Johnston Patrick B, LaPlant Betsy, McPhail Ellen, Habermann Thomas M, Inwards David J, Micallef Ivana N, Colgan Joseph P, Nowakowski Grzegorz S, Ansell Stephen M, Witzig Thomas E
Mayo Clinic College of Medicine and Mayo Foundation, Rochester, MN, USA.
Mayo Clinic Division of Hematology, Rochester, MN, USA.
Lancet Haematol. 2016 Jul;3(7):e309-16. doi: 10.1016/S2352-3026(16)30040-0. Epub 2016 Jun 5.
The PI3K-mTORC pathway is upregulated in diffuse large B-cell lymphoma (DLBCL) and can be targeted with the mTOR complex 1 (mTORC1) inhibitor everolimus. Everolimus has activity in relapsed DLBCL. These data provide the rationale to combine everolimus with standard treatment for DLBCL of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone delivered in a 21-day cycle (R-CHOP-21) for six cycles.
We did a phase 1 and feasibility study (NCCTG 1085) of oral everolimus 10 mg/day plus R-CHOP-21 in patients aged at least 18 years with new, untreated, CD20-positive DLBCL (stages II-IV) in the NCCTG (Alliance) National Cancer Institute Cooperative Group (USA). Patients received standard R-CHOP-21 (intravenous rituximab 375 mg/m(2), intravenous cyclophosphamide 750 mg/m(2), intravenous doxorubicin 50 mg/m(2), and intravenous vincristine 1·4 mg/m(2) [maximum 2·0 mg] all on day 1 of the 21-day cycle; and oral prednisone 100 mg/m(2) each day on days 1-5 of the cycle) for six cycles with scheduled subcutaneous pegfilgrastim 6 mg on day 2 of each cycle. We tested two schedules: everolimus given in the fasting state either on days 1-10 or days 1-14 of the R-CHOP cycle. The primary endpoint of the phase 1 portion of this study was to establish the maximum tolerated dose of everolimus that could be combined with R-CHOP-21. The primary endpoint of the feasibility portion of the study was to determine the feasibility of the regimen, which was assessed by determining the rate of significant toxicity. Secondary endpoints were the proportion of patients who achieved an overall response, a complete response, event-free survival at 12 months and 24 months from enrolment, progression-free survival, and overall survival; relapse of DLBCL; and duration of response. We deemed patients as assessable for the primary endpoint in the phase 1 portion if they completed the first cycle as planned. In the feasibility portion, all patients who received at least one dose of everolimus were included. This trial is registered with ClinicalTrials.gov, number NCT01334502.
Between March 21, 2012, and Sept 15, 2014, we enrolled 26 patients into the study. Two were ineligible, therefore results are presented for 24 eligible patients. Nine patients were enrolled into the phase 1 portion of the trial (three given everolimus on days 1-10, and six given everolimus on days 1-14) without any dose-limiting toxicities; therefore, everolimus 10 mg/day given on days 1-14 with R-CHOP-21 was tested in 15 additional patients for a total of 24. One (5%, 95% CI 0-24%) of 21 patients had a toxicity during the feasibility phase-a treatment delay of 12 days due to grade 3 hypokalaemia possibly related to everolimus. The median follow-up was 21·5 months (IQR 17-29). 23 (96%, 95% CI 79-100%) of 24 patients achieved an overall response, and all 23 (96%, 79-100%) also attained a complete metabolic response by PET. The remaining patient withdrew consent after in cycle 1 and attained a complete response with R-CHOP alone. All 24 (100%) patients met 12-month event-free survival, and nine had sufficient follow-up data to be event-free at 24 months. None of the 24 patients had died by the last follow-up (March 30, 2016), and none had had a relapse with DLBCL. Because no events occurred during the study or follow-up, we were unable to assess the duration of response or progression-free survival. The most common grade 3-4 adverse events were haematological; the most common of these was grade 4 neutropenia in 18 (75%) of 24 patients. Five (21%) of 24 had grade 3 febrile neutropenia.
The mTORC1 inhibitor everolimus given for 14 days in combination with R-CHOP-21 for patients with DLBCL is safe. These findings suggest that drugs that target the PI3K-mTORC pathway add benefit when combined with standard R-CHOP. The everolimus with R-CHOP regimen should be tested against standard R-CHOP alone in a randomised trial, to support the benefits of this novel combination noted in this study.
