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INVITED REVIEW SERIES: LUNG CANCER PRACTICE, IMPLEMENTING EVIDENCE AROUND THE WORLD SERIES EDITORS: KWUN M. FONG AND NICO VAN ZANWIJK

Molecular targeted therapy in the treatment of advanced stage non-small cell lung cancer (NSCLC) NESARETNAM BARR KUMARAKULASINGHE,1 NICO VAN ZANWIJK2 AND ROSS A. SOO1,3,4 1

Department of Haematology-Oncology, National University Cancer Institute, National University Health System, 3Cancer Science Institute of Singapore, National University of Singapore, Singapore, and 2Asbestos Disease Research Institute, University of Sydney, Concord, New South Wales and 4Department of Surgery, University of Western Australia, Perth, Western Australia, Australia

ABSTRACT Historically, patients with advanced stage non-small cell lung cancer (NSCLC) were treated with chemotherapy alone, but a therapeutic plateau has been reached. Advances in the understanding of molecular genetics have led to the recognition of multiple molecularly distinct subsets of NSCLC. This in turn has led to the development of rationally directed molecular targeted therapy, leading to improved clinical outcomes. Tumour genotyping for EGFR mutations and ALK rearrangement has meant chemotherapy is no longer given automatically as first-line treatment but reserved for when patients do not have a ‘druggable’ driver oncogene. In this review, we will address the current status of clinically relevant driver mutations and emerging new molecular subsets in lung adenocarcinoma and squamous cell carcinoma, and the role of targeted therapy and mechanisms of acquired resistance to targeted therapy. Correspondence: Ross A. Soo, Department of HaematologyOncology, National University Cancer Institute, National University Health System, 1E Kent Ridge Road, NUHS Tower Block Level 7, Singapore119228. Email: [email protected] The Authors: Nesaretnam Barr Kumarakulasinghe is a secondyear trainee in medical oncology at the National University Cancer Institute, National University Health System, Singapore. He has a keen interest in supportive care in medical oncology. Ross A. Soo is a senior consultant at the Department of Haematology-Oncology, National University Cancer Institute, Singapore, an Adjunct Principal Investigator, Cancer Science Institute of Singapore, National University of Singapore, and is a visiting senior consultant at Alexandra Hospital, Singapore. His research interests are lung cancer, translational medicine and early drug development. Professor Nico van Zanwijk, educated in internal and respiratory medicine (MD, PhD, University of Amsterdam), has been active in thoracic oncology since the early 1980s. He founded the Department of Thoracic Oncology at the Netherlands Cancer Institute (1985) and was invited to become the inaugural director of the Asbestos Diseases Research Institute, and a professor at the University of Sydney in 2008. He has (co)-authored more than 250 articles, books and chapters in the thoracic oncology area. Received 24 November 2014; accepted 7 December 2014. Article first published online: 17 February 2015 © 2015 Asian Pacific Society of Respirology

Key words: anaplastic lymphoma kinase, epidermal growth factor receptor, molecular targeted therapy, non-small cell lung cancer. Abbreviations: ALK, anaplastic lymphoma kinase; CI, confidence interval; FDA, Food and Drug Administration; FGFR1, fibroblast growth factor receptor-1; FISH, fluorescence in situ hybridization; HR, hazard ratio; IPASS, Iressa Pan-Asia Study; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SQLC, squamous cell lung carcinoma; TKI, tyrosine kinase inhibitor.

INTRODUCTION Lung cancer remains the number one cause of cancer deaths worldwide.1 In 2014, an estimated 224 210 new cases of lung cancer will be diagnosed, of which the majority of patients are non-small cell lung cancer (NSCLC) and in the advanced stage.2 Historically, patients with advanced stage NSCLC were treated with platinum chemotherapy regardless of histological subtype. Despite an improvement in overall survival (OS) when compared with best supportive care,3 a therapeutic plateau has been reached with a response rate of about 20% and a median survival of 8–10 months.4 Advances in the understanding of molecular genetics in NSCLC have led to the identification of key genetic aberrations in NSCLC. These genetic aberrations (driver mutations) occur in oncogenes that encode signalling proteins that are crucial for cellular proliferation and survival. The concept of oncogene addiction is based on the notion that tumours become greatly dependent on the expression of single oncogenes for survival.5 Oncogene-addicted tumours have been identified in NSCLC and exploited with specific molecular targeted agents. Lung adenocarcinoma is the most common histological subtype of NSCLC, comprising of more than 50% of all NSCLC.6 The importance of specific histological subtypes of NSCLC in the selection of therapy Respirology (2015) 20, 370–378 doi: 10.1111/resp.12490

