START Madrid-FJD, Hospital Fundación Jimenez Diaz, Av. de los Reyes Católicos, 28040, Madrid, Spain.
START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain.
Cancer Immunol Immunother. 2022 Dec;71(12):2985-2998. doi: 10.1007/s00262-022-03191-8. Epub 2022 May 21.
We evaluated MK-4621, an oligonucleotide that binds and activates retinoic acid-inducible gene I (RIG-I), as monotherapy (NCT03065023) and in combination with the anti-programmed death 1 antibody pembrolizumab (NCT03739138).
Patients were ≥ 18 years with histologically/cytologically confirmed advanced/metastatic solid tumors with injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a stable formulation with jetPEI™ twice weekly over a 4-week cycle as monotherapy and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and treatment discontinuation due to AEs.
Fifteen patients received MK-4621 monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 pleural effusion that subsequently resolved, occurred in a patient who received MK-4621/jetPEI™ 0.8 mg plus pembrolizumab. 93% of patients experienced ≥ 1 treatment-related AE with both monotherapy and combination therapy. No patients experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 (27%) had stable disease. Three (10%) patients who received combination therapy had a partial response. Serum and tumor biomarker analyses provided evidence that MK-4621 treatment induced an increase in gene expression of interferon signaling pathway members and associated chemokines and cytokines.
Patients treated with MK-4621 monotherapy or in combination with pembrolizumab experienced tolerable safety and modest antitumor activity, and there was evidence that MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer meaningful clinical benefit.
ClinicalTrials.gov, NCT03065023 and NCT03739138.
我们评估了 MK-4621，一种与视黄酸诱导基因 I（RIG-I）结合并激活的寡核苷酸，作为单药治疗（NCT03065023）以及与抗程序性死亡 1 抗体 pembrolizumab 联合治疗（NCT03739138）。
患者年龄≥18 岁，患有组织学/细胞学确认的晚期/转移性实体瘤，且存在可注射病变。MK-4621（0.2-0.8mg）以稳定制剂的形式通过 jetPEI™每周两次给药，每 4 周为一个周期作为单药治疗，在 6 个周期内每周一次，与每 3 周一次的 200mg pembrolizumab 联合使用，最多 35 个周期。主要终点是剂量限制性毒性（DLT）、治疗相关不良事件（AE）以及因 AE 而停药。
15 名患者接受了 MK-4621 单药治疗，30 名患者接受了 MK-4621 加 pembrolizumab 联合治疗。唯一的 DLT，即随后缓解的 3 级胸腔积液，发生在接受 MK-4621/jetPEI™0.8mg 加 pembrolizumab 的患者中。93%的患者在单药和联合治疗中均出现了≥1 次治疗相关的 AE。MK-4621 单药治疗时，根据 RECIST v1.1 标准，没有患者出现客观缓解；4 名（27%）患者病情稳定。接受联合治疗的 3 名（10%）患者有部分缓解。血清和肿瘤生物标志物分析提供了证据表明，MK-4621 治疗诱导了干扰素信号通路成员和相关趋化因子和细胞因子的基因表达增加。
接受 MK-4621 单药治疗或与 pembrolizumab 联合治疗的患者安全性良好，抗肿瘤活性适度，并有证据表明 MK-4621 激活了 RIG-I 通路。在测试的剂量下，MK-4621 没有带来有意义的临床获益。
ClinicalTrials.gov，NCT03065023 和 NCT03739138。
