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) and progression free survival (PFS) than chemotherapy (10-15). This has been supported by two Cochrane reviews published in 2016 (16) and 2018 (17). The use of Crizotinib for ALK- and ROS1-mutant lung cancers has also been gaining ground (18, 19). It is expected that the treatment algorithm for NSCLC patients with driver mutations will continue to evolve as more studies continue to investigate the efficacy of new and existing molecular agents.

Resistance to Treatment

The use of mutational status can also be used as a predictive factor on whether a patient will be resistant to treatment (20). This allows physicians to spare patients from adverse effects of targeted therapy should benefits of response be minimal in comparison to risk of toxicity.

Objectives

This review aims to analyse the current literature on the use of molecular targets in NSCLC through the following objectives:

1. To establish the frequencies of genetic mutations in NSCLC patients
2. To ascertain factors associated with each mutation
3. To investigate the efficacy of targeted therapy
4. To identify mutations associated with resistance to targeted therapy

Methods

Search Strategy

An electronic search was carried out on PubMed and Scopus to identify studies which would elucidate the research topic and achieve the objectives of this literature review.

The following search strategy was used for both databases:

1. “carcinoma, non-small-cell lung”[MeSH Terms] OR “lung neoplasms”[MeSH Terms] OR ((“lung”[All Fields] OR “bronchogenic”[All Fields] OR “pulmonary”[All Fields]) AND (“cancer”[All Fields] OR “carcinoma”[All Fields] OR “tumour”[All Fields] OR “neoplasm”[All Fields]))

AND

2. “molecular targeted therapy”[MeSH Terms] OR (targeted[All Fields] AND (“therapy”[Subheading] OR “therapeutics”[MeSH Terms]))

AND

3. “mutation”[All Fields] OR “mutations”[All Fields]

Filters Activated

Filters activated for the search strategy included:

Inclusion Criteria

• Articles on a new, authentic study
• Studies that investigate mutations with molecular targets in non-small cell lung cancer
• For studies in which patients receive treatment, at least one of the treatment options should include a molecular targeted therapy
• For studies on the prevalence or incidence of mutations in non-small cell lung cancer, more than one mutation should be investigated

Exclusion Criteria

• Articles not accessible either as a free full text, or articles with restricted access for which permission to obtain a copy was not granted
• Review articles
• Case reports or case series
• Studies evaluating molecular targets in cancers apart from lung cancer
• Studies evaluating molecular targets in other types of lung cancer i.e. small cell lung cancer
• Studies investigating techniques of obtaining tissue samples for molecular testing, or methods of molecular testing
• Studies evaluating economic, administrative, or operational aspects of the topic
• Studies on the clinical presentation of lung cancer
• Studies on other lung diseases with molecular targets e.g. cystic fibrosis
• Laboratory-based, ex-vivo studies on human tissues

Study Selection Process

The search results elicited from PubMed and Scopus were combined and subsequently screened for the removal of duplicates. After which, titles and abstracts of the remaining articles were carefully assessed, with application of the inclusion and exclusion criteria.

Of the 22 abstracts deemed suitable for the literature review, those with full text articles which were not accessible either as free full text, or via the University College Cork (UCC) library portal were further excluded. The remaining 17 papers with full text were carefully read through to select 10 studies which best satisfied the inclusion and exclusion criteria. Lastly, the references of all 10 selected studies were carefully reviewed and another 3 highly relevant landmark trials were suggested for inclusion by the project supervisor, an expert in the field of medical oncology. These 3 studies satisfied the inclusion and exclusion criteria, and were thus included. The selection process is summarised in Figure 1 below and reasons for exclusion are found in Table 1.

Figure 1. Outline of Study Selection Process

Table 1. Overview of studies excluded

Results

A summary of the thirteen studies selected for this review can be found in Tables 2-4. Abbreviations used in the tables are listed in Box 1.

Box 1. Abbreviations used in the results tables