曲妥珠單抗等HER2靶向藥物的問世，大大改善了HER2陽性乳腺癌患者的生存結(jié)局。不過，對曲妥珠單抗耐藥的晚期HER2陽性乳腺癌患者，復(fù)發(fā)率和死亡率仍然較高。HER2陽性乳腺癌通常被大量T淋巴細(xì)胞浸潤，并且與曲妥珠單抗治療后的病理完全緩解和生存結(jié)局密切相關(guān)，晚期HER2陽性乳腺癌可能由于T淋巴細(xì)胞被抑制，引起免疫逃逸和曲妥珠單抗耐藥。細(xì)胞程序性死亡蛋白-1（PD-1）及其受體配體（PD-L1）主要表達(dá)于活化的T淋巴細(xì)胞，可以抑制T淋巴細(xì)胞增殖和免疫細(xì)胞因子產(chǎn)生，屬于免疫檢查點之一。免疫檢查點抑制劑帕博利珠單抗（商品名：可瑞達(dá)、Keytruda，又稱K藥）可以抑制PD-1和PD-L1，恢復(fù)T淋巴細(xì)胞對腫瘤細(xì)胞的殺傷力，從而逆轉(zhuǎn)曲妥珠單抗耐藥，先后由歐加農(nóng)、先靈葆雅、默克研發(fā)，2014年9月4日獲得美國食品藥品管理局（FDA）批準(zhǔn)，2018年7月20日獲得中國國家藥品監(jiān)督管理局（NMPA）批準(zhǔn)。
2019年1月11日，英國《柳葉刀》腫瘤學(xué)分冊在線發(fā)表國際乳腺癌研究協(xié)作組（IBCSG）、乳腺癌國際協(xié)作組（BIG）、澳大利亞墨爾本大學(xué)彼得麥卡倫癌癥中心、悉尼大學(xué)西草地醫(yī)院、昆士蘭大學(xué)貝格福醫(yī)學(xué)研究所、美國哈佛大學(xué)醫(yī)學(xué)院達(dá)納法伯癌癥研究所、比利時布魯塞爾自由大學(xué)朱爾博爾代研究所、列日大學(xué)中心醫(yī)院、法國萊昂貝拉德癌癥中心、西部癌癥研究所、波爾多大學(xué)伯格尼研究所綜合癌癥中心、巴黎第十一大學(xué)古斯塔夫魯西研究所、意大利米蘭大學(xué)歐洲腫瘤研究所、托斯卡納中心普拉托醫(yī)院、奧地利維也納醫(yī)科大學(xué)、瑞士伯爾尼大學(xué)醫(yī)院的PANACEA研究（IBCSG 45-13、BIG 4-13）報告，探討了帕博利珠單抗＋曲妥珠單抗治療曲妥珠單抗耐藥晚期HER2陽性乳腺癌的安全性和抗腫瘤活性。
PANACEA：Anti-PD-1 Monoclonal Antibody in Advanced, Trastuzumab-resistant, HER2-positive Breast Cancer (NCT02129556)
PANACEA（帕那刻亞，希臘語：Παν?κεια）希臘神話治療女神，奧林匹斯眾神之神宙斯的曾孫女、太陽神阿波羅的孫女、醫(yī)神（手持蛇杖）阿斯克勒庇俄斯（Asclepius）與舒緩病痛女神厄庇俄涅（Epione）的女兒。帕那刻亞與她的四個姐妹分別代表阿波羅的一種能力：帕那刻亞代表治療、伊阿索（Iaso）代表康復(fù)、許癸厄亞（Hygieia）代表健康、阿刻索（Aceso）代表治愈、阿格萊亞（Aglaea）代表光明。古代希波克拉底派的醫(yī)生宣讀醫(yī)師誓詞時，除了向阿波羅、阿斯克勒庇俄斯父子宣誓，還要向許癸厄亞、帕那刻亞姐妹宣誓。
該國際多中心非對照1B期和2期研究于2015年2月2日～2017年4月5日從5個國家11個中心入組年齡≥18歲女性、晚期組織學(xué)確診HER2陽性乳腺癌、曲妥珠單抗治療后發(fā)生轉(zhuǎn)移、東部腫瘤協(xié)作組（ECOG）體力評分0～1、轉(zhuǎn)移腫瘤活檢福爾馬林固定石蠟包埋中心評定PD-L1狀態(tài)的患者6例（1B期）和52例（2期）。
1B期研究各3例PD-L1陽性乳腺癌患者每3周分別接受靜脈注射帕博利珠單抗2mg/kg或10mg/kg＋曲妥珠單抗6mg/kg，主要終點為劑量受限毒性反應(yīng)發(fā)生率和2期推薦劑量；不過，2015年8月28日修改方案規(guī)定所有默克贊助研究的帕博利珠單抗固定劑量為每3周200mg。
2期研究40例PD-L1陽性和12例PD-L1陰性乳腺癌患者同時接受固定劑量帕博利珠單抗＋標(biāo)準(zhǔn)劑量曲妥珠單抗，主要終點為PD-L1陽性乳腺癌患者的客觀緩解（完全緩解＋部分緩解）比例。
該研究在美國政府臨床研究登記網(wǎng)站（ClinicalTrials.gov）和歐盟臨床研究登記網(wǎng)站（EudraCT）的編號分別為NCT02129556和2013-004770-10，并且已經(jīng)結(jié)束，分析數(shù)據(jù)截至2017年8月7日。
結(jié)果，1B期研究兩個劑量組均未出現(xiàn)劑量受限毒性反應(yīng)。
2期研究40例PD-L1陽性與12例PD-L1陰性乳腺癌患者相比：
中位隨訪：13.6比12.2個月（四分位：11.6～18.4、7.9-12.2）
客觀緩解：6例（15%，90%置信區(qū)間：7～29）比0例
無進(jìn)展生存：2.7比2.5個月（90%置信區(qū)間：2.6～4.0、1.4～2.7）
總生存：尚未半數(shù)死亡比7.0個月（90%置信區(qū)間：13.1～尚未全部死亡、4.9～9.8）
所有58例患者最常見的任何等級治療相關(guān)不良事件為疲勞（12例患者，21%）。3～5級不良事件、3～5級治療相關(guān)不良事件、嚴(yán)重不良事件分別發(fā)生于29例、17例、29例（50%、29%、50%）患者。最常見的嚴(yán)重不良事件為呼吸困難、肺炎、心包積液、上呼吸道感染，分別為3例、3例、2例、2例（5%、5%、3%、3%）。2期研究1例PD-L1陰性乳腺癌患者死于蘭伯特-伊頓綜合征（自身免疫性神經(jīng)系統(tǒng)疾病，體內(nèi)產(chǎn)生針對神經(jīng)肌肉接頭處突觸前膜鈣或乙酰膽堿通道的自身抗體，使鈣離子不能進(jìn)入神經(jīng)末梢，且末梢釋放乙酰膽堿受體明顯減少，導(dǎo)致肢體骨骼肌無力和植物神經(jīng)功能障礙）。
因此，該研究結(jié)果表明，對于PD-L1陽性、曲妥珠單抗耐藥、晚期、HER2陽性乳腺癌患者，帕博利珠單抗＋曲妥珠單抗安全有效，臨床生存結(jié)局獲益持久。對于該乳腺癌亞型的進(jìn)一步研究，應(yīng)該關(guān)注PD-L1陽性人群，并且對既往治療不多的患者進(jìn)行。
對此，美國軍醫(yī)大學(xué)、德克薩斯大學(xué)MD安德森癌癥中心、圣安東尼奧癌癥合同研究組織發(fā)表同期評論：不斷改善免疫檢查點抑制劑治療乳腺癌的生存結(jié)局。
