HER2-targeting antibody drug conjugate FS-1502 in HER2-expressing metastatic breast cancer: a phase 1a/1b trial

Abstract

Currently approved HER2-targeting antibody-drug conjugates (ADCs) for HER2-positive breast cancer (BC) are associated with safety concerns. In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti-HER2 ADC) with a 3 + 3 design in phase 1a; patients with metastatic HER2-positive BC received FS-1502 at the recommended phase 2 dose (RP2D) in phase 1b. The primary end points were dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D for phase 1a and objective response rate (ORR) for phase 1b. A total of 150 patients with HER2-expressing solid tumors (n = 5) and BC (n = 145) were enrolled (female, n = 146, 97.3%). One DLT each was reported at 3.0 and 3.5 mg/kg; the MTD was not reached. The RP2D was 2.3 mg/kg once every 3 weeks. Five (3.3%) patients experienced pneumonitis; four (2.7%) had grade 3 reversible ocular events. Of 67 HER2-positive BC patients receiving the RP2D, the best ORR was 53.7% (95% CI, 41.1-66.0%), including PRs confirmed (confirmed ORR, 37.5%) and pending for confirmation. FS-1502 was well tolerated with limited ocular and pulmonary findings and demonstrated promising antitumor activity in HER2-positive BC patients.

Fig. 1. Patient dispositions.

^aProgressive disease. ^bPatient withdrew informed consent. ^cAdverse event. ^dStudy termination by the investigator. ^eDeath. ^fOther. Q3W once every 3 weeks, Q4W once every 4 weeks.

Fig. 2. Antitumor activities of FS-1502 at 2.3 mg/kg based on the efficacy analysis set.

A Swimmer plot of treatment duration. B Waterfall plot of best percentage change from baseline in total sum of target lesion diameters. C Kaplan–Meier curve of progression-free survival. A total of 67 patients were included for the analysis. Progression-free survival is presented as median (95% CI).

Fig. 3. Mean (SD) serum concentration versus time curve of FS-1502, total antibody, and unconjugated MMAF over cycle 1 and cycle 3 at a dose of 2.3 mg/kg.

FS-1502 concentration results of 71 patients were included for cycle 1, and results of 46 patients were included for cycle 3. Data are presented as mean (SD). C1 cycle 1, C3 cycle 3, SD standard deviation.