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Adenocarcinoma

ERBB2 3%

Other 12% MET 7%

Squamous cell carcinoma

None 25%

Other 20%

ALK 1% ROS 1 2%

PTEN mutaon/ deleon 15%

BRAF 7%

Unknown 21% EGFR 11%

Figure 1 A simplified overview of genetic aberrations found in non-small cell lung carcinoma. Data adapted from references.8,9

for advanced stage NSCLC was appreciated when a randomized trial showed superior outcomes for platinum-pemetrexed than for platinum-gemcitabine in patients with non-squamous NSCLC.7 More recently, lung adenocarcinoma can be subdivided into clinically relevant molecular subsets, based on specific driver mutations (Fig. 1). Molecular subsets identified in lung adenocarcinoma include mutations in the EGFR, KRAS, HER2, PIK3CA, BRAF, MET genes, and gene rearrangement in ALK, ROS1 and RET (Fig. 1). Squamous cell lung carcinoma (SQLC) is the second most common histological variant of NSCLC, comprising up to 20–30% cases.6 While EGFR mutations are uncommon in squamous cell lung cancer, actionable oncogenes discovered recently in SQLC include fibroblast growth factor receptor-1 (FGFR1) gene amplification, discoidin death receptor 2 (DDR2) gene mutation, and PI3KCA gene amplifications and mutations. In this review, we address the current status of clinically relevant driver mutations and emerging new molecular subsets in lung adenocarcinoma and squamous cell carcinoma. We discuss some of the molecular targeted agents that have been shown to be highly effective in many of these molecular subsets (Table 1).

EGFR mutations EGFR also known as HER1 or ErbB1 is one of the four members of the ErbB receptor tyrosine kinase family.30 EGFR is an attractive target in NSCLC as it is frequently overexpressed, and its activation results in the downstream activation of important signalling pathways, leading to increased cell proliferation, survival, angiogenesis and metastasis.31 Small-molecule EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, were initially introduced in unselected NSCLC patients previously treated with chemotherapy. Other EGFR TKI developed since then includes afatinib and dacomitinib. Retrospective analysis revealed clinical characteristics such as female gender, adenocarcinoma histological subtype, Asian ethnicity and a history of never/light smoking were associated with increased response to EGFR TKI.30 The molecular basis for increased sensi© 2015 Asian Pacific Society of Respirology

PIK3CA mutaon 16%

KRAS 32% DDR2 Mutaon 4%

FGFR1 amplificaon 15%

EGFR amplificaon 9%

tivity to EGFR TKI was subsequently identified to be due to somatic activating mutations in exon 18–21 of EGFR (commonly exon 19 deletions and L858R point mutation in exon 21) that encode the tyrosine kinase domain of the EGFR.30 In-frame deletions within exon 19 and L858R substitution in exon 21 make up the majority of the sensitizing EGFR mutations, contributing approximately 45% and 40%, respectively.31 The remaining 5–10% of mutations involve nucleotide substitutions in exon 18 and in-frame insertions in exon 20. Mutations in exon 18 are known to confer sensitivity to EGFR TKI; however, exon 20 in-frame insertions are largely associated with primary resistance to treatment with TKI. EGFR mutations are more frequent in patients with the clinical features described previously. Up to 15% of Caucasians and 30–50% of East Asians with lung adenocarcinoma harbour EGFR mutations.31–34 The incidence is as high as 50–60% in East Asians, who have lung adenocarcinoma and are never smokers.33,35 In patients with untreated NSCLC with sensitizing EGFR mutations, multiple studies have shown EGFR TKI to be superior to chemotherapy in terms of overall response rate (ORR), progression-free survival (PFS) and quality of life (Table 2).11–20,36 The landmark Iressa Pan-Asia Study (IPASS) randomized patients with the clinical phenotype likely to harbour EGFR mutations to gefitinib or carboplatin/paclitaxel. Gefitinib was superior to the platinum doublet (hazard ratio (HR) for progression 0.74 (95% confidence interval (CI): 0.65– 0.85; P < 0.001). However, poorer outcomes were observed in EGFR wild-type NSCLC patients treated with EGFR TKI. In the IPASS study, patients with EGFR wild-type tumours treated with gefitinib had a significantly shorter PFS of 1.5 months versus 6.5 months with chemotherapy.11 Other randomized studies with gefitinib, erlotinib and afatinib in patients molecularly selected for EGFR mutations had a similar improvement in ORR and PFS (Table 2). These studies have provided the basis for the rational selection of treatment based on molecularly defined criteria in the treatment of patients with advanced stage NSCLC. Thus, the selection of patients with advanced stage NSCLC for the first-line treatment with EGFR TKI should be based on EGFR mutation status, and EGFR Respirology (2015) 20, 370–378

