Surufatinib plus tislelizumab as later-line therapy for metastatic colorectal cancer: a single-arm, phase II trial

BACKGROUND: Metastatic colorectal cancer (mCRC) patients who progress following the standard chemotherapy have maintained a favourable performance status. Nevertheless, there are limited effective treatment options, particularly for a considerable proportion of tumours with a microsatellite-stable (MSS) phenotype. Based on strong preclinical evidence demonstrating the synergistic effect between an anti-PD-1 antibody, tislelizumab, and an anti-VEGFR1-3 antibody, surufatinib, we evaluated their efficacy and safety in this population of patients with treatment-refractory disease. METHODS: This single-arm phase II study that recruited patients with histologically confirmed mCRC who had received ≥ 3 previous lines of systemic therapy. Critical eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0 to 1 and measurable disease according to RECIST version 1.1. Patients were administered 200 mg tislelizumab intravenously every 3 weeks combined with surufatinib 250 mg orally once daily until progressive disease, intolerable toxicity, or withdrawal of consent. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the disease control rate (DCR), overall survival (OS), objective response rate (ORR), and safety. RESULTS: Sixteen patients (median age, 58 years) were enrolled between March 2022 and April 2025. The study was prematurely terminated for futility at a pre-planned ad hoc analysis. Only one patient achieved stable disease with a DCR of 6.3%, which did not meet the pre-defined threshold for continuation. The median PFS and OS were 52 days (95% confidence interval (CI): 46–73) and 157 days (95% CI: 91–not reached), respectively. The treatment-related adverse events (TRAEs) were controllable. Grade ≥ 3 TRAEs were encountered in 31.3% of patients. Hypokalaemia (31.3%), hypoalbuminaemia (50.0%), and anaemia (31.3%) were most prevalent. No treatment-related death occurred. CONCLUSIONS: Although there was a sound preclinical rationale and an urgent clinical need for effective later-line therapies of mCRC, tislelizumab combined with surufatinib demonstrated limited antitumour activity and failed to achieve the primary endpoint. This negative trial underscores the treatment difficulties associated with MSS mCRC and emphasises that immunotherapy and anti-angiogenic therapy are insufficient as monotherapies. Future studies should focus on biomarker-informed patient selection and rationally designed combination approaches to overcome resistance to immunotherapy in MSS mCRC. TRIAL REGISTRATION: ChiCTR2200059848. Registration date: 2022/05/12. (Retrospectively registered).