Hitesh Mistry, Christophe Chassagnole, Frances Brightman, Eric Fernandez, David Orrell.
Physiomics plc
Objectives: Combination therapies of targeted agents with generics and/or radiotherapy in oncology are becoming more widespread within the pharmaceutical industry as healthcare providers ask for "game-changing" improvements in response and survival rates at an affordable price. In order to obtain substantial breakthroughs in survival rates, clinical investigators are looking at increasingly complex schedules that are challenging to optimise1. A prominent example of the difficulty of finding the correct schedule in combination therapy is given by the search for clinically effective combinations of EGFR inhibitors with chemotherapy in NSCLC. After a series of expensive Phase 3 failures, pursuing a schedule that was successful in pre-clinical studies2, clinical investigators eventually found a schedule with promising results3. Here we present an initial example highlighting the potential applicability of Virtual TumorTM (VT) Clinical in the above setting.
Methods: We used simulated data from a published tumour size model4 to calibrate our VT model for each of the treatments. The calibration also used data available in the literature to understand the mechanism of action of each compound. The survival model suggested that change in tumour size at week 8 is an important predictor4, thus we simulated Phase 2 and 3 schedules and analysed changes at this time point.
Results: We have shown that our model can qualitatively predict that an intercalated schedule3 is better than simultaneous treatment with an EGFR inhibitor and chemotherapy.
Conclusions: Our initial attempt at bridging our VT technology from the pre-clinical to clinical arena appears to be promising. We are able to qualitatively predict that certain schedules already explored in the clinic for EGFR inhibitors in combination with chemotherapy can lead to very different outcomes depending on the sequence used.
References:
[1] Raben, D. & Bunn, P. A. Biologically Targeted Therapies Plus Chemotherapy Plus Radiotherapy in Stage III Non-Small-Cell Lung Cancer: A Case of the Icarus Syndrome? Journal of Clinical Oncology 30, 3909-3912 (2012).
[2] Davies, A. M. et al. Pharmacodynamic Separation of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Chemotherapy in Non-Small-Cell Lung Cancer. Clinical Lung Cancer 7, 385-388 (2006).
[3] Sangha, R. et al. Intercalated Erlotinib-Docetaxel Dosing Schedules Designed to Achieve Pharmacodynamic Separation. Journal of Thoracic Oncology 6, 2112-2119 (2011).
[4] Wang, Y. et al. Elucidation of relationship between tumor size and survival in non-small-cell lung cancer patients can aid early decision making in clinical drug development. Clin. Pharmacol. Ther. 86, 167-174 (2009).
Reference: PAGE 22 () Abstr 2730 [www.page-meeting.org/?abstract=2730]
Poster: Oncology