1552P - Toward therapeutic drug monitoring of everolimus? Results of an exploratory study of the dose-exposure relationships

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Translational Research
Presenter Sabrina Falkowski
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors S. Falkowski1, M. Deppenweiler2, C. Monchaud3, F. Saint-Marcoux3, M. Laroche2, N. Picard3, L. Venat-Bouvet1, N. Tubiana-Mathieu1, P. Marquet3, J. Woillard3
  • 1Medical Oncology, CHU Limoges - Hopital Dupuytren, 87000 - Limoges/FR
  • 2Department Of Pharmacology, Toxicology And Pharmacovigilance, CHU Limoges - Hopital Dupuytren, 87000 - Limoges/FR
  • 3Department Of Pharmacology, Toxicology And Pharmacovigilance; Inserm Umr 850; Univ Limoges, CHU Limoges - Hopital Dupuytren, 87000 - Limoges/FR

Abstract

Background

The efficacy of everolimus (EVR) has been demonstrated in the treatment of (i) hormone receptor-positive advanced breast cancer (ii) metastatic renal cell cancer and (iii) neuroendocrine tumours of pancreatic origin. The recommended dosage of EVR is 10 mg once daily but contrary to transplantation, therapeutic drug monitoring (TDM) of EVR is not mandatory and no blood trough levels (C0) have been defined. The aims of this study were (i) to determine C0 that could predict the occurrence of toxicities and (ii) to investigate the relationship between polymorphisms of candidate genes and C0.

Methods

This monocentric retrospective observational study was carried out over 4 months in 54 patients on EVR for breast, renal or neuroendocrine cancer. Clinical, biological and radiologic data were collected from the patients' medical records. Toxicity was defined by temporary interruption and/or dose reduction of EVR. Patients' exposure to EVR was dichotomized by ROC curve. The association between exposure and toxicity was then determined using a Cox model for repeated events. The impact of CYP3A4*22 and CYP3A5*3 SNPs on C0 was investigated by generalized estimating equation.

Results

Forty-two patients (77.8%) had breast cancer, 10 (18.5%) had renal cell cancer and 2 (3.7%) had neuroendocrine cancer. Toxicity (all grades) was reported in 75.9% of the patients (EVR discontinuation in 25.9% patients). Haematological disorders were observed in the majority of toxicity cases (22%). The EVR C0 threshold determined by ROC analysis was 26.3 µg/L (Sen = 0.38,Spe = 0.88). The risk of toxicity was increased 4-fold for C0 > 26.3 µg/L (HR= 4.12, IC95% = [1.48-11.5], p = 0.0067). C0 was significantly lower in carriers of at least one CYP3A5*1 allele (intercept(expressors) = 10.72 ± 1.45, ßnon expressors = +6.32 ± 2.22, p = 0.0044). No association between carriers of CYP3A4*22 variant and blood trough C0 was found.

Conclusions

An EVR C0 > 26.3 µg/L was associated with an increased 4-fold risk of toxicity, with a specificity of 88%. The genetic polymorphism CYP3A5*3 has an important impact on EVR exposure. These results provide elements of proof in favour of using EVR TDM in oncology.

Clinical trial identification

No clinical trial

Legal entity responsible for the study

CHU Dupuytren, Limoges

Funding

INSERM UMR 850; CHU Dupuytren, Limoges

Disclosure

All authors have declared no conflicts of interest.