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Neoadjuvant chemotherapy with or without camrelizumab in resectableesophageal squamouscell carcinoma: the randomized phase3ESCORT-NEO/NCCES01 trial
新辅助化疗联合或不联合 camrelizumab 治疗可切除食管鳞状细胞癌：随机 3 期 ESCORT-NEO/NCCES01 试验

Received: 29 March 2024 收到日期：2024 年 3 月 29 日
Accepted: 13 May 2024
接受日期：2024 年 5 月 13 日
Published online: 02 July 2024
在线发布：2024 年 7 月 2 日
Check for updates 检查更新

Abstract 摘要

A list of authors and their affiliations appears at the end of the paper Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3NOMO) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; ); camrelizumab, paclitaxel and cisplatin (Cam+TPgroup; ); and paclitaxel with cisplatin (TP group; ), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response ( pCR ), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of and , respectively, compared to in the TP group (Cam+nab-TP versus TP: difference confidence interval (CI) 15.1-32.0, ; Cam+TP versus TP: difference 10.9%, 95% CI3.7-18.1, ). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade treatment-related adverse events during neoadjuvant treatment was for the Cam+nab-TP group, 29.2% for the Cam+TP group and for the TP group; the postoperative complication rates were and , respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior PCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034.
一份作者及其所属机构的名单出现在论文末尾。最近涉及新辅助 camrelizumab（PD-1 抑制剂）加化疗治疗可切除局部晚期食管鳞状细胞癌（LA-ESCC）的单臂研究显示出良好的结果。本多中心、随机、开放标签的 3 期试验旨在进一步评估新辅助 camrelizumab 加化疗后再加用辅助 camrelizumab 的疗效和安全性，与单独的新辅助化疗进行比较。共 391 名可切除的胸部 LA-ESCC 患者（T1b-3N1-3M0 或 T3NOMO）按临床分期（I/II、III 或 IVA）分层，并以 1:1:1 的比例随机分配接受两周期的新辅助治疗。治疗方案包括 camrelizumab、白蛋白结合的紫杉醇和顺铂（Cam+nab-TP 组； ）；camrelizumab、紫杉醇和顺铂（Cam+TP 组； ）；以及紫杉醇与顺铂（TP 组； ），随后进行外科切除。Cam+nab-TP 组和 Cam+TP 组均接受了辅助 camrelizumab 治疗。 双主要终点是由盲法独立评审委员会评估的病理完全缓解率（pCR）和由研究者评估的无事件生存期（EFS）。本研究报告了 pCR 率的最终分析。在意向治疗人群中，Cam+nab-TP 组和 Cam+TP 组的 pCR 率分别显著高于 TP 组的 ，为 和 （Cam+nab-TP 与 TP：差异 ，置信区间（CI）15.1-32.0， ；Cam+TP 与 TP：差异 10.9%，95% CI 3.7-18.1， ）。该研究达到了其 pCR 的主要终点；然而，EFS 尚未成熟。在新辅助治疗期间，Cam+nab-TP 组的治疗相关不良事件发生率为 ，Cam+TP 组为 29.2%，TP 组为 ；术后并发症发生率分别为 和 。新辅助 camrelizumab 加化疗相比单独化疗对局部晚期食管鳞状细胞癌（LA-ESCC）显示出更高的 pCR 率，并具有可耐受的安全性。中国临床试验注册中心标识符：ChiCTR2000040034。


