%0 Journal Article %T Systematic evaluation of pembrolizumab dosing in patients with advanced non-small cell lung cancer %+ Merck & Co. Inc %+ Vall d'Hebron University Hospital [Barcelona] %+ Service de pneumologie [Rennes] = Pneumology [Rennes] %+ Istituto Toscano Tumori %+ Department of Biological Sciences [Nashville] %+ David Geffen School of Medicine [Los Angeles] %+ Institute for Fuel Cell Innovation %+ Imperial College London, London SW7 2AZ, UK. %+ University of California [San Francisco] (UC San Francisco) %+ Weill Medical College of Cornell University [New York] %A Chatterjee, M. %A Turner, D. C. %A Felip, E. %A Lena, H. %A Cappuzzo, F. %A Horn, L. %A Garon, E. B. %A Hui, R. %A Arkenau, H.-T. %A Gubens, M. A. %A Hellmann, M. D. %A Dong, D. %A Li, C. %A Mayawala, K. %A Freshwater, T. %A Ahamadi, M. %A Stone, J. %A Lubiniecki, G. M. %A Zhang, J. %A Im, E. %A de Alwis, D. P. %A Kondic, A. G. %A Fløtten, Ø %Z We thank the patients and their families and caregivers for participating in this study; Rik de Greef and Jeroen Elassaiss-Schaap (Merck & Co., Inc., Kenilworth, NJ, USA) for technical support; and Roger Dansey (Merck & Co., Inc., Kenilworth, NJ, USA) for critical review of the manuscript. Medical writing and editorial assistance was provided by Sarah Adai, MS, and Melanie Leiby, PhD, of the ApotheCom Merck oncology team, Yardley, PA, USA; M. Leiby is currently a full-time employee of Merck & Co., Inc., Kenilworth, NJ, USA. This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA. %< avec comité de lecture %@ 0923-7534 %J Annals of Oncology %I Elsevier %V 27 %N 7 %P 1291-1298 %8 2016-04 %D 2016 %R 10.1093/annonc/mdw174 %M 27117531 %K exposure-response %K Immunotherapy %K non-small cell lung cancer %K PD-L1 %K pembrolizumab %K tumor size modeling %Z Life Sciences [q-bio]/CancerJournal articles %X BACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n=55), 10 mg/kg Q3W (n=238), or 10 mg/kg Q2W (n=156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady-state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and nonlinear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events of interest based on their immune etiology. RESULTS: Overall response rates were 15% (95% confidence interval [CI] 7%-28%) at 2 Q3W, 25% (18%-33%) at 10 Q3W, and 21% (95% CI 14% to 30%) at 10 Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6week indicated a flat relationship (regression slope P\textgreater0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the adverse event incidence to be similar among the clinically tested doses. CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2 mg/kg to 10 mg/kg. These results support the use of a 2-mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.ClinicalTrials.gov registry: NCT01295827 %G English %2 https://univ-rennes.hal.science/hal-01321406/document %2 https://univ-rennes.hal.science/hal-01321406/file/Systematic%20evaluation%20of%20pembrolizumab%20chatterjee2016.pdf %L hal-01321406 %U https://univ-rennes.hal.science/hal-01321406 %~ HL %~ STATS-UR1 %~ TEST-UNIV-RENNES %~ UNIV-RENNES