Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON Study

Jimmy Zhijian He; Vincent Duval; Petra Jauslin; Antonio Gonçalves; Aburough Abegesah; Chunling Fan; KyoungSoo Lim; Xuyang Song; Cecil Chen; Xiaojin Shi; Helen Mann; Lee Krug; Song Ren; Alex Phipps; Megan Gibbs; Diansong Zhou

doi:10.1002/cpt.3063

Population Pharmacokinetics and Exposure-Response Analysis for the CTLA-4 Inhibitor Tremelimumab in Metastatic NSCLC Patients in the Phase III POSEIDON Study

Clin Pharmacol Ther. 2023 Dec;114(6):1375-1386. doi: 10.1002/cpt.3063. Epub 2023 Oct 17.

Authors

Affiliations

¹ Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA.
² Certara, Integrated Drug Development, Basel, Switzerland.
³ Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, AstraZeneca, South San Francisco, California, USA.
⁴ Oncology R&D, Late-Stage Development, AstraZeneca, Gaithersburg, Maryland, USA.
⁵ Oncology Biometrics, Oncology R&D, AstraZeneca, Cambridge, UK.
⁶ Oncology R&D, Late-Stage Development, AstraZeneca, New York, New York, USA.
⁷ Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
⁸ Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, AstraZeneca, Boston, Massachusetts, USA.

PMID: 37777827
DOI: 10.1002/cpt.3063

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03164616.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal, Humanized*
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Carcinoma, Non-Small-Cell Lung*
Humans
Immune Checkpoint Inhibitors / therapeutic use
Lung Neoplasms*
Treatment Outcome

Substances

tremelimumab
Immune Checkpoint Inhibitors
Antibodies, Monoclonal, Humanized

Associated data

ClinicalTrials.gov/NCT03164616