Fig. 1|CONSORT diagram. A total of 411 patients were screened for this study, of whom 391 were successfully enrolled between April 28, 2021, and August 7, 2023.
图 1|CONSORT 图。共有 411 名患者参与了本研究，其中 391 名患者在 2021 年 4 月 28 日至 2023 年 8 月 7 日期间成功入组。
Esophageal cancer is a significant global health issue, ranking seventh in incidence and sixth in mortality among all cancers , with over half of the global esophageal squamous cell carcinoma (ESCC) cases in China . In East Asia, neoadjuvant chemotherapy or chemoradiotherapy is standard for resectable locally advanced ESCC (LA-ESCC), with chemotherapy more prevalent . Studies such as CROSS and NEOCRTEC5010 highlight neoadjuvant chemoradiotherapy's survival benefits over surgery alone , whereas theJCOG 9907 trial shows neoadjuvant chemotherapy improves overall survival (OS) compared to adjuvant therapy . Recent phase 3 trials, including CMISG1701 and JCOG1109 (refs. 8,9), along with a network meta-analysis of randomized controlled trials , have not demonstrated a significant OS advantage when comparing neoadjuvant chemoradiotherapy to chemotherapy for LA-ESCC, leaving the optimal neoadjuvant treatment strategy in question.
食管癌是一个重大的全球健康问题，在所有癌症中发病率排名第七，死亡率排名第六 ，全球超过一半的食管鳞状细胞癌（ESCC）病例发生在中国 。在东亚，针对可切除的局部晚期 ESCC（LA-ESCC），新辅助化疗或化放疗是标准治疗，其中化疗更为普遍 。如 CROSS 和 NEOCRTEC5010 等研究强调新辅助化放疗相较于单纯手术的生存益处 ，而 JCOG 9907 试验显示新辅助化疗相比于辅助治疗改善了总体生存率（OS） 。最近的三期试验，包括 CMISG1701 和 JCOG1109（参考文献 8,9），以及一项随机对照试验的网络荟萃分析 ，在比较新辅助化放疗与 LA-ESCC 的化疗时未显示出显著的 OS 优势，这使得最佳的新辅助治疗策略仍然存在疑问。
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of ESCC. Camrelizumab, a PD-1 inhibitor, has demonstrated promising efficacy and safety in advanced ESCC, including both chemotherapy-refractory and treatment-naive cases, as evidenced by the ESCORT and ESCORT-1st studies . Following these results, China has approved camrelizumab as a second-line monotherapy for advanced or metastatic ESCC, and in combination with chemotherapy (paclitaxel and cisplatin, TP) as a first-line treatment. Several phase 1b and 2 trials assessing neoadjuvant immunotherapy with camrelizumab and chemotherapy for LA-ESCC report high pathological complete response (pCR) rates of to (refs. 13-18). Our latest retrospective analysis suggests that neoadjuvant chemotherapy plus immunotherapy showed better 3-year OS rates ( versus ) and 3-year disease-free survival (DFS) rates ( versus ) compared to neoadjuvant chemoradiotherapy . Despite these promising results, there remains a lack of phase 3 confirmatory studies to further validate these findings.
免疫检查点抑制剂（ICIs）彻底改变了食管鳞状细胞癌（ESCC）的治疗。Camrelizumab，一种 PD-1 抑制剂，在晚期 ESCC 中显示出良好的疗效和安全性，包括化疗耐药和治疗初始病例，ESCORT 和 ESCORT-1st 研究对此提供了证据 。在这些结果之后，中国已批准 camrelizumab 作为晚期或转移性 ESCC 的二线单药治疗，并与化疗（紫杉醇和顺铂，TP）联合使用作为一线治疗。几项评估 camrelizumab 与化疗联合的术前免疫治疗的 1b 期和 2 期试验报告了高病理完全缓解（pCR）率，范围为 到 （参考文献 13-18）。我们最新的回顾性分析表明，术前化疗加免疫治疗的 3 年总生存率（OS）为 对比 ，3 年无病生存率（DFS）为 对比 ，优于术前化疗放疗 。尽管这些结果令人鼓舞，但仍缺乏 3 期确认性研究来进一步验证这些发现。
Beyond selecting the optimal combination of treatment modalities, refining the chemotherapy regimen is crucial for enhancing neoadjuvant treatment outcomes in ESCC. The TP regimen is commonly used, yet nab-paclitaxel, an innovative albumin-bound formulation of paclitaxel, has shown a superior therapeutic profile compared to traditional paclitaxel. This preference for nab-paclitaxel, especially when combined with immunotherapy in LA-ESCC, is supported by several phase 2 studies . Our retrospective analysis further substantiates this, revealing that neoadjuvant immunotherapy with nab-paclitaxel and cisplatin (nab-TP) achieves higher pCR rates than the combination of immunotherapy with TP regimen . Against this backdrop, we initiated the ESCORT-NEO/NCCESO1 study, a phase 3, open-label, randomized trial aimed at assessing the efficacy and safety of neoadjuvant camrelizumab plus either TP or nab-TP, as compared to TP alone, in patients with resectable LA-ESCC.
在选择最佳治疗方式组合的基础上，优化化疗方案对于提高食管鳞状细胞癌（ESCC）新辅助治疗的效果至关重要。TP 方案是常用的治疗方案，但纳米白蛋白结合紫杉醇（nab-paclitaxel）作为一种创新的白蛋白结合紫杉醇制剂，其治疗效果优于传统紫杉醇。尤其是在局部晚期食管鳞状细胞癌（LA-ESCC）中，nab-paclitaxel 与免疫治疗联合使用的偏好得到了几项二期研究的支持 。我们的回顾性分析进一步证实了这一点，显示与 TP 方案联合的免疫治疗相比，nab-paclitaxel 与顺铂（nab-TP）的新辅助免疫治疗实现了更高的完全病理缓解率（pCR） 。在此背景下，我们启动了 ESCORT-NEO/NCCESO1 研究，这是一个三期、开放标签、随机试验，旨在评估新辅助 camrelizumab 联合 TP 或 nab-TP 的疗效和安全性，与单独 TP 相比，针对可切除的 LA-ESCC 患者。

