Customised , Individualised Treatment of Metastatic Non-Small-Cell Lung Carcinoma ( NSCLC )

A series of phase II and randomised phase III trials in Asia and Europe have confirmed recently that advanced stage non-small-cell lung carcinoma patients with adenocarcinoma subtypes harbouring specific mutations when subjected to targeted therapy experience equivalent survival outcomes as those treated with chemotherapy and are spared from its side effects. The concept of chemotherapy for all is fading, and therapy optimisation has emerged as a paradigm shift in treatment. This article briefly describes cellular mechanisms involved in lung carcinogenesis which provide a molecular basis for targeted therapy. Advances in molecular biology have improved our understanding of mechanisms involved in primary or secondary drug resistance. Evolving biomarkers of prognostic and predictive importance, and the impact of translational research on outcomes are also covered. A marker is considered prognostic if it predicts the outcome, regardless of the treatment, and predictive if it predicts the outcome of a specific therapy.

A ccording to the global cancer incidence report, lung cancer is the most common malignancy and a leading cause of cancer-related death worldwide. 1In the USA, non-small-cell lung carcinoma (NSCLC) accounts for approximately 87% of all the cases of lung cancer with adenocarcinoma as the most prevalent subtype (40%). 2 In Oman, NSCLC accounts for 88% of all lung cancers, with adenocarcinoma in 34% of cases, and squamous cell carcinoma (SCC) in 22%. 3 Despite diagnostic advances, lung cancer continues to present in advanced stages and as many as 50% of the patients have unresectable disease (stages IIIb-IV), and perhaps an even higher percentage in the developing world [Table 1]. 2 Certain clinical parameters have an impact on the outcome of the disease.Gender affects outcomes as females generally are diagnosed at a younger age and earlier stage, and perhaps have an inherent greater longevity.Different races also have different 5-year relative survival rates.In a study done between 2001-07, the 5-year survival rates were as follows: white men 13.7%; white women 18.3%; black men 11.6%; black women 14.5%. 2 Weight loss,

