背景:派姆单抗是某些晚期/转移性非小细胞肺癌(NSCLC)患者的一线治疗方案。pembrolizumab与其他免疫疗法的组合可以增强肿瘤细胞杀伤和临床结果。Epacadostat是吲哚胺2,3-双加氧酶1的选择性抑制剂,后者是参与色氨酸对犬尿氨酸代谢的免疫调节酶,可抑制T细胞介导的免疫反应。
方法:在这项随机II期研究中,表达高(≥50%)程序性死亡-配体1(PD-L1)水平的转移性NSCLC患者接受了每21天200mg帕姆单抗+每日2次口服epacadostat100mg(联合)或匹配的安慰剂(对照).主要目标是客观缓解率(ORR);次要目标是无进展生存期(PFS),总生存期(OS),反应持续时间(DOR)和安全性/耐受性。
结果:154例患者被随机分组(每组77例)。联合组和对照组的中位(范围)随访为6.8个月(0.1-11.4)和7.0个月(0.2-11.9)。分别确认的ORR在组间相似(组合:32.5%,95%CI22.2-44.1;对照:39.0%,95%CI28.0-50.8;差异:-6.5,95%CI-21.5-8.7;单侧P=0.8000)。在联合组和对照组中,平均(范围)DOR为6.2个月(1.9至6.5),未达到(1.9至8.6),分别。虽然没有正式测试,联合组和对照组的中位PFS分别为6.7和6.2个月,分别,两组均未达到中位OS。对照组犬尿氨酸循环水平从C1D1升高到C2D1(P<0.01),联合组从C1D1降低到C2D1(P<0.01),但大多数患者未恢复正常。最常见的严重不良事件(AEs)(≥2%)是肺炎(4.0%),贫血(2.7%),联合治疗组肺不张(2.7%)和肺炎(2.7%)和肺炎(3.9%),对照组肺炎(2.6%)和低血压(2.6%)。报告了两例因药物相关的不良事件而死亡,在对照组中。
结论:在pembrolizumab治疗PD-L1高转移性NSCLC的基础上添加epacadostat通常耐受性良好,但未显示出改善的治疗效果。当与检查点抑制剂联合使用时,评估使犬尿氨酸水平正常化的较高剂量的epacadostat可能是必要的。
背景:ClinicalTrials.gov,NCT03322540。注册2017年10月26日。
BACKGROUND: Pembrolizumab is a first-line therapy for certain patients with advanced/metastatic non-small cell lung cancer (NSCLC). Combining pembrolizumab with other immunotherapies may enhance tumor cell killing and clinical outcomes. Epacadostat is a selective inhibitor of indoleamine 2,3-dioxygenase 1, an immuno-regulatory enzyme involved in tryptophan to kynurenine metabolism that inhibits T cell-mediated immune responses.
METHODS: In this randomized phase II study, patients with metastatic NSCLC expressing high (≥ 50%) programmed death-ligand 1 (PD-L1) levels received pembrolizumab 200 mg every 21 days plus oral epacadostat 100 mg twice daily (combination) or matching placebo (control). The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety/tolerability.
RESULTS: 154 patients were randomized (77 per group). Median (range) follow-up was 6.8 months (0.1-11.4) and 7.0 months (0.2-11.9) in the combination and control groups, respectively Confirmed ORR was similar between groups (combination: 32.5%, 95% CI 22.2-44.1; control: 39.0%, 95% CI 28.0-50.8; difference: - 6.5, 95% CI - 21.5 to 8.7; 1-sided P = 0.8000). Median (range) DOR was 6.2 months (1.9 + to 6.5 +) and not reached (1.9 + to 8.6 +) in the combination and control groups, respectively. Although not formally tested, median PFS was 6.7 and 6.2 months for the combination and control groups, respectively, and median OS was not reached in either group. Circulating kynurenine levels increased from C1D1 to C2D1 (P < 0.01) in the control group and decreased from C1D1 to C2D1 (P < 0.01) in the combination group but were not normalized in most patients. The most frequent serious adverse events (AEs) (≥ 2%) were pneumonia (4.0%), anemia (2.7%), atelectasis (2.7%) and pneumonitis (2.7%) in the combination group and pneumonia (3.9%), pneumonitis (2.6%) and hypotension (2.6%) in the control group. Two deaths due to drug-related AEs were reported, both in the control group.
CONCLUSIONS: Addition of epacadostat to pembrolizumab therapy for PD-L1-high metastatic NSCLC was generally well tolerated but did not demonstrate an improved therapeutic effect. Evaluating higher doses of epacadostat that normalize kynurenine levels when given in combination with checkpoint inhibitors may be warranted.
BACKGROUND: ClinicalTrials.gov, NCT03322540. Registered 10/26/2017.