Safety and efficacy of AMG 655 in combination with paclitaxel and carboplatin (PC) in patients with advanced non-small cell lung cancer (NSCLC)

Abstract

e19048 Background: AMG 655 is an investigational, fully human IgG1 monoclonal agonist antibody that binds human death receptor 5 (DR5), activates caspases, and induces apoptosis in sensitive tumor cells. The primary objective of this phase 1b study was to determine the maximum tolerated dose (up to a target dose of 15 mg/kg) of AMG 655 that can be safely administered with PC. Methods: Eligibility included: ≥ 18-years old, untreated, advanced NSCLC, and ECOG PS 0 or 1. Patients (pts) were enrolled in sequential dose cohorts of AMG 655 (5 or 15 mg/kg) + P (200 mg/m2) and C (AUC = 6 mg/mL x min) IV every 3 weeks for up to 6 cycles. After completion/discontinuation of PC, pts may continue AMG 655 as monotherapy. Endpoints include: incidence of dose- limiting toxicities (DLT); adverse events (AE); pharmacokinetics (PK); levels of plasma genomic (g)DNA, serum caspase 3/7 activity, and M65 (cell death and apoptosis biomarkers); objective tumor response rate (by RECIST), and progression-free survival (PFS). Results: As of 09/08, 12 pts enrolled and received ≥ 1 dose of AMG 655 + PC. Ten were men; 11 had ECOG 1, and median (range) age = 68.5 (50–83) years. Median (range) time on AMG 655 = 5.2 (0.2–8.3) months; all pts have discontinued treatment. There was 1 DLT: grade 3 hyponatremia (15-mg/kg cohort). Five (42%) pts had grade 3 AE including neutropenia and dyspnea (2 pts each); 3 (25%) had grade 4 AE (2 with neutropenia, 1 with pulmonary embolism). After one 5- or 15-mg/kg dose of AMG 655 + PC, AMG 655 PK values (serum clearance, Cmax, AUC) were similar to the first-in-human study (LoRusso et al. JCO 2007; 25: abstr 3534) indicating no effect of PC on PK of AMG 655. Data also indicate no effect of AMG 655 on PK of PC. Plasma gDNA, serum caspse 3/7 activity, and serum M65 levels increased significantly from baseline 24 h after administration of AMG 655 + PC. Best overall tumor response: 1 complete response, 3 partial responses, 3 stable disease, and 3 progressive disease (2 pts had no on-treatment tumor assessments). Median (95% CI) PFS = 5.1 months (1.5, 7.0). Conclusions: AMG 655 administered with PC appears to be well tolerated with expected PK properties not altered by PC. A randomized phase 2 trial (AMG 655 ± PC) is ongoing. [Table: see text]