Evolution of Systemic Chemotherapy in Advanced/Metastatic NSCLC
Patients with advanced or metastatic NSCLC have traditionally been treated with systemic therapy if they carry a performance status of zero to two.0] Cisplatin or carboplatin is the cytotoxic backbone when considering palliative chemotherapy. 11In 1995, a large meta-analysis revealed a 27% risk reduction in death and one year survival enhancement of 10% when comparing chemotherapy to best supportive care (BSC). 12he Cochrane Collaboration Group upheld the advantage of platinum doublets which were associated with higher response rates (RR) and an absolute benefit of 5% improvement in one-year survival. 13e Eastern Cooperative Oncology Group (ECOG) E1594 study is regarded as a reference trial of advanced NSCLC comparing four different chemotherapy regimens with each other (i.e.cisplatin combined in three arms with paclitaxel, gemcitabine, and docetaxel, respectively and the fourth arm comprising carboplatin and paclitaxel).The RR improved from 10 to 19%, and the median survival improved to 9.1 months for 431 females, and 7.4 months for 726 males.The survival increased to approximately 33% in the first year and 11% in the second year.Essentially, all arms revealed similar median survival, but the regimen comprising cisplatin and gemcitabine was associated with longer time to progression (TTP), whereas carboplatin and paclitaxel was the least toxic amongst the four arms, and regarded as their reference doublet combination for future studies. 10ther large phase III trials validated the results  Vascular endothelial growth factor (VEGF) was discovered by Harold Dvorak and Donald Senger in 1983, and subsequently sequenced by Napoleone Ferrara's group in 1989. 15,16It was well-established that small tumours fail to thrive after attaining sizes as small as a few millimeters until they derive their independent vasculature.This in fact is carried out by the release of VEGF-A and other ligands that bind to the extracellular domain on the tumour cell VEGF receptors [Figure 1].This initiates of the platinum doublets used in the E1594 trial and these doublets emerged as a standard of care for patients with well-preserved organ function in performance status (PS) 0-1, and with slightly higher toxicity in selected PS 2 cases.
Towards the end of the last decade, histology emerged as a strong predictor for response and enhanced survival in non-squamous NSCLC.Data from phase II and randomised phase III trials of patients having the adenocarcinoma subtype, including large cell carcinoma and bronchioalveolar carcinoma (BAC), confirmed improvement in median survival beyond 10 months after the addition of pemetrexed.A phase III study revealed survival approaching a statistically significant 12.6 months in the pemetrexed cisplatin arm compared to 11 months in gemcitabine cisplatin arm in adenocarcinoma subtypes. 14The survival was 10.4 versus 6.7 months for the experimental arm in large cell carcinoma.SCC, however, did poorly with the addition of pemetrexed where median overall survival (OS) remained at <10 months.The combination therefore emerged as an option for non-squamous subtypes, reaching a median survival time in excess of 12 months, while cisplatin plus gemcitabine or docetaxel remained the standard treatment for SCC.Bevacizumab blocks the VEGF-A and prevents binding to the VEGF receptor while the complex is recognised and eliminated by the immune system.Bevacizumab exerts its action through the following proposed mechanisms.Antivascular effects lead to the regression of the tumour vasculature and reduce tumour size.Antiangiogenesis inhibits neo-angiogenesis and recurrent blood vessel growth in the tumour.Antipermeability decreases vascular permeability, and oedema in the tumour microenvironment, reducing pleural fluid volume.
After promising results from a US phase II trial by Johnson et al. in 2004, a series of large randomised phase III trials of bevacizumab were initiated [Figure 2]. 17A subset analysis of a phase III trial by Sandler et al. revealed interesting findings: patients with an adenocarcinoma subtype had a survival advantage of 3.9 months. 18dditionally, patients who developed hypertension on bevacizumab had a superior OS. 19 Also, elderly patients (>70 years) showed a trend of higher RR and (progression-free survival) PFS but no gains in OS.They also experienced more toxicity.The outcome of patients on maintenance bevacizumab showed promise on retrospective review and, therefore, a series of successful phase III maintenance trials were initiated to test its relevance.
The addition of bevacizumab to pemetrexed and platinum improved survival outcomes in adenocarcinoma histology in two phase II trials. 20,21A randomised phase III maintenance trial (AVAPERL 1) in PS 0-1 advanced adenocarcinoma patients was initiated using pemetrexed-cisplatin plus bevacizumab followed by continuation bevacizumab with or without pemetrexed. 22The interim results seem promising, as the addition of bevacizumab was well tolerated and associated with a superior PFS of 3.6 months.The median OS for the bevacizumab arm was 15.7 months, but for the pemetrexed bevacizumab arm; an OS level has not yet been reached.The Pointbreak study (900 patients) with advanced non-squamous NSCLC used pemetrexed + carboplatin + bevacizumab induction followed by pemetrexed + bevacizumab maintenance (arm A) and compared it with paclitaxel + carboplatin + bevacizumab induction followed by bevacizumab maintenance (arm B).Though it failed to reach the primary endpoint of enhancing OS, the maintenance arm A improved the survival outcomes (PFS and OS) compared to maintenance arm B. 23 Whether the gain in survival is because of pemetrexed or bevacizumab remains to be defined.The ECOG E 5508 trial is underway to address this question. 24n a meta-analysis of 2,252 patients from 5 randomised trials with advanced NSCLC, Andre et al. reported that the addition of bevacizumab to platinum doublets increased RR, enhanced PFS by 1.4 months, extended OS by 1 month, and was associated with a significant 11% reduction in death.However, the combination was associated with slightly higher toxicity and mortality and therefore warrants careful patient selection. 25ased on promising survival gains from a colorectal study (BRITE), 26 the ARIES trial 27 in NSCLC, and another American retrospective analysis of non-squamous NSCLC, 28 a large multiinstitutional, randomised trial called Avastin in all Lung Lines (AVAll) was initiated and is currently recruiting patients to evaluate the role of post-progression bevacizumab. 29Nearly all key trials exploring the efficacy of the addition of bevacizumab to standard platinum doublets showed a consistent improvement in RR, PFS, and median survival rates in adenocarcinoma subtypes -The yellow bars show the subset analysis for ECOG4599 trial.
-The red bar is the control (chemotherapy arm) of ECOG 4599 trial.

