Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study.
Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study.
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DOI：
10.1016/s1470-2045(16)30565-4
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发表时间：
2017-01
期刊：
影响因子：
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通讯作者：
SCRX16-001 investigators
中科院分区：
文献类型：
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作者：
Rudin CM;Pietanza MC;Bauer TM;Ready N;Morgensztern D;Glisson BS;Byers LA;Johnson ML;Burris HA 3rd;Robert F;Han TH;Bheddah S;Theiss N;Watson S;Mathur D;Vennapusa B;Zayed H;Lally S;Strickland DK;Govindan R;Dylla SJ;Peng SL;Spigel DR;SCRX16-001 investigators
Rovalpituzumab tesirine是一种针对delta-样蛋白3 （DLL3）的抗体-药物偶联物，DLL3是一种在肿瘤启动细胞中发现的新靶点，在超过80%的小细胞肺癌患者中表达。我们的目的是评估rovalpituzumab tesirine在一个或多个先前治疗方案后进展的患者中的安全性和活性。我们在美国的10个癌症中心进行了一期开放标签研究。符合条件的患者年龄为18岁或以上，组织学或细胞学证实为小细胞肺癌或大细胞神经内分泌肿瘤，并伴有可测量的进展性疾病（根据实体瘤反应评价标准[RECIST]， 1.1版），先前接受过一种或两种化疗方案，包括铂类方案。我们将患者分配到剂量递增或扩展队列，范围从0.05 mg/kg到0.8 mg/kg，每3周静脉注射一次或每6周静脉注射一次罗伐单抗特西汀，然后研究每6周0.3 mg/kg和0.4 mg/kg以及每3周0.2 mg/kg的剂量方案。主要目的是评估rovalpituzumab tesirine的安全性，包括最大耐受剂量和剂量限制性毒性作用。意向治疗分析的主要活性终点是客观反应。本研究已在ClinicalTrials.gov注册，编号NCT01901653。该研究已停止登记；本报告的重点是小细胞肺癌队列。在2013年7月22日至2015年8月10日期间，纳入了82例患者，其中包括74例小细胞肺癌患者和8例大细胞神经内分泌癌患者，所有患者均接受了至少一剂rovalpituzumab tesirine。rovalpituzumab tesirine的剂量限制毒性作用发生在每3周0.8 mg/kg的剂量下，包括4级血小板减少症（在该剂量水平下的2例患者中）和4级肝功能检查异常（1例患者）。在74例小细胞肺癌患者中，最常见的3级或更严重的治疗相关不良事件是血小板减少（8例[11%]）、胸腔积液（6例[8%]）和脂肪酶升高（5例[7%]）。74例患者中有28例（38%）发生与药物相关的严重不良事件。rovalpituzumab tesirine的最大耐受剂量为0.4 mg/kg / 3周；推荐的2期剂量和方案为每6周0.3 mg/kg。在有效剂量的rovalpituzumab tesirine （0.2 mg/kg或0.4 mg/kg每3周或0.3 mg/kg或0.4 mg/kg每6周），60名可评估患者中有11名（18%）有确认的客观反应。60例可评估患者中有11例（18%）证实客观缓解，其中26例患者中有10例（38%）证实DLL3高表达（在50%或更多的肿瘤细胞中表达）。Rovalpituzumab tesirine显示出令人鼓舞的单药抗肿瘤活性和可控的安全性。进一步开发rovalpituzumab tesirine治疗表达dll3的恶性疾病是必要的。
Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted.