Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Oncode Institute, Utrecht, the Netherlands.
BMC Cancer. 2023 Mar 4;23(1):205. doi: 10.1186/s12885-023-10663-2.
In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile.
Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses.
Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB.
Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings.
Clinical trial registration: NCT02925234. First registration date: 05/10/2016.
在这项研究中，我们旨在评估 PD-L1 抑制剂度伐利尤单抗在药物再发现方案（DRUP）中各种错配修复缺陷（dMMR）或微卫星不稳定高（MSI-H）肿瘤中的疗效和安全性。这是一项临床研究，根据患者的肿瘤分子特征，对接受标签适应证以外药物治疗的患者进行治疗。
符合条件的患者为患有 dMMR/MSI-H 实体瘤且已用尽所有标准治疗方案的患者。患者接受度伐利尤单抗治疗。主要终点是临床获益（CB）（客观缓解（OR）或稳定疾病≥16 周）和安全性。使用 Simon 样两阶段模型招募患者，第一阶段有 8 名患者，如果第一阶段至少有 1/8 名患者有 CB，则第二阶段有 24 名患者。在基线时，获得新鲜冷冻活检以进行生物标志物分析。
共纳入 26 名患者，10 种不同癌症类型。2 名患者（2/26，8%）被认为主要终点不可评估。13 名患者（13/26，50%）观察到 CB，其中 7 名患者（7/26，27%）出现 OR。其余 11 名患者（11/26，42%）疾病进展。中位无进展生存期和总生存期分别为 5 个月（95%CI，2-未达到）和 14 个月（95%CI，5-未达到）。未观察到意外毒性。我们发现无 CB 患者的结构性变异（SV）负担明显更高。此外，我们观察到无 CB 患者 JAK1 移码突变明显富集，IFN-γ 表达明显降低。
度伐利尤单抗在接受过治疗的 dMMR/MSI-H 实体瘤患者中耐受性良好，且提供持久缓解。高 SV 负担、JAK1 移码突变和低 IFN-γ 表达与缺乏 CB 相关；这为更大规模的研究提供了验证这些发现的依据。
临床试验注册：NCT02925234。首次注册日期：2016 年 5 月 10 日。