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Table 1 Outcome to chemotherapy and molecular targeted therapy according to molecular subtype in patients with advanced stage non-small cell lung cancer Therapy Platinum doublet Platinum doublet + bevacizumab EGFR TKI Gefitinib Erlotinib Afatinib CO-1686 AZ9291 ALK TKI Crizotinib Crizotinib Ceritinib Alectinib ROS1 Crizotinib BRAF inhibitor Dabrafenib MET TKI Crizotinib

Patient population

Molecular subtype

ORR%

PFS (months)

Median OS (months)

Reference

8–10.3 12.3

4,10

9.2–10.8 9.7–13.1 13.6–13.7 Not reached

21.6–34.8 19–22.7 22.1 NR

11–15

64

NR

NR

22

74 65 66 93.5

10.9 7.7 7.0 NR

NR 20.3 NR NR

23

ROS1 fusions

56

NR

NR

27

Previously treated

BRAF V600E

40

NR

NR

28

Untreated and previously treated

MET amp

33

NR

NR

29

Untreated Untreated

Unselected Unselected

15–22 35

Untreated Untreated Untreated Resistant to other EGFR TKI Resistant to other EGFR TKI

EGFR EGFR EGFR EGFR T790M

62–74 64–83 56–67 58

EGFR T790M

Untreated Pre-treated Untreated Untreated

EML4-ALK

Untreated and previously treated

3.1–4.5 6.2

10

16–18 19,20 21

24 25 26

ALK, anaplastic lymphoma kinase; BRAF, V-Raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; EML4, echinoderm microtubule associated protein like 4; MET, hepatocyte growth factor receptor; NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

Table 2 Phase III studies evaluating first line EGFR TKI patients with advanced stage NSCLC harbouring EGFR mutations

Study IPASS11,36 (EGFR mutant subset) First SIGNAL12 (EGFR mt subset) WJTOG13,14 NEJSG15 OPTIMAL16,17 EURTAC18 LUX-LUNG 319 LUX-LUNG 620

Treatment

Response rate (%)

Gefitinib Paclitaxel/carboplatin Gefitinib Cisplatin/gemcitabine Gefitinib Cisplatin/docetaxel Gefitinib Carboplatin/paclitaxel Erlotinib Carboplatin/gemcitabine Erlotinib Platinum doublet Afatinib Cisplatin/pemetrexed Afatinib Cisplatin/Gemcitabine

71 47 85 38 62 32 74 31 83 36 64 18 56 23 66.9 23

Progression-free survival (HR; 95% CI) 0.48; 0.36–0.64 0.544; 0.269–1.10 0.49; 0.34–0.71 0.30; 0.22–0.41 0.16; 0.10–0.26 0.37; 0.25–0.54 0.58; 0.43–0.78 0.28; 0.20–0.39

Median survival (months); HR; 95% CI 21.6 versus 21.9 1.00; 0.76–1.33 27.2 versus 25.6 1.043; 0.498–2.182 34.8 versus 37.3 1.252; 0.883–1.775 30.5 versus 23.6 0.887; 0.634–1.241 22.7 versus 28.9 1.04; 0.69–1.68 19.3 versus 19.5 1.04; 0.65–1.68 Not reported 22.1 versus 22.2 0.95; 0·68–1.33

