1906 - Exposure-response analyses of ALK-inhibitors crizotinib and alectinib in NSCLC patients

Background

Crizotinib and alectinib are first and second generation ALK-inhibitors, respectively, indicated for the treatment of ALK+ NSCLC. At the currently used fixed doses, interpatient variability in exposure is high (40%), while the registration studies suggest that exposure might be linked to efficacy (FDA Reviews). Therefore, the aim of this study was to explore whether exposure to crizotinib and alectinib is related to efficacy in a real life patient (pt) cohort.

Methods

A retrospective observational study was performed. ALK+ NSCLC pts who were treated with crizotinib or alectinib and of whom pharmacokinetic (PK) samples were drawn as part of routine care were included. Calculated minimum plasma concentration (C_min) was taken as a measure of exposure. Efficacy endpoint was progression free survival (PFS). Univariable and multivariable exposure-response analyses were performed using previously proposed thresholds of 235 µg/L for crizotinib and 435 µg/L for alectinib (Verheijen 2017). Variables taken into account were WHO performance status (PS) and previous lines of therapy for crizotinib, and WHO PS and previous treatment with ALK-inhibitors for alectinib.

Results

In total, 100 pts were included in this study (48 crizotinib, 52 alectinib), of whom 376 PK samples were eligible for analysis (235 crizotinib, 141 alectinib). Median number of samples per pt was 3 (range 1 – 15). Median C_min per pt was 244 µg/L (IQR 176 – 344 µg/L) for crizotinib and 517 µg/L (IQR 369 – 659 µg/L) for alectinib. For crizotinib, median PFS was 5.7 vs 17.4 months (mo) for pts with median C_min < 235 µg/L (48%) and ≥ 235 µg/L, respectively (log rank test, p = 0.08). In multivariable analysis C_min < 235 µg/L resulted in a HR of 1.79 (95% CI 0.90 – 3.59, p = 0.10). For alectinib, median PFS was 12.6 mo vs not reached yet after 20 mo for pts with C_min < 435 µg/L (37%) and ≥ 435 µg/L, respectively (log rank test, p = 0.04). Multivariable analysis resulted in a HR of 3.86 (95% CI 1.19 – 12.58, p = 0.025). Thus far, this could not be explained by bias.

Conclusions

This study shows that exposure to alectinib is associated with efficacy in a real life patient cohort. Therefore, therapeutic drug monitoring might be appropriate to individualize treatment and improve treatment outcomes.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital.

Funding

Has not received any funding.

Disclosure

S.A. Burgers: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche Advisory / Consultancy: MSD. N. Steeghs: Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Incyte. All other authors have declared no conflicts of interest.