RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with HER2-positive and HER2-low expressing advanced or metastatic breast cancer: A pooled analysis of two studies.
Authors: Jiayu Wang, Yunjiang Liu, Qingyuan Zhang, Jifeng Feng, Jianmin Fang, Xuelian Chen, Yiqun Han, Qing Li, Pin Zhang, Peng Yuan, Fei Ma, Yang Luo, Ying Fan, Ruigang Cai, Shanshan Chen, Qiao Li, Yiqun Li, Binghe Xu
Journal: Journal of Clinical Oncology (2021)

1022 Background: Currently, there are no standard ≥3 line regimens recommended for HER2-positive (IHC 3+, or IHC 2+/FISH+) advanced or metastatic breast cancer, and no recommended HER2-targeting treatment for HER2-low expressing (IHC 2+/FISH-, or IHC 1+) population. RC48-ADC is an innovative HER2-targeting antibody-drug conjugate with a cleavable linker and a potent microtubule inhibitor payload MMAE that has a bystanding effect in tumor cell killing. Methods: C001 CANCER (NCT02881138) was a dose-escalation phase I study (0.5, 1.0, 1.5, 2.0, and 2.5 mg/kg) with the 3+3 design among HER2-positive patients. C003 CANCER (NCT03052634) was a phase Ib study with 1.5, 2.0, and 2.5 mg/kg doses in the HER2-positive subgroup and 2.0 mg/kg dose in both IHC 2+/FISH-, and IHC 1+ HER2-low expressing subgroup. C003 CANCER is currently ongoing for IHC 1+ patients. Pooled analysis of the two studies was conducted for the efficacy and safety of RC48-ADC in HER2-positive or HER2-low expressing subgroups. Results: At the time of data cutoff (December 31, 2020), 118 female breast cancer patients were enrolled and treated with RC48-ADC. 70 patients (59.3%) were HER2-positive and 48 patients (40.7%) were HER2-low expressing. At baseline, 77 patients (65.3%) had liver metastases, 50 patients (42.4%) were ECOG PS 1, 47 patients (39.8%) had received ≥3 prior chemotherapy regimens. In the HER2-positive subgroup, ORRs for 1.5, 2.0, and 2.5 mg/kg doses were 22.2% (95% CI: 6.4%, 47.6%), 42.9% (95% CI: 21.8%, 66.0%), and 40.0% (95% CI: 21.1%, 61.3%). mPFSs for 1.5, 2.0, and 2.5 mg/kg cohorts were 4.0 months (95% CI: 2.6, 7.6), 5.7 months (95% CI: 5.3, 8.4) and 6.3 months (95% CI: 4.3, 8.8). In the HER2-low expressing subgroup, the ORR and mPFS were 39.6% (95% CI: 25.8%, 54.7%) and 5.7 months (95% CI: 4.1, 8.3). ORR and mPFS for IHC2+/FISH- patients were 42.9% (15/35) and 6.6 months (95% CI: 4.1, 8.5). For IHC1+ patients, even though the COVID-19 pandemic led to treatment postpone for some patients, ORR and mPFS reached 30.8% (4/13) and 5.5 months (95% CI: 2.7, 11.0). The common treatment-related adverse events (TRAEs) were AST increased (64.4%), ALT increased (59.3%), hypoesthesia (58.5%), white blood cell count decreased (48.3%), and neutrophil count decreased (47.5%); most were grade 1-2 in severity. Neutrophil count decreased (16.9%), GGT increased (12.7%), and fatigue (11.9%) were the grade 3 and above TRAEs occurring in ≥ 10% of the overall population. Conclusions: RC48-ADC showed consistent efficacy in HER2-positive and HER2-low expressing subgroups. The 2.0 mg/kg Q2W showed a more favorable benefit-risk ratio than other dose levels. No new safety signals were observed. Further studies are initiated to evaluate the efficacy and safety of RC48-ADC in various settings. Clinical trial information: NCT02881138; NCT03052634 .