普那布林是一种 GEF-H1 释放剂，具有免疫增强功能。我们报告了一项多中心 I/II 期研究 (NCT03575793) 的结果，该研究评估普那布林联合纳武单抗和伊匹单抗治疗复发性 SCLC。在 I 期中，使用 3  3 设计入组患者以确定剂量限制性毒性 (DLT)和推荐的 2 期剂量 (RP2D)。患者在每个 21 天周期的第一天接受纳武单抗 (1 mg/kg)、易普利姆玛 (3 mg/kg) 和普那布林（剂量递增），持续 4 个周期，然后用普那布林和纳武单抗维持治疗。在 II 期研究中，招募了复发性 PD(L)1 抑制剂耐药性 SCLC 患者。主要目标是中位无进展生存期 (PFS)。在 2018 年 9 月至 2023 年 2 月期间，入组了 39 名患者，其中 36 名患者接受了研究治疗并可进行安全性评估（16 名患者处于 I 期；20 名患者处于 II 期）。在I期剂量递增中，有2个DLT； 3 级精神状态改变持续 <24 小时和 3 级输液反应。普那布林 RP2D 确定为 30 mg/m2。常见的 TRAE 包括呕吐 (44%)、恶心 (42%) 和输液反应 (36%)； 6% 的患者有 ≥ 3 级 TRAE。 5 名患者 (14%) 出现 ≥ 3 级 irAE；没有出现免疫相关肺炎病例。在 27 名患者的疗效分析中，中位 PFS 为 1.6 个月（95% CI 1.2 至 2.7），该试验未达到预先指定的目标中位 PFS 3.5 个月。 4 名接受 30 mg/m2 治疗的患者获得 PR（确诊 1 例，未确诊 3 例）； 5 名患者具有 SD，CBR 为 33%。在 I 期接受较低 20 mg/m2 剂量治疗的 8 名患者中，有 2 名已确诊 PR，其中 1 名患者接受药物治疗超过 90 个周期。中位 OS 和随访时间分别为 5.5 个月和 2.5 个月。普那布林与纳武单抗和易普利姆玛联合用药在 30 mg/m2 的剂量下是可耐受的。虽然 PD-1 耐药 SCLC 的临床反应有限，但一些患者的反应持续时间较长。该组合的 ≥ 3 级 irAE 数量低于预期。版权所有 © 2024。由 Elsevier B.V. 出版。

Plinabulin is a GEF-H1 releasing agent with an immune-enhancing function. We report results from a multicenter Phase I/II study (NCT03575793) assessing plinabulin in combination with nivolumab and ipilimumab for the treatment of recurrent SCLC.In Phase I, patients were enrolled using a 3 + 3 design to determine dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg), and plinabulin (in escalating doses) on day 1 of each 21-day cycle for 4 cycles followed by maintenance with plinabulin and nivolumab. In phase II, patients with recurrent PD(L)1 inhibitor resistant SCLC were enrolled. The primary objective was median progression-free survival (PFS).Between 9/2018 and 2/2023, 39 patients were enrolled, and 36 patients received study treatment and were evaluable for safety (16 in Phase I; 20 in Phase II). In the phase I dose-escalation, there were 2 DLTs; grade 3 altered mental status lasting <24 h and grade 3 infusion reaction. The Plinabulin RP2D was determined to be 30 mg/m2. Common TRAEs were vomiting (44 %), nausea (42 %), and infusion reaction (36 %); 6 % of patients had a ≥grade 3 TRAE. Five patients (14 %) had ≥grade 3 irAEs; there were no cases of immune-related pneumonitis. In the efficacy analysis in 27 patients, the median PFS was 1.6 months (95 % CI 1.2 to 2.7) and the trial did not meet the pre-specified target median PFS of 3.5 months. Four patients treated at 30 mg/m2 had PR (confirmed 1, unconfirmed 3); 5 patients had SD with a CBR of 33 %. Two of 8 patients treated in phase I at the lower 20 mg/m2 dose had confirmed PR, with 1 patient on the drug regimen for >90 cycles. The median OS and follow-up time were 5.5 months and 2.5 months respectively.Plinabulin in combination with nivolumab and ipilimumab was tolerable at the dose of 30 mg/m2. While the clinical responses in PD-1 resistant SCLC were limited, some patients had a long duration of response. The number of ≥grade 3 irAE with the combination were lower than expected.Copyright © 2024. Published by Elsevier B.V.