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/m² 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 infection-related), 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 non-Hodgkin lymphoma, partly because of longer durations of response than pina, and an overall benefit–risk favouring R-pola.

Funding

F Hoffmann-La Roche.

中文翻译：

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复发或难治性非霍奇金淋巴瘤患者中的Polatuzumab vedotin或pinatuzumab vedotin加rituximab：2期随机研究（ROMULUS）的最终结果

背景

抗体-药物偶联物（ADC）的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，第2期研究的目的是比较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中的利妥昔单抗加波拉（R-pola）或皮纳（R-pina）。

方法

在6个国家/地区的39个研究地点进行的第2期随机研究中，使用动态分级随机方案将患者随机分配（1：1），以接受R-pola或R-pina（375 mg / m ²利妥昔单抗加每21天2·4 mg / kg ADCs，直至疾病进展或长达1年的不可接受的毒性。在患者入组并随机分配后，治疗分配并未掩盖给研究者，患者或申办者。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.gov上注册，编号为NCT01691898，并且尚未开放。

发现

在2012年9月27日至2013年10月10日之间招募了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，并进行了治疗。81例弥漫性大B细胞淋巴瘤患者和41例滤泡性淋巴瘤患者符合分析条件。在接受R-pina治疗的42例弥漫性大B细胞淋巴瘤患者中，有25例（60％，95％CI 43-74）达到了客观缓解，11例（26％，95％CI 14-42）达到了完全缓解。 。在该队列中接受R-pola治疗的39例患者中，有21例（54％，95％CI 37-70）达到了客观缓解，而8例（21％，95％CI 9-36）达到了完全缓解。在滤泡性淋巴瘤队列中接受R-pina治疗的21例患者中，有13例（62％，95％CI 38-82）达到了客观缓解，其中一例（5％，95％CI 0·1-24）达到了完全缓解。回复。在该队列中接受R-pola治疗的20例患者中，有14例（70％，95％CI 46-88）达到了客观缓解，而9例（45％，95％CI 23-68）达到了完全缓解。在弥漫性大B细胞淋巴瘤队列中，接受R-pina治疗的42例患者中有33例（79％）发生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％] ] 5级不良事件，其中五个与感染有关，在接受R-pola治疗的39例患者中有30例（77％）（最常见的是中性粒细胞减少症[23％]，贫血[8％]和腹泻[8％] ；没有5级不良事件）。在滤泡性淋巴瘤队列中，接受R-pina治疗的21例患者中有13例发生了3-5级不良事件（62％）（最常见的是中性粒细胞减少症[29％]和高血糖症[14％]；

解释

对于患有复发性或难治性弥漫性大B细胞淋巴瘤和滤泡性淋巴瘤的患者，R-pina和R-pola是潜在的治疗选择。研究资助者选择将Pola用于非霍奇金淋巴瘤的进一步发展，部分原因是其响应时间比pina长，并且有利于R-pola的总体获益风险。

资金

霍夫曼·拉罗什（F Hoffmann-La Roche）。