activating mutations were described in lung cancer over a decade ago, and in that time, targeted therapy with epidermal growth factor receptor (

) tyrosine kinase inhibitors (TKIs) have become the treatment of choice as first-line therapy. Targeted therapy improves responses and progression-free survival when compared with chemotherapy in these patients with advanced disease. Despite improvements in outcomes, resistance develops and the majority of patients expe- rience tumor progression and are not cured. The intro- duction of third-generation 

TKIs that effectively block activating mutations and the T790M resistance mutation while sparing wild-type 

has led to improved outcomes following the development of resis- tance. The future of 

therapy will explore the use  of these agents and combinations to potentially delay or eliminate resistance to increase efficacy and ultimately survival. This review will focus on current therapies used in the first-line setting for advanced 

mutation positive non—small cell lung cancer (NSCLC) followed by emerging data that may lead to a transition in the choice for initial therapy in these patients.

Lung cancer is the leading cause of cancer related mortality worldwide in both men and women.

 Patients with advanced epidermal growth factor receptor (EGFR) mutated non—small-  cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and afatinib, show improved progression-free survival (PFS) compared with standard chemo- therapy as first-line therapy.

 Unfortunately, patients develop resistance through multiple routes, including acquired 

 In order to combat this resistance, second- and third-generation 

TKIs have been developed.  In order to prevent or delay the development of resistance, multiple strategies have been investigated, such as the  combina- tion of high-dose pulses with low-dose continuous 

TKI therapy or co-targeting bypass signaling pathways as in the com- bined inhibition of both 

 The development of third-generation TKIs has improved patient outcomes; however, therapeutic resistance still occurs. As the options for therapy increase, the available data should be considered in choosing a frontline treatment.

TKIs have been established as frontline therapy for patients with metastatic 

mutant lung. Differentiating between these treatment options requires an evaluation of the studies that have been performed.

The IPASS trial led the field, and was a randomized, phase 3 trial that compared gefitinib to carboplatin and paclitaxel  in 1217 previously untreated never or light ex-smokers  with advanced NSCLC, but did not require 

mutation. The pri- mary endpoint was PFS, and at 12 months, the PFS was 24.9% with gefitinib and 6.7% with carboplatin/paclitaxel. In the sub- group of patients with an 

mutation, PFS was significantly longer among those who received gefitinib.

mutation had improved PFS with chemotherapy, highlighting the importance of molecularly testing for activating 

A randomized, phase 3 trial compared gefitinib versus carboplatin/paclitaxel in previously untreated patients with 

 Analysis of the first 200 patients revealed that PFS was significantly longer in patients in the gefitinib group resulting in early termination. The gefitinib group had a median PFS of 10.8 versus 5.4 months in the chemotherapy group and a higher response rate of 73.7% versus 30.7%.

A third study comparing gefitinib and cisplatin plus docetaxel had similar results.

 This randomized, phase 3 study involved   177 previously untreated patients diagnosed with stage IIIB/IV NSCLC or postoperative recurrence with 

mutations and evaluated PFS as the primary endpoint. The gefitinib group had significantly longer median PFS compared with the cisplatin   plus docetaxel group (9.2 versus 6.3  months).

A randomized, phase 3 trial compared erlotinib with  carbo- platin/gemcitabine in 165 patients with stage IIIB/IV NSCLC and 

mutations.5 The analysis of PFS included 82 patients in the erlotinib group and 72 in the chemotherapy   group. Median PFS was significantly longer in the patients treated with erlotinib than those treated with chemotherapy (13.1 versus 4.6 months).

The EURTAC trial compared erlotinib versus platinum-based chemotherapy for first-line treatment of patients with advanced NSCLC with 

mutations in a randomized, phase 3 trial.

   In that study, 86 patients received erlotinib and 87 received standard chemotherapy. The preplanned interim analysis showed the study met its primary endpoint and enrollment was stopped. The median PFS in the erlotinib group was 9.7 months com-  pared with 5.2 months in the chemotherapy  group.

The LUX-Lung 3 study was a randomized, phase 3 trial  that compared afatinib to pemetrexed/cisplatin in  previously

untreated EGFR-positive stage IIIB/IV NSCLC patients.

 The study enrolled 345 patients who were randomly assigned in a  2:1 ratio and stratified by 

mutation (exon 19 deletion, L858R, or other). The median PFS was 11.1 months for the afatinib group and 6.9 months for the chemotherapy group. Median PFS among patients with exon 19 deletions and L858R deletions was 13.6 months for afatinib and 6.9 months for chemotherapy. The LUX-Lung 6 trial randomized 364 patients with previ- ously untreated 

mutation positive stage IIIB/IV NSCLC to receive either afatinib (242 patients) or gemcitabine-cisplatin (122 patients) a 2:1 ratio and stratified patients by 

muta- tion (exon 19 deletion, L858R, or other).4 Median PFS in the afatinib group was 11.0 months and 5.6 months in the gemcit- abine-cisplatin group.

A pooled analysis of LUX-Lung 33 and LUX-Lung 64 in- cluded 631 of the 709 patients randomized and evaluated overall survival (OS) in patients with exon 19 (n = 355) and exon 21 mutations (n = 276).

