Retifanlimab versus placebo in combination with platinum-based chemotherapy in patients with first-line non-squamous or squamous metastatic non-small-cell lung cancer (POD1UM-304): a phase 3, multiregional, placebo-controlled, double-blind, randomised study.

We aimed to evaluate the efficacy of the PD-1 inhibitor retifanlimab plus platinum-based chemotherapy as first-line treatment for non-squamous or squamous metastatic NSCLC.

我们的目标是评估PD-1抑制剂retifanlimab联合基于铂的化疗作为非鳞状或鳞状转移性NSCLC的一线治疗的有效性。

Methods

POD1UM-304 was a phase 3, multiregional, placebo-controlled, double-blind, randomised study conducted in approximately 124 hospitals and private clinical centres in 16 countries.

POD1UM-304 是一项在16个国家的大约124家医院和私人临床中心进行的3期、多区域、安慰剂对照、双盲、随机研究。

Male and female adults aged 18 years or older with squamous or non-squamous stage IV NSCLC (staging by American Joint Committee on Cancer version 8) with Eastern Cooperative Oncology Group performance status 0 or 1 and no previous systemic therapy for metastatic NSCLC were eligible.

年龄在18岁或以上的男性和女性成年患者，患有美国癌症联合委员会第8版分期的IV期鳞状或非鳞状非小细胞肺癌（NSCLC），且东部肿瘤协作组（Eastern Cooperative Oncology Group）的体能状态评分为0或1，未接受过转移性NSCLC的全身治疗，符合入选条件。

Patients were randomly assigned (2:1) using interactive response technology to receive intravenous retifanlimab 375 mg or matching placebo on day 1 of each 21-day cycle plus standard platinum-based chemotherapy according to tumour histology for up to 2 years.

患者通过交互式响应技术随机分配（2:1），在每个21天的周期的第一天接受静脉注射retifanlimab 375 mg或匹配安慰剂，加上根据肿瘤组织学的标准铂类化疗，最多2年。

Patients with non-squamous NSCLC received pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 for four cycles, or carboplatin area under the curve (AUC) 5 on day 1 for four cycles, followed by pemetrexed 500 mg/m2 on day 1 of each subsequent 21-day cycle, all administered intravenously, until disease progression or unacceptable toxicity.

非鳞状NSCLC患者接受pemetrexed 500 mg/m2加顺铂 75 mg/m2在第一天，连续四个周期，或卡铂曲线下面积（AUC）5在第一天，连续四个周期，随后在每个后续的21天周期的第一天接受pemetrexed 500 mg/m2，所有药物均通过静脉注射，直到疾病进展或出现不可接受的毒性。

Patients with squamous NSCLC received intravenous carboplatin AUC 6 plus intravenous paclitaxel 200 mg/m2 on day 1 for four cycles or intravenous nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 for four cycles.

患有鳞状非小细胞肺癌的患者接受了静脉注射卡铂AUC 6加静脉注射紫杉醇200 mg/m2，在第1天进行四个周期，或静脉注射nab-紫杉醇100 mg/m2，在第1、8、15天进行四个周期。

Treatment with retifanlimab or placebo was given for up to 35 cycles, unless there was disease progression, unacceptable toxicity, or withdrawal of consent.

除非疾病进展、出现不可接受的毒性或撤回同意，否则给予retifanlimab或安慰剂治疗最多35个周期。

Randomisation was stratified by PD-L1 expression tumour proportion score, geographical region, and predominant tumour histology.

随机化是根据PD-L1表达肿瘤比例评分、地理区域和主要肿瘤组织学类型进行分层的。

The primary endpoint was overall survival, defined as time from randomisation until death due to any cause, analysed in the full analysis set.

主要终点是总生存，定义为从随机化到因任何原因导致死亡的时间，在完整分析集中进行分析。

Safety was evaluated in all randomly assigned patients who received at least one dose of study drug.

所有随机分配并至少接受一次研究药物的患者均进行了安全性评估。

This trial is registered with ClinicalTrials.gov (NCT04205812) and is active but no longer enrolling.

该试验已在ClinicalTrials.gov注册（NCT04205812），目前仍在进行中，但已停止招募。

Results

Between Sept 11, 2020, and March 14, 2023, 1388 patients were assessed for eligibility, 583 of whom were randomly assigned to retifanlimab plus chemotherapy (n=391) or placebo plus chemotherapy (n=192). 381 (65%) patients had non-squamous NSCLC and 202 (35%) had squamous NSCLC; 467 (80%) patients were male and 116 (20%) were female.

在2020年9月11日至2023年3月14日期间，共有1388名患者被评估是否符合入选标准，其中583名患者被随机分配接受retifanlimab加化疗(n=391)或安慰剂加化疗(n=192)。381名（65%）患者患有非鳞状非小细胞肺癌（NSCLC），202名（35%）患者患有鳞状NSCLC；467名（80%）患者为男性，116名（20%）为女性。

Median age was 64 years (IQR 58-68).

中位年龄为64岁（四分位数间距58-68）。

Median overall survivalwas longer in the retifanlimab plus chemotherapy group than in the placebo plus chemotherapy group (18·1 months [95% CI 16·2-21·0] vs 13·4 months [11·0-16·7]; hazard ratio0·75 [95% CI 0·60-0·93]; p=0·0042).

Retifanlimab 加化疗组的中位总生存期比安慰剂加化疗组更长（18.1个月 [95% 置信区间 16.2-21.0] 对比 13.4个月 [11.0-16.7]；风险比为0.75 [95% 置信区间 0.60-0.93]；p=0.0042）。

Overall, higher incidences of treatment-emergent adverse events that were serious (158 [41%] of 389 vs 57 [30%] of 190), grade 3 or worse (238 [61%] vs 103 [54%]), or led to retifanlimab or placebo dose delay (169 [43%] vs 67 [35%]) or discontinuation (33 [8%] vs nine [5%]) were observed in the retifanlimab plus chemotherapy group than in the placebo plus chemotherapy group.

总体而言，在接受Retifanlimab 加化疗的患者中，观察到的治疗相关不良事件发生率较高，包括严重不良事件（389例中的158例 [41%] 对比 190例中的57例 [30%]）、3级或更高级别的不良事件（238例 [61%] 对比 103例 [54%]），以及导致Retifanlimab 或安慰剂剂量延迟（169例 [43%] 对比 67例 [35%]）或停药（33例 [8%] 对比九例 [5%]）的不良事件。

The proportions of fatal COVID-19-related treatment-emergent adverse events were similar in the retifanlimab plus chemotherapy group and the placebo plus chemotherapy group (four [1%] vs five [3%]).

与安慰剂加化疗组相比，接受retifanlimab加化疗组的COVID-19相关致命治疗后不良事件的比例相似（四例[1%]对比五例[3%]）

interpretation

Retifanlimab improved overall survivalcompared with placebo when added to platinum-based chemotherapy, with a safety profile that is representative of previous PD-1 and PD-L1 inhibitor-chemotherapy combinations.

当retifanlimab与基于铂的化疗联合使用时，与单独使用安慰剂相比，总生存有所改善，其安全性特征代表了之前PD-1和PD-L1抑制剂与化疗联合使用的典型情况。

Adding retifanlimab to first-line chemotherapy could be a potential treatment option for patients with squamous or non-squamous metastatic NSCLC.

将雷替芬利单抗加入一线化疗可能是鳞状或非鳞状转移性非小细胞肺癌患者的潜在治疗选择。

funding

Incyte.

Incyte 公司。