Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial
Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): an open-label, single-arm, phase 2a clinical trial
复制标题
DOI：
10.1016/s2213-2600(20)30390-8
复制
发表时间：
2021-06-02
影响因子：
76.2
通讯作者：
Thomas, Anne
中科院分区：
文献类型：
--
作者：
Fennell, Dean A.;King, Amy;Thomas, Anne
恶性间皮瘤仍然是一种无法治愈的癌症，在复发性疾病的情况下没有有效的治疗方法。同源重组缺陷预测对聚（ADP-核糖）聚合酶（PARP）抑制剂的敏感性。在间皮瘤中，调节DNA修复的BRCA 1相关蛋白1羧基末端水解酶（BAP 1）经常发生突变。我们的目的是测试的假设，BAP 1缺陷或BRCA 1缺陷间皮瘤将是敏感的PARP抑制rucaparib.Methods我们做了一个单中心，开放标签，单臂，2A期试验在英国莱斯特，前瞻性分子分层（间皮瘤分层治疗1 [MIST 1]）。年龄≥ 18岁的患者，在至少一个疗程的全身治疗后，经放射学检查进展，组织学证实，恶性间皮瘤;细胞质-BAP 1缺陷或BRCA 1缺陷间皮瘤（胸膜或腹膜或其他原发性定位），并符合其他入选标准，被视为合格。所有同意参加研究的合格患者均接受rucaparib 600 mg口服，每日两次，共6个周期，每次28天，或直至疾病进展、不可接受的毒性、撤回同意或死亡。每6周通过CT扫描测量反应。主要结局是所有接受研究药物的患者在12周时的疾病控制（完全缓解、部分缓解或疾病稳定）;次要结局是安全性和毒性特征、客观缓解率（完全或部分缓解的比例）和24周时的疾病控制率。招聘现已结束。该试验在ClinicalTrials.gov注册，NCT 03654833。结果在2019年2月9日至6月10日期间，我们招募了26名分子和临床合格的患者。26例患者中有10例（38%）BAP 1阴性和BRCA 1阴性，23例（89%）BAP 1阴性，13例（50%）BRCA 1阴性。12周时的疾病控制率为58%（95% CI 37-77; 26例患者中的15例），24周时为23%（9-44; 26例患者中的6例）。Rucaparib耐受性良好，166例不良事件中有15例（9%）为3级或4级，26例患者中有9例（35%），无死亡。最常见的1-2级不良事件为恶心（26例患者中的18例[69%]）、疲乏（14例患者[54%]）和食欲减退（10例患者[38%]）。最常见的3-4级不良事件为上呼吸道感染（3例患者[12%]）和贫血（3例患者[12%]）。26例患者中有8例（31%）接受了所有6个周期的rucaparib治疗。9名患者（35%）发生了一次或多次剂量减少。解释Rucaparib在BAP 1阴性或BRCA 1阴性间皮瘤患者中符合预先规定的成功标准，显示出有希望的活性和可控的毒性。计划进一步研究同源重组缺陷突变，以完善间皮瘤中PARP抑制的预测性生物标志物的鉴定。
Background Malignant mesothelioma remains an incurable cancer, with no effective treatments in the setting of relapsed disease. Homologous recombination deficiency predicts sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. In mesothelioma, BRCA1-associated protein 1 carboxy-terminal hydrolase (BAP1), which regulates DNA repair, is frequently mutated. We aimed to test the hypothesis that BAP1-deficient or BRCA1-deficient mesotheliomas would be sensitive to PARP inhibition by rucaparib.Methods We did a single-centre, open-label, single-arm, phase 2a trial in Leicester, UK, with prospective molecular stratification (Mesothelioma-Stratified Therapy 1 [MiST1]). Patients aged 18 years or older who had radiologically progressing, histologically confirmed, malignant mesothelioma after at least one course of systemic treatment; with cytoplasmic-BAP1-deficient or BRCA1-deficient mesothelioma (pleural or peritoneal or other primary localisation), and who met the other inclusion criteria, were deemed eligible. All eligible patients who consented to take part were given rucaparib 600 mg twice a day orally, for six cycles of 28 days, or until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response was measured by CT scan every 6 weeks. The primary outcome was disease control (complete response, partial response, or stable disease) at 12 weeks in all patients who received study drug; secondary outcomes were the safety and toxicity profile, objective response rate (proportion of complete or partial responses), and disease control rate at 24 weeks. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03654833.Findings Between Feb 9 and June 10, 2019, we enrolled 26 molecularly and clinically eligible patients. Ten (38%) of 26 patients were BAP1 negative and BRCA1 negative, 23 patients (89%) were BAP1 negative, and 13 patients (50%) were BRCA1 negative. Disease control rate at 12 weeks was 58% (95% CI 37-77; 15 of 26 patients), and at 24 weeks was 23% (9-44; six of 26 patients). Rucaparib was well tolerated, with 15 (9%) of 166 adverse events being grade 3 or 4, which were seen in nine (35%) of 26 patients, and there were no deaths. The most common grade 1-2 adverse events were nausea (18 [69%] of 26 patients), fatigue (14 patients [54%]), and decreased appetite (ten patients [38%]). The most common grade 3-4 adverse events were upper respiratory tract infection (three patients [12%]) and anaemia (three patients [12%]). All six cycles of rucaparib were received by eight (31%) of 26 patients. One or more dose reductions occurred in nine patients (35%).Interpretation Rucaparib in patients with BAP1-negative or BRCA1-negative mesothelioma met the prespecified criteria for success, showing promising activity with manageable toxicity. Further investigation of homologous recombination deficiency mutations is planned to refine the identification of predictive biomarkers for PARP inhibition in mesothelioma.