Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer.
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.



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 non-linear 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 (AEs) of interest based on their immune etiology.



Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). 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 AE incidence to be similar among the clinically tested doses.



No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC.



NCT01295827.
Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, USA.
M
M
Chatterjee
Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, USA.
D C
DC
Turner
Thoracic Tumors Group, Vall d'Hebron University Hospital, Barcelona, Spain.
E
E
Felip
Pneumonology Service, Centre Hospitalier Universitaire Rennes, Rennes, France.
H
H
Lena
Department of Medical Oncology, Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy.
F
F
Cappuzzo
Department of Medicine, Vanderbilt Ingram Cancer Center, Nashville, USA.
L
L
Horn
Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, USA.
E B
EB
Garon
Department of Medical Oncology, Westmead Hospital and the University of Sydney, Sydney, Australia.
R
R
Hui
Department of Medical Oncology, Sarah Cannon Research Institute UK and University College London, London, UK.
H-T
HT
Arkenau
Department of Medicine, University of California, San Francisco, San Francisco.
M A
MA
Gubens
Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.
M D
MD
Hellmann
Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, USA.
D
D
Dong
Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, USA.
C
C
Li
Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, USA.
K
K
Mayawala
Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, USA.
T
T
Freshwater
Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, USA.
M
M
Ahamadi
Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, USA.
J
J
Stone
Oncology Clinical Research, Merck & Co., Inc., Kenilworth.
G M
GM
Lubiniecki
Biostatistics and Research Design Sciences, Merck & Co., Inc., Kenilworth, USA.
J
J
Zhang
Oncology Clinical Research, Merck & Co., Inc., Kenilworth.
E
E
Im
Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, USA.
D P
DP
De Alwis
Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, USA.
A G
AG
Kondic
Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway oystein.flotten@helse-bergen.no.
Ø
Ø
Fløtten
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D060890:B7-H1 Antigen / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C582435:pembrolizumab; C512478:EGFR protein, human; D066246:ErbB Receptors
PD-L1; exposure–response; immunotherapy; non-small-cell lung cancer; pembrolizumab; tumor size modeling