	For years, the progress in treating non—small-cell lung cancer (NSCLC) had reached a plateau. In the last decade, primarily because of molecular oncology, translational research has emerged as the foundation for new therapies for this resistant disease. Recently, we have seen a paradigm shift in our approach to NSCLC. New and relevant studies are examining the role of histology, biomarkers, and growth factor receptor inhibitors in the treatment of NSCLC. The expanding role of identifying “driver mutations” will lead to more effective therapies. This review explores some of the emerging options for the treatment of NSCLC.

	The National Cancer Institute estimated that 222,520 individuals (116,750 men and 105,770 women) were diagnosed with and 157,300 individuals (86,200 men and 71,000 women) died of cancer of the lung and bronchus in 2010.

 The cure rate for this disease is estimated to be only 15%.

	Results of 2 major trials should help us to better define our screening strategies. Previous lung cancer screening trials showed that screening did not decrease mortality. However, several shortcomings in these trials may have failed to detect a small screening benefit.

	The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial began in November 1993 and ended in July 2001. This was a randomized controlled study that included 154,901 participants aged 55-74 years and was initiated specifically to determine whether screening would reduce mortality rates from PLCO cancers. Participants received a baseline chest radiograph (CXR), followed by 3 annual single-view CXRs at the 10 US screening centers versus a usual-care control group. The results showed that lung cancer mortality was not reduced when annual CXR screening was compared with usual care in high-risk individuals.

	From August 2002 through April 2004, the National Lung Screening Trial enrolled 53,454 persons at high risk for lung cancer at 33 medical centers in the United States.

 Eligible participants were between 55 and 74 years of age at the time of randomization, had a history of cigarette smoking of at least 30 pack years, and, if former smokers, had quit within the previous 15 years. Persons who had previously received a diagnosis of lung cancer, had undergone chest computed tomography (CT) within 18 months before enrollment, had hemoptysis, or had an unexplained weight loss of more than 6.8 kg (15 lb) in the preceding year were excluded. Participants were randomly assigned to undergo 3 annual screenings with either low-dose CT or single-view postero/anterior chest radiography. The study demonstrated a 20% reduction in lung cancer deaths with low-dose helical CT screening in high-risk patients compared with a conventional CXR.

	Surgery is the primary treatment modality for patients with early-stage operable NSCLC. Approximately half of these patients eventually experience relapse after resection, with a much higher proportion of distant metastases than local recurrences. The 5-year survival rates for NSCLC range from 45% to 50% in stage I, 30% to 35% in stage II, 15% in stage IIIA, 5% in stage IIIB, and only 1% in stage IV.

	The International Adjuvant Lung Cancer Trial, the largest cisplatin-based adjuvant study, showed positive results after a median follow-up of 56 months, but the significant effect was no longer present after a median follow-up of 90 months.

 The lack of long-term survival may be because of the toxicity of chemotherapy or other comorbidities. In the recently updated Medical Research Council meta-analysis and in the Lung Adjuvant Cisplatin Evaluation, the 5-year absolute benefit of chemotherapy compared with placebo ranged from 4% to 5.3% (

 The most common chemotherapy regimen in the trials and the most robust data for adjuvant chemotherapy outside the United States are with the use of vinorelbine (Navelbine) and cisplatin. This regimen does not enjoy such popularity in the United States.

	A subgroup analysis of the JBR10 National Cancer Institute—Canada adjuvant study and Adjuvant Navelbine International Trialist Association trials showed no benefit for stage IB disease.

 The Cancer and Leukemia Group B (CALGB 9633) trial is the only randomized study to look at the role of adjuvant chemotherapy exclusively in stage IB disease.

 The study compared carboplatin and paclitaxel with observation in 344 patients. The trial was closed early at 4 years when the first interim analysis showed a survival advantage of 12% (hazard ratio [HR] = 0.62). A subgroup analysis of CALGB 9633 showed a benefit for patients with tumors ≥4 cm in diameter (

 = .043). Unfortunately, the benefit disappeared at 5 years. A meta-analysis consisting of 2353 patients with stage IB disease reported that adjuvant chemotherapy is effective for this subgroup.

