治疗女神与曲妥珠单抗耐药乳腺癌

　　曲妥珠单抗等HER2靶向药物的问世，大大改善了HER2阳性乳腺癌患者的生存结局。不过，对曲妥珠单抗耐药的晚期HER2阳性乳腺癌患者，复发率和死亡率仍然较高。HER2阳性乳腺癌通常被大量T淋巴细胞浸润，并且与曲妥珠单抗治疗后的病理完全缓解和生存结局密切相关，晚期HER2阳性乳腺癌可能由于T淋巴细胞被抑制，引起免疫逃逸和曲妥珠单抗耐药。细胞程序性死亡蛋白-1（PD-1）及其受体配体（PD-L1）主要表达于活化的T淋巴细胞，可以抑制T淋巴细胞增殖和免疫细胞因子产生，属于免疫检查点之一。免疫检查点抑制剂帕博利珠单抗（商品名：可瑞达、Keytruda，又称K药）可以抑制PD-1和PD-L1，恢复T淋巴细胞对肿瘤细胞的杀伤力，从而逆转曲妥珠单抗耐药，先后由欧加农、先灵葆雅、默克研发，2014年9月4日获得美国食品药品管理局（FDA）批准，2018年7月20日获得中国国家药品监督管理局（NMPA）批准。

　　2019年1月11日，英国《柳叶刀》肿瘤学分册在线发表国际乳腺癌研究协作组（IBCSG）、乳腺癌国际协作组（BIG）、澳大利亚墨尔本大学彼得麦卡伦癌症中心、悉尼大学西草地医院、昆士兰大学贝格福医学研究所、美国哈佛大学医学院达纳法伯癌症研究所、比利时布鲁塞尔自由大学朱尔博尔代研究所、列日大学中心医院、法国莱昂贝拉德癌症中心、西部癌症研究所、波尔多大学伯格尼研究所综合癌症中心、巴黎第十一大学古斯塔夫鲁西研究所、意大利米兰大学欧洲肿瘤研究所、托斯卡纳中心普拉托医院、奥地利维也纳医科大学、瑞士伯尔尼大学医院的PANACEA研究（IBCSG 45-13、BIG 4-13）报告，探讨了帕博利珠单抗＋曲妥珠单抗治疗曲妥珠单抗耐药晚期HER2阳性乳腺癌的安全性和抗肿瘤活性。

• PANACEA：Anti-PD-1 Monoclonal Antibody in Advanced, Trastuzumab-resistant, HER2-positive Breast Cancer (NCT02129556)

• PANACEA（帕那刻亚，希腊语：Πανάκεια）希腊神话治疗女神，奥林匹斯众神之神宙斯的曾孙女、太阳神阿波罗的孙女、医神（手持蛇杖）阿斯克勒庇俄斯（Asclepius）与舒缓病痛女神厄庇俄涅（Epione）的女儿。帕那刻亚与她的四个姐妹分别代表阿波罗的一种能力：帕那刻亚代表治疗、伊阿索（Iaso）代表康复、许癸厄亚（Hygieia）代表健康、阿刻索（Aceso）代表治愈、阿格莱亚（Aglaea）代表光明。古代希波克拉底派的医生宣读医师誓词时，除了向阿波罗、阿斯克勒庇俄斯父子宣誓，还要向许癸厄亚、帕那刻亚姐妹宣誓。

　　该国际多中心非对照1B期和2期研究于2015年2月2日～2017年4月5日从5个国家11个中心入组年龄≥18岁女性、晚期组织学确诊HER2阳性乳腺癌、曲妥珠单抗治疗后发生转移、东部肿瘤协作组（ECOG）体力评分0～1、转移肿瘤活检福尔马林固定石蜡包埋中心评定PD-L1状态的患者6例（1B期）和52例（2期）。

　　1B期研究各3例PD-L1阳性乳腺癌患者每3周分别接受静脉注射帕博利珠单抗2mg/kg或10mg/kg＋曲妥珠单抗6mg/kg，主要终点为剂量受限毒性反应发生率和2期推荐剂量；不过，2015年8月28日修改方案规定所有默克赞助研究的帕博利珠单抗固定剂量为每3周200mg。

　　2期研究40例PD-L1阳性和12例PD-L1阴性乳腺癌患者同时接受固定剂量帕博利珠单抗＋标准剂量曲妥珠单抗，主要终点为PD-L1阳性乳腺癌患者的客观缓解（完全缓解＋部分缓解）比例。

　　该研究在美国政府临床研究登记网站（ClinicalTrials.gov）和欧盟临床研究登记网站（EudraCT）的编号分别为NCT02129556和2013-004770-10，并且已经结束，分析数据截至2017年8月7日。

　　结果，1B期研究两个剂量组均未出现剂量受限毒性反应。

　　2期研究40例PD-L1阳性与12例PD-L1阴性乳腺癌患者相比：

• 中位随访：13.6比12.2个月（四分位：11.6～18.4、7.9-12.2）

• 客观缓解：6例（15%，90%置信区间：7～29）比0例

• 无进展生存：2.7比2.5个月（90%置信区间：2.6～4.0、1.4～2.7）

• 总生存：尚未半数死亡比7.0个月（90%置信区间：13.1～尚未全部死亡、4.9～9.8）

　　所有58例患者最常见的任何等级治疗相关不良事件为疲劳（12例患者，21%）。3～5级不良事件、3～5级治疗相关不良事件、严重不良事件分别发生于29例、17例、29例（50%、29%、50%）患者。最常见的严重不良事件为呼吸困难、肺炎、心包积液、上呼吸道感染，分别为3例、3例、2例、2例（5%、5%、3%、3%）。2期研究1例PD-L1阴性乳腺癌患者死于兰伯特-伊顿综合征（自身免疫性神经系统疾病，体内产生针对神经肌肉接头处突触前膜钙或乙酰胆碱通道的自身抗体，使钙离子不能进入神经末梢，且末梢释放乙酰胆碱受体明显减少，导致肢体骨骼肌无力和植物神经功能障碍）。

　　因此，该研究结果表明，对于PD-L1阳性、曲妥珠单抗耐药、晚期、HER2阳性乳腺癌患者，帕博利珠单抗＋曲妥珠单抗安全有效，临床生存结局获益持久。对于该乳腺癌亚型的进一步研究，应该关注PD-L1阳性人群，并且对既往治疗不多的患者进行。

　　对此，美国军医大学、德克萨斯大学MD安德森癌症中心、圣安东尼奥癌症合同研究组织发表同期评论：不断改善免疫检查点抑制剂治疗乳腺癌的生存结局。

相关阅读

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

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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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