Table of Contents                               .     Page       .

1 Student Declaration        3

2 Abstract          4

3 Introduction         5

4 Objectives         6

5 Methodology         6 – 10

6 Results          7 – 21

7 Discussion          22 – 23

8 Conclusion         24

9 Acknowledgements        25

10 References         26 – 29

11 Appendices         30

 Abstract

Introduction: Molecular targeted therapy has been gaining traction in the treatment of advanced non-small cell lung cancer (NSCLC) in place of traditional standard chemotherapy. Given the growing significance of molecular agents, it is crucial for us to have an understanding of the genetic profile of NSCLC patients and assess the efficacy of targeted agents in terms of measurable outcomes such as progression free survival (PFS), overall survival (OS), and response rate (RR). Additionally, knowledge of treatment-resistant mutations will also play a crucial role in the care of patients with advanced NSCLC.

Objectives: This review aims to analyse the current literature on (i) frequencies of genetic mutations in different populations, (ii) demographic, clinical and histological factors associated with each mutation, (iii) efficacies of the various classes of molecular agents, and (iv) establish the role of treatment-resistant mutations in NSCLC patients.

Methods: A literature search was performed on two databases, PubMed and Scopus to identify articles which addressed the research question. Inclusion and exclusion criteria were applied to the search results to select studies for the literature review. A total of 13 studies were critically appraised and summarised. The results of each study were further analysed and synthesised.

Results: 13 studies were included in the literature review. 4 studies highlighted the heterogeneity of genetic profiles across different populations with EGFR and KRAS mutations being prominent ones. 6 studies assessed the efficacy of targeted therapy. Out of these 6 studies, 3 showed that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) and anaplastic lymphoma kinase (ALK) TKIs were superior to standard chemotherapy, 2 demonstrated clinical activity in B-raf proto-oncogene (BRAF) and human epidermal growth factor receptor 2 (HER2) mutation inhibitors but were unable to comment on whether they are superior to chemotherapy, and 1 concluded that MEK1/MEK2 inhibitors were non-superior to standard chemotherapy. Finally, 3 studies sought to identify mutations that conferred resistance to targeted therapy and they include (i) EGFR T790M, (ii) echinoderm microtubule associated protein like 4–anaplastic lymphoma kinase (EML4-ALK), and (iii) P13k/Akt/mTOR pathway mutations.

Conclusions: The scene of molecular targets in advanced NSCLC is a heterogenous and evolving one. Key driver mutations in NSCLC include EGFR, ALK, and Kirsten ras oncogene (KRAS) mutations. Their frequencies vary in different patient populations. The ‘typical’ patient with mutation-associated NSCLC tend to be EGFR mutation positive, East Asian, female, light or non-smokers, with adenocarcinoma histology. EGFR TKIs and ALK TKIs are superior to standard chemotherapy in the treatment of advanced NSCLC but other classes of targeted therapy require more research to clarify their definitive role in the treatment of metastatic disease. A key treatment-resistant mutation for EGFR TKIs is the EGFR T790M mutation, which is fortunately low in frequency. More research is expected to be conducted in the area of molecular therapy and the treatment algorithm for NSCLC patients is expected to continually evolve.

Introduction

Lung cancer

According to the World Health Organisation (WHO), lung cancer is the leading cause of all cancers and the leading cause of cancer-related deaths (1), with 80-85% being non-small cell lung cancers (2, 3). Additionally, an estimated 50% of all lung cancer patients diagnosed have metastatic disease, where 5-year survival rates are as low as 4% (4, 5).

Genetic Profile of Non-Small Cell Lung Cancer (NSCLC) patients

Given that NSCLC forms the majority of lung cancers and is associated with key driver mutations crucial to the treatment of metastatic disease (6), it is vital for us to have an understanding of the genetic profile of this population. Examples of key mutations include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, Kirsten ras oncogene (KRAS), and B-raf proto-oncogene (BRAF) mutations (7, 8).

Targeted Therapy

Over the past two decades, the management of NSCLC has become increasingly targeted. Today, treatment for metastatic NSCLC is driven by molecular agents specific to a patient’s mutational status (9). The use of EGFR tyrosine kinase inhibitors (TKIs) in patients with sensitising mutations have been supported by multiple landmark trials on the basis of greater response rates (RR)