CI, confidence interval; EGFR, epidermal growth factor receptor; HR, hazard ratio; TKI, tyrosine kinase inhibitor.

mutation testing should be performed routinely at the time of diagnosis. EGFR TKI is generally well tolerated. Common side-effects of EGFR TKI include acne-form rash, dry Respirology (2015) 20, 370–378

skin, pruritus and diarrhoea. When compared with chemotherapy, there were less grade 3 or 4 adverse effects, lower rates of discontinuation and dose modification.11,16,18,36 © 2015 Asian Pacific Society of Respirology

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Despite initial responses to EGFR TKI, all patients eventually progress.37 Studies involving repeat biopsies before and following EGFR TKI progression have identified several mechanisms of secondary resistance. A mutation in exon 20 of EGFR (T790M) is seen in approximately 50% of patients with acquired resistance to EGFR TKI.37 Other mechanisms of resistance include MET amplification (5%), HER-2 amplification (8%), PI3K mutations (5%) and transformation to small cell lung cancer (14%).38,39 As T790M mutation is the most common mechanism of acquired resistance to EGFR TKI, EGFR TKI targeting T790M mutant EGFR has been developed and will be discussed later. Molecular targeted agents already exist or are being developed against other pathways implicated in acquired resistance, such as HER2, PIK3CA and MET. Hence, a repeat biopsy at point of progression may provide insight into the mechanism of resistance, and therefore improve treatment strategies to overcome resistance. The second-generation irreversible EGFR TKI, such as dacomitinib and afatinib, is pan-ErbB inhibitors with in vitro activity against both activating EGFR mutations and the T790M resistance mutation. Despite promising preclinical activity, the clinical efficacy of dacomitinib and afatinib remains to be established in patients with acquired resistance to first-generation EGFR TKI. In a randomized trial of afatinib versus placebo in patients with pretreated advanced stage NSCLC with prior treatment with EGFR TKI, the OS was not increased.40 A similar outcome was seen with dacomitinib versus placebo in a comparable patient population.41 The efficacy of afatinib in the first-line setting for patients with NSCLC harbouring EGFR mutations is established.19,20 Third-generation EGFR TKI (CO-1686 and AZD9291) are more T790M selective, clinically more potent and less toxic than the current EGFR TKI. Preliminary results of both CO-1686 and AZD929 are highly promising given their improved tolerability and clinical activity. Early-phase studies in patients with advanced stage NSCLC treated with prior EGFR TKI and documented T790M mutations treated with CO-1686 or AZD9291 have reported an ORR of 58% and 64%, respectively.21,22 These results further emphasize the importance of conducting molecular analysis at the time of disease progression to enable better treatment selection.

Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) gene rearrangement The EML4-ALK gene rearrangement, a result from an inversion within chromosome 2p, is a newly identified driver oncogene in lung adenocarcinoma. The fusion between EML4 and ALK results in a chimeric protein that is constitutively active and promotes tumourigenesis via the PI3K-AKT, MAPK and JAKSTAT pathways.42 The EML4-ALK gene rearrangement is usually detected by fluorescence in situ hybridization (FISH) or immunohistochemistry.43 ALK gene rearrangements are uncommon, occurring in about 4–7% of all NSCLC, and more likely in © 2015 Asian Pacific Society of Respirology

