Updated safety, efficacy, and pharmacokinetics (PK) results from the phase I study of BGB-A317, an anti-programmed death-1 (PD-1) mAb in patients with advanced solid tumors

Background BGB‐A317 is a humanized IgG4 anti‐PD‐1 mAb with high specificity and affinity (KD=0.15 nM) for PD‐1. It blocks PD‐L1 and PD‐L2 binding and inhibits PD‐1‐mediated negative signaling in T cell lines and tumor growth in a number of allogeneic xenograft models. Methods A phase I, multicenter study was conducted to evaluate the safety, tolerability, PK and antitumor activity of BGB‐A317 in patients with advanced solid tumors. A 3+3 dose escalation design was undertaken. Patients received escalating doses of BGB‐A317 intravenously at 0.5, 2, 5 and 10 mg/kg once every two weeks (Q2W). Additional patients were treated at 2 and 5 mg/kg once every three weeks (Q3W). Results As of 27 July 2016, 103 patients were treated across 4 dose‐escalating cohorts of BGB‐A317 Q2W (0.5 mg/kg, n=3; 2 mg/kg, n=6; 5 mg/kg, n=6 and 10 mg/kg, n=7) and 4 dose‐expansion cohorts (2 mg/kg, Q2W, n=20; 2 mg/kg, Q3W, n=21; 5 mg/kg Q2W, n=20 and 5 mg/kg, Q3W, n=20). One DLT (1/6) of grade 3 colitis was observed in the 5 mg/kg Q2W dose‐escalating cohort. Maximum tolerated dose was not reached. Recommended phase II dose is 5 mg/kg Q3W. The most common treatment‐emergent adverse events (AEs) were grade (G) 1‐2 fatigue (42%), nausea (30%), diarrhea (25%), abdominal pain (22%) and constipation (21%). Treatment‐related G3 AEs included fatigue (n=2), hypotension (n=2), back pain (n=1), colitis (n=1), diabetes mellitus (n=1), diabetic ketoacidosis (n=1), dyspnea (n=1), elevated ALT (n=1), hyperglycaemia (n=1), hypoxia (n=1) and pneumonitis (n=1). Population PK analysis was conducted using 411 observed BGB‐A317 serum concentrations from 31 patients who received doses of 0.5, 2, 5 and 10 mg/kg Q2W and 13 patients who received doses of 2 and 5 mg/kg Q3W. BGB‐A317 PK is linear and the terminal elimination half‐life is 16 days. Patients' body weight is not a significant covariate on the clearance of A317. Among 99 evaluable patients, preliminary evidence of anti‐tumor activities included 16 patients have partial responses (5 to be confirmed) and 20 patients exhibit stable disease. 13 responding patients remain on treatment, ranging from 18 to 38 weeks. Conclusions BGB‐A317 demonstrates a favorable safety profile with AEs in keeping with the class effect. Early promising anti‐tumor activity has been observed. BGB‐A317 PK is linear and systemic clearance is not affected by body weight, which supports fixed dosing. The expanded phase IB study in selected cancer types is ongoing. (Figure Presented).