INTRODUCTION Induction of PD-L1 expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring EML4-ALK rearrangements. We assessed safety and activity of ceritinib plus nivolumab in these patients. METHODS In this open-label, phase 1B, multicenter, dose-escalation and expansion study, previously treated (ALK inhibitor [ALKi]/chemotherapy) or treatment-naïve patients with stage IIIB/IV ALK-rearranged NSCLC received nivolumab 3 mg/kg intravenously every 2 weeks plus ceritinib (450 mg/300 mg) daily with low-fat meal. RESULTS In total, 36 patients were treated (450 mg cohort [n=14]; 300 mg cohort [n=22]). In the 450 mg cohort, four patients experienced DLTs. In the 300 mg cohort, two patients experienced DLTs. Among ALKi-naïve patients, the overall response rate (ORR) was 83% (95% CI 35.9-99.6) in the 450 mg cohort and 60% (95% CI 26.2-87.8) in the 300 mg cohort. Among ALKi-pretreated patients, the ORR was 50% (95% CI 15.7-84.3) in the 450 mg cohort and 25% (5.5-57.2) in the 300 mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 as compared to those who were negative for PD-L1 with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% [95% CI 35.1-87.2] patients had confirmed responses as compared to those with negative PD-L1 staining (31% [95% CI 11.0-58.7]). Most frequently reported grade 3/4 adverse events were increased alanine aminotransferase (ALT) (25%), increased gamma-glutamyl transferase (22%), increased amylase (14%), increased lipase (11%), and maculopapular rash (11%). Incidence of all grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% patients in the 450 mg and 300 mg cohorts, respectively; no grade 4 rash was reported. CONCLUSION Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.

中文翻译：

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色瑞替尼加纳武单抗治疗晚期 ALK 重排非小细胞肺癌患者：一项开放标签、多中心、1B 期研究的结果

引言 在携带 EML4-ALK 重排的 NSCLC 模型中，已经报道了由于组成型致癌信号导致 PD-L1 表达的诱导。我们评估了色瑞替尼加纳武单抗在这些患者中的安全性和活性。方法 在这项开放标签、1B 期、多中心、剂量递增和扩展研究中，既往接受过治疗（ALK 抑制剂 [ALKi]/化疗）或接受过治疗的 IIIB/IV 期 ALK 重排 NSCLC 患者接受纳武单抗 3 mg/kg每 2 周静脉注射一次，加色瑞替尼 (450 mg/300 mg) 每日一次，低脂餐。结果 总共有 36 名患者接受了治疗（450 mg 队列 [n=14]；300 mg 队列 [n=22]）。在 450 mg 队列中，4 名患者经历了 DLT。在 300 mg 队列中，两名患者经历了 DLT。在 ALKi 初治患者中，总缓解率 (ORR) 为 83%（95% CI 35.9-99。6) 在 450 mg 队列中和 60% (95% CI 26.2-87.8) 在 300 mg 队列中。在 ALKi 预处理的患者中，450 mg 队列的 ORR 为 50% (95% CI 15.7-84.3)，300 mg 队列的 ORR 为 25% (5.5-57.2)。与具有重叠 CI 的 PD-L1 阴性患者相比，PD-L1 阳性患者的 ORR 点估计值更高（例如，PD-L1 的临界值≥1%，64% [95% CI 35.1-87.2] 与 PD-L1 染色阴性的患者相比，患者有确认的反应（31% [95% CI 11.0-58.7]）。最常报告的 3/4 级不良事件是丙氨酸氨基转移酶 (ALT) 升高（25 %)、γ-谷氨酰转移酶升高 (22%)、淀粉酶升高 (14%)、脂肪酶升高 (11%) 和斑丘疹 (11%)。两个队列中所有级别皮疹（分组术语）的发生率为 64% ; 在 450 mg 和 300 mg 队列中，分别有 29% 和 14% 的患者报告了 3 级皮疹；没有报告 4 级皮疹。结论色瑞替尼加纳武单抗有活性；ORR 似乎与基线的 PD-L1 相关。毒性，尤其是皮疹，比单一药物更常见。