Purpose: In this phase Ib/II study, we aimed to evaluate the safety and efficacy of PDR001, an anti-PD-1 antibody, in combination with imatinib in patients with treatment-refractory gastrointestinal stromal tumor (GIST). Patients and Methods: Advanced GIST patients whose disease had progressed on imatinib, sunitinib, and regorafenib were enrolled. In phase Ib, the standard 3+3 dose escalation scheme was applied. PDR001 400 mg intravenously every 4 weeks plus imatinib (300 mg and 400 mg daily for dose levels I and II, respectively) was given. The primary outcome for phase II was the disease control rate (DCR) at 12 weeks. Exploratory biomarker analysis was performed based on PD-L1 immunohistochemistry, next-generation sequencing, and multiplexed immunohistochemistry. Results: No dose-limiting toxicity was observed in the phase Ib part (n=10), and dose level 2 was selected as the recommended phase II dose. In the phase II part (n=29), there was no objective response and the DCR at 12 weeks was 37.9%, not meeting the primary efficacy endpoint. For patients in phase Ib–dose level II and phase II (n=36), the median progression-free survival (PFS) and overall survival were 2.3 and 9.5 months, respectively. The most common grade 3–4 adverse event was anemia. Exploratory biomarker analysis indicated that a higher CD8+ T cell density was associated with a favorable PFS, but to a limited degree. Tumor mutation burden and PD-L1 were not associated with better PFS. Conclusion: In patients with treatment-refractory GIST, PDR001 in combination with imatinib was generally tolerable, but it was not effective.

中文翻译：

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PDR001 联合伊马替尼治疗晚期难治性胃肠道间质瘤 I/II 期研究的临床和生物标志物分析

目的：在这项 Ib/II 期研究中，我们旨在评估 PDR001（一种抗 PD-1 抗体）与伊马替尼联合治疗难治性胃肠道间质瘤 (GIST) 患者的安全性和有效性。患者和方法：纳入接受伊马替尼、舒尼替尼和瑞戈非尼治疗后疾病进展的晚期 GIST 患者。在Ib期，应用标准的3+3剂量递增方案。每 4 周静脉注射 PDR001 400 mg，加伊马替尼（剂量水平 I 和 II 分别为每天 300 mg 和 400 mg）。 II 期的主要结局是 12 周时的疾病控制率 (DCR)。基于 PD-L1 免疫组织化学、下一代测序和多重免疫组织化学进行探索性生物标志物分析。结果：Ib期部分（n=10）未观察到剂量限制性毒性，选择剂量水平2作为II期推荐剂量。在II期部分（n=29），没有客观缓解，12周时的DCR为37.9%，未达到主要疗效终点。对于 Ib 期-剂量水平 II 期和 II 期患者 (n=36)，中位无进展生存期 (PFS) 和总生存期分别为 2.3 个月和 9.5 个月。最常见的 3-4 级不良事件是贫血。探索性生物标志物分析表明，较高的 CD8+ T 细胞密度与良好的 PFS 相关，但程度有限。肿瘤突变负荷和 PD-L1 与更好的 PFS 无关。结论：在治疗难治性GIST患者中，PDR001联合伊马替尼总体上可耐受，但效果不佳。