Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA.
Department of Medical Oncology, BC Cancer Centre for Lymphoid Cancer, Vancouver, BC, Canada; Department of Medicine, The University of British Columbia, Vancouver, BC, Canada.
Lancet Oncol. 2022 Aug;23(8):1055-1065. doi: 10.1016/S1470-2045(22)00335-7. Epub 2022 Jul 5.
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.
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.
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.
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.
F Hoffmann-La Roche and Genentech.
Mosunetuzumab 是一种靶向 CD20×CD3 T 细胞的双特异性单克隆抗体，可将 T 细胞重定向以消除恶性 B 细胞。在一项 1 期研究中，mosunetuzumab 在复发或难治性 B 细胞淋巴瘤患者中具有良好的耐受性和活性，这些患者接受了两种或多种先前的治疗。
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 个中心进行了一项单臂、多中心、2 期研究。所有患者年龄均在 18 岁及以上，组织学确诊为滤泡性淋巴瘤（1-3a 级），东部合作肿瘤学组体能状态为 0-1。患者患有复发或难治性疾病，先前接受过两种或两种以上的治疗，包括抗 CD20 治疗和烷化剂。静脉内给予 mosunetuzumab 21 天周期，第 1 周期剂量递增：第 1 天 1 毫克，第 8 天 2 毫克，第 15 天和第 1 天 60 毫克，第 3 天及以后 30 毫克。根据国际协调计划标准由研究者评估为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则继续治疗最多 17 个周期。主要终点是所有入组患者的独立审查委员会评估的完全缓解率（最佳缓解）；主要疗效分析比较了观察到的 IRC 评估的完全缓解率与接受泛 class I PI3K 抑制剂 copanlisib 的类似患者人群中 14%的历史对照完全缓解率。所有入组患者均进行了安全性评估。这项研究在 ClinicalTrials.gov 注册，编号为 NCT02500407，正在进行中。
2019 年 5 月 2 日至 2020 年 9 月 25 日期间，我们共招募了 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（60.0%[95%CI 49.1-70.2]）记录了完全缓解。观察到的完全缓解率明显高于 copanlisib 的历史对照完全缓解率 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 例患者中有 40 例[44%]），主要为 1 级（23 例[26%]）和 2 级（15 例[17%]），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减少（90 例患者中有 24 例[27%]）、低磷血症（15 例[17%]）、高血糖症（7 例[8%]）和贫血（7 例[8%]）。42 例（47%）患者发生严重不良事件。无治疗相关的 5 级（即致命）不良事件发生。
固定剂量的 mosunetuzumab 具有良好的安全性，并诱导高完全缓解率，允许作为门诊方案在复发或难治性滤泡性淋巴瘤和两种或两种以上先前治疗的患者中使用。
罗氏控股公司和基因泰克。
