Results From the Phase III Randomized Trial of Onartuzumab Plus Erlotinib Versus Erlotinib in Previously Treated Stage IIIB or IV Non-Small-Cell Lung Cancer: METLung. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. Third‐line or fourth‐line chemotherapy in non‐small‐cell lung cancer patients with relatively good performance status Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy. Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. Third-Line Chemotherapy in Advanced Non-small Cell Lung Cancer: Identifying the Candidates for Routine Practice Sunitinib plus erlotinib versus placebo plus erlotinib in patients with previously treated advanced non-small-cell lung cancer: a phase III trial. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. Is there a third line option after chemotherapy and TKI failure in advanced non-small cell lung cancer? Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Pemetrexed versus erlotinib in pretreated patients with advanced non–small cell lung cancer: A Hellenic Oncology Research Group (HORG) randomized phase 3 study Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer.
Purpose The phase III OAM4971 g study ( METLung ) examined the efficacy and safety of onartuzumab plus erlotinib in patients with locally advanced or metastatic non-small-cell lung cancer selected by MET immunohistochemistry whose disease had progressed after treatment with a platinum-based chemotherapy regimen . Patients and Methods Patients were r and omly assigned at a one-to-one ratio to receive onartuzumab ( 15 mg/kg intravenously on day 1 of each 21-day cycle ) plus daily oral erlotinib 150 mg or intravenous placebo plus daily oral erlotinib 150 mg . The primary end point was overall survival ( OS ) in the intent-to-treat population . Secondary end points included median progression-free survival , overall response rate , biomarker analysis , and safety . Results A total of 499 patients were enrolled ( onartuzumab , n = 250 ; placebo , n = 249 ) .  Median OS was 6.8 versus 9.1 months for onartuzumab versus placebo ( stratified hazard ratio [ HR ] , 1.27 ; 95 % CI , 0.98 to 1.65 ; P = .067 ) , with a greater number of deaths in the onartuzumab arm ( 130 [ 52 % ] v 114 [ 46 % ] ) . Median progression-free survival was 2.7 versus 2.6 months ( stratified HR , 0.99 ; 95 % CI , 0.81 to 1.20 ; P = .92 ) , and overall response rate was 8.4 % and 9.6 % for onartuzumab versus placebo , respectively . Exploratory analyses using MET fluorescence in situ hybridization status and gene expression showed no benefit for onartuzumab ;  patients with EGFR mutations showed a trend toward shorter OS with onartuzumab treatment ( HR , 4.68 ; 95 % CI , 0.97 to 22.63 ) . Grade 3 to 5 adverse events were reported by 56.0 % and 51.2 % of patients , with serious AEs in 33.9 % and 30.7 % , for experimental versus control arms , respectively . Conclusion Onartuzumab plus erlotinib did not improve clinical outcomes , with shorter OS in the onartuzumab arm , compared with erlotinib in patients with MET-positive non-small-cell lung cancer BACKGROUND Atezolizumab is a humanised antiprogrammed death-lig and 1 ( PD-L1 ) monoclonal antibody that inhibits PD-L1 and programmed death-1 ( PD-1 ) and PD-L1 and B7 - 1 interactions , reinvigorating anticancer immunity . We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer . METHODS We did a r and omised , open-label , phase 3 trial ( OAK ) in 194 academic or community oncology centres in 31 countries . We enrolled patients who had squamous or non-squamous non-small-cell lung cancer , were 18 years or older , had measurable disease per Response Evaluation Criteria in Solid Tumors , and had an Eastern Cooperative Oncology Group performance status of 0 or 1 . Patients had received one to two previous cytotoxic chemotherapy regimens ( one or more platinum based combination therapies ) for stage IIIB or IV non-small-cell lung cancer . Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel , CD137 agonists , anti-CTLA4 , or therapies targeting the PD-L1 and PD-1 pathway were excluded . Patients were r and omly assigned ( 1:1 ) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block r and omisation ( block size of eight ) via an interactive voice or web response system . Co primary endpoints were overall survival in the intention-to-treat ( ITT ) and PD-L1-expression population TC1/2/3 or IC1/2/3 ( ≥1 % PD-L1 on tumour cells or tumour-infiltrating immune cells ) . The primary efficacy analysis was done in the first 850 of 1225 enrolled patients . This study is registered with Clinical Trials.gov , number NCT02008227 . FINDINGS Between March 11 , 2014 , and April 29 , 2015 , 1225 patients were recruited . In the primary population , 425 patients were r and omly assigned to receive atezolizumab and 425 patients were assigned to  receive  docetaxel  .  Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression population s. In the ITT population , overall survival was improved with atezolizumab compared with docetaxel ( median overall survival was 13·8 months [ 95 % CI 11·8 - 15·7 ] vs 9·6 months [ 8·6 - 11·2 ] ; hazard ratio [ HR ] 0·73 [ 95 % CI 0·62 - 0·87 ] , p=0·0003 ) . Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab ( n=241 ) compared with docetaxel ( n=222 ; median overall survival was 15·7 months [ 95 % CI 12·6 - 18·0 ] with atezolizumab vs 10·3 months [ 8·8 - 12·0 ] with docetaxel ; HR 0·74 [ 95 % CI 0·58 - 0·93 ] ; p=0·0102 ) . Patients in the PD-L1 low or undetectable subgroup ( TC0 and IC0 ) also had improved survival with atezolizumab ( median overall survival 12·6 months vs 8·9 months ; HR 0·75 [ 95 % CI 0·59 - 0·96 ] ) . Overall survival improvement was similar in patients with squamous ( HR 0·73 [ 95 % CI 0·54 - 0·98 ] ; n=112 in the atezolizumab group and n=110 in the docetaxel group ) or non-squamous ( 0·73 [ 0·60 - 0·89 ] ; n=313 and n=315 ) histology . Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab ( 90 [ 15 % ] of 609 patients ) versus docetaxel ( 247 [ 43 % ] of 578 patients ) . One treatment-related death from a respiratory tract infection was reported in the docetaxel group . INTERPRETATION To our knowledge , OAK is the first r and omised phase 3 study to report results of a PD-L1-targeted therapy , with atezolizumab treatment result ing in a clinical ly relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer , regardless of PD-L1 expression or histology , with a favourable safety profile . FUNDING F. Hoffmann-La Roche Ltd , Genentech , BACKGROUND Nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , disrupts PD-1-mediated signaling and may restore antitumor immunity . METHODS In this r and omized , open-label , international phase 3 study , we assigned patients with nonsquamous non-small-cell lung cancer ( NSCLC ) that had progressed during or after platinum-based doublet chemotherapy  to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS Overall survival was longer with nivolumab than with docetaxel .  The median overall survival was 12.2 months ( 95 % confidence interval [ CI ] , 9.7 to 15.0 ) among 292 patients in the  nivolumab group and 9.4 months ( 95 % CI , 8.1 to 10.7 ) among 290 patients in the docetaxel group ( hazard ratio for death , 0.73 ; 96 % CI , 0.59 to 0.89 ; P=0.002 ) . At 1 year , the overall survival rate was 51 % ( 95 % CI , 45 to 56 ) with nivolumab versus 39 % ( 95 % CI , 33 to 45 ) with docetaxel . With additional follow-up , the overall survival rate at 18 months was 39 % ( 95 % CI , 34 to 45 ) with nivolumab versus 23 % ( 95 % CI , 19 to 28 ) with docetaxel . The response rate was 19 % with nivolumab versus 12 % with docetaxel ( P=0.02 ) . Although progression-free survival did not favor nivolumab over docetaxel ( median , 2.3 months and 4.2 months , respectively ) , the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel ( 19 % and 8 % , respectively ) . Nivolumab was associated with even greater efficacy  than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression ( ≥1 % , ≥5 % , and ≥10 % ) of the PD-1 lig and . Treatment-related adverse events of grade 3 or 4 were reported in 10 % of the patients in the nivolumab group , as compared with 54 % of those in the docetaxel group . CONCLUSIONS Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy  , overall survival was longer with nivolumab than with docetaxel . ( Funded by Bristol-Myers Squibb ; CheckMate 057 Clinical Trials.gov number , NCT01673867 . ) BACKGROUND Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles . On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer ( NSCLC ) , we aim ed to assess efficacy and safety of this combination in a phase 3 trial . METHODS In our double-blind , placebo-controlled , r and omised phase 3 trial ( BeTa ) , we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment . Patients were r and