Wehler Thomas, Thomas Michael, Schumann Christian, Bosch-Barrera Joaquim, Viñolas Segarra Nuria, Dickgreber Nicolas J, Dalhoff Klaus, Sebastian Martin, Corral Jaime Jesus, Alonso Miriam, Hynes Scott M, Lin Ji, Hurt Karla, Bence Lin Aimee, Calvo Emiliano, Paz-Ares Luis
III. Medical Department, University Hospital Mainz, Mainz, Germany; 5th Medical Department, University Hospital Saarland, Homburg, Germany.
Department of Thoracic Oncology, Thoraxklinik, Thoraxklinik im Universitätsklinikum Heidelberg, Translational Lung Research Center, Heidelberg, Germany.
Lung Cancer. 2017 Jun;108:212-216. doi: 10.1016/j.lungcan.2017.03.001. Epub 2017 Mar 6.
This phase 2 portion of a phase 1/2 study examined the efficacy and safety of LY2603618, a selective checkpoint kinase 1 inhibitor, combined with pemetrexed and cisplatin (LY+Pem+Cis) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). This multicenter, randomized, controlled, open-label study (NCT01139775) enrolled patients with stage IV nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized (2:1) to LY+Pem+Cis or pemetrexed and cisplatin (Pem+Cis). Induction therapy comprised four 21-day cycles of 500 mg/m pemetrexed and 75mg/m cisplatin on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm). Maintenance therapy comprised 500mg/m pemetrexed on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm) until disease progression. The primary endpoint was progression-free survival (PFS). Enrollment was permanently halted before target enrollment was met due to a greater number of thromboembolic events in the LY+Pem+Cis arm. Sixty-two patients were enrolled (LY+Pem+Cis, n=39; Pem+Cis, n=23). Bayesian and frequentist analysis demonstrated superior PFS in the LY+Pem+Cis arm vs the Pem+Cis arm (median [90% confidence interval]: LY+Pem+Cis, 4.7 months [4.-7.1]; Pem+Cis, 1.5 months [1.3-2.9]; P=0.022). Seven patients in the LY+Pem+Cis arm (vs 0 in the Pem+Cis arm) experienced serious thromboembolic events: pulmonary embolism (n=5), ischemic stroke (n=1), and cerebrovascular accident (n=1). Although the primary endpoint was met, the combination of LY2603618+Pem+Cis will not be further developed for treating advanced nonsquamous NSCLC due to the potential increased risk of thromboembolic events with this combination. ClinicalTrials.gov Identifier: NCT01139775.
这项1/2期研究的2期部分，考察了选择性检查点激酶1抑制剂LY2603618联合培美曲塞和顺铂（LY+Pem+Cis）用于晚期非鳞状非小细胞肺癌（NSCLC）患者的疗效和安全性。这项多中心、随机、对照、开放标签研究（NCT01139775）纳入了IV期非鳞状NSCLC且东部肿瘤协作组体能状态≤1的患者。患者按2:1随机分组至LY+Pem+Cis组或培美曲塞和顺铂（Pem+Cis）组。诱导治疗包括4个21天周期，第1天给予500mg/m²培美曲塞和75mg/m²顺铂（两组均如此），第2天给予275mg LY2603618（LY+Pem+Cis组）。维持治疗包括第1天给予500mg/m²培美曲塞（两组均如此），第2天给予275mg LY2603618（LY+Pem+Cis组），直至疾病进展。主要终点为无进展生存期（PFS）。由于LY+Pem+Cis组血栓栓塞事件较多，在达到目标入组人数前研究被永久终止。共入组62例患者（LY+Pem+Cis组，n = 39；Pem+Cis组，n = 23）。贝叶斯分析和频率论分析显示，LY+Pem+Cis组的PFS优于Pem+Cis组（中位数[90%置信区间]：LY+Pem+Cis组，4.7个月[4.0 - 7.1]；Pem+Cis组，1.5个月[1.3 - 2.9]；P = 0.022）。LY+Pem+Cis组有7例患者（Pem+Cis组为0例）发生严重血栓栓塞事件：肺栓塞（n = 5）、缺血性卒中（n = 1）和脑血管意外（n = 1）。尽管达到了主要终点，但由于LY2603618与培美曲塞和顺铂联合使用可能增加血栓栓塞事件风险，该联合方案不会进一步用于晚期非鳞状NSCLC的治疗。ClinicalTrials.gov标识符：NCT01139775。
