Combination of anlotinib and irinotecan in the second-line treatment of patients with advanced colorectal cancer: An open-label, multicenter phase I/II study.

Abstract

e16036 Background: Efficacious therapeutic options for advanced colorectal cancer (CRC) are limited, and treatment outcomes remain to be improved in the second-line setting. Anlotinib is a multi-target antiangiogenic small molecule that primarily inhibits VEGFR1/2/3. We conducted this open-label, multi-center phase 1/2 study to evaluate the safety and efficacy of anlotinib plus irinotecan in patients with previously treated advanced CRC. Methods: We enrolled patients with advanced CRC whose disease had progressed after first-line systemic therapy and had not previously received irinotecan. In the 3+3 dose escalation (phase 1) part of the trial, patients received anlotinib (8mg, 10mg and 12mg, po, 2 weeks on/1 week off) in combination with fixed-dose irinotecan (180mg/m2, iv, q2w) to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). In the dose-expansion (phase 2) part, patients were treated with the RP2D of anlotinib and irinotecan. The primary endpoints were MTD and objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and disease control rate (DCR). Results: A total of 31 patients were enrolled from 2 centers between May 2018 and Jan 2020. The median follow-up duration was 12.48m (95% CI 7.43-15.24). Anlotinib was well tolerated in combination with irinotecan with no MTD identified in the phase 1 part, and the RP2D was therefore 12mg. Twenty-eight patients were evaluable for efficacy analysis. Eight patients achieved partial response (PR), in which 6 had confirmed PR and 2 were unconfirmed. The ORR was 21.4% (95%CI 8.3%-41.0%) and the DCR was 100% (95%CI 87.7%-100%). The median PFS and OS were 6.97m (95%CI 3.71-11.20) and 13.87m (95%CI 11.47-NR), respectively. All patients were included in the safety analysis. The most common grade 3 treatment-related adverse events (AEs) (≥5%) were diarrhea (16.1%), neutropenia (12.9%), fatigue (6.5%) and hypertension (6.5%). Grade 4 AEs included neutropenia (6.5%) and thrombocytopenia (3.2%). There were no treatment-related deaths. Conclusions: The combination of anlotinib and irinotecan had promising anti-tumor activity in the second-line treatment of advanced CRC with a manageable safety profile. Clinical trial information: NCT03545711 . [Table: see text]