Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial

Xuefeng Fang; Ning Zhu; Chenhan Zhong; Liuhong Wang; Jun Li; Shanshan Weng; Hanguang Hu; Caixia Dong; Dan Li; Yongmao Song; Dong Xu; Jianwei Wang; Lifeng Sun; Jian Wang; Zhanhuai Wang; Hongfeng Cao; Xiujun Liao; Ningjuan Yu; Qian Xiao; Mi Mi; Suzhan Zhang; Kefeng Ding; Ying Yuan

doi:10.1016/j.eclinm.2023.102123

Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial

EClinicalMedicine. 2023 Jul 27:62:102123. doi: 10.1016/j.eclinm.2023.102123. eCollection 2023 Aug.

Authors

Xuefeng Fang¹, Ning Zhu¹, Chenhan Zhong¹, Liuhong Wang², Jun Li³, Shanshan Weng¹, Hanguang Hu¹, Caixia Dong¹, Dan Li¹, Yongmao Song³, Dong Xu³, Jianwei Wang³, Lifeng Sun³, Jian Wang³, Zhanhuai Wang³, Hongfeng Cao³, Xiujun Liao³, Ningjuan Yu¹, Qian Xiao³, Mi Mi¹, Suzhan Zhang⁴, Kefeng Ding^{3

4

5

6}, Ying Yuan^{1

4

5

6}

Affiliations

¹ Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
² Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
³ Department of Colorectal Surgery and Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
⁴ Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
⁵ Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, Zhejiang, 310009, China.
⁶ Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.

Abstract

Background: Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Chemotherapy and anti-angiogenesis therapy have been reported to potentially promote immunotherapy response. This study aims to assess the preliminary anti-tumor activity and safety of sintilimab plus bevacizumab, oxaliplatin and capecitabine as a treatment option for patients with RAS-mutant MSS mCRC.

Methods: This study was an open-label, single-arm, phase II trial in China. Patients with unresectable, RAS-mutant and MSS metastatic colorectal adenocarcinoma received treatment by intravenous sintilimab (200 mg, day 1) plus bevacizumab (7.5 mg/kg, day 1), oxaliplatin (135 mg/m², day 1) and oral capecitabine (1 g/m², day 1-14) in each 21-day cycle. The primary endpoints included objective response rate (ORR) and adverse events. Biomarker analysis was performed to identify potential predictors of good response to treatment. This study is registered with ClinicalTrials.gov, number NCT04194359.

Findings: Between April 2021 and December 2021, 25 patients were enrolled. Two (8%) patients showed complete response (CR), 19 (76%) had partial response (PR) and 4 (16%) presented with stable disease. ORR reached 84% (95% CI, 63.9-95.5) and the disease control rate was 100% (95% CI, 86.3-100). The median progression-free survival (PFS) was 18.2 months for the full analysis set. The most common treatment-related adverse events (TRAEs) in all grades were anemia (21/25, 84%), neutropenia (20/25, 80%), and hand-foot syndrome (14/25, 56%). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25, 12%) and increased alanine transaminase (2/25, 8%). No grade 5 adverse events occurred. In the exploration of biomarkers, 5 patients could be characterized as TTN/OBSCN "double-hit" after treatment, and the copy number variants burden was significantly decreased in tumor tissues after treatment compared with the baseline. Nanostring panel RNA sequencing analysis indicated a better tumor immune microenvironment cell infiltration in CR/PR patients compared with non-CR/PR patients as well as the PFS-long (≥12.5 months) group compared with the PFS-short group.

Interpretation: Combination treatment with sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line treatment demonstrated a promising antitumor activity and a manageable safety profile in RAS-mutant, MSS and unresectable mCRC. Exploratory biomarker assessment analysis showed that some RAS-mutant and MSS patients changed into "immune-hot" subtype after the treatment.

Funding: This study was supported by the Key R&D Program of Zhejiang Province (2021C03125 to Ying Yuan), the National Natural Science Foundation of China (81872481 to Ying Yuan, 82072624 to Kefeng Ding), the Fundamental Research Funds for the Central Universities (No. 226-2022-00009 to Kefeng Ding), and the Zhejiang Provincial Natural Science Foundation of China (No. LY22H160024 to Hanguang Hu).

Keywords: Immune checkpoint inhibitors; Metastatic colorectal cancer; Microsatellite stable; PD-1; RAS mutation.

Associated data

ClinicalTrials.gov/NCT04194359