UNIVERSITY OF CALGARY

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UNIVERSITY OF CALGARY
Treatment at Disease-progression in EGFR-mutated NSCLC Patients: Results from a single
Canadian Institution
by
Roxana Alina Tudor
A THESIS
SUBMITTED TO THE FACULTY OF GRADUATE STUDIES
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE
DEGREE OF MASTER OF SCIENCES
GRADUATE PROGRAM IN MEDICAL SCIENCE
CALGARY, ALBERTA
SEPTEMBER, 2016
© Roxana Alina Tudor 2016

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Abstract
Optimal treatment beyond disease-progression (PD) in non-small cell lung cancer (NSCLC)
patients harboring activating epidermal growth factor receptor (EGFR) mutations, treated with
tyrosine kinase inhibitors (TKIs), is not well-defined.
In this retrospective study, the following aims were set out: 1) compare outcomes and profile of
EGFRmut+ NSCLC patients to large cohorts of lung-cancer patients from the Glans-Look lung
cancer database -GLD; 2) examine the frequency of continuing TKI treatment beyond PD in
EGFRmut+ patients; 3) examine overall survival (OS) and post-progression survival (PPS)
according to clinicopathological characteristics and; 4) propose a new PD-scoring model to help
guide subsequent treatment formulation.
Compared to the GLD-NSCLC cohort without systemic chemotherapy, EGFRmut+ patients were
more likely to be younger, female and Asian. Further, continuing TKI treatment beyond PD was
associated with improved OS and PPS vs. discontinuation of TKI. A non-independent
relationship between EGFRmutation type and smoking history was identified.

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Preface
This thesis is original and has been written in partial fulfillment of the requirement for the
degree of Master of Science in the Medical Sciences Graduate Program at the University of
Calgary.

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Acknowledgements
First and foremost, I would like to thank my supervisor, Dr. Gwyn Bebb, for accepting
me into his research group. Dr. Bebb has contributed to a rewarding graduate school experience
by offering guidance and intellectual freedom in my work, supporting my attendance at the 16th
World Lung Cancer Conference (Denver, Co) and the European Society Medical Oncology 2016
Congress (Copenhagen, Denmark), as well as introducing me to various leaders in thoracic
oncology, meanwhile demanding high quality and precision in my work. Furthermore, I would
like to thank my co-supervisor, Dr. Karen Kopciuk, for all the support and patience provided
throughout the statistical analyses of my thesis. Lastly, I would like to thank my committee
members, Dr. Darren Brenner, Dr. Alain Tremblay and Dr. Paul MacEachern for their interest in
my thesis project, and offering in-depth perspectives and guidance.
I am also grateful for the funding that allowed me to pursue graduate school studies in a
medical area I am truly passionate about and finally, I would like to thank my parents for their
constant love and support.

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Table of Contents
Abstract ………………………………………………………………………………………….. ii
Preface ………………………………………………………………………………………….. iii
Acknowledgements ……………………………………………………………………………... iv
Table of Contents …………………………………………………………………………….. v-vi
List of Tables …………………………………………………………………………………... vii
List of Figures ……………………………………………………………………………….… viii
List of Abbreviations …………………………………………………………………………….ix
Chapter 1: Introduction ……………………………………………………………………... 1-2
Chapter 2: Background ……………………………………………………………………. 3-16
2.1 Lung-cancer 3-4
2.2 Treatment of advanced non-small cell lung cancer (NSCLC) 4
2.3 EGFRmut+ NSCLC patients and EGFR-TKIs 5
2.3.1 Epidermal growth factor receptor (EGFR) function and
its role in NSCLC 5-10
2.4 Defining disease-progression (PD) 10-16
Chapter 3: Thesis Aims and Objectives …………………………………………………. 17-19
Chapter 4: Materials and Methods ………………………………………………………. 20-31
4.1 Population cohort selection 20
4.2 Data collection 20-22
4.3 Treatment methods 22
4.4 Disease-progression criteria 22-24
4.5 Statistical analyses 25-31
4.5.1 Descriptive and time to event statistics 25-26
4.5.2 Multi-state model (MSM) 26-27
4.5.2(a) Overall survival (OS) analysis via multi-state modeling 27-28
4.5.2(b) Post-progression survival (PPS) analysis via Cox PH regression models
with propensity score weights 29-30
Chapter 5: Results ………………………………………………………………………… 31-72
5.1 Overview: EGFRmut+ NSCLC cohort 31-38