[Combination of anlotinib and irinotecan in the second-line treatment of metastatic colorectal cancer: a multicenter phase 1/2 trial].

Objective: To evaluate the safety and efficacy of anlotinib plus irinotecan in the second-line treatment of patients with metastatic colorectal cancer (mCRC). Methods: This prospective phase 1/2 study was conducted in 2 centers in China (Cancer Hospital of Chinese Academy of Medical Sciences and Jiangsu Province Hospital). We enrolled patients with mCRC whose disease had progressed after first-line systemic therapy and had not previously treated with irinotecan to receive anlotinib plus irinotecan. In the phase 1 of the trial, patients received anlotinib (8 mg, 10 mg or 12 mg, po, 2 weeks on/1 week off) in combination with fixed-dose irinotecan (180 mg/m(2), iv, q2w) to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). In the phase 2, patients were treated with the RP2D of anlotinib and irinotecan. The primary endpoints were MTD and objective response rate (ORR). Results: From May 2018 to January 2020, a total of 31 patients with mCRC were enrolled. Anlotinib was well tolerated in combination with irinotecan with no MTD identified in the phase 1, and the RP2D was 12 mg. Thirty patients were evaluable for efficacy analysis. Eight patients achieved partial response, and 21 had stable disease, 1 had progressive disease. The ORR was 25.8% and the disease control rate was 93.5%. With a median follow-up duration of 29.5 months, the median progression-free survival and overall survival were 6.9 months (95% CI: 3.7, 9.3) and 17.6 months (95% CI: 12.4, not evaluated), respectively. The most common grade 3 treatment-related adverse events (≥10%) were neutropenia (25.8%) and diarrhea (16.1%). There was no treatment-related death. Conclusion: The combination of anlotinib and irinotecan has promising anti-tumor activity in the second-line treatment of mCRC with a manageable safety profile.目的： 探讨安罗替尼联合伊立替康用于转移性结直肠癌患者二线治疗的安全性和疗效。 方法： 研究为前瞻性Ⅰ/Ⅱ期临床研究，在中国医学科学院肿瘤医院和江苏省人民医院开展。研究入组经一线治疗失败且未接受过伊立替康治疗的晚期结直肠癌患者，给予安罗替尼联合伊立替康治疗。研究分Ⅰ期和Ⅱ期两部分。Ⅰ期阶段，伊立替康采用固定剂量(180 mg/m(2)静脉输注，每2周重复)，安罗替尼进行剂量递增(8、10和12 mg每日1次口服，连续2周停药1周，每3周重复)，观察剂量限制性不良反应，并确定Ⅱ期推荐剂量，应用于Ⅱ期阶段的治疗。主要研究终点为安罗替尼的最大耐受剂量和联合治疗的客观有效率(ORR)。 结果： 2018年5月至2020年1月，共纳入31例晚期结直肠癌患者。Ⅰ期阶段未观察到剂量限制性不良反应，未达到最大耐受剂量，Ⅱ期阶段安罗替尼的推荐剂量确定为12 mg/d。全组患者中30例可评估疗效，部分缓解8例，疾病稳定21例，疾病进展1例；ORR为25.8%(8/31)，疾病控制率为93.5%(29/31)。中位随访时间29.5个月，全组患者的中位无进展生存时间为6.9个月(95% CI：3.7~9.3个月)，中位总生存时间为17.6个月(95% CI：12.4个月~未达到)。全组患者中发生率>10%的3~4级治疗相关不良事件为粒细胞减少(25.8%，8/31)和腹泻(16.1%，5/31)，未发生治疗相关死亡事件。 结论： 安罗替尼联合伊立替康在晚期结直肠癌患者的二线治疗中表现出良好的安全性和抗肿瘤活性。.