First-line serplulimab plus HLX04 and XELOX versus placebo plus bevacizumab and XELOX in metastatic colorectal cancer: A phase 2/3 study.
Authors: Feng Wang, Zi-Xian Wang, Junjie Peng, Xinjun Liang, Ying Cheng, Yanhong Deng, Kehe Chen, Mingjun Zhang, Jingdong Zhang, Wei Wang, Bangwei Cao, Yongdong Jin, Meili Sun, Yuan Lin, Suxia Luo, Zhen Li, Liu Yang, Jing Li, Qingyu Wang, Rui-Hua Xu
Journal: Journal of Clinical Oncology (2024)

3569 Background: This is a randomized, double-blind, multicenter phase 2/3 study comparing the efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus HLX04 (an approved bevacizumab biosimilar) and XELOX chemotherapy vs. placebo plus bevacizumab and XELOX as first-line treatment for metastatic colorectal cancer (mCRC). Interim analysis presented at the 2024 ASCO Gastrointestinal Cancers Symposium showed improvement in progression-free survival (PFS), and duration of response (DOR) for the serplulimab arm. Here we present the updated results with an extended follow-up duration of 24.2 months and the subgroup analysis results. Methods: In the phase 2 part, 114 patients with mCRC and no prior systemic therapy were randomized 1:1 (serplulimab arm, n = 57; placebo arm, n = 57) to receive intravenous (IV) serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (IV oxaliplatin [130 mg/m 2 ] and oral capecitabine [1000 mg/m 2 ]) (group A) or placebo plus bevacizumab and XELOX (group B) once every 3 weeks. Stratification factors were PD-L1 expression level, ECOG PS score, and primary tumor site. The primary endpoint was independent radiological review committee (IRRC)-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: By the data cutoff of December 15, 2023, continuing improvements in PFS (16.8 vs. 10.7 months; stratified HR 0.62, 95% CI 0.33–1.12) and DOR (19.4 vs. 12.6 months; stratified HR 0.33, 95% CI 0.13–0.85) were observed for group A compared to group B. 55/112 (49.1%) patients in the efficacy evaluable set has died; 24/55 (43.6%) patients in group A and 31/57 (54.4%) in group B. Median overall survival (OS) was not reached (NR) in group A, and 21.2 months in group B (stratified HR 0.75, 95% CI 0.43–1.30). Subgroup analysis showed similar trends towards an improved median OS for key subgroups including microsatellite stable (MSS) (NR vs. 21.2 months; stratified HR 0.73, 95% CI 0.39–1.37), KRAS-mutant (21.9 vs. 18.2 months; unstratified HR 0.72, 95% CI 0.37–1.39), and liver metastasis (NR vs. 20.2 months; unstratified HR 0.75, 95% CI 0.40–1.41) patients. The estimated OS rate at 2 years was 53.7% (95% CI 39.1–66.2), and 43.1% (95% CI 29.5–55.9) in group A, and group B, respectively. 38 (69.1%) patients in group A and 34 (59.6%) in group B had grade ≥3 treatment-related adverse events. Serplulimab/placebo-related deaths occurred in 2 (3.6%) patients in group A and 1 (1.8%) patient in group B. Conclusions: With an extended follow-up duration, improved survival benefits demonstrated with the addition of serplulimab were maintained in the first-line treatment of mCRC, alongside a manageable safety profile. These results support serplulimab plus HLX04 and XELOX as a promising first-line treatment option for mCRC that warrants further investigation. Clinical trial information: NCT04547166 .