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* Corresponding author 1 Merck & Co. Inc 2 Vall d-Hebron University Hospital Barcelona 3 Service de pneumologie 4 Istituto Toscano Tumori 5 Department of Biological Sciences Nashville 6 University of California - Los Angeles School of Medicine 7 Institute for Fuel Cell Innovation 8 Imperial College London, London SW7 2AZ, UK. 9 UCSF - University of California San Francisco 10 Weill Cornell Medical College, New York

Abstract : 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 registry: NCT01295827

Keywords : exposure-response Immunotherapy non-small cell lung cancer PD-L1 pembrolizumab tumor size modeling

Autor: M. Chatterjee - D. C. Turner - E. Felip - H. Lena - F. Cappuzzo - L. Horn - E. B. Garon - R. Hui - H.-T. Arkenau - M. A. Gubens -



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