摘要

AIM:The phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non-small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC.
PATIENTS AND METHODS:A 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1-14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination.
RESULTS:All 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a '14 days on, 7 days off' schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients.
CONCLUSION:Combining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.

译文

目的: 磷脂酰肌醇 3-激酶 (PI3K) 通路是非小细胞肺癌的潜在治疗靶点。本研究旨在评估 pan-PI3K 抑制剂 pictilisib 与一线治疗方案的联合应用，一线治疗方案是研究时的标准治疗方案。
患者和方法: 在 21 天周期的第 1-14 天，使用 60 mg pictilisib 的起始日剂量进行 3 3 剂量递增研究。根据贝伐珠单抗的资格和非小细胞肺癌组织学，患者还每 3 周接受紫杉醇卡铂或培美曲塞顺铂 ± 贝伐珠单抗。该研究的主要目的是评估安全性和耐受性，并确定剂量限制毒性 (DLTs) 、最大耐受剂量 (MTD) 和推荐的第二阶段剂量 (RP2D), 对于每个组合。
结果: 所有 66 名接受治疗的患者都经历了至少一次不良事件 (AE)。分级 ≥ ⅲ 级的不良事件、严重不良事件和死亡分别发生在 57 例 (86.4%) 、 56 例 (84.8%) 和 9 例 (13.6%) 患者中。三名患者报告了研究的四个部分的 DLTs。在任何一个 arm 中都没有达到 MTD，并且在 “14 天，7 天” 的时间表中，pictilisib 的 RP2D 被确定为 330 毫克 (胶囊) 或 340 毫克 (片剂)。最佳确认应答是 29 例 (43.9%) 患者的部分应答和 20 例 (30.9%) 患者的稳定疾病。
结论: 从安全性的角度来看，将 pictilisib 与各种标准护理一线治疗方案相结合在非小细胞肺癌患者中是可行的，并观察到鼓励初步的抗肿瘤活性。