National Cancer Institute of the US National Institutes of Health.
磷脂酰肌醇-3激酶-哺乳动物雷帕霉素靶蛋白复合物1（PI3K-mTORC）通路在弥漫性大B细胞淋巴瘤（DLBCL）中上调，可使用mTOR复合物1（mTORC1）抑制剂依维莫司进行靶向治疗。依维莫司对复发的DLBCL具有活性。这些数据为将依维莫司与DLBCL的标准治疗方案利妥昔单抗联合环磷酰胺、阿霉素、长春新碱和泼尼松（每21天为一个周期，即R-CHOP-21方案）联合使用六个周期提供了理论依据。
我们在美国国家癌症研究所合作组织（美国）的NCCTG（联盟）开展了一项1期可行性研究（NCCTG 1085），纳入年龄至少18岁、新诊断的、未经治疗的、CD20阳性DLBCL（II-IV期）患者，给予口服依维莫司10 mg/天加R-CHOP-21方案治疗。患者接受标准的R-CHOP-21方案（静脉注射利妥昔单抗375 mg/m²、静脉注射环磷酰胺750 mg/m²、静脉注射阿霉素50 mg/m²、静脉注射长春新碱1.4 mg/m²[最大剂量2.0 mg]，均在21天周期的第1天给药；口服泼尼松100 mg/m²，在周期的第1-5天每天给药）六个周期，每个周期的第2天皮下注射聚乙二醇化非格司亭6 mg。我们测试了两种给药方案：依维莫司在禁食状态下于R-CHOP周期的第1-10天或第1-14天给药。本研究1期部分的主要终点是确定可与R-CHOP-21联合使用的依维莫司的最大耐受剂量。研究可行性部分的主要终点是确定该方案的可行性，通过确定严重毒性发生率进行评估。次要终点包括达到总体缓解、完全缓解以及入组后12个月和24个月无事件生存、无进展生存和总生存的患者比例；DLBCL复发情况；以及缓解持续时间。如果患者按计划完成第一个周期，我们认为其可用于1期部分主要终点的评估。在可行性部分，纳入所有接受至少一剂依维莫司的患者。本试验已在ClinicalTrials.gov注册，注册号为NCT01334502。
2012年3月21日至2014年9月15日，我们共纳入26例患者进行研究。2例不符合纳入标准，因此对24例符合条件的患者进行了结果分析。9例患者纳入试验的1期部分（3例在第1-10天给予依维莫司，6例在第1-14天给予依维莫司），未出现任何剂量限制性毒性；因此，在另外15例患者中测试了依维莫司10 mg/天在第1-14天与R-CHOP-21联合使用的方案，共计24例患者。21例患者中有1例（5%，95%CI为0-24%）在可行性阶段出现毒性反应，因3级低钾血症导致治疗延迟12天，可能与依维莫司有关。中位随访时间为21.5个月（四分位间距17-29个月）。24例患者中有23例（96%，95%CI为79-100%）达到总体缓解，所有23例（96%，79-100%）通过PET也达到了完全代谢缓解。其余1例患者在第1周期后撤回同意书，仅接受R-CHOP方案治疗并达到完全缓解。所有24例（100%）患者均达到12个月无事件生存，9例有足够的随访数据在24个月时无事件生存。至最后一次随访（2016年3月30日），24例患者均未死亡，也无DLBCL复发。由于研究期间或随访期间未发生任何事件，我们无法评估缓解持续时间或无进展生存情况。最常见的3-4级不良事件为血液学事件；其中最常见的为24例患者中有18例（75%）出现4级中性粒细胞减少。24例患者中有5例（21%）出现3级发热性中性粒细胞减少。
对于DLBCL患者，mTORC1抑制剂依维莫司与R-CHOP-21联合使用14天是安全的。这些发现表明，靶向PI3K-mTORC通路的药物与标准R-CHOP联合使用时可增加疗效。依维莫司与R-CHOP方案应在随机试验中与单独的标准R-CHOP方案进行对比，以证实本研究中所观察到的这种新型联合方案的益处。
美国国立卫生研究院国家癌症研究所。