 Most clinicians use a cutoff of ≥4 cm to justify adjuvant chemotherapy in stage IB patients. A current study, Eastern Cooperative Oncology Group (ECOG) 1505, is randomizing completely resected stage IB (≥4 cm)—stage IIIA NSCLC patients to a cisplatin-containing doublet with or without bevacizumab.

 Postoperative adjuvant cisplatin-based chemotherapy is now the standard treatment for patients with resectable NSCLC ≥4 cm in size.

	The standard of care for stage IV NSCLC is to give 4-6 cycles of chemotherapy.

 In advanced disease, there does not appear to be any advantage when cisplatin is combined with gemcitabine, docetaxel, or paclitaxel, or for the regimen of carboplatin and paclitaxel. The overall response rates are approximately 19%, and the median survival is 7.9 months. Histology matters, and patients with adenocarcinoma survive longer than those with squamous cell NSCLC. This difference is reflected in the induction chemotherapy regimen selected.

 Socinski et al reported a randomized trial comparing nab-paclitaxel and carboplatin with Cremophor-based paclitaxel and carboplatin as first-line therapy in advanced NSCLC.

 The response rate was 41% for the patients with squamous cell histology and 26% for the patients with nonsquamous cell histology. The reason for this difference is not entirely clear; however, it is known that albumin binds to the endothelial receptor gp60. By a process called endocytosis, the albumin-bound paclitaxel is bound with the protein caveolin 1 and forms calveolae, which facilitates the transport of the agent across the cell membrane to the tumor environment. Caveolin 1 is overexpressed in squamous cell tumors. In the peritumoral milieu, secreted protein acidic and rich in cysteine (SPARC) is present, which binds to albumin and is important for cell growth and proliferation. This protein is inhibited by nab-paclitaxel, allowing more drug to reach the tumor, which may explain the differential benefit of this agent in squamous cell tumors.

	In stable or responding patients, there has been a great deal of interest in extending the disease-free survival (DFS) and hopefully the overall survival (OS). The 2 common paradigms are called either “continuation maintenance,” in which 1 or more of the induction drugs are continued after the initial 4-6 cycles, or “switch maintenance,” in which different agents are begun after induction.

	Five phase III randomized trials are investigating the role of continuation maintenance chemotherapy in advanced NSCLC patients who have responded or remained stable after 4 cycles of a platinum-containing regimen. While most have shown an improvement in progression-free survival (PFS), none of the trials has shown a benefit in OS.

 This is also true for the recent PARAMOUNT trial.

 The trial investigated whether pemetrexed continuation maintenance therapy improved PFS after pemetrexed-cisplatin induction therapy in patients with advanced nonsquamous NSCLC. Pemetrexed continuation maintenance resulted in a 36% reduction in the risk of progression. The median independently reviewed PFS was 3.9 months (95% CI, 3.0-4.3) in the pemetrexed maintenance arm and 2.6 months (95% CI, 2.2-2.9) in the control arm. No OS has been reported.

	Three phase III studies examined the role of switch maintenance. In the study by Depierre et al, participants with stage IV disease received 4 cycles of induction chemotherapy with mitomycin-ifosfamide-cisplatin, and participants with stage IIIB disease received 2 cycles of the identical chemotherapy followed by the addition of 60 Gy of radiotherapy.

 Responders were randomly assigned to vinorelbine or observation. A total of 6 months of vinorelbine was given if a response was maintained. Only 23% of the patients completed the 6 months of vinorelbine. There was no difference in PFS or OS. In fact, maintenance vinorelbine was associated with additional toxicity. A trial conducted by Fidias et al began with the induction regimen of 4 cycles of gemcitabine and carboplatin.

 Stable or responding patients went on to receive immediate or delayed docetaxel at progression. Because of intervening factors, 40% of the patients were never able to receive delayed docetaxel. There was significant PFS in the group that received immediate docetaxel versus the delayed group, but no difference in OS was seen. The third study was conducted by Ciuleanu et al.