 OS was significantly longer in  the del19-positive tumors in the afatinib group than in the chemotherapy group (31.7 versus 20.7 months). There were   no significant differences by treatment group for patients with 

L858R-positive tumors. This study showed that OS was improved for patients with del19 

The LUX-Lung 7 trial was a randomized phase 2B trial that compared first-line treatment with either afatinib or gefitinib  in patients with 

 In the study, 160 patients received afatinib and 159 patients received gefitinib until disease progression. PFS was 11.0 months with afatinib and 10.9 months with gefitinib and median  time

to treatment failure was 13.7 months with afatinib and 11.5 months with gefitinib, and the results were statistically signifi- cant. Furthermore, survival was increased with afatinib at 27.9 versus 24.5 months, but the result was not   significant.

The current frontline options with afatinib, erlotinib, and ge- fitinib offer improved outcomes over standard chemotherapy in 

-mutant NSCLC patients. Toxicities are manageable and most commonly include rash, and skin toxicity, and diarrhea.

 Despite the benefit to patients, progression invariably occurs so we must consider novel strategies that might increase  survival.=

Enhancing outcomes for patients may require combination therapy or new generation inhibitors that can prevent or over- come resistance mechanisms. The strategies with early results include combination erlotinib and bevacizumab, afatinib and cetuximab, and osimertinib as first-line therapy for 

mu- tant NSCLC, and other agents and combinations are under investigation.

A randomized, phase 2 study in 154 patients with stage IIIB/ IV or recurrent non-squamous NSCLC with 

mutations  and no previous therapy for advanced disease compared erlo- tinib alone versus erlotinib plus bevacizumab.

 The median PFS was 16.0 months in the erlotinib plus bevacizumab group   and 9.7 months in the erlotinib alone group. Additional studies are ongoing to confirm these results and assess  toxicities.

Osimertinib, a third-generation EGFR TKI, is approved  as treatment for patients with 

TKI resistance due to emergence of the T790M mutation, and demonstrated  over 50% objective response rate (ORR).

 With the hypothesis that early treatment with osimertinib can prevent the emergence of T790M as a mechanism of resistance and improve PFS, cohorts were studied using osimertinib as first-line therapy. Sixty pa- tients from 2 phase 1 expansion cohorts of the original AURA trial received either 80 mg per day (n = 30) or 160 mg per day   (30 patients) of osimertinib as first-line therapy. The ORR was 77%. Median PFS was 19.3 months for the 160 mg dose, and  has not yet been reached for the 80 mg dose.

  This early data   are promising, and a phase 3 trial (FLAURA) is evaluating the efficacy of osimertinib in treatment-naïve 

mutation posi- tive NSCLC patients  (NCT02296125).

Afatinib plus cetuximab demonstrated clinical activity in 

-mutated lung cancers with acquired resistance compared with gefitinib or erlotinib, both with and without T790M mutations in a phase 1b study.

  This combination is now   being studied as a frontline therapy for 

Central nervous system (CNS) metastases, including leptome- ningeal carcinomatosis, are a challenge in patients with 

mutation positive lung cancer. Progression within the brain  often occurs in the absence of systemic tumor growth due to inadequate drug concentration in the CNS. Pulse dose erlotinib has been shown to be tolerated while increasing penetration   into the brain.

 A phase 1 study evaluated twice weekly pulse dose erlotinib at 1200-mg days 1 and 2 followed by 50 mg   on days 3 to 7 in treatment-naïve NSCLC patients with 

 The study demonstrated similar survival and responses seen in phase 3 trials, but of the 34 patients enrolled, none had progression in an untreated metastasis or developed new CNS metastases while on study. Additional trials evaluat-  ing activity of next-generation 

inhibitors in patients with CNS metastases are planned.

TKIs is effective, but patients develop resis- tance, most commonly due to T790M. Molecular analysis of cir- culating tumor cells or cell-free DNA may provide a strategy for monitoring changes in tumor genotypes and the development of drug resistant mutations during treatment. One study found  that the T790M was detectable in pretreatment tumor biopsies and circulating tumor cells during treatment and that T790M mutations were associated with reduced PFS (7.7 versus 16.5 months), and an increase in the number of cells with T790M mutations correlated with disease  progression.

TKIs in the frontline setting are ongoing and the results are forthcoming. These trials will help clarify the optimal use of TKIs in 

mutation positive NSCLC, and future studies will address the question of proper sequencing of therapy to provide the best outcomes for patients. The timing of third-generation EGFR inhibitors, such  as earlier use of osimertinib will likely lead to new mechanisms  of resistance, the emergence of the C797S 

 Additional studies to understand these mecha- nisms and therapies to overcome resistance will be  needed.

Emily A. Barber is with the University of California, Irvine, and Karen L. Reckamp is with the City of Hope Comprehensive Cancer Center.

Karen Reckamp discloses that she has provided consultant services to Amgen, Ariad, Astellas, Nektar, and received research support (to institution) from Ariad, Bris-   tol Myers Squibb, Boehringer Ingelheim, Clovis, Eisai, Novartis, Pfizer, Xcovery, Adaptimmune, Medimmune,  Stemcentrx.

: Karen L. Reckamp, MD, City of Hope City of Hope Comprehensive Cancer Center, 1500 E. Du- arte Road, Bldg 51, Duarte, CA 91010. phone: (626)   256-4673,

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This review will focus on current therapies used in the first-line setting for advanced EGFR mutation positive non–small cell lung cancer (NSCLC) followed by emerging data that may lead to a transition in the choice for initial therapy in these patients.

Emily A. Barber, BS

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