Exposure–Response Analysis of Osimertinib in Patients with Advanced Non-Small-Cell Lung Cancer
Thomas Rodier,
Alicja Puszkiel,
Evelina Cardoso,
David Balakirouchenane,
Céline Narjoz,
Jennifer Arrondeau,
Vincent Fallet,
Nihel Khoudour,
Monia Guidi,
Michel Vidal,
Xavier Declèves,
Chantal Csajka,
Jérôme Alexandre,
Jacques Cadranel,
Elizabeth Fabre,
Marie Wislez,
François Goldwasser,
Benoit Blanchet
Affiliations
Thomas Rodier
Biologie du Médicament-Toxicologie, Hôpital Cochin, AP-HP, 75014 Paris, France
Alicja Puszkiel
Biologie du Médicament-Toxicologie, Hôpital Cochin, AP-HP, 75014 Paris, France
Evelina Cardoso
School of Pharmaceutical Sciences, University of Geneva, 1205 Geneva, Switzerland
David Balakirouchenane
Biologie du Médicament-Toxicologie, Hôpital Cochin, AP-HP, 75014 Paris, France
Céline Narjoz
Department of Clinical Biochemistry, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France
Jennifer Arrondeau
Medical Oncology, Cochin-Port Royal, AP-HP, Université Paris Cité, 75006 Paris, France
Vincent Fallet
Department of Pulmonology and Thoracic Oncology, Tenon Hospital, Assistance Publique Hôpitaux de Paris and GRC 4, Theranoscan, Sorbonne Université, 75020 Paris, France
Nihel Khoudour
Biologie du Médicament-Toxicologie, Hôpital Cochin, AP-HP, 75014 Paris, France
Monia Guidi
Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1205 Geneva, Switzerland
Michel Vidal
Biologie du Médicament-Toxicologie, Hôpital Cochin, AP-HP, 75014 Paris, France
Xavier Declèves
Biologie du Médicament-Toxicologie, Hôpital Cochin, AP-HP, 75014 Paris, France
Chantal Csajka
Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland
Jérôme Alexandre
Medical Oncology, Cochin-Port Royal, AP-HP, Université Paris Cité, 75006 Paris, France
Jacques Cadranel
Department of Pulmonology and Thoracic Oncology, Tenon Hospital, Assistance Publique Hôpitaux de Paris and GRC 4, Theranoscan, Sorbonne Université, 75020 Paris, France
Elizabeth Fabre
Department of Thoracic Oncology, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France
Marie Wislez
Department of Thoracic Oncology, Cochin-Port Royal, AP-HP, Université Paris Cité, 75006 Paris, France
François Goldwasser
Medical Oncology, Cochin-Port Royal, AP-HP, Université Paris Cité, 75006 Paris, France
Benoit Blanchet
Biologie du Médicament-Toxicologie, Hôpital Cochin, AP-HP, 75014 Paris, France
High interindividual variability (IIV) of the clinical response to epidermal growth factor receptor (EGFR) inhibitors such as osimertinib in non-small-cell lung cancer (NSCLC) might be related to the IIV in plasma exposure. The aim of this study was to evaluate the exposure–response relationship for toxicity and efficacy of osimertinib in unselected patients with advanced EGFR-mutant NSCLC. This retrospective analysis included 87 patients treated with osimertinib. Exposure–toxicity analysis was performed in the entire cohort and survival analysis only in second-line patients (n = 45). No significant relationship between occurrence of dose-limiting toxicity and plasma exposure was observed in the entire cohort (p = 0.23, n = 86). The median overall survival (OS) was approximately two-fold shorter in the 4th quartile (Q4) of osimertinib trough plasma concentration (>235 ng/mL) than in the Q1–Q3 group (12.2 months [CI95% = 8.0–not reached (NR)] vs. 22.7 months [CI95% = 17.1–34.1]), but the difference was not statistically significant (p = 0.15). To refine this result, the exposure–survival relationship was explored in a cohort of 41 NSCLC patients treated with erlotinib. The Q4 erlotinib exposure group (>1728 ng/mL) exhibited a six-fold shorter median OS than the Q1–Q3 group (4.8 months [CI95% = 3.3-NR] vs. 22.8 months (CI95% = 10.6–37.4), p = 0.00011). These results suggest that high exposure to EGFR inhibitors might be related to worse survival in NSCLC patients.