e p i d e r m a l g r o w t h fa c t o r r e c e p t o r (egfr)
EGFR is a trans-membrane cellular protein receptor located on the cell surface.The gene that codes for EGFR protein is located in 7p11-13.It consists of 26 exons, of which the first 14 code for the extracellular ligand binding domain, exon 15 for the transmembrane domain, and the last 11 for the intracellular domain.The ATP-binding site and intrinsic TK activity is also coded by exons 16-26. 43t is generally expressed at low levels in a wide variety of normal tissues.Excessive expression or activation of EGFR is able to induce malignant transformation.5][46] A form of EGFR MUT (EGFRvIII) is implicated in carcinogenesis with TK activity. 47ceptor activation is generally initiated by the binding of EGF or related ligands, leading to receptor homodimerisation or heterodimerisation, which activates intrinsic TK activity of the receptors leading to autophosphorylation of tyrosine residues.Mutations or over-expression in the TK domain of the EGFR gene increase the activity of the intracellular signalling cascades through Ras/Raf/ MAPK and PI3K/Akt/mTOR pathways [Figure 1], leading to events which result in over-proliferation, differentiation, enhanced survival, inhibition of apoptosis, neo-angiogenesis, and metastases, and is associated with a poorer prognosis. 48,49etermination of EGFR gene mutations has clinical relevance as it allows the optimisation of therapy and has emerged as one of the most important single predictive molecular markers in clinical oncology.1][52] These agents inhibit the TK and adversely compete with ATP for the critical ATP-binding site located in the intracellular domain inhibiting the intrinsic tyrosine kinase enzyme activity.Cetuximab is a monoclonal antibody that binds the extracellular domain of EGFR effectively and prevents the subsequent intracellular cascade of events and the inhibition of malignant transformation [Figure 1].Certain clinical subgroups of patients derive a greater benefit from tyrosine kinase inhibitors (TKI) therapy by virtue of the presence of an EGFR MUT .4] The EGFR MUT are found in exons 18-21 of the EGFR gene. 43th PS 0-1 [Figure 2].However, the 4,000 patients (>65 years) from the SEER database were recently analysed and the addition of bevacizumab was not found to be advantageous in the elderly population. 30hen a single cellular target is blocked, the cancer cell finds an alternative pathway to proliferate and hence provides a rationale for dual or multitargeted therapy.2][33][34] Multi-TKI (i.e.6] In the MISSION trial, sorafenib failed to improve the OS, but the PFS, TTP, RR, and disease control rate (DCR) improved substantially. 37ATTLE, a phase II study, incorporated heavily pretreated NSCLC patients with PS 0-2 (2-5 lines failures, brain metastases allowed).The study compared the effects of erlotinib in the EGFR mutation-positive group, which validated results of earlier randomised trials, versus vandetanib and erlotinib, which showed enhanced activity in the VEGFR2-expressing subsets versus erlotinib and bexarotene showing activity in cyclin D1 expressing and EGFR amplified patients with improved outcomes versus.sorafenib which was associated with a dismal outcome in EGFR-mutation positive subsets. 38,39Multi-TKI roles in the metastatic setting remain under investigation.However, there is emerging data of multi-TKI use in RET translocations (1%) in adenocarcinoma subtype.
BIBF 1120, a triple angio-kinase inhibitor (active against FGFR, PDGFR, and VEGFR) in the second-or third-line setting was found to be associated with tumour shrinkage in patients with adenocarcinoma. 40Its use is being explored in combination with docetaxel and pemetrexed. 41,42ith advances in molecular biology and genetics, newer markers of significance are being explored to determine their prognostic or predictive value, and non-squamous NSCLC has emerged as a classical model of studying cancer genetics.Discovery of key cellular markers and their targeting has started to bring a paradigm shift in the management of advanced adenocarcinoma subtypes and will be the focus of the following discussion.

TargeTing The epidermal growTh facTor recepTor (egfr) lung
The different types of EGFR mutations provide information on whether patients with these mutations are likely to benefit from TKIs (erlotinib or gefitinib) [50][51][52]56 [Table 2]. An ndividual matching the clinical criteria above carries a 50% chance of harbouring the mutation, but this is not the sole criteria used to commence TKI therapy.EGFR MUT are present in 30-50% of East Asians and approximately 10% of Caucasians having NSCLC.Its exact incidence in Arabian Gulf countries or Oman is not known.Well to moderately differentiated tumours have more frequent EGFR MUT than their poorly differentiated counterparts.57 Adenocarcinoma, which is thyroid transcription factor 1 (TTF1) negative, will usually harbour a wild-type (normal) EGFR (EGFR WT ).58,59 Around 30% of SCCs overexpress the EGFR protein (not the gene) on immune-staining, and TKI provides a similar advantage to this subtype.The evidence of adding a TKI in SCC comes from the subset analysis of the SATURN study and the exploratory retrospective analyses from the NCIC BR.21 trial according to which these agents enhance PFS and OS irrespective of histology when used as maintenance and second-line salvage therapy, respectively.60,61 Similarly, data from the FLEX trial recommend use of cetuximab with induction chemotherapy in SCC expressing the EGFR protein.EGFR mutations rarely occur in never smoking SCC patients, and therefore are not routinely determined.

