乳腺癌易感基因BRCA1和BRCA2是重要的抑癌基因，如果发生致病突变，容易引起乳腺癌等恶性肿瘤，尤其HER2阴性或三阴性等难治型乳腺癌。OlympiAD研究已经证实，奥拉帕利（多腺苷二磷酸核糖聚合酶PARP抑制剂）可以显著改善晚期乳腺癌BRCA突变患者的生存。临床前研究还表明，奥拉帕利＋度伐利尤单抗（程序性死亡蛋白配体PD-L1抑制剂）可以进一步提高抗肿瘤活性。此外，与其他遥不可及的靶向药物相比，度伐利尤单抗、奥拉帕利已先后于2019年12月6日、2020年1月20日被国家药品监督管理局批准进入中国内陆（中文商品名：英飞凡、利普卓）。
2020年8月6日，英国《柳叶刀》肿瘤学分册发表美国阿斯利康、宾夕法尼亚大学、亨利·福特医疗中心、圣路易斯华盛顿大学、法国古斯塔夫·鲁西研究所、巴黎萨克雷大学、巴黎第十一大学、图卢兹大学、波尔多癌症治疗中心、巴黎第五大学科钦医院、里昂南方中心医院、里昂第一大学、全国卵巢癌乳腺癌研究协作组、韩国首尔大学医院、成均馆大学三星首尔医院、瑞士格劳宾登州立医院、英国阿斯利康、曼彻斯特大学、克里斯蒂肿瘤医院、曼彻斯特学术健康科学中心、以色列查姆·示巴医疗中心、特拉维夫大学的MEDIOLA研究报告，探讨了奥拉帕利＋度伐利尤单抗治疗晚期乳腺癌BRCA突变患者的安全性和有效性。
MEDIOLA: A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination With Olaparib (PARP Inhibitor) in Patients With Advanced Solid Tumors (NCT02734004)
该国际多中心非盲1～2期临床研究于2016年6月14日～2017年5月2日从英国、美国、以色列、法国、瑞士、韩国18家医疗中心入组年龄≥18岁（韩国≥19岁）BRCA突变HER2阴性晚期乳腺癌恶化患者34例，其中三阴性乳腺癌18例（53%），既往化疗失败不超过2个方案。每天2次口服300毫克奥拉帕利连续4周，随后每天2次口服奥拉帕利300毫克＋每4周静脉注射度伐利尤单抗1.5克，直至疾病进展。主要终点为安全性、耐受性、12周疾病控制（完全缓解＋部分缓解＋疾病稳定）比例。对接受至少一次研究治疗药物的34例患者进行安全性分析，并对30例可分析疗效的患者进行药物活性分析。入组已经完成，研究仍在进行。
结果，11例（32%）患者发生≥3级不良事件，发生比例最高的不良事件：
贫血4例（12%）
中性粒细胞减少3例（9%）
胰腺炎2例（6%）
3例（9%）患者由于不良事件中断治疗，4例（12%）患者发生6次严重不良事件，未见治疗所致死亡。
对于可分析疗效的30例患者，12周时疾病控制24例，12周疾病控制比例达80%（90%置信区间：64.3～90.9）。
因此，该小样本非对照初步研究结果表明，奥拉帕利＋度伐利尤单抗双药联合的抗肿瘤活性和安全性令人鼓舞，故有必要进一步开展大样本随机对照临床研究对奥拉帕利±度伐利尤单抗的长期临床结局进行比较，并确定治疗能否获益的预测指标。
相关链接
Lancet Oncol. 2020 Aug 6. Online ahead of print.
Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study.
Susan M Domchek, Sophie Postel-Vinay, Seock-Ah Im, Yeon Hee Park, Jean-Pierre Delord, Antoine Italiano, Jerome Alexandre, Benoit You, Sara Bastian, Matthew G Krebs, Ding Wang, Saiama N Waqar, Mark Lanasa, Joon Rhee, Haiyan Gao, Vidalba Rocher-Ros, Emma V Jones, Sakshi Gulati, Anna Coenen-Stass, Iwanka Kozarewa, Zhongwu Lai, Helen K Angell, Laura Opincar, Pia Herbolsheimer, Bella Kaufman.
University of Pennsylvania, Philadelphia, PA, USA; Henry Ford Medical Center, Detroit, MI, USA; Washington University School of Medicine, Saint Louis, MO, USA; AstraZeneca, Gaithersburg, MD, USA; Gustave Roussy, Villejuif, France; Université Paris Saclay, Université Paris-Sud, Villejuif, France; Institut Universitaire du Cancer de Toulouse, Toulouse, France; Institut Bergonié, Bordeaux, France; Hopital Cochin, Paris, France; Institut de Cancérologie des Hospices Civils de Lyon, Centre d'Investigation de Therapeutiques en Oncologie et H ematologie de Lyon, Centre Hospitalier Lyon-Sud, Lyon, France; Univ Lyon, Université Claude Bernard Lyon 1, Lyon, France; Groupe des Investigateurs Nationaux pour les Cancers de l Ovaire et du sein-GINEGEPS, Paris, France; Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Kantonsspital Graubuenden, Chur, Switzerland; The University of Manchester and The Christie NHS Foundation Trust, Manchester, UK; Manchester Academic Health Science Centre, Manchester, UK; AstraZeneca, Cambridge, UK; Chaim Sheba Medical Center, Tel Hashomer, Israel; Tel Aviv University, Tel Aviv, Israel.
BACKGROUND: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer.
METHODS: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1.5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004.
FINDINGS: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64.3-90.9) of 30 patients eligible for activity analysis had disease control at 12 weeks.
INTERPRETATION: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy.
FUNDING: AstraZeneca
DOI: 10.1016/S1470-2045(20)30324-7
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