TY - JOUR
T1 - Exposure–Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting
AU - Boosman, René J.
AU - Jebbink, Merel
AU - Veldhuis, Wouter B.
AU - Groenland, Stefanie L.
AU - van Veggel, Bianca A.M.H.
AU - Moeskops, Pim
AU - de Langen, Adrianus J.
AU - Beijnen, Jos H.
AU - Smit, Egbert F.
AU - Huitema, Alwin D.R.
AU - Steeghs, Neeltje
N1 - Funding Information:
N. Steeghs provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma. N Steeghs received research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, ADCtherapeutics, Amgen, Array, Ascendis Pharma, Astex, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, Celgene, CellCentric, Cresecendo, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech, Genmab, Gilead, GlaxoSmithKline, Incyte, InteRNA, Janssen/Johnson&Johnson, Kinate, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Numab, Pfizer, Pierre Fabre, Regeneron, Roche, Sanofi, Seattle Genetics, Servier, Taiho, Takeda (outside the submitted work).
Funding Information:
A.J. de Langen received grants from BMS, MSD, Boehringer, AstraZeneca and non-financial support from Merck Serono and Roche, outside the submitted work.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2022/10
Y1 - 2022/10
N2 - BACKGROUND: Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure-response relationships of osimertinib in a real-life setting.METHODS: A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (C
min,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship.
RESULTS: A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 - 19.1) months and 9.3 (95% CI: 7.2 - 11.1) months for patients with C
min,pred < 166 µg/L and C
min,pred ≥ 166 µg/L, respectively (p = 0.03). In the multivariate analysis, a C
min,pred < 166 µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 - 2.01; p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 - 7.08; p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91).
CONCLUSION: In our real-life cohort, no exposure-response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.
AB - BACKGROUND: Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure-response relationships of osimertinib in a real-life setting.METHODS: A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (C
min,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship.
RESULTS: A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 - 19.1) months and 9.3 (95% CI: 7.2 - 11.1) months for patients with C
min,pred < 166 µg/L and C
min,pred ≥ 166 µg/L, respectively (p = 0.03). In the multivariate analysis, a C
min,pred < 166 µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 - 2.01; p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 - 7.08; p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91).
CONCLUSION: In our real-life cohort, no exposure-response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.
KW - exposure–response analysis
KW - NSCLC
KW - osimertinib
KW - pharmacokinetics-pharmacodynamics
KW - Acrylamides
KW - Aniline Compounds
KW - Humans
KW - Antineoplastic Agents/therapeutic use
KW - ErbB Receptors/genetics
KW - Pyrimidines
KW - Lung Neoplasms/drug therapy
KW - Carcinoma, Non-Small-Cell Lung/drug therapy
KW - Protein Kinase Inhibitors/therapeutic use
KW - Retrospective Studies
KW - Indoles
KW - Mutation
UR - http://www.scopus.com/inward/record.url?scp=85136219373&partnerID=8YFLogxK
U2 - 10.1007/s11095-022-03355-2
DO - 10.1007/s11095-022-03355-2
M3 - Article
C2 - 35978149
AN - SCOPUS:85136219373
SN - 0724-8741
VL - 39
SP - 2507
EP - 2514
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 10
ER -