TAR-200 plus cetrelimab versus cetrelimab monotherapy as neoadjuvant therapy in patients with muscle-invasive bladder cancer who are ineligible for or decline neoadjuvant cisplatin-based chemotherapy (SunRISe-4): interim analysis of a randomised, open-label phase 2 trial.

We aimed to evaluate neoadjuvant TAR-200 plus cetrelimab (anti-PD-1) versus cetrelimab monotherapy in this setting.

我们旨在评估在这种情况下，新辅助TAR-200联合cetrelimab（抗PD-1）与cetrelimab单药治疗的效果。

Methods

SunRISe-4 is a randomised, open-label, phase 2 trial being conducted at 109 investigative centres in ten countries worldwide.

SunRISe-4 是一项正在进行的随机、开放标签、2期试验，在全球10个国家的109个研究中心进行。

Eligible patients were aged 18 years or older, were newly diagnosed with histologically confirmed muscle-invasive bladder cancer (stage cT2-cT4 N0M0), had an Eastern Cooperative Oncology Group performance status of 0-1, were scheduled to undergo radical cystectomy, and were deemed ineligible for or declined platinum-based neoadjuvant chemotherapy.

符合条件的患者年龄在18岁或以上，新诊断为组织学证实的肌肉浸润性膀胱癌（cT2-cT4 N0M0期），东部肿瘤协作组体能状态评分为0-1，计划接受根治性膀胱切除术，并且被认为不符合或拒绝接受铂类药物为基础的新辅助化疗。

Patients were randomly assigned (5:3) in blocks of eight using an interactive web response system to receive four cycles of intravesical TAR-200 (225 mg gemcitabine) plus intravenous cetrelimab (360 mg) every 21 days or four cycles of intravenous cetrelimab (360 mg) monotherapy every 21 days.

患者通过互动网络响应系统以8人一组的方式随机分配（5:3），接受每21天一次的四次膀胱内TAR-200（225毫克吉西他滨）联合静脉注射cetrelimab（360毫克）治疗，或每21天一次的四次静脉注射cetrelimab（360毫克）单药治疗。

Randomisation was stratified by results of transurethral resection of bladder tumour (visibly complete vs incomplete and ≤3 cm) and tumour stage (cT2 vs cT3-4a at initial diagnosis).

随机分组根据经尿道膀胱肿瘤切除术的结果（肉眼完全切除与不完全切除且≤3厘米）和肿瘤分期（初始诊断时cT2与cT3-4a）进行分层。

The primary endpoint was centrally confirmed pathological complete response in the efficacy-evaluable set.

主要终点是集中确认的疗效可评估集中的病理完全缓解。

As this was a prespecified interim analysis and all patients had not completed treatment, efficacy-evaluable set was defined as all patients who had radical cystectomy or progressive disease or death before radical cystectomy.

由于这是预先设定的中期分析，并且并非所有患者都已完成治疗，因此疗效可评估集被定义为所有已接受根治性膀胱切除术或在根治性膀胱切除术前疾病进展或死亡的患者。

Safety was analysed in all patients who received at least one dose of study drug.

对所有至少接受了一剂研究药物的患者进行了安全性分析。

This trial is registered with ClinicalTrials.gov, NCT04919512, and is ongoing.

该试验已在ClinicalTrials.gov注册，注册号为NCT04919512，目前仍在进行中。

Results

From July 7, 2022, to May 31, 2024, 196 patients were assessed for eligibility and 122 were randomly assigned (TAR-200 plus cetrelimab n=80, cetrelimab monotherapy n=42). 120 patients received at least one dose of study drug.

从2022年7月7日至2024年5月31日，共有196名患者被评估是否符合资格，其中122名患者被随机分配（TAR-200加cetrelimab组n=80，cetrelimab单药治疗组n=42）。120名患者至少接受了一次研究药物的治疗。

Mean age was 70·7 years (SD 7·9); 102 (85%) participants were male, 18 (15%) were female, 81 (68%) were White, 28 (23%) were Asian, and 11 (9%) were other races.

