Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
Department of Biotherapy Center, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
Lancet Oncol. 2024 Jul;25(7):843-852. doi: 10.1016/S1470-2045(24)00203-1. Epub 2024 Jun 6.
PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer.
We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18-75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0-1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1-14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing.
Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5-23·5) months. 28 (54%; 95% CI 35-68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39-80) had a pathological complete response. 38 (73%; 95% CI 59-84) of 52 patients had a complete response. Grade 3-5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis.
Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach.
The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center.
For the Chinese translation of the abstract see Supplementary Materials section.
PD-1 阻断在转移性和新辅助环境中均对错配修复缺陷型结直肠癌具有高度疗效。我们旨在探索 PD-1 阻断联合血管生成抑制剂新辅助治疗的活性和安全性，以及在局部晚期错配修复缺陷型结直肠癌患者中进行器官保留的可行性。
我们在中国中山大学肿瘤防治中心和广东省中医院启动了一项单臂、开放标签、Ⅱ期试验（NEOCAP）。年龄在 18-75 岁之间、未经治疗的错配修复缺陷或微卫星不稳定高或 POLE/POLD1 突变的局部晚期结直肠癌（直肠癌 cT3 或 N+，结肠癌 T3 伴有浸润≥5mm 或 T4，伴有或不伴有 N+）且东部肿瘤协作组体能状态评分为 0-1 的患者被纳入研究，并在第 1 天和第 14 天接受 200mg 卡瑞利珠单抗静脉注射，第 1 天至 14 天接受 250mg 阿帕替尼口服治疗，每 3 周一次，共 3 个月，随后进行手术，如患者未进行手术则继续治疗 6 个月。临床完全缓解的患者无需手术，继续采用观察等待策略。主要终点是病理或临床完全缓解患者的比例。纳入的合格患者至少接受了一个周期的新辅助治疗，并在基线评估后至少有一次肿瘤反应评估，纳入活性分析，至少接受一剂研究药物的患者纳入安全性分析。该研究在 ClinicalTrials.gov（NCT04715633）上注册，正在进行中。
2020 年 9 月 29 日至 2022 年 12 月 15 日期间，共纳入 53 例患者，其中 1 例患者因错配修复有功能和微卫星稳定而被排除在活性分析之外。23 例（44%）患者为女性，29 例（56%）为男性。中位随访时间为 16.4 个月（IQR 10.5-23.5）。28 例（54%；95%CI 35-68）患者临床完全缓解，其中 24 例采用观察等待策略，包括 20 例结肠癌和多发性结直肠原发癌患者。52 例患者中有 23 例（44%）接受了原发肿瘤手术，其中 14 例（61%；95%CI 39-80）患者病理完全缓解。52 例患者中 38 例（73%；95%CI 59-84）患者完全缓解。53 例患者中有 20 例（38%）发生 3-5 级不良事件，最常见的是氨基转移酶升高（6 例[11%]）、肠梗阻（4 例[8%]）和高血压（4 例[8%]）。53 例患者中有 6 例（11%）发生药物相关严重不良事件。1 例患者因治疗相关免疫性肝炎死亡。
局部晚期错配修复缺陷或微卫星不稳定高的结直肠癌患者，新辅助卡瑞利珠单抗联合阿帕替尼显示出有希望的抗肿瘤活性。应高度警惕免疫相关不良事件。不仅在直肠癌患者中，而且在有临床完全缓解的结肠癌患者中，器官保留似乎也很有前景。需要更长时间的随访来评估观察等待策略的肿瘤学结果。
国家自然科学基金、广东省基础与应用基础研究基金、中山大学肿瘤防治中心癌症创新研究计划。
