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.

Figure 1

Schematic representation of the integrated semimechanistic PK/PD model describing (A) vemurafenib-meditated efficacy under non-resistant conditions through inhibition of the MAPK pathway and the cell cycle, and (B) acquisition of resistance to vemurafenib by the upregulation of the MAPK pathway and abemaciclib-mediated efficacy through cell cycle arrest and increased dependence on Total Rb for survival. Arrowheads denote positive relationships, flatheads denote negative relationships. Red arrows indicate route of efficacy; purple arrows indicate elevation of baseline biomarker levels as a result of vemurafenib resistance. Shaded boxes denote observed compartments. Parameters are defined in the text.

Figure 2

Visual predictive check of the biomarker model in A375 xenograft-bearing mice following a single 15 mg kg⁻¹ oral dose of vemurafenib. The circles denote observed pMEK, pERK, Cyclin D1, pRb, TopoIIα, pHH3 and Total Rb data in treated tumours, expressed as a percentage of the control value observed in the vehicle group. The solid and dotted lines represent the median, and the 5th and 95th percentiles of 1000 individual model simulations, respectively.

Figure 3

Visual predictive check of the tumour growth model in A375 xenograft-bearing mice for two studies: (A) after treatment with vehicle (top left) or with vemurafenib 15 mg kg⁻¹ twice a day for 48 days, subsequently continuing with vemurafenib treatment (top right) or switching to 90 mg kg⁻¹ abemaciclib every day for a further 28 days (bottom centre); and (B) after treatment with vehicle (top left) or with vemurafenib 10 mg kg⁻¹ twice a day (top right) or abemaciclib 45 mg kg⁻¹ every day alone (bottom left) or in combination for 21 days (bottom right). The circles denote observed A375 tumour size data. The solid and dotted lines represent the median, and the 5th and 95th percentiles of 1000 individual model simulations, respectively.

Figure 4

Simulations of the PK/biomarker/tumour growth model for four long-term dosing scenarios: (A) vemurafenib 15 mg kg⁻¹ twice a day given continuously, (B) vemurafenib 15 mg kg⁻¹ twice a day and abemaciclib 50 mg kg⁻¹ every day in combination, both given continuously, (C) vemurafenib 15 mg kg⁻¹ twice a day given on an intermittent 2 weeks on/1 week off schedule, (D) intermittent vemurafenib 15 mg kg⁻¹ twice a day in combination with continuous abemaciclib 50 mg kg⁻¹ every day.