 The JMEN study began with an induction platinum-containing regimen for 4 cycles. Pemetrexed or bevacizumab could not be included in the induction regimen. Patients whose disease did not progress were randomized to pemetrexed versus best supportive care versus placebo plus best supportive care for NSCLC. A majority of the patients in both arms went on to receive additional chemotherapy. There was evidence of improved PFS (2.6 mo) and OS (5.2 mo) in the patients with nonsquamous cell histology, but no difference in PFS or OS was observed in the patients with squamous cell histology.

	Platinum-containing regimens in combination with bevacizumab or cetuximab, followed by continuation maintenance of the targeted agent, have been shown to result in an improvement in OS.

 ECOG study E4599 was the first randomized study to show a survival benefit from the addition of bevacizumab.

 The patients had to have an ECOG performance score of 0 or 1. The study included patients with stage IIIB or IV disease. Patients in the bevacizumab arm received the drug during induction, which consisted of up to 6 cycles of paclitaxel and carboplatin. Those in the bevacizumab arm who responded or remained stable received bevacizumab maintenance until progression. The control group, who received paclitaxel and carboplatin, never received any bevacizumab or maintenance therapy. The OS was extended by 2 months in the group that received bevacizumab. The study highlighted the controversy regarding the value of bevacizumab in patients with NSCLC. In the FLEX trial, patients with stage IIIB or IV disease received induction chemotherapy with up to 6 cycles of vinorelbine and cisplatin.

 Patients who did not progress were randomized to cetuximab or placebo until progression or unacceptable toxicity. There was a 1.2 month improvement in OS. This study highlighted the controversy regarding the need for bevacizumab in induction and/or maintenance therapy in patients with advanced NSCLC. In contrast, the AVAIL study failed to show a survival benefit when cisplatin was combined with gemcitabine and bevacizumab,

 and the BMS-099 study also showed no benefit when cetuximab was added to carboplatin and paclitaxel.

	The PointBreak study is a phase III trial comparing the phase II study of 4 cycles of pemetrexed, carboplatin, and bevacizumab followed by maintenance pemetrexed and bevacizumab with the superior arm of the E4599 trial consisting of up to 6 cycles of paclitaxel, carboplatin, and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous NSCLC.

 Accrual has been met and the results are awaited. The study has 2 variables and may be difficult to interpret. Accurate evaluation of the advantage of maintenance antibodies would require a phase III randomized study comparing bevacizumab, cetuximab, and placebo. EGOG study 5508 is planning to answer the question of the optimal maintenance regimen in advanced NSCLC.

 All patients receive 4 cycles of induction chemotherapy with carboplatin, paclitaxel, and bevacizumab. The patients are then randomized to either pemetrexed, bevacizumab, or the combination. There is no placebo arm, however.

	The epidermal growth factor receptor (EGFR) is a cell surface protein. When activated, it has an important role in cell proliferation, adhesion, migration, angiogenesis, apoptosis, and cell survival. Approximately 10% of North Americans and up to 40% of persons of Asian descent harbor activating mutations in the EGFR. This condition leads to up-regulation of the EGFR protein and uncontrolled proliferation of the tumor.

	Gefitinib and erlotinib are 2 oral, reversible tyrosine kinase inhibitors that block the binding of adenosine triphosphate to its binding pocket in the EGFR moiety. They then inhibit autophosphorylation and block downstream signaling primarily through the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. These agents interrupt the activating mutations of the EGFR, primarily by binding to deletions in exon 19 and the L858R point mutation in exon 21 of the EGFR. Gefitinib and erlotinib have shown remarkable activity in patients with stage IV NSCLC who harbor these mutations.

 The usual doses of gefitinib and erlotinib are 250 mg/day and 150 mg/day, respectively. The major side effects are rash, diarrhea, and fatigue.

	Gefitinib and erlotinib have been studied in many different settings. In 2004, it was discovered that activating mutations in the EGFR correlate with the response to gefitinib.

 The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) BR.19 trial randomized 503 patients with resected stage IB-IIIA NSCLC from September 2002 until April 2005.