omly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab ( bevacizumab group ) or erlotinib plus placebo ( control group ) according to a computer-generated r and omisation sequence by use of an interactive voice response system . The primary endpoint was overall survival in all enrolled patients . Patients , study staff , and investigators were masked to treatment assignment . We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses . This trial is registered with Clinical Trials.gov , number NCT00130728 . FINDINGS Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group ( hazard ratio [ HR ] 0·97 , 95 % CI 0·80 - 1·18 , p=0·7583 ) . Median overall survival was 9·3 months ( IQR 4·1 - 21·6 ) for patients in the bevacizumab group compared with 9·2 months ( 3·8 - 20·2 ) for controls . Progression-free survival seemed to be longer in the bevacizumab group ( 3·4 months [ 1·4 - 8·4 ] ) than in the control group ( 1·7 months [ 1·3 - 4·1 ] ; HR 0·62 , 95 % CI 0·52 - 0·75 ) and objective response rate suggested some clinical activity of bevacizumab and erlotinib . However , these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done , to control type I error rate . In the bevacizumab group , 130 ( 42 % ) of 313 patients with safety  data had a serious adverse event , compared with 114 ( 36 % ) controls . There were 20 ( 6 % ) grade 5 adverse events , including two arterial thromboembolic events , in the bevacizumab group , and 14 ( 4 % ) in the control group . INTERPRETATION Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC . FUNDING Genentech PURPOSE To confirm the promising phase II results of docetaxel monotherapy , this phase III trial was conducted of chemotherapy for patients with advanced non-small-cell lung cancer ( NSCLC ) who had previously failed platinum-containing chemotherapy . PATIENTS AND METHODS A total of 373 patients were r and omized to receive either docetaxel 100 mg/m(2 ) ( D100 ) or 75 mg/m(2 ) ( D75 ) versus a control regimen of vinorelbine or ifosfamide ( V/I ) . The three treatment groups were well-balanced for key patient characteristics . RESULTS Overall response rates were 10.8 % with D100 and 6.7 % with D75 , each significantly higher than the 0.8 % response with V/I ( P = .001 and P = .036 , respectively ) . Patients who received docetaxel had a longer time to progression ( P = .046 , by log-rank test ) and a greater progression-free survival at 26 weeks ( P = .005 , by chi(2 ) test ) . Although overall survival was not significantly different between the three groups , the 1-year survival was significantly greater with D75 than with the control treatment ( 32 % v 19 % ; P = .025 , by chi(2 ) test ) . Prior exposure to paclitaxel did not decrease the likelihood of response to docetaxel , nor did it impact survival . There was a trend toward greater efficacy in patients whose disease was platinum-resistant rather than platinum-refractory and in patients with performance status of 0 or 1 versus 2 . Toxicity was greatest with D100 , but the D75 arm was well-tolerated . CONCLUSION This first r and omized trial in this setting demonstrates that D75 every 3 weeks can offer clinical ly meaningful benefit to patients with advanced NSCLC whose disease has relapsed or progressed after platinum-based chemotherapy PURPOSE To evaluate whether treatment with single-agent docetaxel would result in longer survival than would best supportive care in patients with non-small-cell lung cancer who had previously been treated with platinum-based chemotherapy .  Secondary end points included assessment of response ( docetaxel arm only ) , toxicity , and quality of life . PATIENTS AND METHODS Patients with performance statuses of 0 to 2 and stage IIIB/IV non-small-cell lung cancer with either measurable or evaluable lesions were eligible for entry onto the study if they had undergone one or more platinum-based chemotherapy regimens and if they had adequate hematology and biochemistry parameters . They were excluded if they had symptomatic brain metastases or if they had previously been treated with paclitaxel .  Patients were stratified by performance status and best response to cisplatin chemotherapy and were then r and omized to treatment with docetaxel 100 mg/m(2 ) ( 49 patients ) or 75 mg/m(2 ) ( 55 patients ) or best supportive care . Patients in both arms were assessed every 3 weeks . RESULTS One hundred four patients ( 103 of whom were eligible for entry onto the study ) were well balanced for prognostic factors . Of 84 patients with measurable lesions , six ( 7 . 