Disitamab vedotin combined with fruquintinib in patients with HER2-expressing or HER2 mutation/amplified metastatic colorectal cancer refractory to at least two standard regimens: A prospective, exploratory, single-arm study.

Abstract

e15562 Background: Human epidermal receptor growth factor 2 (HER2) -expressing or amplified has been identified in 2-6% of patients with stage III/IV colorectal cancer (CRC).however,there are currently no approved HER2-targeted therapies for CRC in China. Herein, we aimed to investigate the antitumor activity and safety of Disitamab vedotin , a novel humanized anti-HER2 antibody conjugate linked to monomethyl auristatin E via a cleavable linker, in combined with fruquintinib in patients with HER2-expressing or -amplified metastatic colorectal cancer. Methods: In this prospective, exploratory, single-arm study, patients diagnosed pathologically with mCRC, 18-75 years old harboring HER2 expression or HER2 mutation/amplification, and received at least two prior lines of treatment. HER2 expression was defined as animmunohistochemical [IHC]score of 1+, 2+ or 3+, or mutation/amplification identified by NGS. Patients received RC48 2.5mg/kg intravenously every 2 weeks. Meanwhile, fruquintinib was administered orally at 3 mg once daily until disease progression, death, intolerable toxicity, withdrawal of consent. The primary endpoint was ORR ; the secondary endpoints included DCR, PFS, OS and safety. Results: A total of 24 patients were enrolled from Nov 25, 2022 to Dec 16, 2024.HER2 statuses are as follows: 11 patients had IHC 1+ (one of whom had HER2 amplification), 6 had IHC 2+, 4 had IHC 3+, and 3 had HER2 amplification. In the metastatic setting, patients had received a median of 3 prior lines of therapy (range, 2-6). The ORR was 13.6% (3/22) and DCR was 77.3% (17/22). The median PFS was 4.11 months (95% CI: 2.56-5.65) and the median OS was 10.45 months (95% CI: 5.93-13.97). The 9-month OS rate was 55.0%, and the 12-month OS rate was 40.7%. Among the 14 patients with HER2 IHC 2+, IHC 3+ and HER2- amplification, the ORR was 23.1% (3/13), and the DCR was 84.6% (11/13)，the median PFS was 5.78 months (95% CI: 3.33-8.24) and the 9-month OS rate was 66.1%, the 12-month OS rate was 45.3%. 22 (91.7%) patients experienced adverse events , of whom 6 (27.3%) experienced grade 3 TRAEs . The most common grade 3 TRAEs were leukopenia (12.5%), neutropenia (8.3%), hyponatremia (4.2%) and hypokalemia (4.2%). No grade 4 or 5 TRAEs were observed. Additionally, 8 (33.3%) patients required dose reduction. And No patients experienced dose interruption or discontinuation due to TRAEs. Conclusions: The combination of RC48 and fruquintinib has demonstrated promising efficacy and a manageable safety in patients with HER2 -expressing or -amplified mCRC who have failed at least two lines of standard treatments.Patients with HER2 IHC 2+, 3+ and amplification appear to derive greater benefit from this therapeutic regimen. Clinical trial information: NCT05661357 .