肿瘤瞭望消化时讯

ESMO ASIA 2024丨从徐瑞华教授等中国研究者入选的TiP摘要看结直肠癌最新研发动向

肿瘤瞭望消化时讯

编者按：2024年12月6~8日，欧洲肿瘤内科学会亚洲年会（ESMO ASIA）于新加坡召开。会议聚焦亚洲地区的肿瘤学最新进展，旨在为参会者提供一个分享和讨论肿瘤领域最新研究成果、临床试验和治疗策略的平台。

TiP是Trial in Progress（正在进行的研究）摘要的代码，编码格式为"xxTiP"，也就是仅有研究设计尚未开始，或已经开始但尚未结束的研究。从这些初步研究中我们可以洞察到相关领域中有潜力的研究方向，为大家开展临床研究提供思路。本次会议中，中国结直肠癌领域TIP摘要研究共有9个，本文整理了其中4个，另外5项均由中山大学附属第六医院黄俊教授领衔，将在下篇文章中进行分享，敬请期待！


摘要号：119TiP

标题：IBI310（抗CTLA-4抗体）联合信迪利单抗（抗PD-1抗体）作为可切除微卫星高度不稳定/错配修复缺陷（MSI-H/dMMR）结肠癌新辅助治疗的随机、对照、多中心Ⅲ期研究

讲者：徐瑞华教授 中山大学肿瘤防治中心

背景

对于结肠癌，特别是MSI-H/dMMR类型的肿瘤，鉴于传统新辅助化疗在此亚群中的疗效有限，因此，开发有效的新辅助治疗方案显得尤为迫切。PD-1抑制剂联合或不联合CTLA-4抑制剂在转移性MSI-H/dMMR结直肠癌中显示出良好的疗效，但尚未有任何一种方案在新辅助治疗环境中被批准用于局部肿瘤。在2024年ASCO年会中，我们一项随机、对照、Ⅰb期研究已表明（摘要号：3505），与单独使用信迪利单抗相比，IBI310联合信迪利单抗新辅助治疗MSI-H/dMMR结肠癌可显著提高病理完全缓解（pCR）率。

试验设计

本研究是一项正在中国进行的Ⅲ期研究（Neoshot），旨在评估IBI310联合信迪利单抗作为新辅助治疗与单独根治性手术相比，在Ⅱb~Ⅲ期MSI-H/dMMR结肠癌中的疗效。共计划入组350例患者（pts），并按1:1的比例随机分配至试验组和对照组。分层因素包括基线影像学风险评估（高风险：T4或N2 vs. 低风险：T1~3和N1）和肿瘤位置（左侧 vs. 右侧）。主要入组标准包括：（1）年龄≥18岁；（2）未经治疗的结肠腺癌；（3）Ⅱb~Ⅲ期（cT4或cN+[AJCC第8版]）；（4）适合R0切除；（5）MSI-H或dMMR；（6）ECOG PS 0或1。在试验组中，患者接受新辅助治疗，包括第1周期IBI310 1 mg/kg联合信迪利单抗200 mg，第2周期信迪利单抗200 mg，首次给药后36~56天内进行根治性手术。在对照组中，患者不接受新辅助治疗，直接进行根治性手术。是否使用奥沙利铂联合卡培他滨的辅助化疗由研究者根据术后病理评估和临床指南决定。主要终点是试验组的pCR率和无事件生存期。次要终点包括R0切除率、总生存期、安全性、药代动力学和免疫原性。

临床试验识别号

NCT05890742


摘要号：118TiP

标题：新辅助CAPOX联合SCT510（贝伐珠单抗生物类似药）和finotonlimab治疗高危可切除结直肠癌肝转移（CRLM）：一项多中心Ⅱ期研究

讲者：邱文生教授 青岛大学附属医院

背景

手术切除仍然是结直肠肝转移瘤（CRLM）根治性治疗的主要手段。包括化疗或联合免疫治疗（IO）在内的术前治疗提高了适合根治性手术患者的比例。然而，微卫星稳定（MSS）肿瘤对免疫治疗的反应较差。因免疫治疗和抗血管生成的协同作用，所以将两者的联合使用可能会改善MSS CRLM的应答率。SCT510是一种重组抗VEGF抗体，已证明其安全性、药代动力学和免疫原性与贝伐珠单抗相当。finotonlimab是一种新型抗PD-1药物，已证明对实体瘤治疗有效。在此，我们开展了一项前瞻性Ⅱ期研究（NEO CPLUS），以评估CAPOX联合SCT510和 finotonlimab新辅助治疗高风险可切除CRLM的疗效和安全性。