 The trial was closed prematurely. The study showed that adjuvant gefitinib after complete resection of early-stage NSCLC did not confer DFS or OS advantage in the overall population. In a subset analysis, there was no advantage in the patients with 

 mutations. A retrospective study done at Memorial Sloan-Kettering Cancer Center in patients with completely resected stage I-III lung adenocarcinoma who received adjuvant gefitinib or erlotinib showed a DFS benefit for patients with the EGFR-activating mutations in exon 19 or 21.

 RADIANT is a study to evaluate the effectiveness of erlotinib versus placebo following complete surgical removal of the tumor with or without chemotherapy after surgery in stage IB-IIIA NSCLC patients with 

 mutations. The study is ongoing, but is no longer recruiting participants.

	The INTACT I and 2 and the TRIBUTE 1 and 2 studies looked at combination platinum-containing doublets with or without gefitinib and erlotinib, respectively.

 There was no difference in response rate, PFS, or OS in any of the arms. Gefitinib and erlotinib have been compared with placebo in patients with NSCLC who have failed chemotherapy. In the Iressa Survival Evaluation in Lung Cancer trial, gefitinib showed a small but significant 0.4-month benefit over placebo in time to treatment failure, but no significant benefit in OS.

 The NCIC CTG BR.21 researchers studied erlotinib. The results showed both a statistically significant PFS of 0.4 month and a statistically significant increase in OS with erlotinib compared with placebo, after first-line or second-line chemotherapy (6.7 mo vs 4.7 mo).

 Because of these results, the FDA issued a New Labeling and Distribution Program for gefitinib. Gefitinib would still be available to a specific subset of patients who: (1) were receiving and continuing to benefit from the drug; (2) had previously received and benefited from the drug in the past; or (3) were now receiving the drug as newly enrolled patients in a clinical trial.

	Gefitinib is still widely used in Europe and Asia. Subgroup analysis showed that patients of Asian descent, women, and patients with no history of smoking have a better response to gefitinib or erlotinib.

	The EGFR tyrosine kinase inhibitors have been studied in maintenance therapy. Gefitinib has been compared with docetaxel after failure of first-line chemotherapy in NSCLC. In a noninferiority trial, the Iressa NSCLC Trial Evaluating Response and Survival versus Taxotere (INTEREST) demonstrated that gefitinib was noninferior to docetaxel after frontline chemotherapy.

	The Sequential Tarceva in Unresectable NSCLC (SATURN) trial randomized 889 patients with nonprogressing stage IV NSCLC after a platinum-based doublet to either erlotinib or placebo.

 In the randomized patients, the median PFS and OS was 4 weeks and both were statistically significant. In an interesting subset analysis, patients with the EGFR mutation had significantly longer PFS (HR = 0.10) but not OS, probably due to crossover. The patients with adenocarcinoma had longer PFS and OS; however, the patients with squamous cell histology had longer PFS but not OS. This study led to the approval of erlotinib as maintenance therapy in patients who do not experience progression after 4 cycles of a platinum induction regimen. In the ATLAS trial, 1160 patients with advanced NSCLC were treated with a platinum doublet and bevacizumab. After 4 cycles, the patients were continued on bevacizumab and randomized to erlotinib or placebo.

 The trial stopped early because the primary endpoint of PFS was reached; however, the total predetermined accrual goal was still met. No OS benefit was demonstrated on further follow-up. The BeTa trial studied the role of erlotinib with or without bevacizumab after failure of standard first-line chemotherapy in advanced NSCLC.

 The primary endpoint of improved OS was not met; however, there was a benefit in PFS of 1.7 months.

	A study from Japan examined the role of switch maintenance gefitinib versus continuation of chemotherapy after 2-6 cycles of a platinum-containing doublet.

 There was a PFS advantage of gefitinib over the chemotherapy, but the endpoint of improved OS was not met.

	The Iressa Pan-Asia Study (IPASS) was a landmark study conducted in Asia. Patients with adenocarcinoma of the lung (nonsmokers or former light smokers) who had not received chemotherapy for advanced disease were randomized to gefitinib or chemotherapy with carboplatin and paclitaxel.

