A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors
A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors
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DOI：
10.1159/000500571
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发表时间：
2019-01-01
期刊：
影响因子：
3.5
通讯作者：
Borazanci, Erkut
中科院分区：
文献类型：
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作者：
Hong, David;Rasco, Drew;Borazanci, Erkut
工作背景：伊布替尼是一种一流的，每日一次的布鲁顿酪氨酸激酶抑制剂，在美国被批准用于治疗各种B细胞恶性肿瘤。临床前数据表明，伊曲替尼与程序性死亡配体1（PD-L1）抑制剂在实体瘤中具有协同抗肿瘤活性。本研究评估了伊鲁替尼联合durvalumab（一种PD-L1靶向抗体）治疗复发性/难治性实体瘤患者的效果。研究方法：这项开放标签、多中心、Ib/II期研究入组了既往接受过治疗的III/IV期胰腺癌、乳腺癌或非小细胞肺癌（NSCLC）患者。Ib期确定了推荐的II期剂量（RP 2D）。在II期研究中，患者接受RP 2D治疗，以评价伊曲替尼+durvalumab的安全性和抗肿瘤活性。结果：RP 2D被鉴别为伊鲁替尼560 mg p.o.每日一次和durvalumab 10 mg/kg i. v.每2周一次，122例患者接受RP 2D治疗。中位年龄为61岁，大多数患者（94%）为IV期疾病。胰腺癌的总体缓解率（完全或部分缓解）为2%，乳腺癌为3%，NSCLC为0%。胰腺癌、乳腺癌和NSCLC队列的中位无进展生存期分别为1.7、1.7和2.0个月。胰腺癌、乳腺癌和NSCLC队列的中位总生存期分别为4.2、4.2和7.9个月。在不同肿瘤类型中观察到的安全性特征与伊曲替尼和durvalumab的已知安全性特征一致。所有患者中≥ 5%的≥ 3级不良事件为低钠血症（10%）、呼吸困难（7%）、斑丘疹（7%）、肺炎（7%）、贫血（6%）和腹泻（6%）。结论：每日560 mg伊鲁替尼和每2周一次10 mg/kg durvalumab的联合用药具有可接受的安全性特征。在我们的研究人群中，伊曲替尼-durvalumab联合给药的抗肿瘤活性有限。
Background: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. Methods: This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab. Results: The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade >= 3 adverse events in >= 5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). Conclusions: The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.