PMID- 27117531
OWN - NLM
STAT- MEDLINE
DCOM- 20171227
LR  - 20220420
IS  - 1569-8041 (Electronic)
IS  - 0923-7534 (Print)
IS  - 0923-7534 (Linking)
VI  - 27
IP  - 7
DP  - 2016 Jul
TI  - Systematic evaluation of pembrolizumab dosing in patients with advanced 
      non-small-cell lung cancer.
PG  - 1291-8
LID - 10.1093/annonc/mdw174 [doi]
AB  - 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. PATIENTS AND 
      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 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. RESULTS: 
      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. CONCLUSIONS: 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. CLINICALTRIALSGOV REGISTRY: NCT01295827.
CI  - (c) The Author 2016. Published by Oxford University Press on behalf of the European 
      Society for Medical Oncology. All rights reserved. For permissions, please email: 
      journals.permissions@oup.com.
FAU - Chatterjee, M
AU  - Chatterjee M
AD  - Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, 
      USA.
FAU - Turner, D C
AU  - Turner DC
AD  - Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, 
      USA.
FAU - Felip, E
AU  - Felip E
AD  - Thoracic Tumors Group, Vall d'Hebron University Hospital, Barcelona, Spain.
FAU - Lena, H
AU  - Lena H
AD  - Pneumonology Service, Centre Hospitalier Universitaire Rennes, Rennes, France.
FAU - Cappuzzo, F
AU  - Cappuzzo F
AD  - Department of Medical Oncology, Istituto Toscano Tumori, Ospedale Civile, 
      Livorno, Italy.
FAU - Horn, L
AU  - Horn L
AD  - Department of Medicine, Vanderbilt Ingram Cancer Center, Nashville, USA.
FAU - Garon, E B
AU  - Garon EB
AD  - Department of Medicine, David Geffen School of Medicine at the University of 
      California, Los Angeles, Los Angeles, USA.
FAU - Hui, R
AU  - Hui R
AD  - Department of Medical Oncology, Westmead Hospital and the University of Sydney, 
      Sydney, Australia.
FAU - Arkenau, H-T
AU  - Arkenau HT
AD  - Department of Medical Oncology, Sarah Cannon Research Institute UK and University 
      College London, London, UK.
FAU - Gubens, M A
AU  - Gubens MA
AD  - Department of Medicine, University of California, San Francisco, San Francisco.
FAU - Hellmann, M D
AU  - Hellmann MD
AD  - Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell 
      Medical College, New York.
FAU - Dong, D
AU  - Dong D
AD  - Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, 
      USA.
FAU - Li, C
AU  - Li C
AD  - Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, 
      USA.
FAU - Mayawala, K
AU  - Mayawala K
AD  - Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, 
      USA.
FAU - Freshwater, T
AU  - Freshwater T
AD  - Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, 
      USA.
FAU - Ahamadi, M
AU  - Ahamadi M
AD  - Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, 
      USA.
FAU - Stone, J
AU  - Stone J
AD  - Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, 
      USA.
FAU - Lubiniecki, G M
AU  - Lubiniecki GM
AD  - Oncology Clinical Research, Merck & Co., Inc., Kenilworth.
FAU - Zhang, J
AU  - Zhang J
AD  - Biostatistics and Research Design Sciences, Merck & Co., Inc., Kenilworth, USA.
FAU - Im, E
AU  - Im E
AD  - Oncology Clinical Research, Merck & Co., Inc., Kenilworth.
FAU - De Alwis, D P
AU  - De Alwis DP
AD  - Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, 
      USA.
FAU - Kondic, A G
AU  - Kondic AG
AD  - Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc., Kenilworth, 
      USA.
FAU - Flotten, O
AU  - Flotten O
AD  - Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway 
      oystein.flotten@helse-bergen.no.
LA  - eng
SI  - ClinicalTrials.gov/NCT01295827
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20160426
PL  - England
TA  - Ann Oncol
JT  - Annals of oncology : official journal of the European Society for Medical 
      Oncology
JID - 9007735
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (B7-H1 Antigen)
RN  - 0 (CD274 protein, human)
RN  - DPT0O3T46P (pembrolizumab)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal/*administration & dosage/adverse effects
MH  - Antibodies, Monoclonal, Humanized/*administration & dosage/adverse effects
MH  - B7-H1 Antigen/genetics
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics
MH  - Disease-Free Survival
MH  - Dose-Response Relationship, Drug
MH  - Drug-Related Side Effects and Adverse Reactions/pathology
MH  - ErbB Receptors/genetics
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Staging
MH  - *Prognosis
MH  - Treatment Outcome
PMC - PMC6276906
OTO - NOTNLM
OT  - PD-L1
OT  - exposure-response
OT  - immunotherapy
OT  - non-small-cell lung cancer
OT  - pembrolizumab
OT  - tumor size modeling
EDAT- 2016/04/28 06:00
MHDA- 2017/12/28 06:00
PMCR- 2017/07/01
CRDT- 2016/04/28 06:00
PHST- 2015/11/10 00:00 [received]
PHST- 2016/04/04 00:00 [accepted]
PHST- 2016/04/28 06:00 [entrez]
PHST- 2016/04/28 06:00 [pubmed]
PHST- 2017/12/28 06:00 [medline]
PHST- 2017/07/01 00:00 [pmc-release]
AID - S0923-7534(19)35698-4 [pii]
AID - mdw174 [pii]
AID - 10.1093/annonc/mdw174 [doi]
PST - ppublish
SO  - Ann Oncol. 2016 Jul;27(7):1291-8. doi: 10.1093/annonc/mdw174. Epub 2016 Apr 26.