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多腺苷二磷酸核糖聚合酶（PARP）抑制劑、程序性死亡受體-1（PD-1）抑制劑是目前兩大網(wǎng)紅靶向藥物。不過(guò)，兩藥單獨(dú)治療晚期三陰性乳腺癌患者的臨床效果有限。 2019年6月13日，《美國(guó)醫(yī)學(xué)會(huì)雜志》腫瘤學(xué)分冊(cè)在線發(fā)表凱斯西儲(chǔ)大學(xué)醫(yī)院、華盛頓大學(xué)、西雅圖癌癥治療聯(lián)盟、哈佛大學(xué)達(dá)納法伯癌癥研究所、貝斯以色列女執(zhí)事醫(yī)療中心、田納西孟菲斯西部醫(yī)院、洛杉磯西達(dá)賽奈醫(yī)療中心、德克薩斯大學(xué)圣安東尼奧健康科學(xué)中心、萊文癌癥研究所、梅奧醫(yī)學(xué)中心、阿拉巴馬大學(xué)伯明翰分校、北卡羅來(lái)納大學(xué)教堂山分校萊恩伯格綜合癌癥中心、弗吉尼亞大學(xué)、喬治城大學(xué)醫(yī)院、伯靈頓萊希醫(yī)院、塔夫茨大學(xué)、葛蘭素史克旗下特薩羅、斯坦福大學(xué)的研究報(bào)告，探討了PARP抑制劑尼拉帕利＋PD-1抑制劑培布珠單抗治療晚期或轉(zhuǎn)移性三陰性乳腺癌患者的有效性和安全性。 TOPACIO (KEYNOTE-162): Phase 1/2 Clinical Study of Niraparib in Combination With Pembrolizumab (MK-3475) in Patients With Advanced or Metastatic Triple-Negative Breast Cancer and in Patients With Recurrent Ovarian Cancer (NCT02657889) 該多中心非盲單組二期研究于2017年1月3日～10月4日從美國(guó)34家醫(yī)院入組晚期或轉(zhuǎn)移性三陰性乳腺癌女性55例（中位年齡54歲，范圍32～90歲），無(wú)論BRCA基因是否突變或程序性死亡配體1（PD-L1）是否表達(dá)，每天口服尼拉帕利200毫克、每21天靜脈注射200毫克。2017年1月3日～2018年10月29日進(jìn)行數(shù)據(jù)收集，2018年10月29日～2019年2月27日進(jìn)行數(shù)據(jù)分析。主要終點(diǎn)為客觀緩解（完全緩解＋部分緩解），次要終點(diǎn)為安全性、疾病控制（完全緩解＋部分緩解＋疾病穩(wěn)定）、緩解持續(xù)時(shí)間、無(wú)進(jìn)展生存和總生存。 結(jié)果，剔除8例未復(fù)查患者（1例由于臨床進(jìn)展、7例由于不良反應(yīng)）后，根據(jù)實(shí)體腫瘤緩解評(píng)估標(biāo)準(zhǔn)（RECIST）1.1版對(duì)其余47例患者進(jìn)行療效分析：
截至2018年10月29日開始數(shù)據(jù)分析時(shí)，7例患者仍在接受治療，中位緩解持續(xù)時(shí)間尚未到達(dá)。 對(duì)于15例BRCA突變型可評(píng)估患者：
對(duì)于27例BRCA野生型可評(píng)估患者：
最常見的≥3級(jí)治療相關(guān)不良事件：貧血10例（18%），血小板減少8例（15%）、疲勞4例（7%）。免疫相關(guān)不良事件8例（15%），其中3級(jí)2例（4%）；未見新的安全問(wèn)題。 因此，該研究結(jié)果表明，對(duì)于晚期或轉(zhuǎn)移性三陰性乳腺癌患者，尼拉帕利＋培布珠單抗可以提供令人鼓舞的抗腫瘤活性，尤其對(duì)于BRCA突變型患者的緩解率更高。聯(lián)合療法安全性可接受，值得開展三期研究對(duì)更多患者進(jìn)行驗(yàn)證。 對(duì)此，紐約州立布法羅大學(xué)羅斯威爾·帕克綜合癌癥中心（由布法羅大學(xué)外科教授羅斯威爾·帕克創(chuàng)辦）、俄勒岡醫(yī)科大學(xué)奈特癌癥研究所（由耐克創(chuàng)始人菲爾·奈特資助）發(fā)表同期述評(píng)：免疫檢查點(diǎn)PD-1抑制劑＋PARP抑制劑用于復(fù)發(fā)性鉑類耐藥卵巢癌和轉(zhuǎn)移性三陰性乳腺癌。 JAMA Oncol. 2019 Jun 13. [Epub ahead of print] Open-Label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer. Shaveta Vinayak, Sara M. Tolaney, Lee Schwartzberg, Monica Mita, Georgia McCann, Antoinette R. Tan, Andrea E. Wahner-Hendrickson, Andres Forero, Carey Anders, Gerburg M. Wulf, Patrick Dillon, Filipa Lynce, Corrine Zarwan, John K. Erban, Yinghui Zhou, Nathan Buerstatte, Julie R. Graham, Sujata Arora, Bruce J. Dezube, Melinda L. Telli. Case Comprehensive Cancer Center, University Hospitals, Case Western Reserve University, Cleveland, Ohio; Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle; Dana-Farber Cancer Institute, Boston, Massachusetts; The West Clinic, Memphis, Tennessee; Cedars-Sinai Medical Center, Los Angeles, California; University of Texas Health Science Center at San Antonio; Levine Cancer Institute, Atrium Health, Charlotte, North Carolina; Mayo Clinic Rochester, Rochester, Minnesota; University of Alabama at Birmingham, Birmingham, Alabama; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill; University of North Carolina at Chapel Hill; Beth Israel Deaconess Medical Center, Boston, Massachusetts; University of Virginia, Charlottesville; Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC; Lahey Hospital and Medical Center, Burlington, Massachusetts; Tufts Medical Center, Boston, Massachusetts; TESARO: A GSK Company, Waltham, Massachusetts; Stanford University School of Medicine, Stanford, California. This open-label phase 2 clinical trial evaluates the clinical activity and safety of combination niraparib and pembrolizumab treatment in women with advanced or metastatic triple-negative breast cancer. QUESTION: Does combination therapy with niraparib plus pembrolizumab provide any clinical change or safety benefit in patients with advanced or metastatic triple-negative breast cancer? FINDINGS: Among 47 of 55 patients enrolled in this open-label, single-arm, phase 2 study who were eligible for efficacy evaluation, combination niraparib plus pembrolizumab achieved an objective response rate of 21% and a disease control rate of 49%, with a median duration of response not yet reached. MEANING: Combination niraparib plus pembrolizumab offers promising antitumor activity in patients with advanced or metastatic triple-negative breast cancer, warranting further investigation. IMPORTANCE: Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC). OBJECTIVE: To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC. DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019. INTERVENTIONS: Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival. RESULTS: Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected. CONCLUSIONS AND RELEVANCE: Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02657889 DOI: 10.1001/jamaoncol.2019.1029 JAMA Oncol. 2019 Jun 13. [Epub ahead of print] Immune Checkpoint and Poly(ADP-Ribose) Polymerase Inhibition for Recurrent Platinum-Resistant Ovarian and Metastatic Triple-Negative Breast Cancers. Kunle Odunsi, Tanja Pejovic. Roswell Park Comprehensive Cancer Center, Buffalo, New York; Knight Cancer Institute, Oregon Health & Science University, Portland. DOI: 10.1001/jamaoncol.2019.1009
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