Results 结果

Patient disposition 患者处置

A total of 411 patients were screened for this study, of whom 391 were successfully enrolled between April 28, 2021, and August 7, 2023. In the Cam+nab-TP, Cam+TP and TP groups, 132,130 and 125 patients, respectively, were allocated and received neoadjuvant therapy; although the TP group initially had 129 before 4 withdrew consent. Consequently, the intention-to-treat (ITT) populations were 132, 130 and 129, with safety set (SS) populations of 132, 130 and 125, respectively (Fig. 1). As of the data cutoff on October 8, 2023, the median follow-up duration was 8.2 months (interquartile range (IQR), 3.5-15.6 months). The median age of all patients was 63 years (range, ), with being male. Among these patients, were in clinical stage I (all cT1N1), were stage II, were stage III and were stage IVA. Tumors were located in the upper, middle and lower thoracic esophagus for and patients, respectively. Baseline characteristics were essentially balanced across all three groups (Table 1).
共有 411 名患者参与了本研究，其中 391 名患者在 2021 年 4 月 28 日至 2023 年 8 月 7 日期间成功入组。在 Cam+nab-TP、Cam+TP 和 TP 组中，分别有 132、130 和 125 名患者被分配并接受了新辅助治疗；尽管 TP 组最初有 129 名患者，但有 4 名患者撤回了同意。因此，意向治疗（ITT）人群分别为 132、130 和 129，安全性集（SS）人群分别为 132、130 和 125（图 1）。截至 2023 年 10 月 8 日的数据截止日期，中位随访时间为 8.2 个月（四分位数范围（IQR），3.5-15.6 个月）。所有患者的中位年龄为 63 岁（范围， ），其中 为男性。在这些患者中， 处于临床 I 期（均为 cT1N1）， 为 II 期， 为 III 期， 为 IVA 期。肿瘤分别位于上、中和下胸食管的 和 名患者中。基线特征在所有三个组之间基本平衡（表 1）。