相關(guān)閱讀
Lancet Oncol. 2019 Feb 11. [Epub ahead of print]
Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial.
Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, Campone M, Biganzoli L, Bonnefoi H, Jerusalem G, Bartsch R, Rabaglio-Poretti M, Kammler R, Maibach R, Smyth MJ, Di Leo A, Colleoni M, Viale G, Regan MM, André F; International Breast Cancer Study Group and the Breast International Group.
Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia; Dana-Farber Cancer Institute, Boston, MA, USA; Institute Jules Bordet, Brussels, Belgium; Centre Léon Bérard, Lyon, France; Westmead Hospital and the University of Sydney, Sydney, NSW, Australia; University of Milano, Milan, Italy; European Institute of Oncology IRCCS, Milan, Italy; Institut de Cancérologie de l'Ouest, Saint-Herblain, Nantes, France; Ospedale di Prato-AUSL Toscana Centro, Prato, Italy; Institut Bergonié Comprehensive Cancer Center, Université de Bordeaux, Bordeaux, France; International Breast Cancer Study Group, CHU Liège, Liège University, Liège, Belgium; Medical University of Vienna, Vienna, Austria; University Hospital Inselspital, Bern, Switzerland; International Breast Cancer Study Group Coordinating Center, Bern, Switzerland; International Breast Cancer Study Group and Central Pathology Office, Bern, Switzerland; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; International Breast Cancer Study Group and Ospedale di Prato-AUSL Toscana Centro, Prato, Italy; Harvard Medical School, Boston, MA, USA; Institut Gustave Roussy, Université Paris Sud, INSERM U981, Villejuif, France.
BACKGROUND: HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer.
METHODS: We did this single-arm, multicentre, phase 1b-2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed.
FINDINGS: Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13.6 months (IQR 11.6-18.4) for patients with PD-L1-positive tumours, and 12.2 months (7.9-12.2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7-29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3-5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3-5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2.
INTERPRETATION: Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients.
FUNDING: Merck, International Breast Cancer Study Group.
PMID: 30765258
PII: S1470-2045(18)30812-X
DOI: 10.1016/S1470-2045(18)30812-X
Lancet Oncol. 2019 Feb 11. [Epub ahead of print]
Improving the outcomes of checkpoint inhibitors in breast cancer.
Peoples GE.
Uniformed Services University of the Health Sciences, Bethesda, MD, USA; MD Anderson Cancer Center, Houston, TX, USA; Cancer Insight, San Antonio, TX, USA.
PMID: 30765259
PII: S1470-2045(19)30068-3
DOI: 10.1016/S1470-2045(19)30068-3
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