Purpose: Recurrent small cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted. Patients and Methods: This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety and a recommended phase II dose (RP2D). The phase II primary objective was to determine overall response rate (ORR), with secondary objectives of duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Immunohistochemistry of pre- and on-treatment tumor biopsies and pharmacokinetics analysis were performed. Results: Twenty-two patients enrolled (phase I, n=12; phase II n=10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLTs) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 toxicity-evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; 3 patients discontinued treatment for toxicity. In phase II, 3/10 patients experienced DLTs triggering a stopping rule. The ORR was 4/19 (21%, 95% CI 6 to 46%). The median DoR, PFS and OS were 4.6 mo, 2.2 mo (95% CI 1.3 to 7.6 mo) and 6.6 mo (95% CI 4.3 to not reached). SLFN11, EZH2 and SCLC subtyping markers did not correlate with response. MHC-I protein expression increased in 4/4 patients with paired biopsies, including 3/3 responders; two responders demonstrated subtype switching on treatment. Conclusions: Valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat may warrant further investigation in SCLC.

中文翻译：

---

EZH1/2 抑制剂 valemetostat (DS-3201b) 联合伊立替康治疗复发性小细胞肺癌患者的 I/II 期研究


目的：复发性小细胞肺癌（SCLC）的有效治疗方法很少。 EZH2-SLFN11 通路是可能成为靶点的获得性化疗耐药性的驱动因素。患者和方法：这项 I/II 期试验研究了 valemetostat（一种 EZH1/2 抑制剂）与固定剂量伊立替康治疗复发性 SCLC 患者的疗效。 I 期的主要目标是评估安全性和推荐的 II 期剂量 (RP2D)。 II 期的主要目标是确定总体缓解率 (ORR)，次要目标是缓解持续时间 (DoR)、无进展生存期 (PFS) 和总体生存期 (OS)。对治疗前和治疗中的肿瘤活检进行免疫组织化学分析，并进行药代动力学分析。结果：22 名患者入组（I 期，n=12；II 期 n=10）；一名患者在治疗前撤回同意。剂量递增中的三种剂量限制性毒性 (DLT) 导致每日口服 valemetostat 100 mg，选择作为 RP2D。在 21 名可进行毒性评估的患者中，最常见（≥20%）的治疗相关不良事件是腹泻、疲劳、恶心和皮疹； 3名患者因毒性而停止治疗。在 II 期中，3/10 的患者经历了 DLT，触发了停止规则。 ORR 为 4/19（21%，95% CI 6 至 46%）。中位 DoR、PFS 和 OS 分别为 4.6 个月、2.2 个月（95% CI 1.3 至 7.6 个月）和 6.6 个月（95% CI 4.3 至未达到）。 SLFN11、EZH2 和 SCLC 亚型标记与反应不相关。 4/4 的配对活检患者（包括 3/3 的应答者）中 MHC-I 蛋白表达增加；两名反应者在治疗中表现出亚型转换。结论：Valemetostat 和伊立替康对复发性 SCLC 不耐受，但显示出疗效。 Valemetostat 可能需要对 SCLC 进行进一步调查。