Department of Medical Oncology, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain.
University of Alabama, Birmingham, AL, USA.
BMC Cancer. 2023 Jul 28;23(1):708. doi: 10.1186/s12885-023-11153-1.
In this phase Ib/II open-label study, tumor immune suppression was targeted in patients with advanced refractory solid tumors and patients with recurrent/refractory non-small cell lung cancer (NSCLC) using galunisertib with nivolumab.
Eligible patients were ≥ 18 years old, had an Eastern Cooperative Oncology Group performance status ≤ 1, and were treatment-naive for anti-programmed cell death-1, its ligand, or transforming growth factor β receptor 1 kinase inhibitors. Phase Ib was an open-label, dose-escalation assessment of the safety and tolerability of galunisertib with nivolumab in patients with advanced refractory solid tumors. Phase II evaluated the safety of galunisertib with nivolumab in NSCLC patients who had received prior platinum-based treatment but were immuno-oncology agent-naive.
This trial was conducted between October 2015 and August 2020. No dose-limiting toxicities were observed in phase I. In the phase II NSCLC cohort (n = 25), patients received 150 mg twice daily galunisertib (14 days on/14 days off dosing schedule for all phases) plus nivolumab at 3 mg/kg (intravenously every 2 weeks). In this phase, the most frequent treatment-related adverse events (AEs) were pruritus (n = 9, 36%), fatigue (n = 8, 32%), and decreased appetite (n = 7, 28%). No grade 4 or 5 treatment-related AEs were observed. Six (24%) patients had confirmed partial response (PR) and 4 (16%) had stable disease; 1 additional patient had confirmed PR after initial pseudo-progression. The median duration of response was 7.43 months (95% confidence interval [CI]: 3.75, NR). Among the 7 responders, including the delayed responder, 1 had high PD-L1 expression (≥ 50%). The median progression-free survival was 5.26 months (95% CI: 1.77, 9.20) and the median overall survival was 11.99 months (95% CI: 8.15, NR). Interferon gamma response genes were induced post-treatment and cell adhesion genes were repressed, although the association of these observations with tumor response and clinical outcomes was not statistically powered due to limited samples available.
The study met its primary endpoint as galunisertib combined with nivolumab was well tolerated. Preliminary efficacy was observed in a subset of patients in the Phase 2 NSCLC cohort.
Trial registered with ClinicalTrials.gov (NCT02423343; 22.04.2015).
在这项 Ib/II 期开放标签研究中，使用 galunisertib 联合 nivolumab 靶向治疗晚期难治性实体瘤和复发性/难治性非小细胞肺癌（NSCLC）患者的肿瘤免疫抑制。
符合条件的患者年龄≥18 岁，东部合作肿瘤学组（ECOG）体能状态≤1，且未接受过抗程序性细胞死亡-1、其配体或转化生长因子β受体 1 激酶抑制剂治疗。Ib 期为 galunisertib 联合 nivolumab 治疗晚期难治性实体瘤患者的安全性和耐受性的开放标签、剂量递增评估。II 期评估 galunisertib 联合 nivolumab 在接受过铂类治疗但未接受过免疫肿瘤药物治疗的 NSCLC 患者中的安全性。
这项试验于 2015 年 10 月至 2020 年 8 月进行。在 I 期未观察到剂量限制毒性。在 II 期 NSCLC 队列（n=25）中，患者接受 150mg 每日两次 galunisertib（所有阶段的 14 天/14 天停药方案）加 3mg/kg nivolumab（每 2 周静脉注射一次）。在这一阶段，最常见的治疗相关不良事件（AE）是瘙痒（n=9，36%）、疲劳（n=8，32%）和食欲下降（n=7，28%）。未观察到 4 或 5 级治疗相关 AE。6 名（24%）患者有确认的部分缓解（PR），4 名（16%）患者有稳定疾病；1 名患者在初始假性进展后有确认的 PR。反应的中位持续时间为 7.43 个月（95%置信区间[CI]：3.75，NR）。在 7 名应答者中，包括延迟应答者，有 1 名患者 PD-L1 表达较高（≥50%）。无进展生存期的中位值为 5.26 个月（95%CI：1.77，9.20），总生存期的中位值为 11.99 个月（95%CI：8.15，NR）。治疗后诱导了干扰素γ反应基因，抑制了细胞黏附基因，但由于样本有限，这些观察结果与肿瘤反应和临床结局的关联未进行统计学分析。
该研究达到了主要终点，因为 galunisertib 联合 nivolumab 耐受性良好。在 II 期 NSCLC 队列的部分患者中观察到初步疗效。
临床试验.gov 注册（NCT02423343；2015 年 4 月 22 日）。