373 younger patients, never or light smokers, adenocarcinomas with signet ring, or acinar histology.42,44–47 It is seen in up to 33% in patients with NSCLC after exclusion of EGFR and KRAS mutants. EML4-ALK rearrangements are largely mutually exclusive from other driver mutations in NSCLC.42 ALK inhibitors include crizotinib, and more recently ceritinib and alectinib. In a phase III study in patients with untreated advanced stage NSCLC with ALK rearrangement treated with crizotinib versus chemotherapy, crizotinib had a significantly higher ORR (74% vs 45%) and prolonged PFS (10.9 months vs 7 months).23 In a phase III study of pretreated patients with advanced stage ALK rearranged NSCLC, crizotinib was significantly superior to standard single agent chemotherapy in terms of ORR (65% vs 20%) and PFS (7.7 months vs 3 months).24 Multiple mechanisms of acquired resistance to crizotinib have been reported, including a secondary mutation in the ALK tyrosine kinase domain (most commonly the L1196M mutation), ALK copy number gain, and the appearance of new oncogene drivers such as EGFR and KRAS mutations.48 Knowledge of the different mechanisms of acquired resistance may impact on subsequent treatment strategies. ALKdirected treatment, such as second-generation ALK TKI, may be directed towards tumours with ALK mutations or copy number gain, whereas resistant tumours secondary to new driver oncogenes may benefit more from chemotherapy. Ceritinib, a second-generation ALK TKI, is active in ALK-positive tumours that are treatment-naïve or have failed crizotinib therapy. In treatment-naïve and resistant to crizotinib patients treated with ceritinib, the ORR was 66% and 55%, respectively.25 Ceritinib was recently approved by the US Food and Drug Administration (FDA) in the treatment of patients with ALK positive, metastatic NSCLC with disease progression on or are intolerant to crizotinib. In ALK inhibitor-naïve patients treated with alectinib, another second-generation ALK TKI, the ORR was 93.5%.26

ROS1 translocation v-ROS1 is an oncogene product of the avian sarcoma RNA tumour virus UR2. ROS1 translocation occurs as a result of genetic translocations between the ROS-1 gene with various fusion partners, such asTPM3, SDC4, SLC34A2, CD74, EZR, LRIG3 and FIG1.49 The ROS-1 tyrosine kinase belongs to the insulin receptor family, and shares a similar structure to ALK within the tyrosine kinase domain and at the ATP-binding site.49 ROS1 translocations are usually detected by FISH or immunohistochemistry. Patients with ROS1 translocations tend to be younger, never smokers with adenocarcinoma histological subtype and is seen in about 3% of NSCLC.49–51 Preclinical studies have shown crizotinib is active in tumours harbouring the ROS1 translocation.50,52 Preliminary results of patients with ROS1 fusions treated with crizotinib have reported an ORR of 56%.27 Respirology (2015) 20, 370–378

374 BRAF mutations BRAF is a member of the RAF kinase family of serine/ threonine protein kinases that mediate tumourigenesis by phosphorylation of MEK and downstream activation of the ERK signalling pathway.53 BRAF mutations are observed in 1–3% of NSCLC, and about 50% of BRAF mutations are BRAF V600E mutations.53–55 BRAF mutations in NSCLC are more likely in adenocarcinoma, and BRAF V600E mutations are more frequent in women and never smokers.53,54 The BRAF inhibitors dabrafenib and vemurafenib are active in NSCLC harbouring BRAF V600E mutations. In a phase I/II study, dabrafenib had an ORR of 40% and a disease control rate of 60% in pretreated patients with the V600E BRAF mutations.28 Based on these results, dabrafenib received a breakthrough therapy designation from the FDA for its potential as a treatment for patients with advanced stage NSCLC with BRAF V600E mutations who have received at least one prior line of platinum chemotherapy. MET expression MET is a tyrosine kinase receptor, which upon activation induces cell proliferation, motility, scattering, invasion, metastasis, angiogenesis and epithelial to mesenchyme transition.56 MET can be dysregulated by various mechanisms, such as overexpression, genomic amplification, mutations and alternative splicing. MET overexpression determined by immunohistochemistry is seen in 25–50%56 and MET amplification in 7% of NSCLC. Multiple MET inhibitors are currently being evaluated. In preliminary data presented recently, in patients with NSCLC harbouring MET amplifications assessed by FISH treated with crizotinib, the ORR was 33%.29 In a subset of patients with high MET amplification, the ORR was 67%. KRAS mutation The KRAS protein is a member of the RAS family of guanosine triphosphatases. KRAS mutations result in a constitutively active KRAS, resulting in oncogenesis. KRAS mutations portend a worse outcome with increased risk of recurrence in early-stage disease and poorer survival in metastatic stage.57 It is associated with adenocarcinoma subtype and smoking, and is more common in Caucasian than East Asian patients.58,59 Early attempts to inhibit KRAS in advanced NSCLC were unsuccessful, and efforts are currently focused on targeting pathways downstream to KRAS, such as MEK. The oral MEK inhibitor selumetinib has shown activity in combination with chemotherapy. In a randomized study, previously treated patients with KRAS mutations randomized to chemotherapy or chemotherapy and selumetinib had a significantly increased ORR (37% vs 0%) and prolonged PFS (5.3 months vs 2.1 months), and a suggestion of increased OS (9.4 months vs 5.2 months).60 Respirology (2015) 20, 370–378

