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Assessing models for changes in tumour size over time and how they relate to survival times.

Assessing models for changes in tumour size over time and how they relate to survival times.

Raluca Eftimie

Division of Mathematics, University of DundeeDundee, UK

Northern Research Partnership Early Career Researcher Engagement and Exchanges with Business and Industry


28 May 2014

The background to the research
• There are still many unanswered questions regarding how, or even if, changes in tumour size relate to patient survival. In addition, to our best knowledge most survival models in the existing literature have never been tested on independent data sets. Such a test is the main purpose of this study. The testing of survival models on independent data sets is vital to establishing the validity of the selected approach.
• Although melanoma is not the most prevalent skin cancer, it does have one of the highest mortality rates. In the US alone, it is estimated that 76,000 new cases will be diagnosed in 2014, and about 10,000 people will die this year. (http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics)

How the research will add to medical science or improve patient care?
• In assessing the relationship between tumour size changes and survival, this research should enable an earlier evaluation of how well a new treatment is likely to affect survival times for patients with metastatic melanoma.
• We will also address a key basic science question regarding growth laws applicable to clinical tumours. A recent article has highlighted that there remains considerable uncertainty regarding appropriate growth laws for human tumours (http://cancerres.aacrjournals.org/content/early/2013/02/07/0008-5472.CAN-12-4355).

The aims and objectives of the research
The overall aim of this project is to assess whether mechanistic models for tumour growth offer any functional advantage over empirical investigations of how changes in tumour size ( e.g. at week 8) relate to survival times .

Specific Objectives are:
• Build and test different mechanistic models of tumour growth.
• Assess if there is a relationship between empirical tumour size changes and survival.
• Assess if there is a relationship between parameter values from the different growth law models and survival.
• Also determine the prospective use of a survival model built using one drug and tested with data from other drugs within a similar diseases setting.

How the research will be conducted
• The research will be conducted using data from three drugs approved in the metastatic melanoma setting: Vemurafenib, Trametnib and Dabrafenib. The data from one of these studies will be used to select a tumour growth law model used to develop a survival model. The data from the other two drugs will be used as a validation set.

How the findings will be interpreted and communicated to patients and/or the public
• Publication in an open access format
• Summary available through a dedicated project webpage hosted by the main investigator.

[{ "PostingID": 354, "Title": "GSK-BRF112680", "Description": "Medicine: dabrafenib, Condition: Cancer, Phase: 1, GSK Clinical Study ID: BRF112680, Sponsor: GSK." },{ "PostingID": 357, "Title": "GSK-BRF113710", "Description": "Medicine: dabrafenib, Condition: Melanoma, Phase: 2, GSK Clinical Study ID: BRF113710, Sponsor: GSK." },{ "PostingID": 434, "Title": "GSK-BRF113683", "Description": "Medicine: dabrafenib, Condition: Cancer, Phase: 3, GSK Clinical Study ID: BRF113683, Sponsor: GSK." },{ "PostingID": 517, "Title": "GSK-MEK113583", "Description": "Medicine: trametinib, Condition: Cancer, Phase: 2, GSK Clinical Study ID: MEK113583, Sponsor: GSK." },{ "PostingID": 518, "Title": "GSK-MEK114267", "Description": "Medicine: trametinib, Condition: Melanoma, Phase: 3, GSK Clinical Study ID: MEK114267, Sponsor: GSK." },{ "PostingID": 519, "Title": "GSK-MEK111054", "Description": "Medicine: trametinib, Condition: Solid Tumours, Phase: 1, GSK Clinical Study ID: MEK111054, Sponsor: GSK." },{ "PostingID": 1369, "Title": "ROCHE-NO25026 (BRIM3)", "Description": "A randomized, open-label, controlled, multicenter, global study on progression-free and overall survival in previously untreated patients with unresectable stage IIIC or stage IV melanoma with V600E BRAF mutation receiving RO5185426 or dacarbazine

Medicine: vemurafenib, Condition: malignant melanoma of skin, Phase: 3, Clinical Study ID: NO25026 (BRIM3), Sponsor: Roche" },{ "PostingID": 1370, "Title": "ROCHE-NP22657 (BRIM2)", "Description": "An open-label multicenter study on the efficacy of continuous oral dosing of RO5185426 on tumour response in previously treated patients with metastatic melanoma

Medicine: vemurafenib, Condition: malignant melanoma of skin, Phase: 2, Clinical Study ID: NP22657 (BRIM2), Sponsor: Roche" }]

Statistical Analysis Plan

Mistry, H.B., Orrell, D. & Eftimie, R. Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma. Cancer Chemother Pharmacol 81, 325-332 (2018). https://doi.org/10.1007/s00280-017-3486-3