Phase 1b/2 trial of fruquintinib plus sintilimab in treating advanced solid tumours: The dose-escalation and metastatic colorectal cancer cohort in the dose-expansion phases

Ye Guo; Weijie Zhang; Jieer Ying; Yanqiao Zhang; Yueyin Pan; Wensheng Qiu; Qingxia Fan; Qi Xu; Yue Ma; Gang Wang; Jing Guo; Weiguo Su; Songhua Fan; Panfeng Tan; Yan Wang; Yang Luo; Hui Zhou; Jin Li

doi:10.1016/j.ejca.2022.12.004

Phase 1b/2 trial of fruquintinib plus sintilimab in treating advanced solid tumours: The dose-escalation and metastatic colorectal cancer cohort in the dose-expansion phases

Eur J Cancer. 2023 Mar:181:26-37. doi: 10.1016/j.ejca.2022.12.004. Epub 2022 Dec 13.

Authors

Ye Guo¹, Weijie Zhang², Jieer Ying³, Yanqiao Zhang⁴, Yueyin Pan⁵, Wensheng Qiu⁶, Qingxia Fan², Qi Xu³, Yue Ma⁴, Gang Wang⁵, Jing Guo⁶, Weiguo Su⁷, Songhua Fan⁷, Panfeng Tan⁷, Yan Wang⁸, Yang Luo⁸, Hui Zhou⁸, Jin Li⁹

Affiliations

¹ Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
² The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
³ Zhejiang Cancer Hospital, Hangzhou, China.
⁴ Harbin Medical University Cancer Hospital, Harbin, China.
⁵ Anhui Provincial Hospital, Hefei, China.
⁶ The Affiliated Hospital of Qingdao University, Qingdao, China.
⁷ HUTCHMED Limited, Shanghai, China.
⁸ Innovent Biologics, Inc., Suzhou, China.
⁹ Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China. Electronic address: lijin@csco.org.cn.

PMID: 36628898
DOI: 10.1016/j.ejca.2022.12.004

Abstract

Background: Fruquintinib (anti-vascular endothelial growth factor 1/2/3) plus sintilimab (anti-programmed death-1) demonstrated enhanced anti-tumour effects versus monotherapy in a preclinical study. We investigated the combination in patients with advanced solid tumours, including metastatic colorectal cancer (mCRC).

Methods: In this phase 1b/2, open-label, multi-centre, multi-cohort dose-escalation and dose-expansion study, patients with advanced solid tumours (dose-escalation) or mCRC (one cohort in dose-expansion) received different doses of fruquintinib plus a fixed dose of sintilimab once every 4 weeks (Q4W) or 3 weeks (Q3W). Primary objectives were safety, tolerability, and the preliminary efficacy. This study is registered at ClinicalTrials.gov, NCT03903705.

Findings: By the data cut-off date (30th December 2021), 23 patients were enrolled in the dose-escalation and 37 patients in the mCRC cohort of the dose-expansion; 44 patients with mCRC who received sintilimab Q3W were pooled for analysis. One dose-limiting toxicity event (grade 3 troponin T increased) occurred during the dose escalation. Grade ≥3 treatment-related adverse events occurred in 43.5% and 47.7% of patients in the dose-escalation phase and pooled mCRC analysis, respectively. Among patients treated with the recommended phase 2 dose (fruquintinib 5 mg once daily, 2 weeks on/1 week off, plus sintilimab 200 mg Q3W) in pooled mCRC analysis, the objective response rate was 23.8% (95% CI 8.2-47.2), median progression-free survival was 6.9 months (95% CI 5.4-8.3), and overall survival was 14.8 months (95% CI 8.8-not reached); in patients with mismatch repair-proficient mCRC, these were 20.0% (95% CI 4.3-48.1), 6.9 months (95% CI 4.8-10.1), and 20.0 months (95% CI 8.1-not reached), respectively.

Interpretation: Fruquintinib plus sintilimab was well tolerated in patients with advanced solid tumours and showed promising efficacy in mCRC.

Keywords: Advanced solid tumors; Fruquintinib; Metastatic colorectal cancer; Sintilimab.

Publication types

Clinical Trial, Phase I
Clinical Trial, Phase II
Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal, Humanized / adverse effects
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Benzofurans* / adverse effects
Colonic Neoplasms*
Humans
Rectal Neoplasms* / etiology

Substances

sintilimab
HMPL-013
Antibodies, Monoclonal, Humanized
Benzofurans

Associated data

ClinicalTrials.gov/NCT03903705