TargeTing The egfr inTracellular domain: T yrosine kinase inhibiTors (Tkis)
After successful preclinical studies, evidence that the EGFR MUT correlated with response to TKI in clinical practice first emerged in 2004 from phase II trials in previously treated NSCLC patients.
Trials of salvage TKIs have been undertaken.In the IDEAL 1 trial, gefitinib was used in patients pretreated with two or fewer previous chemotherapy regimens, while in IDEAL 2 the same agent was used in pretreated NSCLC patients who received more than two regimens. 62,63In 210 patients, the RR were 18-19% and there were median survival gains of 7.6-8 months in the IDEAL 1 trial.The RR was 11.8% and median OS was 6.5 months in the IDEAL 2 trial.The subset analyses revealed that Asian, never smoking females having adenocarcinoma (especially BAC) reacted with a predictable response to gefitinib.The ISEL, a phase III study, used gefitinib as first salvage in NSCLC after one or more prior chemotherapy failures.Survival was increased in patients who were Asians or never smokers. 53NTEREST, a phase III trial, utilised gefitinib versus docetaxel in a second-line salvage setting.The TKI was associated with a superior quality of life (QoL) and fewer side effects. 64Erlotinib was also used as a monotherapy in patients with NSCLC who progressed on 1-2 previous chemotherapies in the phase III BR.21 trial against BSC, and was associated with improvement in disease-related symptoms, superior TTP, and median OS enhancement by 2 months. 61hase III trials of concurrent use of TKIs with chemotherapy have also been conducted.TALENT was a negative trial (>1,172 patients) with two arms that used carboplatin and paclitaxel with or without erlotinib. 65The RR, PFS, and OS remained unchanged when the TKI was used concurrent with chemotherapy as compared to chemotherapy alone.The TRIBUTE study utilised cisplatin and gemcitabine alone or concurrent with erlotinib and validated the results of the TALENT trial. 66However, subset analyses revealed increased survival in never smokers.INTACT 1 and INTACT 2 also used carboplatin and paclitaxel alone or concurrent The OPTIMAL trial was conducted by the Chinese Thoracic Oncology Group, and involved 23 centres using erlotinib. 51,52The trial also validated results from the IPASS study.In subgroup analyses, PFS was 15.3 months in exon 19 del and 12.5 months in L585R mutation.[72][73][74] At disease progression on TKIs, patients may still be treated with salvage platinum doublets.
The TORCH trial revealed that in unselected advanced NSCLC patients, first-line erlotinib (followed by cisplatin gemcitabine at progression) was inferior in terms of OS compared with the standard sequence of first-line chemotherapy followed by erlotinib at progression. 75TAILOR is another phase III trial, where 218 evaluable patients (EGFR WT ) were subjected to second-line docetaxel or erlotinib.The PFS was superior in the docetaxel arm with an absolute difference in 6 months PFS of 12% and remains a negative trial for TKI in wild type EGFR. 76rgeTing The egfr exTracellular domain: ceTuximab After encouraging results from phase II trials of the addition of cetuximab to induction chemotherapy in metastatic NSCLC, phase III trials were initiated.The monoclonal antibody binds to the extracellular ligand binding domain of the EGFR, blocking the intracellular cell signalling [Figure 1].FLEX (First Line Erbitux in Lung Cancer trial) is a key phase III, randomised trial comparing the addition of cetuximab to cisplatin and vinorelbine, given for 6 cycles and cetuximab continued as maintenance therapy until progression of disease or unacceptable toxicity versus chemotherapy alone.The median OS was superior. 77Moreover, a high EGFR expression was associated with a better survival with the addition of cetuximab.Survival figures were also superior for females, those of Asian ethnicity, in those who developed acne, and in those having adenocarcinoma.The addition of cetuximab to chemotherapy was found to be as effective in SCC with a prolongation of one year survival by 19%. 78Another USA-based trial looked at unselected NSCLC patients treated with taxane plus cetuximab, which enhanced median OS. 79 The addition of cetuximab to platinum doublets remains a reasonable option in distinct PS 0-1 patients, as erlotinib without improvement in efficacy. 67,68ALGB 30406, presented in ASCO 2012, reveals erlotinib efficacy as singlet or concurrent with paclitaxel carboplatin in never or light smokers, harboring adenocarcinoma.Erlotinib was found to have similar efficacy in EGFR MUT in this phase II setting whether used as a singlet, and with higher toxicity or when used in combination with chemotherapy. 69There is a hint of TKI continuation concurrent with chemotherapy in some NSCLC cases associated with flare-up of the disease on discontinuation of the TKI.TKI use concurrent with chemotherapy remains investigational and necessitates further study in the context of a phase III trials.
Trials comparing TKIs to chemotherapy as initial therapy have also been carried out.70][71][72][73][74] Similar efficacy, superior tolerability, and less toxicity made TKI a new therapeutic option for adenocarcinoma subtypes, as well as its potential use in PS 3 and selected PS 4 cases.67][68][70][71][72][73][74] In the Iressa Pan-Asia Study (IPASS), a phase III, multicentre, randomised trial of advanced NSCLC, 1,217 patients from East Asia were randomly assigned to receive daily TKI orally versus a platinum doublet every 3 weeks for 6 cycles. 50rossover was allowed.One-third of the patients had an EGFR MUT .The objective RR was statistically and numerically superior in the gefitinib arm in all clinical subgroups, with marked improvement of RR in the EGFR MUT -positive subgroup.However, the median OS remained similar, and mutationnegative patients benefited from chemotherapy but did extremely poorly with gefitinib (RR = 1%).The TKI are therefore not indicated in EGFR WT .The OS was similar in the EGFR MUT positive or negative groups and is possibly due to crossover in the two arms.The survival was also superior in patients with a high EGFR gene copy number, however, at the expense of mild toxicity.
shown in the algorithm in Figure 3.It is reasonable to consider adding cetuximab to platinum doublets in patients with SCC (30% of these express the EGFR protein) and then use it as maintenance in those stablising after induction therapy, where it adds 1 month to OS.

