Abstract PD4-06: Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer
Authors: Xu Binhe , Wang Jiayu , Fang Jianmin , Chen Xuelian , Han Yiqun , Li Qing , Zhang Pin , Yuan Peng , Ma Fei , Luo Yang , Fan Ying , Cai Ruigang , Chen Shanshan , Li Qiao 
Published: March 2020

Abstract
Background: RC48-ADC is a novel HER2-targeting antibody-drug conjugate (ADC) that selectively delivers anticancer agent MMAE into HER2 overexpression tumor cells. We report the clinical outcomes of RC48-ADC in the HER2 positive metastatic breast cancer (MBC) which consist of phase 1 study (C001 CANCER, NCT02881138) and phase 1b study (C003 CANCER, NCT03052634).
Methods: Patients with HER2 positive (IHC 3+ or IHC 2+ & FISH amplification) locally advanced or metastatic breast cancer were enrolled in both studies. C001 CANCER was a dose-escalation study (0.5, 1.0, 1.5, 2.0 and 2.5 mg/kg) with 3+3 design aiming to evaluate the maximum tolerated dose (MTD). C003 CANCER was an open-label, parallel design with 3 dose cohorts (1.5, 2.0 and 2.5 mg/kg, Q2W) aiming to determine the recommended phase 2 dose. Pooled analysis of two studies was conducted for the efficacy and safety profile.
Results: In C001 CANCER, 3 (0.5 mg/kg), 3 (1.0 mg/kg), 3 (1.5 mg/kg), 6 (2.0 mg/kg) and 9 patients (2.5 mg/kg) were enrolled in each dose cohort respectively. In C003 CANCER, 46 patients were enrolled in 1.5 mg/kg (15 patients), 2.0 mg/kg (15 patients) and 2.5 mg/kg (16 patients) cohorts. All of the 70 patients were included in the pooled analysis. At baseline, most patients had visceral metastasis (87.1%) and received no less than 2 lines of chemotherapy (78.6%) for MBC. Forty-seven patients (67.1%) had previously received trastuzumab for (neo)adjuvant or MBC treatment previously. About half of patients (42.9%) had previously received anti-HER2 tyrosine kinase inhibitor therapy and 24 patients (34.3%) had received ≥ 2 lines of anti-HER2 therapy. In C001 CANCER, MTD was not reached. No response was observed in 0.5 mg/kg and 1.0 mg/kg cohorts. As reported, the most common treatment-related adverse events (TRAEs) were AST increased (62.9%), ALT increased (61.4%), leukopenia (51.4%), hypoesthesia (51.4%) and neutropenia (51.4%), which were mostly classified as grade 1 or 2. Grade 3 or 4 TRAEs were reported in 29 patients (41.4%,), mainly neutropenia (21.4%), asthenia (15.7%), and leukopenia (10.0%). Adverse events of special interest (AESI), consisting of varied AEs under the categories of liver function abnormal, hematologic toxicities, neurotoxicity and gastrointestinal disorders, were reported in 50 patients (71.4%), 47 patients (67.1%), 40 patients (57.1%), and 31 patients (44.3%), respectively. TRAEs leading to dose reduction or interruption were more frequent in 2.5 mg/kg cohort. Treatment-related serious adverse events (SAEs) occurred in 4 patients (5.7%), and the most common treatment-related SAE was ileus (in 2 patients, 2.9%). The confirmed overall response rate (cORR) was 31.4% (22/70). The clinical benefit rate (CBR) was 38.6%. The median progression-free survival (mPFS) was 5.8 months. For the 64 patients who received ≥ 1.5 mg/kg treatment, the cORR was 34.4% (22/64); the median PFS was 6.2 months. Specifically, for the dose levels of 1.5 mg/kg, 2.0 mg/kg and 2.5 mg/kg, the cORR was 22.2%, 42.9% and 36.0%, respectively; the mPFS was 6.2 months, 6.0 months, and 6.3 months, respectively.
Conclusion: RC48-ADC was demonstrated good tolerability and promising efficacy when administrated Q2W in the patients with HER2-positive MBC. Comparing with the other dose levels, 2.0 mg/kg Q2W was proved to be a more favorable option for MBC in terms of benefit/risk balance. Accordingly, the phase 2 study which evaluates the efficacy of RC48-ADC 2.0 mg/kg Q2W versus capecitabine + lapatinib in the HER2 positive MBC was underway (clinicaltrials.gov: NCT03500380). What’s more, an additional cohort of C003 CANCER exploring preliminary efficacy of 2.0 mg/kg Q2W on low HER2-expression MBC, and a phase 3 study for low HER2-expression MBC are also in the plan.
Citation Format: Binhe Xu, Jiayu Wang, Jianmin Fang, Xuelian Chen, Yiqun Han, Qing Li, Pin Zhang, Peng Yuan, Fei Ma, Yang Luo, Ying Fan, Ruigang Cai, Shanshan Chen, Qiao Li. Early clinical development of RC48-ADC in patients with HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-06.