Tafasitamab plus lenalidomide and R-CHOP versus R-CHOP for first-line treatment of patients with high-risk diffuse large B-cell lymphoma (frontMIND): a global, phase 3, randomised, double-blind, placebo-controlled trial.

We aimed to investigate the addition of tafasitamab (an Fc-enhanced anti-CD19 monoclonal antibody) and lenalidomide to R-CHOP (tafa-len-R-CHOP) in patients with high-risk aggressive B-cell lymphomas.

我们旨在研究将tafasitamab（一种Fc增强型抗CD19单克隆抗体）和雷那度胺添加到R-CHOP（tafa-len-R-CHOP）中，用于治疗高风险侵袭性B细胞淋巴瘤患者。

Methods

frontMIND is a phase 3, randomised, double-blind, placebo-controlledstudy conducted at 298 centres in North America, South America, Europe, and the Asia-Pacific region.

frontMIND 是一项在北美、南美、欧洲和亚太地区298个中心进行的3期、随机、双盲、安慰剂对照研究。

Patients aged 18-80 years with previously untreated, high-intermediate-risk or high-risk DLBCL or high-grade B-cell lymphoma (HGBL) were randomly allocated (1:1), stratified by International Prognostic Index (IPI) or age-adjusted IPI and geographical region, to receive six 21-day cycles of standard R-CHOP (rituximab 375 mg/m2 intravenous on day 1, cyclophosphamide 750 mg/m2 intravenous on day 1, doxorubicin 50 mg/m2 intravenous on day 1, vincristine 1·4 mg/m2 [maximum 2 mg] intravenous on day 1, and prednisone or prednisolone 100 mg/day orally on days 1-5); patients in the tafa-len-R-CHOP group additionally received tafasitamab (12 mg/kg intravenous on days 1, 8, and 15) plus lenalidomide (25 mg/day orally on days 1-10), while those in the R-CHOP group received matching placebos.

年龄在18-80岁之间，之前未接受过治疗，具有高-中等风险或高风险的弥漫性大B细胞淋巴瘤（DLBCL）或高级别B细胞淋巴瘤（HGBL）的患者被随机分配（1:1），根据国际预后指数（IPI）或年龄调整的IPI以及地理区域进行分层，接受六个21天周期的标准R-CHOP治疗（第1天静脉注射利妥昔单抗375 mg/m2，环磷酰胺750 mg/m2，多柔比星50 mg/m2，长春新碱1·4 mg/m2 [最大剂量2 mg]，以及第1-5天口服泼尼松或泼尼松龙100 mg/天）；tafa-len-R-CHOP组的患者另外接受tafasitamab（第1、8、15天静脉注射12 mg/kg）加雷尼替尼（第1-10天口服25 mg/天），而R-CHOP组的患者则接受相应的安慰剂。

The primary endpoint was investigator-assessed progression-free survival(defined as time from randomisation to disease progression or death from any cause), analysed in the intention-to-treatpopulation; safety was included as a secondary endpoint among all patients who received at least one dose of study treatment.

主要终点是研究者评估的无进展生存期（定义为从随机分组到疾病进展或任何原因导致的死亡的时间），在意向治疗人群中进行分析；安全性作为次要终点，包括所有至少接受一次研究治疗的患者。

The trial is registered with ClinicalTrials.gov (NCT04824092) and EUDRA-CT (2020-002990-84) and is active but no longer enrolling.

该试验已在ClinicalTrials.gov（NCT04824092）和EUDRA-CT（2020-002990-84）注册，并且目前仍在进行中，但已不再招募新患者。

Results

Between May 11, 2021, and March 2, 2023, 1229 patients were screened, among whom 899 were randomly allocated: 448 (50%) to the tafa-len-R-CHOP group and 451 (50%) to the R-CHOP group.

在2021年5月11日至2023年3月2日期间，共筛查了1229名患者，其中899名被随机分配：448名（50%）进入tafa-len-R-CHOP组，451名（50%）进入R-CHOP组。

At the time of primary analysis (median follow-up 35·2 months [95% CI 35·0-35·4]), progression-free survivalwas improved in the tafa-len-R-CHOP group versus the R-CHOP group (hazard ratio[HR] 0·75 [95% CI 0·59-0·96]; p=0·0194), with 2-year progression-free survivalrates of 71·1% (66·3-75·4) with tafa-len-R-CHOP versus 62·9% (57·9-67·5) with R-CHOP.

在主要分析时点（中位随访时间35.2个月[95%置信区间35.0-35.4]），tafa-len-R-CHOP组的无进展生存期优于R-CHOP组（风险比[HR] 0.75 [95%置信区间0.59-0.96]；p=0.0194），tafa-len-R-CHOP组的2年无进展生存率为71.1%（66.3-75.4），而R-CHOP组为62.9%（57.9-67.5）。

Interim HR for overall survivalwas 0·85 (0·63-1·14).

中期总生存的危险比为0.85（95%置信区间0.63-1.14）。

The overall rate of grade 3 or higher treatment-emergent adverse events was higher with tafa-len-R-CHOP (384 [87%] of 443) than with R-CHOP (340 [76%] of 447).

与R-CHOP相比，tafa-len-R-CHOP治疗相关的3级或更高级别的不良事件总体发生率更高（tafa-len-R-CHOP组443例中有384例[87%]，而R-CHOP组447例中有340例[76%]）。

Additionally, a higher rate of fatal treatment-emergent adverse events was observed with tafa-len-R-CHOP (26 [6%]) than with R-CHOP (17 [4%]).

此外，与R-CHOP相比，观察到tafa-len-R-CHOP治疗相关的致命不良事件发生率更高（26例[6%]比17例[4%]）。

However, the number of overall deaths in the study was lower with tafa-len-R-CHOP than with R-CHOP (82 [19%] vs 97 [22%]).

然而，研究中tafa-len-R-CHOP组的总死亡人数低于R-CHOP组（82例[19%]对比97例[22%]）。

Based on disposition data, rates of premature discontinuation of all study drugs were similar in the tafa-len-R-CHOP group (71 [16%] of 443) and R-CHOP group (66 [15%] of 447).

根据处置数据，tafa-len-R-CHOP组（443人中有71人[16%]）和R-CHOP组（447人中有66人[15%]）所有研究药物的提前停药率相似。

interpretation

Progression-free survivalwas significantly improved with tafa-len-R-CHOP versus R-CHOP; however, the safety profile indicated increases in adverse events, including treatment-emergent adverse events leading to death, with the addition of tafasitamab and lenalidomide.

与R-CHOP相比，tafa-len-R-CHOP显著改善了无进展生存期；然而，安全性概况表明，包括导致死亡的治疗后不良事件在内的不良事件有所增加，这是由于添加了tafasitamab和来那度胺。

Overall survivaldata are immature; follow-up is ongoing.

总生存数据尚不成熟；随访正在进行中。

Further analyses, including of circulating tumor DNA, will help to assess whether deeper molecular responses are contributing to the progression-free survivalbenefit observed with tafa-len-R-CHOP.

进一步的分析，包括循环肿瘤DNA的分析，将有助于评估更深层次的分子反应是否有助于观察到的tafa-len-R-CHOP治疗无进展生存期的益处。

Tafa-len-R-CHOP might represent a potential new first-line treatment for patients with high-risk DLBCL or HGBL.

Tafa-len-R-CHOP 可能代表了一种针对高危弥漫大 B 细胞淋巴瘤（DLBCL）或高危血浆细胞样淋巴瘤（HGBL）患者的潜在新一线治疗方法。

funding

Incyte Corporation.

Incyte 公司。