Brown Jennifer R, Hamadani Mehdi, Hayslip John, Janssens Ann, Wagner-Johnston Nina, Ottmann Oliver, Arnason Jon, Tilly Hervé, Millenson Michael, Offner Fritz, Gabrail Nashat Y, Ganguly Siddhartha, Ailawadhi Sikander, Kasar Siddha, Kater Arnon P, Doorduijn Jeanette K, Gao Lei, Lager Joanne J, Wu Bin, Egile Coumaran, Kersten Marie José
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Department of Medicine, West Virginia University, Morgantown, WV, USA; Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
Lancet Haematol. 2018 Apr;5(4):e170-e180. doi: 10.1016/S2352-3026(18)30030-9. Epub 2018 Mar 14.
Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma.
We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia. Patients aged 18 years or older with Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower and relapsed or refractory mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma were enrolled and treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity. The primary endpoint was the proportion of patients in each disease-specific cohort who achieved an overall response, defined as a complete response or partial response. All patients who received more than 4 weeks of treatment and who completed a baseline and at least one post-baseline tumour assessment were analysed for efficacy and all patients were analysed for safety. This study is registered with ClinicalTrials.gov, number NCT01403636, and has been completed.
Between Oct 19, 2011, and July 24, 2013, 167 patients were enrolled (42 with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The median number of previous anticancer regimens was three (IQR 2-4) for patients with lymphoma and four (2-5) for patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Of 164 patients evaluable for efficacy, 30 (18·3%) achieved an overall response (partial, n=22; complete, n=8); 19 (41·3%) of 46 with follicular lymphoma, five (11·9%) of 42 with mantle cell lymphoma, two (4·9%) of 41 with diffuse large B-cell lymphoma, and four (11·4%) of 35 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The safety profile was consistent with that of previous studies of voxtalisib. The most frequently reported adverse events were diarrhoea (in 59 [35%] of 167 patients), fatigue (in 53 [32%]), nausea (in 45 [27%]), pyrexia (in 44 [26%,]), cough (in 40 [24%]), and decreased appetite (in 35 [21%]). The most frequently reported grade 3 or worse adverse events were anaemia (in 20 [12%] of 167 patients), pneumonia (in 14 [8%]), and thrombocytopenia (in 13 [8%]). Serious adverse events occurred in 97 (58·1%) of 167 patients.
Voxtalisib 50 mg given orally twice daily had an acceptable safety profile, with promising efficacy in patients with follicular lymphoma but limited efficacy in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma.
Sanofi.
复发或难治性淋巴瘤或慢性淋巴细胞白血病患者预后较差。针对PI3K多种异构体以及mTOR的疗法可能会增强抗肿瘤活性。我们旨在研究泛PI3K/mTOR抑制剂沃克替尼（也称为XL765或SAR245409）用于复发或难治性淋巴瘤或慢性淋巴细胞白血病/小淋巴细胞淋巴瘤患者的疗效和安全性。
我们在美国、比利时、德国、法国、荷兰和澳大利亚的30家肿瘤诊所进行了一项非随机、开放标签的2期试验。纳入年龄在18岁及以上、东部肿瘤协作组（ECOG）体能状态评分为2分或更低、复发或难治性套细胞淋巴瘤、滤泡性淋巴瘤、弥漫性大B细胞淋巴瘤或慢性淋巴细胞白血病/小淋巴细胞淋巴瘤患者，接受沃克替尼50 mg口服，每日两次，每28天为一个连续给药周期，直至病情进展或出现不可接受的毒性反应。主要终点是每个疾病特异性队列中达到总体缓解（定义为完全缓解或部分缓解）的患者比例。对所有接受治疗超过4周且完成基线和至少一次基线后肿瘤评估的患者进行疗效分析，对所有患者进行安全性分析。本研究已在ClinicalTrials.gov注册，编号为NCT01403636，现已完成。
2011年10月19日至2013年7月24日期间，共纳入167例患者（42例套细胞淋巴瘤、47例滤泡性淋巴瘤、42例弥漫性大B细胞淋巴瘤、36例慢性淋巴细胞白血病/小淋巴细胞淋巴瘤）。淋巴瘤患者既往抗癌方案的中位数为3种（四分位间距2 - 4），慢性淋巴细胞白血病/小淋巴细胞淋巴瘤患者为4种（2 - 5）。在164例可评估疗效的患者中，30例（18.3%）达到总体缓解（部分缓解22例，完全缓解8例）；滤泡性淋巴瘤46例中有19例（41.3%）、套细胞淋巴瘤42例中有5例（11.9%）、弥漫性大B细胞淋巴瘤41例中有2例（4.9%）、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤35例中有4例（11.4%）。安全性与既往沃克替尼研究一致。最常报告的不良事件为腹泻（167例患者中有59例[35%]）、疲劳（53例[32%]）、恶心（45例[27%]）、发热（44例[26%]）、咳嗽（40例[24%]）和食欲减退（35例[21%]）。最常报告的3级或更严重不良事件为贫血（167例患者中有20例[12%]）、肺炎（14例[8%]）和血小板减少（13例[8%]）。167例患者中有97例（58.1%）发生严重不良事件。
每日两次口服50 mg沃克替尼具有可接受的安全性，对滤泡性淋巴瘤患者有一定疗效，但对套细胞淋巴瘤、弥漫性大B细胞淋巴瘤或慢性淋巴细胞白血病/小淋巴细胞淋巴瘤患者疗效有限。
赛诺菲。