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Her-2 mutations Similar to EGFR, HER-2 (ErbB-2) is a member of the ErbB family of tyrosine kinases. HER-2, a major proliferative driver, is dysregulated in NSCLC through amplification, overexpression or mutation.61 HER2 amplification and HER-2 protein overexpressions occurs in about 20% and in 6–35%, respectively, in NSCLC, whereas HER2 mutations are seen in 1–2%. The majority of patients who harbour HER2 mutations are female, never smokers and adenocarcinoma.61,62 In breast cancer, HER-2 overexpression or gene amplification is associated with sensitivity to HER-2 inhibitors, such as trastuzumab, pertuzumab and lapatinib. However, studies of trastuzumab combined with chemotherapy in patients with NSCLC overexpressing HER2 on IHC were negative.63,64 Promising activity with trastuzumab or afatinib has been reported in retrospective studies of patients with NSCLC with HER2 mutations.61,65 RET translocation Translocations between the RET gene and its various fusion partners, CCDC6, KIF5B, NCOA4 and TRIM33, have been detected in 1% of patients with lung adenocarcinoma,66,67 but it can be as frequent as 7–17% in an enriched population of younger patients and never smokers.66,68,69 TKI, such as cabozantinib, vandetanib, sunitinib and ponatinib, which are already approved for other malignancies are known to inhibit RET and are currently being studied in RET-rearranged NSCLC. Other RET inhibitors include regorafenib and lenvatinib. NTRK1 (neurotrophic tyrosine kinase receptor) gene fusions The NTRK1 gene encodes the high-affinity nerve growth factor receptor (TRKA), which leads to cell differentiation and may play a role in specifying sensory neuron subtypes.70 NTRK1 gene fusions with myosin phosphatase-rhointeracting protein gene (MPRIP-NTRK1) and CD74NTRK100 lead to a TRKA kinase fusion protein that is constitutively active and oncogenic.70 NTRK1 gene fusions have been reported in about 3% of NSCLC in tumours without other known oncogenic alterations.70 NTRK inhibitors being investigated include crizotinib, ARRY-470 and lestaurtinib (CEP-701). FGFR1 amplification FGFR1 is a receptor tyrosine kinase that mediates tumourigenesis via the MAPK and PI3K pathways, and has been detected in 13–25% of squamous cell lung cancers.71,72 FGFR1 amplification has been reported to be associated with smoking72 and is uncommon in adenocarcinoma subtype. The prognostic impact of FGFR1 amplifications is variable with some reports of a neutral71 or worse outcome.72 Differences in frequency of FGFR1 amplification and prognostic outcome between studies may be due to differences © 2015 Asian Pacific Society of Respirology

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in sample size studied and cut-off used to define FGFR1 amplification. FGFR inhibitors are being developed in squamous cell lung cancer.73 Preliminary data with BGJ398, a pan FGFR TKI in FGFR1amplified SQLC, showed an ORR of 11.7%.74

DDR2 (Discoidin death receptor 2) mutation The DDR2 is a transmembrane receptor tyrosine kinase that upon activation by collagen promotes cell migration, proliferation and survival.75 Activating mutations in DDR2 are oncogenic and are detected in about 4–5% of SQLC.75,76 DDR2-driven transformation is sensitive to the DDR2 inhibitor dasatinib, a TKI used in the treatment of chronic myeloid leukaemia.75 Response to dasatinib has been described in a patient with SQLC of the lung harbouring a DDR2 kinase domain mutation and synchronous chronic myelogenous leukaemia.77 Dasatinib is currently being investigated in SQLC patients with DDR2 mutations. PI3K pathway aberrations The PI3K signalling pathway is central to cancer cell survival and proliferation. Alterations in the signalling pathway may arise due to amplification or gain of function mutations in the PIK3CA and AKT1 genes or from loss of PTEN function.78 PI3KCA amplifications and mutations in NSCLC have been reported in 37% and 9%, respectively.79,80 Both amplifications and mutations of PI3KCA are poor prognostic factors in SQLC.81 Studies of PIK3CA inhibitors as monotherapy or in combination with chemotherapy are ongoing.

