Sonya C Tate1, Valerie Andre2, Nathan Enas3, Benjamin Ribba4, Ivelina Gueorguieva5. 1. PK/PD, Eli Lilly and Company, Erl Wood Manor, Windlesham, GU20 6PH, UK. Electronic address: tate_sonya@network.lilly.com. 2. Statistics, Eli Lilly and Company, Erl Wood Manor, Windlesham, GU20 6PH, UK. Electronic address: andre_valerie@lilly.com. 3. Statistics, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: enas_nathan_h@lilly.com. 4. Project-Team NuMed, INRIA, Ecole Normale Supérieure de Lyon, Lyon, France. Electronic address: benjamin.ribba@inria.fr. 5. PK/PD, Eli Lilly and Company, Erl Wood Manor, Windlesham, GU20 6PH, UK. Electronic address: gueorguieva_ivelina@lilly.com.
Abstract
PURPOSE: Clinical trials using change in tumour size (CTS) as a primary end-point benefit from earlier evaluation of treatment effect and increased study power over progression-free survival, ultimately resulting in more timely regulatory approvals for cancer patients. In this work, a modelling framework was established to further characterise the relationship between CTS and overall survival (OS) in first-line metastatic breast cancer (mBC). METHODS: Data from three randomised phase III trials designed to evaluate the clinical benefit of gemcitabine combination therapy in mBC patients were collated. Two drug-dependent models were developed to describe tumour growth dynamics: the first for paclitaxel/gemcitabine treatment and the second for docetaxel/gemcitabine treatment. A parametric survival model was used to characterise survival as a function of CTS and baseline patient demographics. RESULTS: While the paclitaxel/gemcitabine model incorporated tumour shrinkage by both paclitaxel and gemcitabine with resistance to paclitaxel, the docetaxel/gemcitabine model incorporated shrinkage and resistance to docetaxel alone. Predictors for OS were CTS at week 8, baseline tumour size and ECOG performance status. Model predictions reveal that for an asymptomatic mBC patient with a 6-cm tumour burden, first-line paclitaxel/gemcitabine treatment offers a median OS of 28.6 months, compared to 26.0 months for paclitaxel alone. CONCLUSION: A modelling framework was established, quantitatively describing the tumour growth inhibitory effects of various gemcitabine combotherapies and the effect of the resulting CTS on survival in first-line mBC. This work further supports the use of early CTS as a go/no-go decision point during phase II clinical evaluation of treatments for mBC.
PURPOSE: Clinical trials using change in tumour size (CTS) as a primary end-point benefit from earlier evaluation of treatment effect and increased study power over progression-free survival, ultimately resulting in more timely regulatory approvals for cancerpatients. In this work, a modelling framework was established to further characterise the relationship between CTS and overall survival (OS) in first-line metastatic breast cancer (mBC). METHODS: Data from three randomised phase III trials designed to evaluate the clinical benefit of gemcitabine combination therapy in mBC patients were collated. Two drug-dependent models were developed to describe tumour growth dynamics: the first for paclitaxel/gemcitabine treatment and the second for docetaxel/gemcitabine treatment. A parametric survival model was used to characterise survival as a function of CTS and baseline patient demographics. RESULTS: While the paclitaxel/gemcitabine model incorporated tumour shrinkage by both paclitaxel and gemcitabine with resistance to paclitaxel, the docetaxel/gemcitabine model incorporated shrinkage and resistance to docetaxel alone. Predictors for OS were CTS at week 8, baseline tumour size and ECOG performance status. Model predictions reveal that for an asymptomatic mBC patient with a 6-cm tumour burden, first-line paclitaxel/gemcitabine treatment offers a median OS of 28.6 months, compared to 26.0 months for paclitaxel alone. CONCLUSION: A modelling framework was established, quantitatively describing the tumour growth inhibitory effects of various gemcitabine combotherapies and the effect of the resulting CTS on survival in first-line mBC. This work further supports the use of early CTS as a go/no-go decision point during phase II clinical evaluation of treatments for mBC.
Authors: Belén P Solans; Ascensión López-Díaz de Cerio; Arlette Elizalde; Luis Javier Pina; Susana Inogés; Jaime Espinós; Esteban Salgado; Luis Daniel Mejías; Iñaki F Trocóniz; Marta Santisteban Journal: Br J Clin Pharmacol Date: 2019-06-14 Impact factor: 4.335