试验设计

NEO CPLUS是一项多中心、单臂、研究者发起的Ⅱ期研究（ChiCTR2400085958）。计划入组约100例患者。符合条件的患者年龄为18~75岁，经组织学证实为可切除、高风险（临床风险评分≥3）的CRLM。可切除性定义为技术上能够实现完全切除，仅存在肝转移，且转移瘤数量≤6个。患者需ECOG PS评分为0~2，MSS/pMMR疾病，且器官功能良好。给予患者3个周期的CAPOX（第1天130 mg/m2奥沙利铂+第1~14天1000 mg/m2卡培他滨，每日两次），SCT510（第1天7.5 mg/kg）和 finotonlimab（第1天200 mg），随后给予1个周期的CAPOX联合 finotonlimab，每21天为一个周期。经过2~4个周期治疗后，根据RECIST 1.1标准评估为影像学缓解或疾病稳定的患者将在4~6周内接受手术，并允许接受4个周期的辅助CAPOX联合SCT510治疗。主要终点是pCR率。次要终点包括1年无进展生存率、主要病理缓解、R0切除、R1切除和安全性。

临床试验识别号

ChiCTR2400085958


摘要号：120TiP

标题：新辅助短程放疗联合化疗和卡度尼利单抗治疗局部晚期直肠癌：一项前瞻性、单臂Ⅱ期试验

讲者：Jiawei Rao（广州，中国）

背景

局部晚期直肠癌（LARC）的标准治疗方案为新辅助放化疗（CRT），该方案显著降低了局部复发的风险，但远处转移的风险依然较高。几项临床试验表明，短程放疗（SCRT）与PD-L1抑制剂的联合使用可能改善肿瘤缓解和预后。卡度尼利单抗（AK104）是一种新型双特异性抗体，同时靶向PD-1和CTLA-4，旨在增强抗肿瘤活性并改善安全性。基于此，将卡度尼利单抗与SCRT及化疗相结合，有望为LARC患者带来更大的临床获益及更优的预后效果。

试验设计

本项Ⅱ期、单中心、单臂临床试验旨在评估术前SCRT联合CAPEOX（卡培他滨和奥沙利铂）及卡度尼利单抗治疗LARC的疗效和安全性。将入组经组织学证实为T3~4/N+M0的直肠腺癌患者。其他关键入组标准包括：年龄18~70岁，ECOG PS 0~1，未接受过治疗，器官功能正常。给予患者1个周期的CAPEOX联合AK104（10 mg/kg iv，第1天，每3周一次），随后进行SCRT（25 Gy，每天5 Gy，在第8~12天给药）和2个周期的CAPEOX联合AK104（10 mg/kg iv，第1天，每3周一次）。在新辅助治疗最后一个周期后2周进行全直肠系膜切除术（TME）。术后，患者接受5个周期的CAPEOX辅助化疗。主要终点是pCR率。次要终点包括主要病理缓解率、R0切除率、1年和3年无病生存率（DFS）、1年和3年总生存率（OS）以及安全性。采用Simon两阶段设计。如果第一阶段15例患者中有6例或更多患者达到pCR，则第二阶段将再入组22例患者。收集肿瘤组织和血液样本以供进一步研究。截至2024年6月，已入组10例患者。

临床试验识别号

ChiCTR2300075658。


摘要号：125TiP

标题：局部晚期结肠直肠癌的预防性腹腔热灌注化疗 (HIPEC)：一项单中心、开放标签、随机对照试验

讲者：Shiyu Xu（中国，广州）

背景

结直肠癌（CRC）是全球第三大常见恶性肿瘤。CRC中腹膜复发相对常见，且进展为腹膜癌（PC）的患者往往预后极差。如何减少腹膜癌并改善预后仍是临床医生面临的挑战。现有研究表明，辅助性腹腔热灌注化疗（HIPEC）可降低卵巢癌、阑尾癌和胃癌的腹膜微转移风险，这为CRC的治疗提供了启示。

试验设计

本研究是一项开放标签、单中心、随机前瞻性临床试验，旨在评估预防性HIPEC是否能降低具有腹膜转移高危因素的cT3~T4a期CRC患者的腹膜复发率，延长总生存期和无病生存期。入组患者年龄为18~75岁，经病理学确诊为结直肠腺癌，无远处转移，适合标准根治性手术，ECOG体能状态评分为0~1，能够耐受术后HIPEC治疗，且在试验前未接受过化疗、放疗或其他抗肿瘤治疗。术中将完全切除肿瘤病灶并进行淋巴结清扫。患者将按1:1的比例随机分配至试验组和对照组。试验组患者术中将放置4根HIPEC导管，并在手术当天或术后第一天接受首次HIPEC治疗（雷替曲塞4 mg，43°C生理盐水3000 ml，持续60分钟）。第二次HIPEC治疗将在术后一周内进行（奥沙利铂130 mg/m2，43°C 5%葡萄糖溶液3000 ml）。两组患者均将在术后一个月左右根据具体情况接受CapeOX/卡培他滨/mFOLFOX6方案的全身化疗。主要终点是3年腹膜复发率；次要终点包括3年DFS、3年和5年总生存率（OS）、术后生活质量、围手术期并发症发生率和HIPEC毒性（术后1个月和6个月）。

