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Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study
The Lancet Oncology ( IF 51.1 ) Pub Date : 2022-07-05 , DOI: 10.1016/s1470-2045(22)00335-7
Lihua E Budde 1 , Laurie H Sehn 2 , Matthew Matasar 3 , Stephen J Schuster 4 , Sarit Assouline 5 , Pratyush Giri 6 , John Kuruvilla 7 , Miguel Canales 8 , Sascha Dietrich 9 , Keith Fay 10 , Matthew Ku 11 , Loretta Nastoupil 12 , Chan Yoon Cheah 13 , Michael C Wei 14 , Shen Yin 14 , Chi-Chung Li 14 , Huang Huang 15 , Antonia Kwan 14 , Elicia Penuel 14 , Nancy L Bartlett 16
Affiliation  

Background

Mosunetuzumab is a CD20 × CD3 T-cell-engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. In a phase 1 study, mosunetuzumab was well tolerated and active in patients with relapsed or refractory B-cell lymphoma. We, therefore, aimed to evaluate the safety and anti-tumour activity of fixed-duration mosunetuzumab in patients with relapsed or refractory follicular lymphoma who had received two or more previous therapies.

Methods

We conducted a single-arm, multicentre, phase 2 study at 49 centres in seven countries (Australia, Canada, Germany, South Korea, Spain, UK, and USA). All patients were aged 18 years or older with histologically confirmed follicular lymphoma (grade 1–3a) and an Eastern Cooperative Oncology Group performance status of 0–1. Patients had disease that was relapsed or refractory to two or more previous lines of treatment, including an anti-CD20 therapy and an alkylating agent. Intravenous mosunetuzumab was administered in 21-day cycles with cycle 1 step-up dosing: 1 mg on cycle 1 day 1, 2 mg on cycle 1 day 8, 60 mg on cycle 1 day 15 and cycle 2 day 1, and 30 mg on day 1 of cycle 3 and onwards. Patients with a complete response by investigator assessment using the International Harmonisation Project criteria completed treatment after cycle 8, whereas patients with a partial response or stable disease continued treatment for up to 17 cycles. The primary endpoint was independent review committee-assessed complete response rate (as best response) in all enrolled patients; the primary efficacy analysis compared the observed IRC-assessed complete response rate with a 14% historical control complete response rate in a similar patient population receiving the pan class I PI3K inhibitor copanlisib. Safety was assessed in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02500407, and is ongoing.

Findings

Between May 2, 2019, and Sept 25, 2020, we enrolled 90 patients. As of the data cutoff date (Aug 27, 2021), the median follow-up was 18·3 months (IQR 13·8–23·3). According to independent review committee assessment, a complete response was recorded in 54 patients (60·0% [95% CI 49·1–70·2]). The observed complete response rate was significantly higher than the historical control complete response rate with copanlisib of 14% (p<0·0001), thereby meeting the primary study endpoint. Cytokine release syndrome was the most common adverse event (40 [44%] of 90 patients) and was predominantly grade 1 (23 [26%] of 90) and grade 2 (15 [17%]), and primarily confined to cycle 1. The most common grade 3–4 adverse events were neutropenia or neutrophil count decreased (24 [27%] of 90 patients), hypophosphataemia (15 [17%]), hyperglycaemia (seven [8%]), and anaemia (seven [8%]). Serious adverse events occurred in 42 (47%) of 90 patients. No treatment-related grade 5 (ie, fatal) adverse event occurred.

Interpretation

Fixed-duration mosunetuzumab has a favourable safety profile and induces high rates of complete remissions, allowing potential administration as an outpatient regimen, in patients with relapsed or refractory follicular lymphoma and two or more previous therapies.

Funding

F Hoffmann-La Roche and Genentech.



