University of Rochester Medical Center, Wilmot Cancer Institute, Rochester, New York, USA.
Humanitas University and Humanitas Clinical and Research Center IRCCS, Milan, Italy.
Cancer Rep (Hoboken). 2023 Jan;6(1):e1662. doi: 10.1002/cnr2.1662. Epub 2022 Jul 19.
Studies suggest that immune checkpoint inhibitors may represent a promising strategy for boosting immune responses and improving the antitumor activity of standard therapies in patients with relapsed/refractory hematologic malignancies.
Phase 1/2 FUSION NHL 001 was designed to determine the safety and efficacy of durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, combined with standard-of-care therapies for lymphoma or chronic lymphocytic leukemia (CLL).
The primary endpoints were to determine the recommended phase 2 dose of the drugs used in combination with durvalumab (durvalumab was administered at the previously recommended dose of 1500 mg every 4 weeks) and to assess safety and tolerability. Patients were enrolled into one of four arms: durvalumab monotherapy (Arm D) or durvalumab in combination with lenalidomide ± rituximab (Arm A), ibrutinib (Arm B), or rituximab ± bendamustine (Arm C). A total of 106 patients with relapsed/refractory lymphoma were enrolled. All but two patients experienced at least one treatment-emergent adverse event (TEAE); those not experiencing a TEAE were in Arm C (diffuse large B-cell lymphoma [DLBCL]) and Arm D (DLBCL during the durvalumab monotherapy treatment period). No new safety signals were identified, and TEAEs were consistent with the respective safety profiles for each study treatment. Across the study, patients with follicular lymphoma (FL; n = 23) had an overall response rate (ORR) of 59%; ORR among DLBCL patients (n = 37) was 18%. Exploratory biomarker analysis showed that response to durvalumab monotherapy or combination therapy was associated with higher interferon-γ signature scores in patients with FL (p = .02).
Durvalumab as monotherapy or in combination is tolerable but requires close monitoring. The high rate of TEAEs during this study may reflect on the difficulty in combining durvalumab with full doses of other agents. Durvalumab alone or in combination appeared to add limited benefit to therapy.
研究表明，免疫检查点抑制剂可能是一种有前途的策略，可以增强复发/难治性血液恶性肿瘤患者的免疫反应，并提高标准治疗的抗肿瘤活性。
FUSION NHL 001 期临床试验旨在确定抗程序性死亡配体 1（PD-L1）抗体 durvalumab 与淋巴瘤或慢性淋巴细胞白血病（CLL）的标准治疗联合应用的安全性和疗效。
主要终点是确定联合使用的药物的 2 期推荐剂量（durvalumab 按先前推荐的每 4 周 1500mg 的剂量给药），并评估安全性和耐受性。患者被纳入以下四个治疗组之一：durvalumab 单药治疗（Arm D）或 durvalumab 联合 lenalidomide±rituximab（Arm A）、ibrutinib（Arm B）或 rituximab±bendamustine（Arm C）。共纳入 106 例复发/难治性淋巴瘤患者。除两名患者外，所有患者均经历了至少一次治疗后出现的不良事件（TEAE）；未发生 TEAE 的患者在 Arm C（弥漫性大 B 细胞淋巴瘤[DLBCL]）和 Arm D（durvalumab 单药治疗期间的 DLBCL）。未发现新的安全性信号，TEAEs 与各研究治疗的安全性特征一致。在整个研究中，滤泡性淋巴瘤（FL；n=23）患者的总体缓解率（ORR）为 59%；37 例弥漫性大 B 细胞淋巴瘤（DLBCL）患者的 ORR 为 18%。探索性生物标志物分析显示，FL 患者对 durvalumab 单药或联合治疗的反应与较高的干扰素-γ特征评分相关（p=0.02）。
durvalumab 单药或联合治疗是可以耐受的，但需要密切监测。本研究中较高的 TEAEs 发生率可能反映了 durvalumab 与其他药物全剂量联合应用的难度。durvalumab 单药或联合治疗对治疗的获益有限。
