一项评估帕博利珠单抗在 EGFR 突变、PD-L1 阳性、初治的晚期 NSCLC 患者中的疗效和安全性的 II 期临床研究。
A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC.
机构信息
David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.
David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California.
出版信息
J Thorac Oncol. 2018 Aug;13(8):1138-1145. doi: 10.1016/j.jtho.2018.03.035. Epub 2018 Jun 1.
BACKGROUND
Despite the significant antitumor activity of pembrolizumab in NSCLC, clinical benefit has been less frequently observed in patients whose tumors harbor EGFR mutations compared to EGFR wild-type patients. Our single-center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with programmed death ligand 1 (PD-L1) expression ≥50%.
METHODS
We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation-positive, advanced NSCLC and PD-L1-positive (≥1%, 22C3 antibody) tumors. Pembrolizumab was administered 200 mg every 3 weeks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab.
RESULTS
Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. Eighty-two percent of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD-L1 expression ≥50%. Only 1 patient had an objective response (9%), but repeat analysis of this patient's tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment-related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern.
CONCLUSIONS
Pembrolizumab's lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.
背景
尽管 pembrolizumab 在 NSCLC 中具有显著的抗肿瘤活性，但与 EGFR 野生型患者相比，肿瘤携带 EGFR 突变的患者临床获益较少。我们在 KEYNOTE-001 试验中的单中心经验表明，pembrolizumab 治疗的 EGFR 突变患者，在接受酪氨酸激酶抑制剂（TKI）治疗之前，具有优于先前接受 TKI 治疗的患者的临床结局。由于 TKI 初治的 EGFR 突变患者通常被排除在 pembrolizumab 研究之外，因此缺乏针对该患者人群的治疗决策数据，特别是在 PD-L1 表达≥50%的患者中。
方法
我们进行了一项 II 期试验（NCT02879994），评估 pembrolizumab 在 TKI 初治的 EGFR 突变阳性、晚期 NSCLC 和 PD-L1 阳性（≥1%，22C3 抗体）肿瘤患者中的疗效。pembrolizumab 每 3 周给药 200mg。主要终点是客观缓解率。次要终点包括 pembrolizumab 的安全性、pembrolizumab 的其他疗效终点以及 pembrolizumab 后 EGFR TKI 的疗效和安全性。
结果
在计划入组的 25 例患者中治疗了 11 例后，由于疗效不佳而停止入组。82%的试验患者为初治，64%有敏感 EGFR 突变，73%有 PD-L1 表达≥50%。仅有 1 例患者有客观缓解（9%），但对该患者肿瘤的重复分析明确显示最初报告的 EGFR 突变是错误的。观察到的治疗相关不良事件与先前使用 pembrolizumab 的经验相似，但在入组后 6 个月内有 2 例死亡，其中 1 例归因于肺炎，这令人担忧。
结论
pembrolizumab 在 TKI 初治、PD-L1+、EGFR 突变的晚期 NSCLC 患者中缺乏疗效，包括 PD-L1 表达≥50%的患者，表明在这种情况下它不是一种合适的治疗选择。
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