City of Hope National Medical Center, Duarte, CA, United States; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States.
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States.
Lung Cancer. 2024 Sep;195:107932. doi: 10.1016/j.lungcan.2024.107932. Epub 2024 Aug 21.
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/m. 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/m 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/m 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/m. 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.
Plinabulin 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，该研究评估了 Plinabulin 联合纳武利尤单抗和伊匹单抗治疗复发性 SCLC 的情况。
在 I 期，采用 3+3 设计入组患者，以确定剂量限制性毒性（DLT）和推荐的 II 期剂量（RP2D）。患者在每个 21 天周期的第 1 天接受纳武利尤单抗（1mg/kg）、伊匹单抗（3mg/kg）和 Plinabulin（递增剂量）治疗，共 4 个周期，随后用 Plinabulin 和纳武利尤单抗维持治疗。在 II 期，入组了复发性 PD(L)1 抑制剂耐药 SCLC 患者。主要终点是中位无进展生存期（PFS）。
在 2018 年 9 月至 2023 年 2 月期间，共入组了 39 名患者，其中 36 名患者接受了研究治疗，并可对安全性进行评估（I 期 16 名；II 期 20 名）。在 I 期剂量递增中，有 2 例 DLT；持续时间<24 小时的 3 级精神状态改变和 3 级输注反应。确定 Plinabulin 的 RP2D 为 30mg/m。常见的 TRAE 为呕吐（44%）、恶心（42%）和输注反应（36%）；6%的患者发生了≥3 级 TRAE。5 名患者（14%）发生了≥3 级免疫相关不良事件；无免疫相关性肺炎病例。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），未达到预先指定的 3.5 个月中位 PFS 目标。在 30mg/m 组的 4 名患者中，有 4 名患者有部分缓解（1 名确认，3 名未确认）；5 名患者疾病稳定（疾病控制率 33%）。在 I 期接受较低的 20mg/m 剂量的 8 名患者中有 2 名确认部分缓解，其中 1 名患者的治疗方案超过 90 个周期。中位 OS 和随访时间分别为 5.5 个月和 2.5 个月。
Plinabulin 联合纳武利尤单抗和伊匹单抗的剂量为 30mg/m 时可耐受。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。联合用药的≥3 级免疫相关不良事件的数量低于预期。