 The PFS at 1 year was significantly better in the gefitinib group (24.9% vs 6.7%). The OS, however, was the same and was thought to be secondary to the high degree of crossover to gefitinib in the patients failing the chemotherapy. Among the IPASS patients, 60% had the EGFR mutation.

	Three studies from Japan examined the role of frontline gefitinib versus frontline chemotherapy in patients with the 

 These studies showed an improvement in PFS but not in OS. The OPTIMAL study from China randomized patients with stage IIIB or IV NSCLC with the EGFR-activating mutations (exon 19 deletion or the L858R point mutation) to erlotinib or placebo until disease progression or unacceptable toxic effects, or up to 4 cycles of gemcitabine plus carboplatin.

 mutation type, histology (adenocarcinoma vs nonadenocarcinoma), and smoking status. The endpoint of median PFS was reached (13.1 mo with erlotinib vs 4.6 mo with chemotherapy; 

	The European Randomized Trial of Tarceva vs Chemotherapy (EURTAC) trial randomized stage IIIB or IV NSCLC Caucasian patients with exon 19 deletions or exon 21 L858R point mutations to erlotinib or 4 cycles of a platinum doublet.

 The objective response rate was 60% for the erlotinib patients and 15% for the chemotherapy group. The endpoint of PFS was 9.4 months in the erlotinib group and 5.2 months in the chemotherapy group. Erlotinib resulted in a significant 63% reduction in the risk of progression compared with the platinum-containing chemotherapy group. The response rate in the chemotherapy group was lower than what is traditionally reported with standard platinum doublets.

	In summary, the gefitinib and erlotinib versus chemotherapy studies in first-line patients with

 mutations have shown a PFS but not an OS benefit. This result is explained by the substantial crossover at disease progression. These studies should not dissuade physicians from using EGFR inhibitors as first-line therapy in patients with 

 mutations. A historical study from Japan found that the survival of patients with 

 mutations after gefitinib approval was 27.2 months; the survival was 13.6 months for patients before gefitinib approval.

 mutation status is unknown, it is reasonable to begin with chemotherapy and switch to an EGFR inhibitor if the patient is found or suspected to have an 

	Identification of the novel transforming gene 

 The authors were able to show that a small inversion within chromosome 2p resulted in the fusion gene containing portions of echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase gene in NSCLC. This fusion transcript occurred in 6.7% of their patients.

 rearrangements are more common in patients who have never smoked or have a smoking history of fewer than 10 pack-years. In this enriched population, the incidence of patients who are 

-positive increases to 15%. Patients with the 

 rearrangement are younger than those without the rearrangement, and the median age is about 50 years. 

 rearrangement is associated with adenocarcinoma. The 

, leads to dependency of the tumor on the activated kinase. This created the environment for the development of an inhibitor of ALK, crizotinib, a oral, small-molecule inhibitor of the ALK tyrosine kinase.

 This targeted agent and the EGFR inhibitors are less toxic and more effective than standard chemotherapy agents.

	The reported response rate for crizotinib is 57% at a median of 6.4 months. There was 1 complete response, and 33% of patients had stable disease. The probability of a 6-month PFS was 72%. The relatively mild side effects included nausea, emesis, diarrhea, edema, constipation, and visual changes.

	New Agents for First-line and Resistant Patients With 

	BIBW 2992 (afatinib, Tomtovok) is an irreversible inhibitor of EGFR/HER1 and HER2, which is active in EGFR-mutated advanced NSLC. The LUX-1 lung trial compared BIBW 2992 plus best supportive care with placebo plus best supportive care in patients with NSCLC failing first- and second-line chemotherapy and erlotinib or gefitinib (LUX-Lung 1).

 There was an improvement (4.4 mo vs 1 mo for placebo) in PFS, but not in OS.

	The LUX-2 Lung trial was a phase II single-arm study of BIBW 2992 in NSCLC patients who failed 1 line of chemotherapy or who were chemotherapy-naïve, and who had an EGFR-activating mutation. This trial showed that the use of afatinib led to a high rate of tumor size reduction (objective response rate of 61%) and a long delay in the progression of cancer by over 1 year (PFS of 14 mo). The OS was superior to what has been reported with erlotinib.

