Ribrag Vincent, Lee Seung Tae, Rizzieri David, Dyer Martin J S, Fayad Luis, Kurzrock Razelle, Andritsos Leslie, Bouabdallah Reda, Hayat Amjad, Bacon Larry, Jiang Yu, Miah Kowser, Delafont Bruno, Hamid Oday, Anyanwu Stephanie, Martinez Pablo, Hess Brian
Department of Hematology, Early Drug Development, Institut Gustave Roussy, Villejuif, France.
Department of Medicine, University of Maryland, Baltimore, MD.
Clin Lymphoma Myeloma Leuk. 2021 May;21(5):309-317.e3. doi: 10.1016/j.clml.2020.12.012. Epub 2020 Dec 17.
Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti-cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity.
In this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity.
As of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks).
The primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.
尽管近期取得了进展，但复发/难治性弥漫性大B细胞淋巴瘤（DLBCL）患者的预后仍然很差。免疫检查点抑制剂在这种情况下疗效有限，但与新型药物联合使用可能会增加获益。度伐利尤单抗（一种抗程序性死亡配体1 [PD-L1] 抗体）与丹伐替森（AZD9150；一种抑制信号转导和转录激活因子3 [STAT3] 的反义寡核苷酸）或曲美木单抗（一种抗细胞毒性T淋巴细胞相关抗原4 [CTLA-4] 抗体）联合治疗可能会增强内源性抗肿瘤活性。
在这项1b期剂量递增和剂量扩展研究中，我们评估了每4周一次20 mg/kg的度伐利尤单抗加每4周一次1 mg/kg的曲美木单抗或2或3 mg/kg的丹伐替森（在第1、3、5、8、15和22天给药，然后每周一次）。治疗持续至疾病进展。主要终点是安全性；次要终点包括疗效、药代动力学和免疫原性。
截至2019年4月4日，32例患者入组并接受治疗，既往接受全身治疗的中位数为2线。21例患者（65.6%）发生了治疗相关不良事件，最常见的是丙氨酸氨基转移酶/天冬氨酸氨基转移酶升高（1-3级）、贫血（1-3级）和疲劳（1级）。总体客观缓解率为6.3%，有2例部分缓解。中位缓解时间为11.0周（范围7.7-14.3周）。中位无进展生存期为7.4周（范围0.1-31.4周），中位总生存期为28.周（范围1.9-115.4周）。
达到了主要终点，度伐利尤单抗联合曲美木单抗/丹伐替森在复发/难治性DLBCL患者中总体耐受性良好；然而，抗肿瘤活性有限。
