Gopal A K, Fanale M A, Moskowitz C H, Shustov A R, Mitra S, Ye W, Younes A, Moskowitz A J
Division of Medical Oncology, Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle.
Division of Cancer Medicine, Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston.
Ann Oncol. 2017 May 1;28(5):1057-1063. doi: 10.1093/annonc/mdx028.
The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study.
We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg two times daily; an increase to 300 mg two times daily was permitted at the time of disease progression.
The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with one complete remission and four partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in three patients and was grade 1-2. There was one adverse event leading to death (hypoxia).
Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response.
ClinicalTrials.gov # NCT01393106.
磷脂酰肌醇-3-激酶δ（PI3Kδ）抑制剂idelalisib已被证明可阻断细胞内下游信号传导，减少促生存趋化因子的产生，并诱导经典型霍奇金淋巴瘤（HL）细胞系凋亡。在其他肿瘤模型中，它还被证明可抑制调节性T细胞和髓源性抑制细胞。我们推测，抑制PI3Kδ通过直接靶向恶性细胞以及调节炎症微环境，将具有直接和间接的抗肿瘤作用。我们在一项II期研究中验证了这一假设。
我们纳入了25例复发/难治性HL患者，中位年龄42岁，此前接受的治疗中位数为5种，其中18例（72%）自体干细胞移植失败，23例（92%）brentuximab vedotin治疗失败，11例（44%）曾接受过放疗。Idelalisib的给药剂量为每日两次，每次150mg；疾病进展时允许增加至每日两次，每次300mg。
Idelalisib治疗的总缓解率为20%（95%置信区间：6.8%，40.7%），中位缓解时间为2.0个月。17例患者（68%）的靶病灶缩小，其中1例完全缓解，4例部分缓解。中位缓解持续时间为8.4个月，中位无进展生存期为2.3个月。最常见的≥3级不良事件是丙氨酸转氨酶升高（2例患者，8%）。3例患者出现腹泻/结肠炎，为1-2级。有1例不良事件导致死亡（缺氧）。
Idelalisib在预处理严重的HL患者中耐受性良好，单药活性中等。与其他新型药物进行合理联合可能会提高缓解率和缓解持续时间。
ClinicalTrials.gov # NCT01393106。
