Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
UNASSIGNED: For the Chinese translation of the abstract see Supplementary Materials section.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: 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.
UNASSIGNED: For the Chinese translation of the abstract see Supplementary Materials section.
摘要：
背景：PD-1阻断在转移性和新辅助设置中对于错配修复缺陷的结直肠癌非常有效。我们旨在探讨局部晚期错配修复缺陷型结直肠癌患者PD-1阻断加血管生成抑制剂的新辅助治疗的活性和安全性，以及器官保存的可行性。
方法：我们启动了单臂，开放标签，2期试验（NEOCAP）在中山大学肿瘤中心和省中医院，广州,中国。18-75岁未治疗的错配修复缺陷或微卫星不稳定性高或POLE/POLD1突变的局部晚期结直肠癌患者（cT3或N+用于直肠癌，和侵袭≥5mm或T4的T3，结肠癌有或没有N）和东部肿瘤协作组表现评分为0-1，并在第1天静脉内给予200mg卡瑞珠单抗，从第1天开始口服250mg阿帕替尼-14，每3周一次，持续3个月，然后进行手术或6个月（如果患者未进行手术）。临床完全缓解的患者没有接受手术，而是采取了观察和等待的方法。主要终点是病理或临床完全缓解的患者比例。活性分析中纳入了符合条件的入选患者，这些患者接受了至少一个新辅助治疗周期，并且在基线评估后至少进行了一次肿瘤反应评估。接受至少一剂研究药物的患者被纳入安全性分析.该研究已在ClinicalTrials.gov（NCT04715633）注册，并且正在进行中。
结果：在2020年9月29日至2022年12月15日之间，招募了53名患者；一名患者被排除在活性分析之外，因为他们被发现是错配修复能力强和微卫星稳定的。23例（44%）患者为女性，29例（56%）为男性。中位随访时间为16·4(IQR10·5～23·5)个月。28例（54％；95％CI35-68）患者临床完全缓解，其中24例患者接受观察等待治疗，包括20例结肠癌和多原发结直肠癌患者。52例患者中有23例（44%）接受了原发肿瘤手术，14例（61%；95%CI39-80）出现病理完全缓解。52例患者中有38例（73％；95％CI59-84）完全缓解。53例患者中有20例（38%）发生3-5级不良事件；最常见的是转氨酶升高（6例[11%]）。肠梗阻（四[8%]），和高血压（四[8%]）。药物相关的严重不良事件发生在53例患者中的6例（11%）。一名患者死于治疗相关的免疫相关性肝炎。
结论：在局部晚期错配修复缺陷或微卫星不稳定性高的结直肠癌患者中，新辅助卡司单抗联合阿帕替尼显示有希望的抗肿瘤活性。应高度警惕地监测免疫相关的不良事件。不仅在直肠癌患者中，器官保存似乎很有希望，而且在那些有临床完全反应的结肠癌患者中也是如此。需要更长时间的随访来评估观察和等待方法的肿瘤学结果。
背景：国家自然科学基金,广东省基础与应用基础研究基金会,和中山大学肿瘤防治中心肿瘤创新研究计划。
■有关摘要的中文翻译，请参见补充材料部分。
方法：我们启动了单臂，开放标签，2期试验（NEOCAP）在中山大学肿瘤中心和省中医院，广州,中国。18-75岁未治疗的错配修复缺陷或微卫星不稳定性高或POLE/POLD1突变的局部晚期结直肠癌患者（cT3或N+用于直肠癌，和侵袭≥5mm或T4的T3，结肠癌有或没有N）和东部肿瘤协作组表现评分为0-1，并在第1天静脉内给予200mg卡瑞珠单抗，从第1天开始口服250mg阿帕替尼-14，每3周一次，持续3个月，然后进行手术或6个月（如果患者未进行手术）。临床完全缓解的患者没有接受手术，而是采取了观察和等待的方法。主要终点是病理或临床完全缓解的患者比例。活性分析中纳入了符合条件的入选患者，这些患者接受了至少一个新辅助治疗周期，并且在基线评估后至少进行了一次肿瘤反应评估。接受至少一剂研究药物的患者被纳入安全性分析.该研究已在ClinicalTrials.gov（NCT04715633）注册，并且正在进行中。
结果：在2020年9月29日至2022年12月15日之间，招募了53名患者；一名患者被排除在活性分析之外，因为他们被发现是错配修复能力强和微卫星稳定的。23例（44%）患者为女性，29例（56%）为男性。中位随访时间为16·4(IQR10·5～23·5)个月。28例（54％；95％CI35-68）患者临床完全缓解，其中24例患者接受观察等待治疗，包括20例结肠癌和多原发结直肠癌患者。52例患者中有23例（44%）接受了原发肿瘤手术，14例（61%；95%CI39-80）出现病理完全缓解。52例患者中有38例（73％；95％CI59-84）完全缓解。53例患者中有20例（38%）发生3-5级不良事件；最常见的是转氨酶升高（6例[11%]）。肠梗阻（四[8%]），和高血压（四[8%]）。药物相关的严重不良事件发生在53例患者中的6例（11%）。一名患者死于治疗相关的免疫相关性肝炎。
结论：在局部晚期错配修复缺陷或微卫星不稳定性高的结直肠癌患者中，新辅助卡司单抗联合阿帕替尼显示有希望的抗肿瘤活性。应高度警惕地监测免疫相关的不良事件。不仅在直肠癌患者中，器官保存似乎很有希望，而且在那些有临床完全反应的结肠癌患者中也是如此。需要更长时间的随访来评估观察和等待方法的肿瘤学结果。
背景：国家自然科学基金,广东省基础与应用基础研究基金会,和中山大学肿瘤防治中心肿瘤创新研究计划。
■有关摘要的中文翻译，请参见补充材料部分。
