Exposure-response (E-R) analysis to facilitate phase III (P3) dose selection for AMG 479 (A479) in combination with gemcitabine (G) to treat metastatic pancreatic cancer (mPC).

263 Background: A479 is an investigational, fully human monoclonal antibody against IGF1R. In a phase II study, 125 pts with mPC were randomized 1:1:1 to A479, placebo (P), or conatumumab in combination with G. Addition of A479 (12 mg/kg IV, Q2W) to G (1000 mg/m 2 ) showed evidence of improved OS and PFS (Kindler, JCO 2010:28 abstr 4035). An E-R analysis was done to inform P3 dose selection for A479. Methods: A population PK model of A479 was constructed using data from multiple studies. An E-R analysis was performed with pts from the A479+G and P+G arms (∼40 pts/arm). The effect of estimated steady-state area under the curve (AUC ss ) on OS and PFS was evaluated with a Cox proportional hazard model. Effects of potential confounding factors on OS- AUC ss and PFS-AUC ss associations were assessed by multivariate analysis. Exposure-safety data were analyzed with descriptive statistics and linear regression. P3 doses for A479 were explored with Monte Carlo simulations using population PK and parametric survival models. Results: There was a positive association between OS or PFS and higher AUC ss in the A479+G arm (P<0.001, <0.001) that remained even when data from the A479+G and P+G arms were combined (P=0.033, 0.022). Pts with AUC ss ≥ median (19.2 mg·h/μL) had longer median OS and PFS (16.0, 7.6 months) than pts with AUC ss < median (4.7, 1.9 months). OS-AUC ss and PFS-AUC ss associations were significant after adjusting for potential confounding factors. Sensitivity E-R analyses were done to confirm the modeling results. The incidence of most adverse events was similar between the AUC ss < and ≥ median groups, although the incidence of grade ≥3 hyperglycemia, neutropenia, and thrombocytopenia trended higher in pts with AUC ss ≥ median. Population PK indicated 1.7-fold higher clearance of A479 in mPC than non-mPC pts. No G-A479 PK interactions were identified. PK simulations showed similar AUC ss of A479 in mPC pts at 20 mg/kg and in non-mPC pts at 12 mg/kg. Simulations projected improved OS and PFS with 20 mg/kg vs 12 mg/kg A479. Conclusions: Increased exposure to A479 is associated with improved clinical outcomes in mPC. This supports the evaluation of 20 mg/kg A479 in P3. [Table: see text]