Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

抗PD-1抗体是复发或难治性结外自然杀伤T细胞淋巴瘤（RR-ENKTL）的有利治疗方法，但完全缓解（CR）率和缓解持续时间（DOR）有待提高。这项 1b/2 期研究调查了信迪利单抗（一种全人源抗 PD-1 抗体）与西达本胺（一种口服亚型选择性组蛋白脱乙酰酶抑制剂）在 38 名 RR-ENKTL 患者中的安全性和有效性。联合治疗的预期客观缓解率（ORR）为80%。患者接受递增剂量的西达本胺，并与固定剂量的信迪利单抗一起服用，周期为 21 天，最长 12 个月。未观察到剂量限制事件，西达本胺的 RP2D 为 30 mg，每周两次。 29 名患者入组第 2 期。在意向治疗人群 (n = 37) 中，总体缓解率为 59.5%，完全缓解率为 48.6%。中位 DOR、无进展生存期 (PFS) 和总生存期 (OS) 分别为 25.3、23.2 和 32.9 个月。最常见的 3 级或以上治疗引起的不良事件 (AE) 是中性粒细胞减少症 (28.9%) 和血小板减少症 (10.5%)，18 名患者 (47.3%) 报告了与免疫相关的 AE。探索性生物标志物评估表明，动态血浆 ctDNA 和 EBV-DNA 的组合发挥着至关重要的预后作用。 STAT3突变显示出不良的预后。尽管没有达到预期的 ORR 结果，但信迪利单抗联合西达本胺显示出具有可控的安全性，并且首次在 RR-ENKTL 中产生了令人鼓舞的 CR 率和 DOR。对于该人群来说，这是一种有前途的治疗选择。