PMID- 37777827
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240411
IS  - 1532-6535 (Electronic)
IS  - 0009-9236 (Linking)
VI  - 114
IP  - 6
DP  - 2023 Dec
TI  - Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 
      Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON 
      Study.
PG  - 1375-1386
LID - 10.1002/cpt.3063 [doi]
AB  - Blockade of CTLA-4 by tremelimumab combined with anti-PD-L1 durvalumab and 
      chemotherapy provided increased antitumor activity and long-term survival 
      benefits in first-line metastatic non-small cell lung cancer (mNSCLC) in the 
      phase III POSEIDON study. We performed population pharmacokinetic modeling for 
      tremelimumab using data from 1,605 patients across 6 studies (including POSEIDON) 
      in multiple tumors (lung cancer, bladder cancer, malignant mesothelioma, and 
      other solid tumors), and identified a 2-compartment model with linear and 
      time-varying clearance for tremelimumab. Cox proportional hazard regression 
      models were applied to 326 patients with mNSCLC from POSEIDON to evaluate the 
      association between exposure metrics and efficacy end points, adjusting for 
      baseline prognostic covariates. Improved progression-free survival (PFS) and 
      overall survival (OS) in the tremelimumab arm (in combination with durvalumab and 
      chemotherapy) was associated with higher tremelimumab exposure (e.g., minimum 
      concentration at 5th dose (C(min,dose5) ) and area under the curve at 5th dose 
      (AUC(dose5) )). However, further case-matching analyses yielded hazard ratios for 
      the comparison of tremelimumab-treated patients in the C(min,dose5) quartile 1 
      (Q1) subgroup with matched chemotherapy-treated patients of 1.04 (95% confidence 
      interval (CI): 0.76-1.44) for OS and 0.99 (95% CI: 0.72-1.36) for PFS, suggesting 
      that the observed apparent exposure-response relationship might be confounded. No 
      relationship between tremelimumab exposure and safety (grade >/=3 
      treatment-emergent adverse events [AEs], AEs of special interest, or 
      discontinuation due to AEs) was identified. These results support the consistent 
      benefit observed with tremelimumab 75 mg every 3 weeks for up to 5 doses in 
      combination with durvalumab and chemotherapy in POSEIDON as first-line therapy 
      for mNSCLC.
CI  - (c) 2023 AstraZeneca. Clinical Pharmacology & Therapeutics published by Wiley 
      Periodicals LLC on behalf of American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - He, Jimmy Zhijian
AU  - He JZ
AD  - Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, 
      AstraZeneca, Gaithersburg, Maryland, USA.
FAU - Duval, Vincent
AU  - Duval V
AUID- ORCID: 0009-0008-0138-7258
AD  - Certara, Integrated Drug Development, Basel, Switzerland.
FAU - Jauslin, Petra
AU  - Jauslin P
AD  - Certara, Integrated Drug Development, Basel, Switzerland.
FAU - Goncalves, Antonio
AU  - Goncalves A
AD  - Certara, Integrated Drug Development, Basel, Switzerland.
FAU - Abegesah, Aburough
AU  - Abegesah A
AD  - Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, 
      AstraZeneca, Gaithersburg, Maryland, USA.
FAU - Fan, Chunling
AU  - Fan C
AD  - Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, 
      AstraZeneca, Gaithersburg, Maryland, USA.
FAU - Lim, KyoungSoo
AU  - Lim K
AD  - Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, 
      AstraZeneca, Gaithersburg, Maryland, USA.
FAU - Song, Xuyang
AU  - Song X
AD  - Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, 
      AstraZeneca, Gaithersburg, Maryland, USA.
FAU - Chen, Cecil
AU  - Chen C
AUID- ORCID: 0000-0003-1542-1505
AD  - Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, 
      AstraZeneca, South San Francisco, California, USA.
FAU - Shi, Xiaojin
AU  - Shi X
AD  - Oncology R&D, Late-Stage Development, AstraZeneca, Gaithersburg, Maryland, USA.
FAU - Mann, Helen
AU  - Mann H
AUID- ORCID: 0000-0001-9426-2332
AD  - Oncology Biometrics, Oncology R&D, AstraZeneca, Cambridge, UK.
FAU - Krug, Lee
AU  - Krug L
AD  - Oncology R&D, Late-Stage Development, AstraZeneca, New York, New York, USA.
FAU - Ren, Song
AU  - Ren S
AD  - Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, 
      AstraZeneca, Gaithersburg, Maryland, USA.
FAU - Phipps, Alex
AU  - Phipps A
AUID- ORCID: 0000-0001-5793-5112
AD  - Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, 
      AstraZeneca, Cambridge, UK.
FAU - Gibbs, Megan
AU  - Gibbs M
AD  - Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, 
      AstraZeneca, Boston, Massachusetts, USA.
FAU - Zhou, Diansong
AU  - Zhou D
AUID- ORCID: 0000-0002-2673-1069
AD  - Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, 
      AstraZeneca, Boston, Massachusetts, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03164616
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231017
PL  - United States
TA  - Clin Pharmacol Ther
JT  - Clinical pharmacology and therapeutics
JID - 0372741
RN  - QEN1X95CIX (tremelimumab)
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Antibodies, Monoclonal, Humanized)
SB  - IM
MH  - Humans
MH  - *Carcinoma, Non-Small-Cell Lung
MH  - *Lung Neoplasms
MH  - Immune Checkpoint Inhibitors/therapeutic use
MH  - Treatment Outcome
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects
MH  - *Antibodies, Monoclonal, Humanized
EDAT- 2023/10/01 06:41
MHDA- 2024/02/12 18:42
CRDT- 2023/10/01 01:46
PHST- 2023/04/20 00:00 [received]
PHST- 2023/09/15 00:00 [accepted]
PHST- 2024/02/12 18:42 [medline]
PHST- 2023/10/01 06:41 [pubmed]
PHST- 2023/10/01 01:46 [entrez]
AID - 10.1002/cpt.3063 [doi]
PST - ppublish
SO  - Clin Pharmacol Ther. 2023 Dec;114(6):1375-1386. doi: 10.1002/cpt.3063. Epub 2023 
      Oct 17.