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/m2) 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 (AUCss) on OS and PFS was evaluated with a Cox proportional hazard model. Effects of potential confounding factors on OS- AUCss and PFS-AUCss 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 AUCss 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 AUCss ≥ median (19.2 mg·h/μL) had longer median OS and PFS (16.0, 7.6 months) than pts with AUCss < median (4.7, 1.9 months). OS-AUCss and PFS-AUCss 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 AUCss < and ≥ median groups, although the incidence of grade ≥3 hyperglycemia, neutropenia, and thrombocytopenia trended higher in pts with AUCss ≥ 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 AUCss 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].

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@article{Lu2011ExposureresponseA, title={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).}, author={Juan Lu and H-W Deng and Reiping Tang and Chi-Yu Hsu and Hedy Lee Kindler and Charles S. Fuchs and Jennifer L. Gansert and Samuel L. Bray and Elwyn Loh and M-j Zhu}, journal={Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, year={2011}, volume={29 4_suppl}, pages={263} }