Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Centro de Hematologia e Oncologia, Hospital Mãe de Deus, Porto Alegre, Brazil.
Lancet Oncol. 2021 May;22(5):678-689. doi: 10.1016/S1470-2045(21)00145-5. Epub 2021 Apr 10.
Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma.
CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing.
Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group.
Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma.
Bayer.
静脉注射泛 PI3K 抑制剂考潘立司他作为单药治疗，在接受至少两种治疗的复发或难治性惰性非霍奇金淋巴瘤患者中显示出疗效和安全性。CHRONOS-3 研究旨在评估考潘立司他联合利妥昔单抗在复发的惰性非霍奇金淋巴瘤患者中的疗效和安全性。
CHRONOS-3 是一项多中心、双盲、随机、安慰剂对照、3 期研究，在亚洲、澳大利亚、欧洲、新西兰、北美、俄罗斯、南非和南美洲的 186 个学术医疗中心进行。患者年龄在 18 岁及以上，东部合作肿瘤学组（ECOG）体能状态为 2 分以下，组织学证实为 CD20 阳性惰性 B 细胞淋巴瘤，在最后一次抗 CD20 单克隆抗体治疗后复发，无进展生存期（PFS）和治疗结束后至少 12 个月（对于至少 6 个月内不愿意或不适合接受化疗的患者），随机（2:1）通过交互语音网络应答系统按块随机分配（块大小为 6）至考潘立司他（60mg，作为 1 小时静脉输注，在第 1、8 和 15 天进行间歇治疗[28 天周期]）联合利妥昔单抗（375mg/m2，在第 1、8、15 和 22 天在第 1 周期中静脉注射，在第 3、5、7 和 9 周期中在第 1 天）或安慰剂联合利妥昔单抗，根据组织学、PFS 和治疗结束后无进展间隔、是否存在大肿块疾病和先前接受 PI3K 抑制剂治疗进行分层。主要终点是全分析集（所有随机患者）的无进展生存期，由盲法中心审查。所有接受至少一剂任何研究药物的患者均进行安全性评估。这项研究在 ClinicalTrials.gov 注册，NCT02367040 号，正在进行中。
2015 年 8 月 3 日至 2019 年 12 月 17 日，共筛选了 652 名符合条件的患者。458 名患者中有 307 名被随机分配至考潘立司他联合利妥昔单抗组，151 名患者被随机分配至安慰剂联合利妥昔单抗组。中位随访时间为 19.2 个月（IQR：7.4-28.8），共有 205 例总事件，考潘立司他联合利妥昔单抗与安慰剂联合利妥昔单抗相比，在无进展生存期（PFS）方面有统计学意义和临床意义的改善；中位 PFS 为 21.5 个月（95%CI：17.8-33.0），13.8 个月（10.2-17.5；风险比：0.52[95%CI：0.39-0.69]；p<0.0001）。最常见的 3-4 级不良事件是高血糖症（考潘立司他联合利妥昔单抗组 307 例患者中有 173 例[56%]，安慰剂联合利妥昔单抗组 146 例患者中有 12 例[8%]）和高血压（考潘立司他联合利妥昔单抗组 307 例患者中有 122 例[40%]，安慰剂联合利妥昔单抗组 146 例患者中有 13 例[9%]）。接受考潘立司他联合利妥昔单抗治疗的 307 例患者中有 145 例（47%）和接受安慰剂联合利妥昔单抗治疗的 146 例患者中有 27 例（18%）发生严重治疗期不良事件。考潘立司他联合利妥昔单抗组有 1 例（<1%）药物相关死亡（肺炎），安慰剂联合利妥昔单抗组无死亡病例。
考潘立司他联合利妥昔单抗在复发的惰性非霍奇金淋巴瘤患者中，与安慰剂联合利妥昔单抗相比，提高了无进展生存期。据我们所知，考潘立司他是第一种安全联合利妥昔单抗的 PI3K 抑制剂，也是第一种在复发的惰性非霍奇金淋巴瘤患者中与利妥昔单抗联合显示出广泛和优越疗效的药物。
拜耳。
