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.

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 .