Younes Anas, Brody Joshua, Carpio Cecilia, Lopez-Guillermo Armando, Ben-Yehuda Dina, Ferhanoglu Burhan, Nagler Arnon, Ozcan Muhit, Avivi Irit, Bosch Francesc, Caballero Barrigón Maria Dolores, Hellmann Andrzej, Kuss Bryone, Ma David D F, Demirkan Fatih, Yağci Münci, Horowitz Netanel A, Marlton Paula, Cordoba Raul, Wrobel Tomasz, Buglio Daniela, Streit Michael, Hodkinson Brendan P, Schaffer Michael, Alvarez John, Ceulemans Rob, Balasubramanian Sriram, de Jong Jan, Wang Shean-Sheng, Fourneau Nele, Jurczak Wojciech
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Lancet Haematol. 2019 Feb;6(2):e67-e78. doi: 10.1016/S2352-3026(18)30217-5. Epub 2019 Jan 11.
Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases.
We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing.
Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]).
The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment.
Janssen R&D.
临床前研究表明，依鲁替尼与免疫检查点阻断之间存在协同抗肿瘤作用。本研究的目的是评估依鲁替尼联合纳武单抗治疗复发或难治性B细胞恶性疾病患者的安全性和活性。
我们在澳大利亚、以色列、波兰、西班牙、土耳其和美国的21家医院进行了一项分为两部分的开放标签1/2a期研究。A部分（剂量递增）的主要目的是评估每日口服依鲁替尼（420 mg或560 mg）联合静脉注射纳武单抗（每2周3 mg/kg）的安全性，以确定复发或难治性高危慢性淋巴细胞白血病或小淋巴细胞淋巴瘤（del17p或del11q）、滤泡性淋巴瘤或弥漫性大B细胞淋巴瘤患者的推荐2期剂量。使用改良的毒性概率区间设计研究剂量优化。B部分扩展阶段的主要目的是确定依鲁替尼和纳武单抗联合用药在四个队列中的初步活性（达到总体缓解的患者比例）：复发或难治性高危慢性淋巴细胞白血病或小淋巴细胞淋巴瘤（del17p或del11q）、滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤和Richter转化。所有接受至少一剂治疗的参与者都纳入了主要分析，分析按疾病队列进行。本试验已在ClinicalTrials.gov注册，编号为NCT02329847。试验正在进行中。
2015年3月12日至2017年4月11日期间，144例患者入组本研究。3例患者在接受研究治疗前死亡；因此，141例患者纳入分析，A部分14例，B部分127例。在弥漫性大B细胞淋巴瘤队列中，420 mg剂量组报告了1例剂量限制性毒性（3级高胆红素血症），5天后缓解。依鲁替尼和纳武单抗联合用药使36例高危慢性淋巴细胞白血病或小淋巴细胞淋巴瘤患者中的22例（61%）、40例滤泡性淋巴瘤患者中的13例（33%）、45例弥漫性大B细胞淋巴瘤患者中的16例（36%）以及20例Richter转化患者中的13例（65%）获得了总体缓解。最常见的所有级别的不良事件为腹泻（141例患者中的47例[33%]）、中性粒细胞减少（44例[31%]）和疲劳（37例[26%]）。141例患者中有11例（8%）发生了导致死亡的不良事件；均未报告与药物相关。最常见的3-4级不良事件为中性粒细胞减少（141例患者中的40例[28%]）和贫血（32例[23%]）。3-4级中性粒细胞减少的发生率在45例弥漫性大B细胞淋巴瘤患者中的8例（18%）至36例慢性淋巴细胞白血病或小淋巴细胞淋巴瘤患者中的19例（53%）之间；3-4级贫血的发生率在40例滤泡性淋巴瘤患者中的5例（13%）至20例Richter转化患者中的7例（35%）之间。最常见的严重不良事件包括贫血（141例患者中的6例[4%]）和肺炎（5例[4%]）。最常见的3-4级免疫相关不良事件为皮疹（141例患者中的11例[8%]）和丙氨酸转氨酶升高（3例[2%]）。
依鲁替尼和纳武单抗联合用药具有可接受的安全性，初步活性与慢性淋巴细胞白血病或小淋巴细胞淋巴瘤、滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤中依鲁替尼单药治疗报告的活性相似。Richter转化患者的临床反应很有前景，支持进一步的临床评估。
杨森研发公司。