Molecular Markers of Significance in Targeted Therapy
With advances in molecular biology and translational research, molecular targets are evolving which are potential targets of newer drugs [Tables 3 and 4].Some key markers of prognostic and predictive value are described below.

m e t a m p l i f i c at i o n
MET is a cell surface receptor with TK activity expressed by normal cells as well as malignant cells. 80It is amplified in 10-20% of NSCLC.Ligand-like hepatocyte growth factor/scatter factor binds to MET, activating downstream cell signalling and leading to cell proliferation, angiogenesis, invasion and metastases.High expression is defined on immunostaining, when >50% cells stain strongly (>3+) or, by an increased gene copy number (>5 copies/cell) as detected by fluorescent in situ hybridisation (FISH).MET and EGFR coamplification occurs rarely-in only 1% of cases.The incidence of MET mutation was highest in Asians (13%), 0% in blacks, and N375S was the commonest mutation. 81MET amplification may lead to acquired resistance to TKI therapy through activation of alternate cell signalling pathways like PI3K in up to 20% of patients. 82,83It is also associated with reduced TTP.The PFS varies inversely with MET overexpression.Patients with high MET had superior survival with chemotherapy (P 0.25).Several MET inhibitors, with or without dual inhibition of EGFR and MET as a potential mechanism to overcome resistance, are currently undergoing trials.MET inhibitors like METMab plus erlotinib versus placebo plus erlotinib were compared in a phase II trial and showed 50% enhancement in PFS and OS in patients with high MET expression. 84atients with low MET expression fared worse with the same combination.ARQ 197 is another MEK inhibitor that showed superior PFS when combined with erlotinib in a phase II trial with a trend towards increased OS. 85 The MetLung trial is a global phase III randomised trial recruiting patients with metastatic or recurrent disease after one previous chemotherapy failure in MET-positive NSCLC.Patients are being randomised to erlotinib plus onartuzumab (MetMab) versus erlotinib plus placebo. 86