中文翻译:

mosunetuzumab(一种双特异性抗体)在复发或难治性滤泡性淋巴瘤患者中的安全性和有效性:一项单臂、多中心、2 期研究

背景

Mosunetuzumab 是一种 CD20 × CD3 T 细胞结合双特异性单克隆抗体,可重定向 T 细胞以消除恶性 B 细胞。在一项 1 期研究中,mosunetuzumab 在复发性或难治性 B 细胞淋巴瘤患者中具有良好的耐受性和活性。因此,我们旨在评估固定持续时间 mosunetuzumab 在接受过两种或两种以上治疗的复发性或难治性滤泡性淋巴瘤患者中的安全性和抗肿瘤活性。

方法

我们在七个国家(澳大利亚、加拿大、德国、韩国、西班牙、英国和美国)的 49 个中心进行了单臂、多中心、2 期研究。所有患者年龄在 18 岁或以上,组织学证实为滤泡性淋巴瘤(1-3a 级),东部肿瘤协作组体能状态为 0-1。患者患有复发或对两种或多种先前治疗线(包括抗 CD20 疗法和烷化剂)无效的疾病。静脉注射 mosunetuzumab 以 21 天为周期给药,第 1 周期递增给药:第 1 周期第 1 天 1 mg,第 1 周期第 8 天 2 mg,第 1 周期第 15 天和第 2 周期第 1 天 60 mg,30 mg第 3 周期的第 1 天及以后。研究者使用国际协调项目标准评估完全缓解的患者在第 8 周期后完成治疗,而部分缓解或疾病稳定的患者继续治疗长达 17 个周期。主要终点是独立审查委员会评估的所有入组患者的完全反应率(作为最佳反应);主要疗效分析比较了在接受泛 I 类 PI3K 抑制剂 copanlisib 的类似患者群体中观察到的 IRC 评估的完全缓解率与 14% 的历史对照完全缓解率。在所有入组患者中评估了安全性。该研究已在 ClinicalTrials.gov 注册,编号为 NCT02500407,并且正在进行中。主要疗效分析比较了在接受泛 I 类 PI3K 抑制剂 copanlisib 的类似患者群体中观察到的 IRC 评估的完全缓解率与 14% 的历史对照完全缓解率。在所有入组患者中评估了安全性。该研究已在 ClinicalTrials.gov 注册,编号为 NCT02500407,并且正在进行中。主要疗效分析比较了在接受泛 I 类 PI3K 抑制剂 copanlisib 的类似患者群体中观察到的 IRC 评估的完全缓解率与 14% 的历史对照完全缓解率。在所有入组患者中评估了安全性。该研究已在 ClinicalTrials.gov 注册,编号为 NCT02500407,并且正在进行中。

发现

在 2019 年 5 月 2 日至 2020 年 9 月 25 日期间,我们招募了 90 名患者。截至数据截止日期(2021 年 8 月 27 日),中位随访时间为 18·3 个月(IQR 13·8-23·3)。根据独立审查委员会的评估,54 名患者获得完全缓解(60·0% [95% CI 49·1–70·2])。观察到的完全缓解率显着高于 copanlisib 的历史对照完全缓解率为 14% (p<0·0001),从而达到了主要研究终点。细胞因子释放综合征是最常见的不良事件(90 名患者中的 40 名 [44%]),主要为 1 级(90 名患者中的 23 [26%])和 2 级(15 [17%]),并且主要局限于第 1 周期. 最常见的 3-4 级不良事件是中性粒细胞减少或中性粒细胞计数下降(90 名患者中的 24 名 [27%])、低磷血症(15 名 [17%])、高血糖症(7 名 [8%])、和贫血(7 [8%])。90 名患者中有 42 名(47%)发生了严重的不良事件。未发生与治疗相关的 5 级(即致命)不良事件。

解释

固定持续时间的 mosunetuzumab 具有良好的安全性,并能诱导较高的完全缓解率,可作为门诊治疗方案用于复发或难治性滤泡性淋巴瘤和两种或多种既往治疗的患者。

资金

F Hoffmann-La Roche 和基因泰克。

更新日期:2022-07-05
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