Definition of an afatinib trough concentration threshold in the treatment of NSCLC

Abstract

Abstract Background Afatinib (AFA), an irreversible ErbB family blocker, is used at the standard starting dose of 40mg for the treatment of patients with EGFR M+ NSCLC. It has been shown previously tolerability guided dose reduction effectively decreases incidence and severity of treatment related adverse events (AEs) during the treatment, and that treatment-related dose reduction was more likely in patients who had higher plasma concentrations of AFA before dose adaptation (Yang et al., Annals of Oncology 2016). After dose reduction, concentrations were similar to those obtained in patients who did not experience AEs, with comparable efficacy. We thus intended to determine a threshold concentration related with dose-reduction or AEs leading to dose-reduction (AELDR). Methods Patients (N\xa0=\xa0390) with AFA treatment, analyzable trough plasma concentration (Cmin) determination at D22 and follow-up of at least 6 months were identified from LUX-Lung (LL3 & LL6) studies. Receiver operating characteristic (ROC) curve analysis (univariable regression model) was performed to assess a discrimination potential of AFA Cmin for AELDR. Results The most discriminating threshold of AFA Cmin associated with dose reduction or AELDR between D22 sampling and M6 is at 34\xa0ng/ml. With this concentration threshold, there is a maximal AUC of 0.63 (95%CI: [0.58 – 0.69], a maximal Younden index of 0.267 (49% sensitivity, 78% specificity), with an odds ratio of 3.37 [2.10 – 5.40]) indicating that dose reduction or AELDR are more frequent in patients with concentration ≥34\xa0ng/mL. The analysis also showed that concentration is more often elevated in female, older (>65y), eastern Asian and low-body weight patients. Conclusions Monitoring of AFA plasma levels might be useful for the management of AEs in patients with NSCLC, especially for patients having factors known to be associated with higher AFA plasma exposure or toxicities. These results support the approach of adapting treatment dose based on plasma concentrations of AFA both forAEs and efficacy. Clinical trial identification NCT01121393, NCT00949650. Legal entity responsible for the study M. Molimard. Funding Boehringer Ingelheim. Disclosure C. Frohn: Full / Part-time employment: Boehringer Ingelheim International GmbH. C. Maritaz: Full / Part-time employment: Boehringer Ingelheim France. All other authors have declared no conflicts of interest.