A first-in-human phase I study of U3-1287 (AMG 888), a HER3 inhibitor, in patients (pts) with advanced solid tumors.

Abstract

3026 Background: Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for the HER family and activates oncogenic signaling pathways. Its overexpression in many solid tumors has been linked to poor prognosis. U3-1287 (AMG 888) is a fully human anti-HER3 monoclonal antibody with demonstrated anticancer activity in preclinical models. This study had 2 parts: based on the observed tolerability of ≤20 mg/kg and pharmacokinetics (PK) study from the dose-escalation phase (part 1), 9, 14, and 20 mg/kg Q2W dosages were given in the dose-expansion phase (part 2). Methods: Pts with non–small cell lung cancer (NSCLC) and other refractory solid tumors thought to express HER3 were eligible. Study assessments included adverse event (AE) rates, PK, and tumor response (per modified RECIST and overall metabolic tumor response by EORTC). Human antihuman antibody (HAHA) responses were measured to assess immunogenicity. Results: Part 2 data (as of 9/24/10) are reported. Pts (N=31) with head and neck (1 pt), breast (1), ovary (1), cecum/appendix (1), colorectal cancer (CRC, 10), and NSCLC (17) tumor types were given 9 (n=10), 14 (n=2), and 20 mg/kg (n=19) of U3-1287 (AMG 888). Pts had a median (range) of 5 (2–10) prior chemotherapy regimens. 11 serious AEs were reported in 10 pts; none were attributable to U3-1287 (AMG 888). 16 pts (51.6%) experienced AEs ≥ grade (Gr) 3, with 1 Gr 5 dyspnea and 1 Gr 4 hypoglycemia. Two AEs ≥ Gr 3 were considered drug-related: Gr 3 anemia and Gr 3 rash. Gr 1/2 drug-related AEs in ≥10% of pts were fatigue, diarrhea, and nausea. Of 21 pts assessed, no HAHA responses were observed (by 21 days postdose). PK analysis (n=15) showed that steady state is reached after 3 dosing cycles for pts receiving 9, 14, or 20 mg/kg. Mean steady state Cmin was >10-fold greater than the threshold concentration required for 90% HER3 inhibition in xenograft models. Eight pts (6 NSCLC, 2 CRC) had a best response of stable disease at or beyond day-70 visit. One pt (NSCLC, 20 mg/kg) had significant tumor shrinkage (26.3%) and partial metabolic response by FDG-PET scan. Conclusions: U3-1287 (AMG 888) is well tolerated, with an absence of detectable HAHA responses. Part 2 data support 9–20 mg/kg Q2W dosage for future studies.