	BIBF 1120 (Vargatef) is a triple angiokinase inhibitor that acts on 3 growth factors simultaneously: vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and fibroblast growth factor receptor. The LUME-1 lung cancer trial is evaluating whether docetaxel plus BIBF 1120 is more effective that placebo plus docetaxel in stage IIIB, stage IV, and recurrent NSCLC.

	The mechanism of resistance to the EGFR tyrosine kinase inhibitors is of much interest. A mutation in a domain on exon 20 of the EGFR receptor called T790M interferes with binding of the EGFR tyrosine kinase inhibitor to the inhibitory docking site.

 Some patients have the T790M mutation at diagnosis, and others acquire the mutation. There is also overexpression of c-MET in about 20% of patients who acquire resistance to the EGFR tyrosine kinase inhibitors. ARQ197 (Tivantinib), a selective inhibitor of the c-MET receptor tyrosine kinase, has been evaluated in this setting. The combination of an EGFR/MET receptor inhibitor is logical in this setting. In a randomized study by Schiller et al, patients receiving second- or third-line therapy and who were erlotinib-naïve were randomized to erlotinib and ARQ 197 or erlotinib and placebo.

 Among the intent-to-treat group, the median PFS was 16.1 weeks for the combination group versus 9.7 weeks in the placebo group (HR = 0.81; 95% CI, 0.57, 1.15; 

 = .23). The treatment was well tolerated.

	A recent study examined the activity and tolerability of afatinib in combination with cetuximab in patients with NSCLC who have an acquired resistance to erlotinib or gefitinib.

 A second mutation in the EGFR molecule at the exon site 20 EGFR T790M is seen in up to 50% of these cases. The combination of afatinib and cetuximab is the first combination to show activity in this setting. A 29% PR was reported in patients who were resistant to gefitinib or erlotinib and expressed the T790M mutation.

	The first Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial was done in patients with stage IIIB, stage IV, or advanced incurable NSCLC who had progressed on at least 1 prior chemotherapy regimen.

 The study required another biopsy before selection of the patient’s next line of therapy. A randomization technique called Bayesian adaptive randomization was used. The purpose of Bayesian adaptive randomization was to identify promising benefits of certain drugs with certain molecular markers as the study proceeds. Patients were selected for 1 of 4 therapies depending on the molecular characteristics of the lung cancer. The options included erlotinib, sorafenib, vandetanib, or erlotinib and bexarotene. BATTLE’s endpoint was disease control at 8 weeks, which recent research has found is a good indicator of OS. A novel phase II clinical trial program, BATTLE showed that patients whose treatment was determined by their tumor biomarkers had better disease control than patients treated nonselectively with the other 3 drugs. The study found, for example, that 61% of patients with a 

 mutation in their tumors who took sorafenib had disease control at 8 weeks, compared with 32% for the other 3 drugs. Erlotinib did best against 

 mutations, vandetanib against high VEGFR-2 expression, and the erlotinib-bexarotene combination fared best with Cyclin D1 defects or amplified numbers of the 

	The overall results showed that 46% of patients in the trial had disease control at 8 weeks, compared with a historical experience of around 30% for advanced-stage NSCLC. Median OS was 9 months, and the 1-year survival was 38%, with only 6.5% of patients experiencing a significant side effect.

	Finally, the National Cancer Institute’s Lung Cancer Mutation Consortium is looking at stage IV adenocarcinoma lung cancer patients to determine whether there is a “driver mutation.” They were able to find to find such a mutation in 54% of the patients. The most common mutations were 

. These findings hopefully will help researchers to develop more targeted therapies.

	These studies are defining a new era in “personalized medicine” for the treatment of lung cancer.

	Steven A. Sandler, MD, is in the section of hematology and oncology at Skokie Hospital in Skokie, Illinois.

	Dr Sandler reports no financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

	Steven A. Sandler, MD, Section of Hematology and Oncology, Skokie Hospital, 9669 N Kenton Ave, Ste 510, Skokie, IL 60076. E-mail: 

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