Background

Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma.

Methods

This completed phase 1b/2, open-label, multicentre, single-arm study (GO29834) evaluated the safety and efficacy of Pola+R+Len in patients with relapsed or refractory diffuse large B-cell lymphoma at 19 sites in three countries (USA, Spain, and UK). Patients (≥18 years old) were eligible for inclusion if they had histologically documented CD20-positive relapsed or refractory diffuse large B-cell lymphoma and Eastern Cooperative Oncology Group performance status of 2 or lower, had received at least one previous line of chemoimmunotherapy, including an anti-CD20 agent, and were ineligible for stem-cell transplantation. The dose-escalation phase (1b) used escalating doses of lenalidomide to find the recommended phase 2 dose. Patients received six 28-day cycles of induction treatment with intravenous rituximab 375 mg/m² and intravenous polatuzumab vedotin 1·8 mg/kg (all cohorts) plus oral lenalidomide at the following doses: 10 mg (cohort A); 15 mg (cohort B); and 20 mg (cohort C). Rituximab and polatuzumab vedotin were administered on day 1 and lenalidomide on days 1–21 of each 28-day cycle. During the dose-expansion phase (2), patients received six 28-day cycles of Pola+R+Len at the recommended phase 2 dose established during dose escalation. In both phases, patients with a complete response or partial response at the end of induction were eligible for post-induction therapy with rituximab 375 mg/m² on day 1 and lenalidomide 10 mg/day on days 1–21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02600897.

Findings

Between July 11, 2017 and Feb 3, 2020, 57 patients were enrolled (median age 71 years [IQR 60–75]; 38 [67%] were male and 19 (33%) were female; 47 [82%] were not Hispanic or Latino; and the median previous lines of therapy was 2 [IQR 1–3]). 18 participants were included in phase 1b and 39 were included in phase 2. Phase 1b confirmed a 20 mg recommended phase 2 dose for lenalidomide. After a median follow-up of 11·8 months (IQR 4·7–25·8), the complete response rate, as assessed by the Independent Review Committee, was 31% (90% CI 20–43). The most common grade 3–4 adverse events were neutropenia (35 [61%] of 57) and thrombocytopenia (eight [14%] of 57). Serious adverse events were reported in 23 (40%) of 57 patients and one patient died due to a treatment-related adverse event (neutropenic sepsis).

Interpretation

Although the combination of Pola+R+Len did not meet the prespecified activity threshold, some patients derived clinical benefit and the regimen had a tolerable safety profile in patients with relapsed or refractory diffuse large B-cell lymphoma.

Funding

Genentech/F Hoffmann-La Roche.

中文翻译：

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Polatuzumab vedotin 联合利妥昔单抗和来那度胺治疗复发或难治性弥漫性大 B 细胞淋巴瘤患者：多中心、单臂、1b/2 期研究队列

背景

弥漫性大B细胞淋巴瘤占非霍奇金淋巴瘤病例的近30%，不适合干细胞移植的复发性或难治性弥漫性大B细胞淋巴瘤患者的治疗选择很少且预后较差。我们的目的是确定polatuzumab vedotin联合利妥昔单抗和来那度胺 (Pola+R+Len) 的新型组合是否能为复发或难治性弥漫性大 B 细胞淋巴瘤患者提供可耐受的治疗选择，并增强抗肿瘤反应。

方法

这项已完成的 1b/2 期、开放标签、多中心、单臂研究 (GO29834) 评估了 Pola+R+Len 在三个国家 19 个地点治疗复发或难治性弥漫性大 B 细胞淋巴瘤患者的安全性和有效性（美国、西班牙和英国）。如果患者（≥ 18 岁）有组织学记录的 CD20 阳性复发或难治性弥漫性大 B 细胞淋巴瘤且东部肿瘤合作组表现状态为 2 或更低，之前至少接受过一种化学免疫治疗，则有资格入选，包括抗 CD20 药物，并且不适合干细胞移植。剂量递增阶段 (1b) 使用递增的来那度胺剂量来确定推荐的 2 期剂量。患者接受六个为期 28 天的诱导治疗周期，静脉注射利妥昔单抗 375 mg/m ²和静脉注射 polatuzumab vedotin 1·8 mg/kg（所有队列）加口服来那度胺，剂量如下： 10 mg（队列 A）；15毫克（B组）；和 20 毫克（C 组）。每个 28 天周期的第 1 天给予利妥昔单抗和 polatuzumab vedotin，第 1-21 天给予来那度胺。在剂量扩展阶段 (2)，患者按照剂量递增过程中确定的推荐 2 期剂量接受 6 个为期 28 天的 Pola+R+Len 周期。在这两个阶段中，诱导结束时完全缓解或部分缓解的患者有资格接受诱导后治疗，在第 1 天使用利妥昔单抗 375 mg/m ² ，在每 28 天的第 1-21 天使用来那度胺 10 mg/天循环最多 6 个循环。剂量递增阶段的主要安全目标是通过剂量限制性毒性反应的发生率来确定最大耐受剂量。剂量扩展阶段的主要疗效结果是独立审查委员会根据 PET-CT 评估的诱导结束时的完全缓解率。分析在安全人群中进行，其中包括接受至少一剂任何研究药物的所有患者，以及功效人群，其中包括以推荐的 2 期剂量接受至少一剂任何研究药物的所有患者。本研究已在ClinicalTrials.gov注册，编号为NCT02600897。

发现

2017年7月11日至2020年2月3日期间，入组了57名患者（中位年龄71岁[IQR 60-75]；38名[67%]为男性，19名（33%）为女性；47名[82%]为非女性西班牙裔或拉丁裔；之前接受过的治疗中位数为 2 [IQR 1-3]）。1b 期纳入了 18 名参与者，2 期纳入了 39 名参与者。1b 期确认了来那度胺的 20 mg 推荐 2 期剂量。中位随访 11·8 个月 (IQR 4·7–25·8) 后，独立审查委员会评估的完全缓解率为 31% (90% CI 20–43)。最常见的 3-4 级不良事件是中性粒细胞减少症（57 例中的 35 例 [61%]）和血小板减少症（57 例中的 8 例 [14%]）。57 名患者中有 23 名（40%）报告了严重不良事件，其中 1 名患者因治疗相关不良事件（中性粒细胞减少性败血症）死亡。

解释

尽管 Pola+R+Len 组合未达到预先设定的活性阈值，但一些患者获得了临床获益，并且该方案在复发或难治性弥漫性大 B 细胞淋巴瘤患者中具有可耐受的安全性。

资金

基因泰克/F霍夫曼-拉罗氏。