Abstract PS8-06: A randomized, open-label phase III study comparing disitamab vedotin (an anti-HER2 monoclonal antibody-MMAE conjugate) with lapatinib plus capecitabine in patients with HER2-positive, advanced breast cancer with liver metastasis

Abstract Background: The prognosis of patients (pts) with HER2-positive, advanced breast cancer with liver metastasis is poor and there is no standard therapy recommended for this pts population. RC48-C006 is a randomized, multicenter, phase II/III clinical trial to compare disitamab vedotin (DV) versus lapatinib+capecitabine (L+C) in HER2-positive locally advanced or metastatic breast cancer in phase II part and in HER2-positive advanced breast cancer with liver metastasis in phase III part (ClinicalTrials.gov Identifier: NCT03500380). Here, we first report the phase III data. Methods: Key inclusion criteria were histologically/cytologically confirmed breast cancer with radiologically confirmed liver metastasis, HER2-positive (defined as IHC 3+ or FISH+), and prior treatment with trastuzumab and taxanes. Pts were randomized at 1:1 (stratification factors: prior lines of chemotherapy [≤1 or 2], and lung metastasis [yes or no]) to receive DV (2.0 mg/kg IV) every 2 weeks or lapatinib (1250 mg, orally daily) + capecitabine (2000 mg/m2, orally daily on days 1-14) every 3 weeks until occurrence of disease progression or unacceptable toxicity. Pts in L+C group were allowed to cross over to receive DV after disease progression. Tumor was assessed every 6 weeks (±7 days) as per RECIST v1.1. The primary endpoint was IRC (Independent Review Committee)-assessed progression-free survival (PFS); secondary endpoints included investigator-assessed PFS, OS, ORR, and DoR. The data cutoff date for this analysis was December 31, 2023. Results: As of the cutoff date, 104 pts from 39 sites in China were randomly assigned (53 in DV group and 51 in L+C group). At a median follow-up of 15.38 months for DV and 19.35 months for L+C, DV significantly improved IRC-assessed PFS vs L+C (median: 9.86 vs 4.90 months; HR: 0.561 [95%CI: 0.350-0.897]; P=0.0143), consistent with investigators’ assessment (HR: 0.621 [95% CI: 0.392-0.985], nominal P=0.0418). OS was immature with 25 events to data cutoff (median: not evaluable [NE] vs 25.92 months for DV vs L+C; HR: 0.563 [95% CI: 0.246-1.289]); after adjusting for crossover (21 pts) using the two-stage method, the HR was 0.410 (95% CI: 0.189-0.944). Per IRC, ORR was 58.5% vs 54.9%, and median DoR was 11.20 vs 6.97 months for DV and L+C groups, respectively. Among all treated pts, 22 (41.5%) of 53 in DV and 20 (40.0%) of 50 in L+C experienced grade ≥3 treatment-emergent adverse events (TEAEs), mostly (incidence ≥5%) neutrophil count decreased (18.9% vs 10.0%), gamma-glutamyltransferase increased (9.4% vs 0.0%), white blood cell count decreased (5.7% vs 4.0%), hypertriglyceridemia (5.7% vs 4.0%), hypokalemia (3.8% vs 8.0%), hand-foot syndrome (0.0% vs 10.0%), and diarrhea (0.0% vs 6.0%). No TEAEs led to death in either group. Conclusion: DV is the first HER2-targeting ADC that demonstrated significant PFS benefit vs L+C and an acceptable safety profile in pts population with HER2-positive breast cancer with liver metastasis. It provides a potential new standard treatment option for these pts. Funding: RemeGen Co., Ltd., Yantai, China. Citation Format: Jiayu Wang, Quchang Ouyang, Weimin Xie, Zhaofeng Niu, Qingyuan Zhang, Xi Yan, Yue'e Teng, Jianying Chang, Ying Cheng, Hongyan Xu, Jingfen Wang, Herui Yao, Zhuangqing Yang, Tao Sun, Zhongsheng Tong, Xinhong Wu, Yongsheng Wang, Enxiang Zhou, Xiangshun Kong, Xujuan Wang, De Zeng, Shanshan Gu, Dandan Gao, Zerui Qu, Chenran Han, Jianmin Fang, Binghe Xu. A randomized, open-label phase III study comparing disitamab vedotin (an anti-HER2 monoclonal antibody-MMAE conjugate) with lapatinib plus capecitabine in patients with HER2-positive, advanced breast cancer with liver metastasis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS8-06.