Neoadjuvant treatment and surgery summary
新辅助治疗和手术总结

Within the ITT population,132,130 and 125 patients in the Cam + nab-TP, Cam+TP and TP groups, respectively, received neoadjuvant therapy. Of these, 3 in the Cam+nab-TP group, 5 in the Cam+TP group and 3 in the TP group did not complete two cycles of neoadjuvant therapy for several reasons; in the Cam+nab-TP group, two patients discontinued due to
在 ITT 人群中，分别有 132、130 和 125 名患者在 Cam + nab-TP、Cam + TP 和 TP 组接受了新辅助治疗。其中，Cam + nab-TP 组有 3 名、Cam + TP 组有 5 名、TP 组有 3 名患者因多种原因未完成两周期的新辅助治疗；在 Cam + nab-TP 组中，有两名患者因中断治疗。

Table 1 | Baseline characteristics of patients in the ITT population
表 1 | ITT 人群患者的基线特征

Variables 变量
Cam+nab-TP
Cam+TP
TP
Age (years) 年龄（岁）
74 (56.1) 79 (60.8) 63 (48.8)
58 (43.9) 51 (39.2) 66 (51.2)
Median (range) 中位数（范围） 63 (44-75) 65 (44-75)
Sex, n (%) 性别, n (%)
Male 男性 116 (87.9) 112 (86.2)
Female 女性 16 (12.1) 18 (13.8) 25 (19.4)
ECOG PS, n (%)
0 105 (79.5) 106 (81.5) 104 (80.6)
1 27 (20.5) 24 (18.5) 25 (19.4)
Tumor location, (%)
肿瘤位置， (%)
Upper 上部 12 (9.2) 19 (14.7)
Middle 中间 69 (52.3) 75 (57.7) 57 (44.2)
Lower 下部 53 (40.2) 43 (33.1) 53 (41.1)
T stage, (%) T 阶段， (%)
T1b 3 (2.3) 1 (0.8) 2 (1.6)
T2 15 (11.4) 13 (10.0) 19 (14.7)
T3 114 (86.4) 116 (89.2) 108 (83.7)
N stage, (%) N 阶段， (%)
NO 20 (15.2) 24 (18.5) 20 (15.5)
N1 71 (53.8) 71 (54.6) 73 (56.6)
N2 38 (28.8) 33 (25.4) 35 (27.1)
N3 3 (2.3) 2 (1.5) 1 (0.8)
Clinical stage, (%)
临床阶段， (%)
I 3 (2.3) 1 (0.8) 2 (1.6)
II 31 (23.5) 34 (26.2) 35 (27.1)
III 95 (72.0) 93 (71.5) 91 (70.5)
IVA 3 (2.3) 2 (1.5) 1 (0.8)
PD-L1 TPS, (%) PD-L1 TPS， （%）
43 (32.6) 59 (45.4) 49 (38.0)
78 (59.1) 61 (46.9) 62 (48.1)
99 (75.0) 98 (75.4) 97 (75.2)
22 (16.7) 22 (16.9) 14 (10.9)
Unknown 未知 11 (8.3) 10 (7.7) 18 (14.0)
PD-L1 CPS, (%) PD-L1 CPS， (%)
14 (10.6) 18 (13.8) 15 (11.6)
109 (82.6) 102 (78.5) 96 (74.4)
68 (51.5) 80 (61.5) 72 (55.8)
55 (41.7) 40 (30.8) 39 (30.2)
Unknown 未知 9 (6.8) 10 (7.7) 18 (14.0)
ECOG PS, Eastern Cooperative Oncology Group performance status; TPS, tumor proportion score; CPS, combined positive score.
