Phase II study of anlotinib in combination with oxaliplatin and capecitabine for patients with RAS/BRAF wild-type metastatic colorectal adenocarcinoma as the first-line therapy

Yue Liu, Qian Xiao, Jinjie He, Hanguang Hu, Jinlin Du, Yuping Zhu, Jiaqi Chen, Zhuo Liu, Jianping Wang, Lifeng Sun, Dong Xu, Jun Li, Xiujun Liao, Jianwei Wang, Yibo Cai, Cheng Cai, Zhekang Jin, Liuhong Wang, Ying Yuan, Kefeng Ding, Yue Liu, Qian Xiao, Jinjie He, Hanguang Hu, Jinlin Du, Yuping Zhu, Jiaqi Chen, Zhuo Liu, Jianping Wang, Lifeng Sun, Dong Xu, Jun Li, Xiujun Liao, Jianwei Wang, Yibo Cai, Cheng Cai, Zhekang Jin, Liuhong Wang, Ying Yuan, Kefeng Ding

Abstract

Background: Anlotinib, an oral small molecule tyrosine kinase inhibitor targeting VEGFR 1/2/3, FGFR 1-4, PDGFR a/β, and c-kit, had demonstrated prolonged progression-free survival (PFS) in refractory metastatic colorectal cancer (mCRC). This multicenter, single-arm, phase II, exploratory study was conducted to evaluate the efficacy and safety of anlotinib combined with capecitabine and oxaliplatin as first-line treatment for unresectable RAS/BRAF wild-type mCRC.

Methods: Patients aged 18-75 with RAS/BRAF wild-type unresectable mCRC, without prior systemic treatment, and ECOG performance status ≤1 were enrolled. Eligible patients received capecitabine (850 mg/m2, p.o., bid, on day 1-14 every 21 days), oxaliplatin (130 mg/m2, i.v., on day 1 every 21 days), and anlotinib (12 mg, p.o., qd, on days 1-14 every 21 days) as induction therapy. Following 6 cycles of therapy, patients who achieved response or stable disease received capecitabine and anlotinib as maintenance therapy until tumor progression. The primary endpoint was objective response rate (ORR) according to RECIST (version: 1.1), and the secondary endpoints were PFS, disease control rate (DCR), duration of response (DOR), and safety.

Results: Between November 2019 and February 2021, 31 patients were enrolled. One patient was excluded for refusing treatment. The primary endpoint of ORR was 76.7% (95% CI, 57.7-90.1) with 1 patient achieving a complete response and 22 patients partial response. DCR was 93.3% (95% CI, 77.9-99.2). At a median follow-up of 14.1 months (95% CI, 9.9-18.3), median PFS was 11.3 months (95% CI, 7.1-14.1), and DOR was 7.9 months (95% CI, 5.5-12.7). Twenty-five (83.3%) patients experienced grade 3 or 4 treatment-emergent adverse events (TEAEs). No grade 5 TEAE was reported. The most common grade 3 or 4 TEAEs (>10%) were hypertension (15/30; 50%), neutrophil count decreased (8/30; 26.7%), and diarrhea (4/30; 13.3%). A total of 18 (60%) patients had TEAEs that resulted in dose reduction, interruptions, or delays.

Conclusions: Anlotinib combined with capecitabine and oxaliplatin showed considerable ORR, DCR, PFS, and DOR in the first-line therapy of mCRC with manageable toxicity profiles.

Trial registration: ClinicalTrials.gov : NCT04080843.

Keywords: Anlotinib; Capecitabine; First-line therapy; Metastatic colorectal cancer; Oxaliplatin.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Therapy procedures (21-day cycle). Oxaliplatin:130mg/m2, ivgtt, d1; anlotinib: 12mg, po, qd, d1–14; capecitabine: 850mg/m2, po, bid, d1–14
Fig. 2
Fig. 2
CONSORT diagram. 30 patients had ≥1 dose of the treatment regimen. b 30 patients received ≥1 dose of treatment regimen and safety had been recorded after administration. c The data cutoff date was October 15, 2021
Fig. 3
Fig. 3
The best change in target lesion diameter from baseline (full analysis set, N = 30)
Fig. 4
Fig. 4
Estimates of the progression-free survival using Kaplan-Meier analysis (full analysis set, N = 30)
Fig. 5
Fig. 5
Swimmer plots of patients. Patients who received anlotinib plus oxaliplatin and capecitabine as first-line therapy in RAS/BRAF wild-type unresectable mCRC

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