽性腫瘤（腫瘤PD-L1表達率≥1%）亞組患者評定的無進展生存和總生存,。第一次中期總生存分析已經報告了最終的無進展生存結果,。根據預設統計學檢驗分層設計，只有當兩組意向治療患者的總生存顯著不同時,，才對PD-L1免疫細胞陽性亞組患者的總生存進行正式分析,。對實際接受治療的患者進行安全性分析。 結果,，兩組各有6例患者未接受治療,，根據截至2019年1月2日的數據，第二次中期分析時,，451例阿特珠單抗組與451例安慰劑組患者相比：
對于369例PD-L1免疫細胞陽性患者，185例阿特珠單抗組與安慰劑184例組患者相比：
根據截至2018年9月3日可獲得的最新安全性數據,，453例阿特珠單抗組與437例安慰劑組患者相比,，發(fā)生率最高的3～4級不良事件：
阿特珠單抗組患者治療相關死亡2例（<1%，其中阿特珠單抗相關自身免疫性肝炎死亡1例,、白蛋白納米紫杉醇相關感染性休克死亡1例）,，安慰劑組患者肝功能衰竭死亡1例（<1%）。2018年4月17日主要臨床數據截止以來,，尚未收到新的治療相關死亡報告,。 因此，該研究第二次與第一次中期總生存分析結果一致,，兩組意向治療患者的總生存相似,。不過，對于PD-L1免疫細胞陽性患者,，阿特珠單抗＋白蛋白納米紫杉醇與單用白蛋白納米紫杉醇相比,，總生存獲益具有臨床意義。由于預設統計學檢驗分層設計,，故無法對該陽性結果進行正式的統計學分析,。對于PD-L1免疫細胞陽性晚期三陰性乳腺癌患者，通常束手無策,，阿特珠單抗＋白蛋白納米紫杉醇可以成為重要的治療選擇之一,。 對此，美國德克薩斯大學MD安德森癌癥中心發(fā)表同期評論：對晚期三陰性乳腺癌患者分而治之,。 Lancet Oncol. 2019 Nov 27. [Epub ahead of print] Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Peter Schmid, Hope S Rugo, Sylvia Adams, Andreas Schneeweiss, Carlos H Barrios, Hiroji Iwata, Véronique Diéras, Volkmar Henschel, Luciana Molinero, Stephen Y Chui, Vidya Maiya, Amreen Husain, Eric P Winer, Sherene Loi, Leisha A Emens; IMpassion130 Investigators. Queen Mary University of London, London, UK; University of California, San Francisco, CA, USA; New York University Langone Medical Center, New York, NY, USA; Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany; Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil; Latin American Cooperative Oncology Group, Porto Alegre, Brazil; Grupo Oncoclínicas, Porto Alegre, Brazil; Aichi Cancer Center Hospital, Nagoya, Japan; Institut Curie, Paris, France; Centre Eugène Marquis, Rennes, France; F Hoffmann-La Roche, Basel, Switzerland; Genentech, South San Francisco, CA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; University of Melbourne, Melbourne, VIC, Australia; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA. BACKGROUND: Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer. METHODS: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice-web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m 2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891. FINDINGS: Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18.5 months (IQR 9.6-22.8) in the atezolizumab group and 17.5 months (8.4-22.4) in the placebo group. Median overall survival in the intention-to-treat patients was 21.0 months (95% CI 19.0-22.6) with atezolizumab and 18.7 months (16.9-20.3) with placebo (stratified hazard ratio [HR] 0.86, 95% CI 0.72-1.02, p=0.078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25.0 months (95% CI 19.6-30.7) with atezolizumab versus 18.0 months (13.6-20.1) with placebo (stratified HR 0.71, 0.54-0.94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018). INTERPRETATION: Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need. FUNDING: F Hoffmann-La Roche and Genentech. DOI: 10.1016/S1470-2045(19)30689-8 Lancet Oncol. 2019 Nov 27. [Epub ahead of print] Building momentum for subsets of patients with advanced triple-negative breast cancer. Wendy A Woodward. University of Texas MD Anderson Cancer Center, Houston, TX, USA. DOI: 10.1016/S1470-2045(19)30737-5
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