Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours

Abstract

Background:Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation.Methods:A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival.Results:The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression.Conclusions:The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.

Systematic Modeling and Design Evaluation of Unperturbed Tumor Dynamics in Xenografts

“…Indeed, Rochetti et al (Rocchetti et al, 2007) demonstrated a good correlation between CT and the active dose used in clinic for several marketed drugs, thus suggesting its potential for scaling efficacy from animal to man, further supporting the use of this preclinical model. To the best of our knowledge, NMLE methodology has been seldom used in the PKPD analysis of mice xenograft data, and if such, most of the studies focused on a limited number of cell lines or tumour types only (Bueno et al, 2008;ParraGuillen et al, 2013;Tate et al, 2014Tate et al, , 2016.…”

From chemotherapy to oncoviruses – modern methods of treatment in metastatic melanoma

“…Although treatment is combined with MEK inhibitors, the acquisition of resistance to BRAF inhibition is still proceeding; thus, prevention of resistance to vemurafenib and dabrafenib remains of special interest for modern pharmacology [1,2,22,23].…”

“…Mimo stosowania terapii skojarzonej z inhibitorami MEK poziom nabywania oporności na inhibitory BRAF nadal się zwiększa, a możliwość zapobiegania wystąpieniu oporności na wemurafenib i dabrafenib stanowi przedmiot szczególnego zainteresowania współczesnej farmakologii [1,2,22,23].…”

“…However, all clinical evidence of the benefit of an intermittent schedule for BRAF inhibitors is restricted to only case series studies [22].…”

“…Jednak dowody kliniczne na korzyści uzyskiwane dzięki stosowaniu schematu terapii przerywanej inhibitorami BRAF ograniczają się jedynie do opisów serii przypadków [22]. iMMUnOterAPiA W ciągu ostatnich kilku lat immunoterapia celowana stała się jedną z najbardziej obiecujących opcji terapeutycznych dla pacjentów z czerniakiem.…”