摘要原文

119TiP - A randomized, controlled, multicenter phase III study of IBI310 (anti-CTLA-4 antibody) plus sintilimab (anti-PD-1 antibody) as neoadjuvant treatment for resectable microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colon cancer

Speakers：Rui-Hua Xu (Guangzhou, CN)

Background

There is a significant unmet clinical need for effective neoadjuvant treatment options for colon cancer, particularly for MSI-H/dMMR tumors, as conventional neoadjuvant chemotherapy has shown limited benefit in this subgroup. PD-1 with or without CTLA-4 inhibitors have shown promising efficacy in metastatic MSI-H/dMMR colorectal cancer, but none of them has yet been approved for localized tumors in the neoadjuvant setting. Our randomized, controlled, phase Ib study has demonstrated a significantly improved pathologic complete response (pCR) rate with neoadjuvant IBI310 plus sintilimab compared to sintilimab alone in MSI-H/dMMR colon cancer (2024 ASCO Annual Meeting, abstract 3505).


Trial design

Here, we present the phase III study (Neoshot), which is ongoing in China to evaluate IBI310 plus sintilimab as neoadjuvant treatment, compared with radical surgery alone for stage IIb-III MSI-H/dMMR colon cancer. A total of 350 patients (pts) will be enrolled and randomized in 1:1 ratio to the experimental and control groups. Stratification factors include baseline imaging risk assessment (high risk: T4 or N2 vs. low risk: T1-3 and N1) and tumor location (left-sided vs. right-sided). The main inclusion criteria are: 1) age ≥18 years; 2) previously untreated colon adenocarcinoma; 3) stage IIb-III (cT4 or cN+ [AJCC 8th edition]); 4) eligible for R0 resection; 5) MSI-H or dMMR; 6) ECOG PS 0 or 1. In the experimental group, pts receive neoadjuvant treatment with IBI310 1 mg/kg plus sintilimab 200 mg in cycle 1 and sintilimab 200 mg in cycle 2, followed by radical surgery within 36-56 days after the first dose. In the control group, pts undergo radical surgery without neoadjuvant therapy. Use of adjuvant chemotherapy with oxaliplatin plus capecitabine is at the investigator’s discretion according to postoperative pathological evaluation and clinical guidelines. The primary endpoints are pCR rate of the experimental group and event-free survival. The secondary endpoints are R0 resection rate, overall survival, safety, pharmacokinetics and immunogenicity.


Clinical trial identification

NCT05890742.


118TiP - Neoadjuvant CAPOX plus SCT510 (bevacizumab biosimilar) and finotonlimab in high-risk resectable colorectal liver metastases (CRLM): A multicenter, phase II study

Speakers：Wensheng Qiu(Qingdao, CN)


Background

Surgical resection remains the mainstay of curative-intent treatment for CRLM. Preoperative care, including chemotherapy or combined with immunotherapy (IO), has increased the proportion of patients (pts) eligible for curative-intent surgery. However, microsatellite stability (MSS) tumors are less likely to respond to IO. Based on the synergy of IO and anti-angiogenesis, their combination may lead to improved response in MSS CRLM. SCT510 is a recombinant anti-VEGF antibody, which has demonstrated equivalent safety, pharmacokinetics, and immunogenicity to bevacizumab. Finotonlimab is a novel anti-PD-1 agent and has proved effective for treating solid tumors. Herein, we conducted a prospective phase II study (NEO CPLUS) to evaluate the efficacy and safety of neoadjuvant CAPOX plus SCT510 and finotonlimab in high-risk resectable CRLM.


Trial design

NEO CPLUS is a multicenter, single-arm, investigator-initiated phase II study (ChiCTR2400085958). Approximately 100 patients will be enrolled. Eligible pts are aged 18-75 years and have histologically confirmed, resectable, high-risk (clinical risk score ≥3) CRLM. Resectability is defined as the technical ability to achieve complete resection, with only liver metastasis, and ≤6 metastatic tumors. Pts must have an ECOG PS of 0-2, MSS/pMMR disease, and adequate organ function. Pts will receive 3 cycles of CAPOX (130 mg/m2 oxaliplatin, day [D] 1 + 1000 mg/m2 capecitabine, D1-14, bid), SCT510 (7.5 mg/kg, D1) and finotonlimab (200 mg, D1), followed by 1 cycle of CAPOX plus finotonlimab in 21-day cycle. After 2-4 cycles, patients who are assessed as having a radiological response or stable disease per RECIST 1.1 will proceed with surgery within 4-6 weeks and be allowed to receive 4 cycles of adjuvant CAPOX plus SCT510. The primary endpoint is pathologic complete response. Secondary endpoints include 1-year progression-free survival rate, major pathological response, R0 resection, R1 resection, and safety.


