Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS)
Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS)
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DOI：
10.1016/s2352-3026(19)30026-2
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发表时间：
2019-05-01
影响因子：
24.7
通讯作者：
Sharman, Jeff
中科院分区：
文献类型：
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作者：
Morschhauser, Franck;Flinn, Ian W.;Sharman, Jeff
抗体-药物偶联物（adc） polatuzumab vedotin （pola）和pinatuzumab vedotin （pina）在1期试验中显示出临床活性和耐受性。这项多中心、开放标签、2期研究的目的是比较利妥昔单抗加pola （R-pola）或pina （R-pina）治疗复发或难治性弥漫性大b细胞淋巴瘤和滤泡性淋巴瘤患者。在6个国家的39个研究地点进行的这项2期随机研究中，患者被随机分配（1:1），通过使用动态分层随机化方案，每21天接受R-pola或R-pina (375 mg/m(2)利妥昔单抗加2.4 mg/kg adc)，直到疾病进展或长达1年的不可接受毒性。在患者入组和随机分配后，治疗分配不向研究者、患者或发起人隐瞒。主要目标是安全性和耐受性，以及抗肿瘤反应。该研究已在ClinicalTrials注册。gov，编号NCT01691898，并已关闭。在2012年9月27日至2013年10月10日期间，81例弥漫性大b细胞淋巴瘤患者和42例滤泡性淋巴瘤患者被招募，并被分配到治疗中。81例弥漫性大b细胞淋巴瘤和41例滤泡性淋巴瘤符合分析条件。在42例接受R-pina治疗的弥漫性大b细胞淋巴瘤患者中，25例（60%,95% CI 43-74）获得客观缓解，11例（26%,95% CI 14-42）获得完全缓解。在接受R-pola治疗的39例患者中，21例（54%,95% CI 37-70）获得了客观缓解，8例（21%,95% CI 9-36）获得了完全缓解。在接受R-pina治疗的21例滤泡性淋巴瘤患者中，13例（62%,95% CI 38-82）获得了客观缓解，1例（5%,95% CI 0.1-24）获得了完全缓解。在该队列中接受R-pola治疗的20例患者中，14例（70%,95% CI 46-88）获得客观缓解，9例（45%,95% CI 23-68）获得完全缓解。在弥漫性大b细胞淋巴瘤队列中，42例接受R-pina的患者中有33例（79%）发生了3-5级不良事件（最常见的是中性粒细胞减少症[29%]和高血糖症[10%]；9例（21%）发生了5级不良事件，其中5例与感染有关）；39例接受R-pola的患者中有30例（77%）发生了5级不良事件（最常见的是中性粒细胞减少症[23%]、贫血[8%]和腹泻[8%]；无5级不良事件）。在滤泡性淋巴瘤队列中，21例接受R-pina的患者中有13例（62%）发生了3-5级不良事件（最常见的是中性粒细胞减少症[29%]和高血糖症[14%]；无5级不良事件），20例接受R-pola的患者中有10例（50%）发生了5级不良事件（最常见的是中性粒细胞减少症[15%]和腹泻[10%]；1例5级不良事件）。R-pina和R-pola是复发或难治性弥漫性大b细胞淋巴瘤和滤泡性淋巴瘤患者的潜在治疗选择。Pola被研究资助者选择用于非霍奇金淋巴瘤的进一步发展，部分原因是反应持续时间比pina更长，并且总体获益风险有利于R-pola。
Background Antibody-drug conjugates (ADCs) polatuzumab vedotin (pola) and pinatuzumab vedotin (pina) showed clinical activity and tolerability in phase 1 trials. The aim of this multicentre, open-label, phase 2 study was to compare rituximab plus pola (R-pola) or pina (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma.Methods In this phase 2 randomised study at 39 investigational sites in six countries, patients were randomly assigned (1: 1), by use of a dynamic hierarchical randomisation scheme, to receive R-pola or R-pina (375 mg/m(2) rituximab plus 2.4 mg/kg ADCs) every 21 days until disease progression or unacceptable toxicity up to 1 year. Treatment allocations were not masked to the investigator, patients or sponsor after the patients were enrolled and randomly assigned. The primary objectives were safety and tolerability, and antitumour response. The study is registered with ClinicalTrials. gov, number NCT01691898, and is closed to accrual.Findings 81 patients with diffuse large B-cell lymphoma and 42 with follicular lymphoma were recruited between Sept 27, 2012, and Oct 10, 2013, and were assigned to treatment. 81 patients with diffuse large B-cell lymphoma and 41 patients with follicular lymphoma were eligible for analysis. Of the 42 patients with diffuse large B-cell lymphoma who received R-pina, 25 (60%, 95% CI 43-74) achieved an objective response and 11 (26%, 95% CI 14-42) achieved a complete response. Of the 39 patients in this cohort who received R-pola, 21 (54%, 95% CI 37-70) achieved an objective response, and eight (21%, 95% CI 9-36) achieved a complete response. Of the 21 patients in the follicular lymphoma cohort who received R-pina, 13 (62%, 95% CI 38-82) achieved an objective response, and one (5%, 95% CI 0.1-24) achieved a complete response. Of the 20 patients in this cohort who received R-pola, 14 (70%, 95% CI 46-88) achieved an objective response, and nine (45%, 95% CI 23-68) achieved a complete response. In the diffuse large B-cell lymphoma cohort, grade 3-5 adverse events occurred in 33 (79%) of 42 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [10%]; nine [21%] grade 5 adverse events, five of which were infectionrelated), and in 30 (77%) of 39 patients receiving R-pola (most common were neutropenia [23%], anaemia [8%] and diarrhoea [8%]; no grade 5 adverse events). In the follicular lymphoma cohort, grade 3-5 adverse events occurred in 13 (62%) of 21 patients receiving R-pina (most common were neutropenia [29%] and hyperglycaemia [14%]; no grade 5 adverse events) and in ten (50%) of 20 patients receiving R-pola (most common were neutropenia [15%] and diarrhoea [10%]; one grade 5 adverse event).Interpretation R-pina and R-pola are potential treatment options in patients with relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma. Pola was selected by the study funder for further development in nonHodgkin lymphoma, partly because of longer durations of response than pina, and an overall benefit-risk favouring R-pola.