k -ras m u tat i o n
Mutations in the Kirsten rat sarcoma virus oncogene homologue gene (k-ras) occurs in approximately 20-30% of NSCLC cases.They are common in mucinous adenocarcinoma (but not in large-cell carcinoma or BAC), in the elderly, in heavy smokers, in stage I and tumour grade I but frequently fall with stage and grade progression, while the only rules out EGFR mutation, but is also a marker of TKI inactivity.To date, patients harbouring the k-ras mutation are best treated with chemotherapy.
In a recent trial comparing docetaxel with or without selumetinib (MEK 1 and 2 inhibitor downstream of k-ras), the combination resulted in superior RR, PFS, and OS in patients with the k-ras mutation.EML4-ALK was isolated from a surgically resected lung adenocarcioma specimen, but originally identified in anaplastic large-cell lymphoma (ALCL). 88,89It occurs in 4-11% of NSCLC.EML4-ALK exhibits activating mutations or translocations of the anaplastic lymphoma kinase aberrant fusion gene (result of a small inversion within short arm of chromosome 2p, in which the EML4 becomes fused to the intracellular kinase domain of ALK).It leads to the activation of downstream cell signalling through PI3K and STAT pathways.
The gene encodes a cytoplasmic chimeric protein with kinase activity, and typically tested positive in younger subjects, having adenocarcinoma of a predominantly signet ring subtype, and in never or occurrence in non-smokers is low.The majority of mutations occur in codon 12 (>90%-guanine to thymine transversion) and 13, and the gene leads to impaired GTPase activity, located towards the inner surface of the cell membrane.This leads to subsequent constitutive activation of RAS signalling, which is downstream of the EGFR, leading to activation of proliferative and antiapoptotic pathways such as ERK.In the early 1990s, it was considered a negative prognostic marker, and perhaps a negative predictive marker responsible for chemo-resistance.However, data from recent trials like TRIBUTE and FLEX negates it. 66,77nlike colorectal cancers, where k-ras mutation is a strong predictor of response to cetuximab, its status in NSCLC could not confirm it to be so on retrospective analyses of FLEX and BMS 099 trials. 77,79 the NCIC BR.21 study, 28% of 731 patients had k-ras genotype. 61The majority was wild type that responded well to TKI, while 15% had a mutation that conferred primary resistance to TKI therapy.Data from TRIBUTE reveals that EGFR and k-ras mutations rarely occur together, and that survival was inferior in the group of patients with k-ras mutation who were treated with chemotherapy plus TKI. 66Hence, the presence of k-ras mutation not light smokers who did not harbour EGFR mutations.Immunohistochemistry (IHC) could detect the protein, and reverse transcription polymerase chain reaction (RT-PCR), gene sequencing, and FISH could detect the break-apart rearrangement. 90The break removes the inhibitory effect of EML4 and ALK initiates carcinogenesis due to its inherent oncogenic activity.EML4-ALK positivity mutually rules out EGFR and k-ras mutations.
Currently, patients with this distinct expression have a similar RR and OS to platinum-based chemotherapy compared to the wild type patients.Crizotinib, an oral ALK inhibitor which produced a 90% clinical benefit (57% objective response rate [ORR]) when used as a second-line compared favourably to salvage second-line chemotherapy which produced a RR of 10% in a phase II trial. 91nother phase II trial (PROFILE 1005) is assessing salvage crizotinib in adenocarcinoma patients treated with one previous platinum, with the finding that the ORRs were 54% and the DCRs were 74%, which was considered safe and tolerable. 92cently, PROFILE 1007 data were presented to the European Society for Medical Oncology.ALKpositive patients who failed one previous platinum doublet were treated with crizotinib compared with chemotherapy (docetaxel or pemetrexed).Crizotinib enhanced PFS (7.7 versus 3 months; P <0.0001), RR (60% versus 20%; P <0.001), and QoL. 93The exact sequencing of the drug still needs to be defined.Currently all patients harbouring wild type EGFR are treated with chemotherapy doublets and crizotinib is reserved as salvage in those who have the EML4-ALK mutation.The new agent is being tested in metastatic setting as frontline treatment.Crizotinib has also been found effective against ROS1 (~1%) mutation in NSCLC.30% of acquired resistance. 101It has also been shown that patients who have developed resistance to TKI, when subjected to chemotherapy, may respond again to the re-introduction of TKI. 102