FUTURE DIRECTION While testing for tumours harbouring EGFR mutation and ALK rearrangement is now commonly practised, with more oncogenes identified, sequential testing for each oncogene becomes inefficient. A recent study demonstrated a proof of principle that testing of multiple driver oncogenes using a multiplex genotyping assay was feasible and enabled an effective selection of lung cancer treatment. Patients with lung adenocarcinomas were tested for 10 driver mutations and were matched to an appropriate targeted agent or clinical study based on their mutation status. Among those with identifiable oncogenic driver mutations (64%), survival was significantly improved for those who received genotype-directed therapy (median OS 3.5 vs 2.4 years, HR = 0.69 (95% CI: 0.53–0.9), P = 0.006).82 New driver oncogenes are continuously being identified in lung adenocarcinoma and squamous cell carcinoma. In a comprehensive genomic study of lung adenocarcinoma, it was found that over 75% of genetic alterations were targetable, with previously unappreciated genes altered and a novel inactivating mutation of MGA described.8 Genomic studies in squamous cell lung cancers from Western and East Asian patients have revealed a very high mutation burden without any clear ethnic variation, © 2015 Asian Pacific Society of Respirology

suggesting that chronic exposures to environmental carcinogens seem to override the subtle genetic variation seen in different ethnic groups.9 Researchers from The Cancer Genome Atlas Network identified 18 recurrent somatic gene mutations, including TP53 (81% SQCC samples), MLL2 (20%), PIK3CA (16%) and CDKN2A (15%).9 In a second study from Korea, a similar spectrum of genetic alterations was discovered, including TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2 and PIK3CA).83 The new data from the lung adenocarcinoma and squamous cell carcinoma studies may increase the number of patients with treatable genetic aberrations as many small molecule inhibitors targeting these genetic aberrations already exist. Given the spectrum of genetic aberrants discovered, the use of next-generation sequencing in clinical practice becomes increasingly relevant. However, many challenges exist regarding the application, selection and interpretation of these new genomic tests. While this review has focused mainly on molecular targeted agents and matching driver oncogenes, other targets in NSCLC exist. Targeted therapies, such as bevacizumab, an antiangiogenic agent, when combined with platinum-paclitaxel, have been shown to improve OS.10 Another therapeutic area that has generated great excitement is targeting molecules that regulate the immune response. Recent progress in the understanding of tumour immunobiology has resulted in the development of new immunotherapies, including monoclonal antibodies that inhibit immune checkpoint pathways. These strategies have shown activity in melanoma and seem to be active in NSCLC as well.84 The antibodies targeting cytotoxic T-lymphocyte antigen-4 and programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) immune checkpoint pathways work by restoring immune responses against cancer cells, and are associated with unusual response patterns and immunerelated adverse events as a result of their mechanisms of action.84–87

CONCLUSION The identification of driver oncogenes has changed the way how NSCLC is classified and managed. NSCLC is no longer seen as a homogenous disease, but as a heterogeneous disease composed of different molecular subtypes. As a consequence, the use of rationally directed molecular targeted therapy has led to an improvement in clinical outcomes. In lung adenocarcinoma, routine tumour genotyping for EGFR mutations and ALK rearrangement has meant chemotherapy is no longer routine but given if patients do not have a targeted agent for matching driver oncogene. Traditionally, tumour biopsies were performed solely to establish a diagnosis; however, this situation has altered. Obtaining tissue to test for EGFR and ALK is now an important step in personalizing therapy in advanced stage NSCLC. In addition, tumour rebiopsy at progression may also provide invaluable insight Respirology (2015) 20, 370–378

376 into the biology of the disease and guide future treatment strategies.

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