Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (P1CC): a single-centre, parallel-group, noncomparative, randomised, phase 2 trial
Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (P1CC): a single-centre, parallel-group, noncomparative, randomised, phase 2 trial
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DOI：
10.1016/s2468-1253(21)00348-4
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发表时间：
2021-12-09
影响因子：
35.7
通讯作者：
Deng, Yanhong
中科院分区：
文献类型：
--
作者：
Hu, Huabin;Kang, Liang;Deng, Yanhong
背景PD-1阻断剂在错配修复缺陷或微卫星不稳定性高转移性结直肠癌患者中非常有效。单药PD-1阻断剂在可切除的错配修复缺陷或微卫星不稳定性高的结直肠癌的新辅助治疗中的作用尚不清楚。我们研究了在有或没有考克斯-2抑制剂塞来昔布的情况下，用托立哌单抗阻断PD-1作为错配修复缺陷或微卫星不稳定性高的局部晚期结直肠癌的新辅助治疗的有效性和安全性。在中山大学附属第六医院（中国广州）进行的II期研究。符合条件的患者年龄为18-75岁，患有组织学证实的错配修复缺陷或微卫星不稳定性高的结直肠癌，临床分期为T3-T4或任何T淋巴结阳性（N+）。东部肿瘤协作组体能评分为0或1，血液学、肝脏和肾脏功能良好。受试者被随机分配（1：1），无任何分层或平衡区组，在手术切除前接受6个周期的治疗，第1天静脉注射toripalimab 3 mg/kg，从每个14天周期的第1天至第14天口服或不口服塞来昔布200 mg，每日2次。由研究者酌情决定是否允许使用toripalimab联合或不联合塞来昔布进行辅助治疗。主要终点是病理学完全缓解的患者比例，病理学完全缓解定义为切除的原发性肿瘤样本和所有采样的区域淋巴结中没有任何存活肿瘤细胞的肿瘤。在改良的意向治疗人群中评估了所有疗效和安全性分析，该人群包括随机分配至治疗组并接受至少一剂toripalimab的所有患者。该试验注册于ClinicalTrials.gov，NCT 03926338，目前正在进行中。结果2019年5月1日至2021年4月1日，筛选了53例患者，其中34例随机分配至toripalimab联合塞来昔布组（n=17）或toripalimab单药治疗组（n=17）。截至数据截止日期（2021年8月10日），中位随访时间为14.9个月（IQR 8-8-17-0）。所有患者均接受研究治疗并接受手术切除;无治疗相关的手术延迟。所有34例患者均行RO切除（>1 mm切除边缘）。托里帕利单抗联合塞来昔布组17例患者中的15例（88% [95% CI 64-99]）和托里帕利单抗单药治疗组17例患者中的11例（65% [38-86]）出现病理学完全缓解。所有患者继续接受辅助toripalimab联合或不联合塞来昔布，总围手术期持续时间为6个月，并且在数据截止时存活且无复发。在新辅助治疗期间，toripalimab + celecoxib组中的10名（59%）患者和toripalirnab单药治疗组中的10名（59%）患者发生了1-2级治疗相关不良事件。在新辅助治疗阶段，34名患者中只有1名（3%）患者（属于toripalimab + celecoxib组）发生了3级或3级以上的治疗相关不良事件，即3级天冬氨酸转氨酶水平升高。在辅助治疗阶段，34名患者中只有一名（3%），即托里帕利单抗单药治疗组中的患者，发生了3级或更高的治疗相关不良事件，即3级天冬氨酸转氨酶和丙氨酸转氨酶水平升高。结肠直肠癌这种治疗具有较高的病理完全缓解率和可接受的安全性，并且不会影响手术。需要长期随访以评估对生存相关终点的影响。版权所有（C）2021爱思唯尔有限公司保留所有权利。
Background PD-1 blockade is highly effective in patients with mismatch repair-deficient or microsatellite instability-high metastatic colorectal cancer. The role of single-agent PD-1 blockade in the neoadjuvant setting for resectable mismatch repair-deficient or microsatellite instability-high colorectal cancer remains unclear. We investigated the efficacy and safety of PD-i blockade with toripaliunab, with or without the COX-2 inhibitor celecoxib, as neoadjuvant treatment for mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancers.Methods The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial was a single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study undertaken at the Sixth Affiliated Hospital of Sun Yatsen University (Guangzhou, China). Eligible patients were aged 18-75 years, had histologically confirmed mismatch repair-deficient or microsatellite instability-high colorectal cancer, had clinical stage T3-T4 or any T with lymph node positivity (N+). Eastern Cooperative Oncology Group performance score of 0 or 1, and adequate haematological, hepatic, and renal function. Participants were randomly assigned (1:1), without any stratification or balanced blocking, to receive toripalimab 3 mg/kg intravenously on day 1, with or without celecoxib 200 mg orally twice daily from day 1 to 14 of each 14-day cycle, for six cycles before surgical resection. Adjuvant treatment with toripalimab with or without celecoxib was permitted at the investigators' discretion. The primary endpoint was the proportion of patients with pathological complete response, defined as tumours without any viable tumour cells in the resected primary tumour sample and all sampled regional lymph nodes. All efficacy and safety analyses were assessed in the modified intention-to-treat population, which included all patients who were randomly assigned to treatment and who received at least one dose of toripalimab. This trial is registered with ClinicalTrials.gov , NCT03926338, and is ongoing.Findings Between May 1,2019, and April 1,2021,53 patients were screened, of whom 34 were randomly assigned to either the toripalimab plus celecoxib group (n=17) or the toripalimab monotherapy group (n=17). As of data cutoff (Aug 10, 2021), median follow-up was 14.9 months (IQR 8-8-17-0). All patients received study treatment and underwent surgical resection; there were no treatment-related surgical delays. All 34 patients had an RO resection (>1 mm resection margin). 15 of 17 patients (88% [95% CI 64-99]) in the toripalimab plus celecoxib group and 11 of 17 patients (65% [38-86]) in the toripalimab monotherapy group had a pathological complete response. All patients continued to receive adjuvant toripalimab with or without celecoxib for a total perioperative duration of 6 months and were alive and free of recurrence at data cutoff. During neoadjuvant treatment, ten (59%) patients in the toripalimab plus celecoxib group and ten (59%) in the toripalirnab monotherapy group had grade 1-2 treatment-related adverse events. Only one (3%) of 34 patients, who was in the toripalimab plus celecoxib group, had a grade 3 or higher treatment-related adverse event during the neoadjuvant phase, which was grade 3 increased aspartate aminotransferase levels. In the adjuvant phase, only one (3%) of 34 patients, who was in the toripalimab monotherapy group, had a grade 3 or higher treatment-related adverse events, which was grade 3 increased aspartate aminotransferase and alanine aminotransferase levels.Interpretation Neoadjuvant toripalimab with or without celecoxib could be a potential therapeutic option for patients with mismatch repair deficient or microsatellite instability-high, locally advanced, colorectal cancer. This treatment was associated with a high pathological complete response rate and an acceptable safety profile, which did not compromise surgery. Longer term follow-up is needed to assess effects on survival-related endpoints. Copyright (C) 2021 Elsevier Ltd. All rights reserved.