Clinical trial identification

ChiCTR2400085958.


120TiP - Neoadjuvant short-course radiotherapy combined with chemotherapy and cadonilimab for patients with locally advanced rectal cancer: A prospective, single-arm phase II trial

Speakers：Jiawei Rao(Guangzhou, CN)


Background

Neoadjuvant chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer (LARC) as it effectively lowers the risk of local recurrence. However, the risk of distant metastasis remains comparatively high. Several clinical trials have suggested that the combination of short-course radiotherapy (SCRT) and PD-(L)1 inhibitor is likely to improve tumor response and prognosis. Cadonilimab (AK104), a novel bispecific antibody simultaneously targeting PD-1 and CTLA-4, is designed to boost anti-tumor activity with improved safety profile.Thus, Cadonilimab, to SCRT combined with chemotherapy might further increase the clinical beneft and prognosis for LARC patients.


Trial design

This phase II, single-center, single-arm clinical trial aims to evaluated the efficacy and safety of preoperative SCRT combined with CAPEOX (capecitabine and oxaliplatin) and cadonilimab in the treatment of LARC. Patients with histologically confirmed T3-4/N+M0 rectal adenocarcinoma will be enrolled. Other key eligibility criteria include: 18-70 years old, ECOG PS 0-1, treatment-naive and normal organ function. Patients (pts) receives 1 cycle of CAPEOX plus AK104 (10 mg/kg iv, d1, q3w) followed by SCRT (25Gy with daily fractions of 5Gy, administered at d8-12 ) and 2 cycles of CAPEOX plus AK104 (10 mg/kg iv, d1, q3w). Total mesorectal excision(TME) is performed 2 weeks after the last cycle of neoadjuvant treatment. After surgery, pts receive 5 cycles of adjuvant CAPEOX treatment. The primary endpoint is pathological complete response (pCR) rate.The secondary endpoints include major pathologic response rate (MPR), R0 resection rate, 1 and 3-year DFS rate, 1 and 3-year OS rate and safety. A Simon two-stage design was used. If 6 or more of the 15 patients achieved pCR in the first stage, another 22 pts would be accrued to the second stage. Tumor tissues and blood samples are collected for further exploration. As of June 2024, 10 patients have been enrolled. Clinical trial identification ChiCTR2300075658.


125TiP - Prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) for locally advanced colorectal cancer: A single-centre, open-label, randomized controlled trial

Speakers：Shiyu Xu(Guangzhou, CN)


Background

Colorectal cancer (CRC) is the third most common malignancy worldwide. Peritoneum recurrence is relatively common in CRC, and patients who progress to peritoneal carcinomatosis (PC) tend to have extremely poor prognosis. How to reduce peritoneal carcinomatosis and improve prognosis still are challenges for clinicians. Existing research have demonstrated that adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) can reduce the risk of peritoneal micrometastasis in ovarian cancer, appendiceal cancer, and gastric cancer, which provide insight in CRC.


Trial design

This study is an open-label, single-center, randomized prospective clinical trial aimed at evaluating whether prophylactic HIPEC can reduce the rate of peritoneal recurrence, prolong survival, and extend disease-free survival in cT3-T4a stage CRC patients with high-risk factors for peritoneal metastasis. Eligible patients are between 18 and 75 years old, with pathologically confirmed colorectal adenocarcinoma, no distant metastasis, eligible for standard curative surgery, ECOG performance status of 0-1, and able to tolerate postoperative HIPEC treatments, and have not received chemotherapy, radiotherapy, or other antitumor treatments prior to the trial. Intraoperatively, tumor lesions will be completely resected with lymphadenectomy performed. These patients will be randomized 1:1 into the experimental group and control group. Patients in experimental group will have four HIPEC catheters placed intraoperatively, and receive the first HIPEC treatment on the day of surgery or the first postoperative day (raltitrexed 4 mg, 43°C NS 3000ml, 60 minutes). The second HIPEC treatment will be administered within one week postoperatively (oxaliplatin 130mg/m2, 43°C 5% GS 3000ml). Both groups will receive systemic chemotherapy with CapeOX/capecitabine/mFOLFOX6 as appropriate one month after surgery. The primary endpoint is the 3-year peritoneal recurrence rate; secondary endpoints include 3-year DFS, 3-year and 5-year OS, postoperative quality of life, perioperative complication rates, and HIPEC toxicity (at 1 month and 6 months postoperatively).

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