ECOG PS，东部合作肿瘤学组表现状态；TPS，肿瘤比例评分；CPS，联合阳性评分。
adverse events (AEs) and one due to patient refusal; in the Cam + TP group, four patients discontinued due to AEs and one due to death; and in the TP group, discontinuations were due to one AE and two instances of patient refusal. A total of 114 (86.4%), 116 (89.2%) and 103 (79.8%) underwent esophagectomy. Reasons for cancellation of esophagectomy included refusal of surgery , surgery intolerability , disease progression , exploratory operation , unresectability , preoperative death and loss to follow-up . Among the exploratory operations, one case in the TP group revealed peritoneal metastasis, while the remaining four cases involved tumors deemed unresectable due to extensive invasion. The median time from the last neoadjuvant treatment to surgery across the Cam+nab-TP, Cam+TP, and TP groups were 5.9 (IQR, 5.0-7.1), 5.7 (IQR, 5.0-7.4) and 5.4 (IQR, 4.9-6.3) weeks, respectively. In terms of types of surgery, the McKeown procedure was the most common, accounting for in the Cam+nab-TP group, in the Cam+TP group and in the TP group. The median number of lymph nodes harvested was 34 (IQR, 24-50), 37 (IQR, 27-48) and 32 (IQR, 27-45), respectively. The median duration of surgery for the Cam+nab-TP, Cam+TP and TP groups was 4.3 hours (range, 2.6-8.9), 4.2 hours (range, 2.8-7.2) and 4.2 hours (range, 2.9-10.8), respectively (Table 2).
不良事件（AEs）和一起因患者拒绝而导致的事件；在 Cam + TP 组中，四名患者因 AEs 而中止治疗，一名因死亡而中止；在 TP 组中，中止治疗的原因包括一起 AE 和两起患者拒绝。共有 114 例（86.4%）、116 例（89.2%）和 103 例（79.8%）接受了食管切除术。取消食管切除术的原因包括拒绝手术 、手术耐受性差 、疾病进展 、探查手术 、不可切除性 、术前死亡 和失访 。在探查手术中，TP 组有一起病例发现腹膜转移，其余四例因广泛浸润被认为不可切除。Cam+nab-TP、Cam+TP 和 TP 组从最后一次新辅助治疗到手术的中位时间分别为 5.9（IQR，5.0-7.1）、5.7（IQR，5.0-7.4）和 5.4（IQR，4.9-6.3）周。在手术类型方面，McKeown 手术是最常见的，分别占 Cam+nab-TP 组的 、Cam+TP 组的 和 TP 组的 。 收集的淋巴结中位数为 34 个（四分位数范围，24-50），37 个（四分位数范围，27-48）和 32 个（四分位数范围，27-45），分别。Cam+nab-TP、Cam+TP 和 TP 组的手术中位持续时间分别为 4.3 小时（范围，2.6-8.9），4.2 小时（范围，2.8-7.2）和 4.2 小时（范围，2.9-10.8）（表 2）。