平均年龄为70.7岁（标准差7.9）；102名（85%）参与者为男性，18名（15%）为女性，81名（68%）为白人，28名（23%）为亚洲人，11名（9%）为其他种族。

In the efficacy-evaluable set (TAR-200 plus cetrelimab n=53, cetrelimab monotherapy n=31), at a median follow up of 23·5 weeks (IQR 8·6-42·0), pathological complete response rates were 42% (22 of 53 patients; 95% CI 28-56) in the TAR-200 plus cetrelimab cohort and 23% (seven of 31 patients; 10-41) in the cetrelimab monotherapy cohort.

在疗效可评估集（TAR-200加cetrelimab组n=53，cetrelimab单药组n=31）中，中位随访时间为23.5周（四分位数间距8.6-42.0），TAR-200加cetrelimab组的病理完全缓解率为42%（53名患者中有22名；95%置信区间28-56），而cetrelimab单药组为23%（31名患者中有7名；10-41）。

In the safety set, at a median follow-up of 10·2 weeks (IQR 1·1-36·9), treatment-related adverse events occurred in 57 (72%) of 79 patients in the TAR-200 plus cetrelimab cohort and in 18 (44%) of 41 patients in the cetrelimab monotherapy cohort.

在安全性集（TAR-200加cetrelimab组n=79，cetrelimab单药组n=41）中，中位随访时间为10.2周（四分位数间距1.1-36.9），TAR-200加cetrelimab组有57名（72%）患者出现与治疗相关的不良事件，而cetrelimab单药组有18名（44%）患者出现此类不良事件。

Grade 3 or worse treatment-related adverse events occurred in nine (11%) patients in the TAR-200 plus cetrelimab cohort and two (5%) in the cetrelimab monotherapy cohort, the most common being haematuria (two [3%] in the TAR-200 plus cetrelimab cohort).

在接受TAR-200联合cetrelimab治疗的队列中，有9名（11%）患者出现了3级或更严重的治疗相关不良事件，而在仅接受cetrelimab单药治疗的队列中，有2名（5%）患者出现了此类不良事件，其中最常见的是血尿（TAR-200联合cetrelimab队列中有2名[3%]患者出现）。

Serious treatment-related adverse events occurred in nine (11%) patients in the TAR-200 plus cetrelimab cohort and one (2%) patient in the cetrelimab monotherapy cohort.

在接受TAR-200联合cetrelimab治疗的队列中，有9名（11%）患者出现了严重的治疗相关不良事件，而在仅接受cetrelimab单药治疗的队列中，有1名（2%）患者出现了此类不良事件。

In the TAR-200 plus cetrelimab cohort, seven (9%) patients had treatment-related adverse events leading to discontinuation of TAR-200 and six (8%) had treatment-related adverse events leading to discontinuation of cetrelimab; there were no treatment related deaths.

在TAR-200联合cetrelimab的队列中，有7名（9%）患者因治疗相关不良事件停用TAR-200，6名（8%）患者因治疗相关不良事件停用cetrelimab；未发生与治疗相关的死亡事件。

In the cetrelimab monotherapy cohort, no patients discontinued due to treatment-related adverse events; there was one death from a treatment-related adverse eventdue to hyperglycaemic, hyperosmolar, non-ketotic syndrome.

在cetrelimab单药治疗队列中，无患者因治疗相关不良事件停药；有一例因治疗相关不良事件导致的死亡，死亡原因为高血糖高渗性非酮症综合征。

interpretation

Neoadjuvant TAR-200 plus cetrelimab showed a high pathological complete response rate with a manageable safety profile.

新辅助TAR-200联合cetrelimab显示出高病理完全缓解率，并具有可管理的安全性特征。

These results support continued investigation of TAR-200 in patients with muscle-invasive bladder cancer planned for radical cystectomy.

这些结果支持继续在计划接受根治性膀胱切除术的肌层浸润性膀胱癌患者中研究TAR-200。

funding

Johnson & Johnson.

强生公司。