Disitamab Vedotin, a HER2-directed Antibody Drug-Conjugate, in Patients with HER2- positive and HER2-low Advanced Breast Cancer：A Phase 1/1b Study

Purpose Disitamab vedotin (DV; RC48-ADC) is an antibody-drug conjugate comprising HER2-directed antibody, linker and monomethyl auristatin E. This phase 1/1b study evaluated the safety and efficacy of DV in HER2-positive and HER2-low advanced breast cancer (ABC). Patients and Methods: In the phase 1 dose-escalation study (C001 CANCER), HER2-positive ABC patients received DV at doses of 0.5–2.5 mg/kg once every two weeks (Q2W) until unacceptable toxicity or progressive disease. The recommended phase 2 dose (RP2D), safety, and pharmacokinetics (PK) were determined. The phase 1b dose-ranging and expansion study (C003 CANCER) enrolled HER2-positive and HER2-low ABC patients receiving DV at doses of 1.5–2.5 mg/kg Q2W and 2.0 mg/kg Q2W, respectively. Results 24 patients in C001 CANCER and 112 patients in C003 CANCER, including 70 patients with HER2-positive ABC and 66 patients with HER2-low ABC, were enrolled. At the PR2D of 2.0 mg/kg Q2W, confirmed objective response rate (ORR) was 42.9% (9/21; 95% CI 21.8–66.0) and 33.3% (22/66; 95% CI 22.2–46.0), with median progression-free survival (PFS) of 5.7 months (95% CI 5.3–8.4) and 5.1 months (95% CI 4.1–6.6) for HER2-positive and HER2-low ABC, respectively. Common (≥ 5%) grade 3 or higher treatment-emergent adverse events included neutrophil count decreased (17.6%), gamma-glutamyl transferase increased (13.2%), asthenia (11.0%), white blood cell count decreased (9.6%), peripheral neuropathy (6.6%), and pain (5.9%). Conclusions DV demonstrated promising efficacy in HER2-positive and HER2-low ABC, with a favorable safety profile at 2.0 mg/kg Q2W. Trail registration: NCT02881138. Registered 20 August 2016; NCT03052634. Registered 09 February 2017;