Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded. Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0–2). Fifty percent of patients were Caucasian, 45% African–American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug–drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. ClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014

中文翻译：

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veliparib 和拉帕替尼在转移性三阴性乳腺癌患者中的开放标签试点研究

聚 (ADP-核糖)-聚合酶抑制剂 (PARPi) 已被批准用于具有生殖系 BRCA1/2 (gBRCA1/2) 突变的癌症患者，并且正在努力将 PARPi 的效用扩展到 BRCA1/2 之外。在具有完整 DNA 修复的三阴性乳腺癌 (TNBC) 的临床前模型中，我们之前已经展示了联合 EGFR 抑制和 PARPi 的诱导合成致死率。在这里，我们报告了拉帕替尼和维利帕尼在转移性 TNBC 患者中的安全性和临床活性。在转移性 TNBC (NCT02158507) 中进行了拉帕替尼和维利帕尼的首次人体试验研究。主要终点是安全性和耐受性。次要终点是客观反应率和药代动力学评估。进行预处理肿瘤活检的基因表达分析。主要资格包括患有可测量疾病的 TNBC 患者和既往基于蒽环类药物和紫杉类药物化疗的患者。排除了具有 gBRCA1/2 突变的患者。招募了 20 名患者，其中 17 名可评估疗效。转移性环境中先前治疗的中位数为 1（范围 0-2）。50% 的患者是白种人，45% 是非裔美国人，5% 是西班牙裔。在可评估的患者中，4 名表现出部分反应，2 名病情稳定。没有剂量限制性毒性。大多数 AE 仅限于 1 级或 2 级，没有发现药物-药物相互作用。探索性基因表达分析表明，与无应答者相比，应答者的基线 DNA 修复途径评分较低，基线免疫原性较高。拉帕替尼加维利帕尼疗法在晚期 TNBC 中具有可控的安全性和有希望的抗肿瘤活性。需要进一步研究 EGFR 抑制和 PARP 抑制的双重治疗。ClinicalTrials.gov，NCT02158507。2014 年 9 月 12 日注册