Conclusion
Bevacizumab and cetuximab have emerged as targeted agents to be used with cisplatin doublets in metastatic adenocarcinoma in patients with PS 0-1 and well preserved organ function.Those harbouring the EGFRMUT in PS 0-3 and highly selected PS 4 are now candidates for oral TKI therapy which offers equal efficacy, superior tolerability, and a lesser and different side effect profile, bringing a paradigm shift in the management of these cancers.There are compelling data for using more or prolonged therapy, and optimising therapy based on histology and genetic mutations, while resistance patterns continue to be recognised.The era of one chemotherapy that fits all is fading as patients' median survival is improving gradually under customised individualised therapy.genetic alterations.Primary resistance affects patients who are refractory to TKI therapy at the time of initiation.Molecular factors identified as predictive of an EGFR TKI response are often EGFR-related due to an increased EGFR gene copy number; activating mutations within the EGFR TKI domain; or resistant EGFR mutants.For example, the presence of insertions in EGFR's exon 20 (5% of all known mutations) precludes the binding of gefitinib or erlotinib to the EGFR TKI domain, conferring resistance. 94Exon 18 (G719S) or exon 21 mutations (T854A), the presence of the k-ras mutation, and the loss of PTEN, B Raf mutations, or overexpression of MAPK and bcl2 also confer primary resistance.
Secondary or acquired resistance generally affects patients who initially respond to TKI therapy but experience a loss of response after 6-12 months.Acquired resistance generally occurs with changes in MET over-expression, which accounts for 20% of resistance to the TKI. 82,836][97] This mutation is responsible for acquired drug resistance in patients receiving TKI therapy over a period of time.Patients harbouring this mutation have an indolent course as the disease is not rapidly fatal and metastasises late.
The LUX1 trial used irreversible TKI (afatinib) that inhibits T790M after failure of first-line TKI with a DCR of 58% versus 19% and a 2.2 month improvement in PFS in favour of the agent. 98The agent was subsequently used in chemo-naive metastatic NSCLC patients in the LUX Lung 3 trial, revealing a superior RR and enhanced PFS of 11.1 months in patients with an exon 19 del and 13.6 months in the L585R mutation when the agent was compared to pemetrexed and cisplatin. 99The LUX Lung 7 and 8 trials compare afatinib versus TKIs (gefitinib and erlotinib) respectively.
AEE788 is a multiple RTK inhibitor that blocks EGFR, VEGFR, and human epidermal growth factor receptor 2 (HER2) pathways and, when combined with a mTOR inhibitor (everolimus), was found to be effective against the T790M mutation. 100umerous unknown mechanisms (e.g.rare D761Y, L747S, T854A mutations, IGF-1R, etc.) account for By 2008, chemotherapy for NSCLC reached a plateau with median survival approaching 10-12 months, while scientific research drifted towards molecular profiling with the evolution of cancer genetics and translational work.Researchers started to study the cell signalling pathways and evaluate means to target cancer cells at the molecular level.Others started to use maintenance therapy in their effort to enhance the median survival time in this aggressive disease.Molecular Targets and Targeted Therapy in Metastatic NSCLC t u m o u r a n g i o g e n e s i s a n d va s c u l a r ta r g e t s : b e va c i z u m a b

Figure 2 :
Figure 2: Continued survival benefit with bevacizumab: 2006 to 2011 showing the major trials undertaken.

87
e c h i n o d e r m m i c r o t u b u l ea s s o c i at e d p r o t e i n -like4 a n a p l a s t i c ly m p h o m a k i n a s e (eml4-alk) m u tat i o n
r e s i s ta n c e t o e p i d e r m a l g r o w t h fa c t o r r e c e p t o r (egfr) t y r o s i n e k i n a s e i n h i b i t o r s (tkis)At some point during the course of disease, NSCLC progresses, despite therapy, because of the emergence of resistance due to underlying

Table 2 :
Epidermal growth factor receptor mutation types, incidence, and sensitivity to tyrosine kinase inhibitors
4. Yang R, Cheung MC, Pedroso FE, Byrne MM, Koniaris LG, Zimmers TA.Obesity and weight loss at presentation of lung cancer are associated with opposite effects on survival.J Surg Res 2011; 170:e75-83. 5. Burdett S, Johnson DH, Stewart L, Tierney J, Le Pechoux C for the NSCLC collaborative group.Supportive care and chemotherapy vs supportive care alone in advanced NSCLC: A meta analysis using individual patient data (IPD) from randomized controlled trials.J Thorac Oncol 2007; 2:S337.6. Luu DCN, Mamet R, Zornosa CC, Niland JC, D' Amico TA, Kalemkerian GP, et al.Retrospective analyses of the impact of age on overall survival in patients with non-small cell lung cancer.J Clin Oncol 2012; e18018.