Primary outcome 主要结果

Within the ITT population, the pCR rate was in the Cam+nab-TP group, markedly higher than the TP group's 4.7% (difference 23.5%, confidence interval (CI), 15.1-32.0; odds ratio (OR), 8.11; , ). The Cam+TPgroup's pCR rate was also significantly greater at , compared to the TP group (difference 10.9%, 95% ; OR, ) (Table 3). Post hoc subgroup analyses of pCR rates for the Cam+nab-TP group versus TP group and TP group versus TP group are presented in Extended Data Figs. 1 and 2. Event-free survival (EFS) data have not matured.
在 ITT 人群中，Cam+nab-TP 组的 pCR 率为 ，明显高于 TP 组的 4.7%（差异 23.5%， 置信区间（CI），15.1-32.0；优势比（OR），8.11； ， ）。Cam+TP 组的 pCR 率也显著高于 TP 组，为 （差异 10.9%，95% ；OR， ）（表 3）。Cam+nab-TP 组与 TP 组以及 TP 组与 TP 组的 pCR 率的事后亚组分析结果见扩展数据图 1 和图 2。事件无生存期（EFS）数据尚未成熟。

Secondary outcomes 次要结果

Within the ITT population, the major pathological response (MPR) rates in the Cam+nab-TP,Cam+TP, and TP groups were and , respectively (Table 3). The R0 resection rates were (113/114), and for the Cam+nab-TP, Cam+TP and TP groups, respectively (Table 2). For the post-neoadjuvant pathological staging (ypTNM) staging, 58 patients ( ) achieved stage I in the Cam+nab-TP group, 46 (39.7%) in the Cam+TP group and 27 (26.2%) in the TP group (Supplementary Table 1). The median residual viable tumor cells were (IQR, ), (IQR, 1-70) and (IQR, 8-80) for Cam+nab-TP, Cam+TP and TPgroups, respectively (Extended Data Fig.3). DFS and OS are not yet mature.
在 ITT 人群中，Cam+nab-TP、Cam+TP 和 TP 组的主要病理反应（MPR）率分别为 和 （表 3）。R0 切除率分别为 Cam+nab-TP 组 （113/114）、Cam+TP 组 和 TP 组 （表 2）。在新辅助治疗后的病理分期（ypTNM）中，Cam+nab-TP 组有 58 名患者（ ）达到了 I 期，Cam+TP 组 46 名（39.7%），TP 组 27 名（26.2%）（补充表 1）。Cam+nab-TP、Cam+TP 和 TP 组的中位残余活性肿瘤细胞分别为 （IQR， ）、 （IQR，1-70）和 （IQR，8-80）（扩展数据图 3）。无病生存期（DFS）和总生存期（OS）尚未成熟。

Safety 安全

In the Cam+nab-TP, Cam+TP and TP groups, the rates of surgical complications of any grade were and (33/103), respectively. Among these, the proportions of Clavien-Dindo (CD) grade 3 or higher complications were (7/114), 12.1% (14/116) and , respectively. Pneumonia and recurrent laryngeal nerve injury were the most common postoperative complications (Table 4 and Supplementary Table 2). One patient ( ) in the Cam+TP group and one patient ( ) in the TP group required reoperation due to adhesive intestinal obstruction and an anastomotic leak, respectively. The 30 -day postoperative mortality rates were in the Cam+nab-TP group (one case of sudden death, cause unknown), in the Cam+TP group (two cases of septic shock) and in the TP group (one case of myocardial infarction). There was one additional death within 90 days postoperatively in the Cam+nab-TP group, due to severe pneumonia (Table 2).
在 Cam+nab-TP、Cam+TP 和 TP 组中，任何等级的手术并发症发生率分别为 和 （33/103）。其中，Clavien-Dindo（CD）3 级或更高级别并发症的比例分别为 （7/114）、12.1%（14/116）和 。肺炎和喉返神经损伤是最常见的术后并发症（表 4 和补充表 2）。在 Cam+TP 组中有一名患者（ ）和在 TP 组中有一名患者（ ）因粘连性肠梗阻和吻合口漏分别需要再次手术。30 天术后死亡率在 Cam+nab-TP 组为 （一例突发死亡，原因不明）、在 Cam+TP 组为 （两例脓毒性休克）和在 TP 组为 （一例心肌梗死）。在 Cam+nab-TP 组中术后 90 天内还有一例因重度肺炎死亡（表 2）。
Regarding treatment-related AEs (TRAEs), the incidence rates were in the Cam+nab-TP group, (108/130) in the Cam+TP group and in the TP group. Grade 3 or higher TRAEs occurred in of the Cam+nab-TP group, of the Cam+TP group and of the TP group (Supplementary Table3). The most prevalent grade 3 or higher TRAEs were neutrophil count decreased and white blood cell count decreased (Table 5 and Supplementary Table 4). The rates of TRAEs leading to chemotherapy discontinuation were for Cam+nab-TP,
关于治疗相关的不良事件（TRAEs），Cam+nab-TP 组的发生率为 ，Cam+TP 组为