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.

中文翻译：

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Pembrolizumab 在 EGFR 突变、PD-L1+、酪氨酸激酶抑制剂 (TKI) 初治晚期 NSCLC 患者中的 II 期研究

背景：尽管帕博利珠单抗在 NSCLC 中具有显着的抗肿瘤活性，但与 EGFR 野生型患者相比，在肿瘤携带 EGFR 突变的患者中观察到的临床益处较少。我们在 KEYNOTE-001 试验中的单中心经验表明，帕博利珠单抗治疗的 EGFR 突变患者（酪氨酸激酶抑制剂（TKI）初治）的临床结果优于先前接受 TKI 治疗的患者。由于 TKI 初治 EGFR 突变体通常被排除在 pembrolizumab 研究之外，因此缺乏指导该患者群体治疗决策的数据，特别是在程序性死亡配体 1 (PD-L1) 表达≥50% 的患者中。方法：我们在 EGFR 突变阳性、晚期 NSCLC 和 PD-L1 阳性（≥1%，22C3 抗体）肿瘤。派姆单抗每 3 周给药 200 毫克。主要终点是客观反应率。次要终点包括派姆单抗的安全性、额外的派姆单抗疗效终点以及派姆单抗后 EGFR TKI 的疗效和安全性。结果：在 25 名计划患者中的 11 名接受治疗后，由于缺乏疗效而停止招募。82% 的试验患者未接受过治疗，64% 有敏感的 EGFR 突变，73% 的 PD-L1 表达≥50%。只有 1 名患者有客观反应 (9%)，但对该患者肿瘤的重复分析明确显示 EGFR 突变的原始报告是错误的。观察到的治疗相关不良事件与之前使用 pembrolizumab 的经验相似，但在入组后 6 个月内有 2 人死亡，包括一种归因于肺炎的病例，令人担忧。结论：派姆单抗在 TKI 初治、PD-L1+、EGFR 突变的晚期 NSCLC 患者（包括 PD-L1 表达≥50% 的患者）中缺乏疗效，表明在这种情况下它不是合适的治疗选择。