1 % ) achieved partial responses ( three patients at each dose level ) . Time to progression was longer for docetaxel patients than for best supportive care patients ( 10.6 v 6.7 weeks , respectively ; P < .001 ) , as was median survival ( 7.0 v 4.6 months ; log-rank test , P = .047 ) . The difference was more significant for docetaxel 75 mg/m(2 ) patients , compared with corresponding best supportive care patients ( 7.5 v 4.6 months ; log-rank test , P = .010 ; 1-year survival , 37 % v 11 % ; chi(2 ) test , P = .003 ) . Febrile neutropenia occurred in 11 patients treated with docetaxel 100 mg/m(2 ) , three of whom died , and in one patient treated with docetaxel 75 mg/m(2 ) . Grade 3 or 4 nonhematologic toxicity , with the exception of diarrhea , occurred at a similar rate in both the docetaxel and best supportive care groups . CONCLUSION Treatment with docetaxel is associated with significant prolongation of survival , and at a dose of 75 mg/m(2 ) , the benefits of docetaxel therapy outweigh the risks Background : Our aim here was to explore treatment efficacy of pemetrexed and docetaxel in non‐small‐cell lung cancer patients who had failed previous chemotherapy and epidermal growth factor receptor‐tyrosine kinase inhibitor therapy . Methods : We retrospectively review ed clinical data of our non‐small‐cell lung cancer patients who received third‐ or fourth‐line chemotherapy with pemetrexed or docetaxel in our institution from January 2006 to December 2009 . Results : One hundred and twenty‐three patients received treatment , including 85 patients with pemetrexed treatment and 38 patients with docetaxel treatment . There was no difference in tumor response rate and toxicity profiles when using pemetrexed as third‐ or fourth‐line treatment , neither was there difference in docetaxel treatment of third‐ versus fourth‐line treatment . There was also no difference between docetaxel and pemetrexed  in response rate and control rate when they were used as fourth‐line treatment . However , docetaxel used in fourth‐line treatment had higher incidence of neutropenia and more frequent need of granulocyte colony‐stimulating factor support compared with pemetrexed in fourth‐line treatment . Median progression‐free survivals ( PFSs ) were 2.6 months and 3.8 months when using pemetrexed as third‐ and fourth‐line treatment , respectively ( p = 0.417 ) . Median PFSs were 3.8 months and 4.8 months when using docetaxel as third‐ and fourth‐line treatment , respectively ( p = 0.882 ) . There was also no difference in PFS between pemetrexed and docetaxel , both in third‐ and fourth‐line treatment . Median survivals were 13.4 , 12.2 , 13.2 , and 13 months for pemetrexed in third‐line , fourth‐line , and docetaxel in third‐line and fourth‐line treatment , respectively . Conclusion : This retrospective study of pemetrexed and docetaxel  showed relatively safe toxicity profile , reasonable response rate , and long survival when used as third‐ and fourth‐line chemotherapy . Thus , it is reasonable to give good performance status patients third‐ and fourth‐line chemotherapy . A phase III r and omized trial is needed for better clarification of these issues BACKGROUND In single-group studies , chromosomal rearrangements of the anaplastic lymphoma kinase gene ( ALK ) have been associated with marked clinical responses to crizotinib , an oral tyrosine kinase inhibitor targeting ALK . Whether crizotinib is superior to st and ard chemotherapy with respect to efficacy is unknown . METHODS We conducted a phase 3 , open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen . Patients were r and omly assigned to receive oral treatment with crizotinib ( 250 mg ) twice daily or intravenous chemotherapy with either pemetrexed ( 500 mg per square meter of body-surface area ) or docetaxel ( 75 mg per square meter ) every 3 weeks . Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study . The primary end point was progression-free survival . RESULTS The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group ( hazard ratio for progression or death with crizotinib , 0.49 ; 95 % confidence interval [ CI ] , 0.37 to 0.64 ; P<0.001 ) . The response rates were 65 % ( 95 % CI , 58 to 72 ) with crizotinib , as compared with 20 % ( 95 % CI , 14 to 26 ) with chemotherapy ( P<0.001 ) . An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy ( hazard ratio for death in the crizotinib group , 1.02 ; 95 % CI , 0.68 to 1.54 ; P=0.54 ) . Common adverse events associated with crizotinib were visual disorder , gastrointestinal side effects , and elevated liver aminotransferase levels , whereas common adverse events with chemotherapy were fatigue , alopecia , and dyspnea . Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy . CONCLUSIONS Crizotinib is superior to st and ard chemotherapy in patients with previously treated , advanced non-small-cell lung cancer with ALK rearrangement . ( Funded by Pfizer ; Clinical Trials.gov number , NCT00932893 . ) PURPOSE This phase III study ( V-15 - 32 ) compared gefitinib ( 250 mg/d ) with docetaxel ( 60 mg/m(2 ) ) in patients ( N = 489 ) with advanced/metastatic non-small-cell lung cancer ( NSCLC ) who had failed one or two chemotherapy regimens . METHODS The primary objective was to compare overall survival to demonstrate noninferiority for gefitinib relative to docetaxel . An unadjusted Cox regression model was used for the primary analysis . RESULTS Noninferiority in overall survival was not achieved ( hazard ratio [ HR ] , 1.12 ; 95.24 % CI , 0.89 to 1.40 ) according to the predefined criterion ( upper CI limit for HR < or= 1.25 ) ; however , no significant difference in overall survival ( P = .330 ) was apparent between treatments . Post study , 36 % of gefitinib-treated patients received subsequent docetaxel , and 53 % of docetaxel-treated patients received subsequent gefitinib . Gefitinib significantly improved objective response rate and quality of life versus docetaxel ;  progression-free survival , disease control rates , and symptom improvement were similar for the two treatments . Grade s 3 to 4 adverse events occurred in 40.6 % ( gefitinib ) and 81.6 % ( docetaxel ) of patients . Incidence of interstitial lung disease was 5.7 % ( gefitinib ) and 2.9 % ( docetaxel ) . Four deaths occurred due to adverse events in the gefitinib arm ( three deaths as a result of interstitial lung disease , judged to be treatment related ; one as a result of pneumonia , not treatment related ) , and none occurred in the docetaxel arm . CONCLUSION Noninferiority in overall survival between gefitinib and docetaxel was not demonstrated according to predefined criteria ; however , there was no statistically significant difference in overall survival . Secondary end points showed similar or superior efficacy for gefitinib compared with docetaxel . Gefitinib remains an effective treatment option for previously treated Japanese patients with NSCLC PURPOSE Histone deacetylase inhibitors ( HDACis ) have been shown to overcome resistance to epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKIs ) linked to epigenetic changes and epithelial-mesenchymal transition ( EMT ) state . This r and omized phase II study evaluated the outcome of erlotinib with and without the isoform selective HDACi , entinostat . PATIENTS AND METHODS Previously treated patients with stage IIIB/IV non-small-cell lung cancer , no prior EGFR-TKIs , and performance status ≤ 2 were r and omly administered erlotinib 150 mg on days 1 through 28 plus entinostat 10 mg orally on days 1 and 15 every 28 days ( EE ) or erlotinib plus placebo ( EP ) . The primary end point was 4-month progression-free survival ( PFS ) rate with additional end points including 6-month PFS rate , PFS , and overall survival ( OS ) . Exploratory analyses included EMT- and EGFR-related biomarker analysis on archival tissue . RESULTS One hundred thirty-two patients were enrolled ( EE , 67 ; EP , 65 ) . The 4-month PFS rate was comparable for both groups ( EE , 18 % v EP , 20 % ; P = .7 ) . In the subset of patients with high E-cadherin levels , OS was longer in the EE group compared with the EP group ( 9.4 v 5.4 months ; hazard ratio , 0.35 ; 95 % CI , 0.13 to 0.92 ; P = .03 ) with a corresponding trend toward increased PFS . The adverse event ( AE ) profile was acceptable , with rash , fatigue , diarrhea , and nausea the most common AEs in both groups . CONCLUSION Erlotinib combined with entinostat did not improve the outcomes of patients in the overall study population when compared with erlotinib monotherapy . High E-cadherin expression levels at time of diagnosis indicate an increased sensitivity to HDACi/EGFR-TKI inhibition providing the basis for a biomarker-driven validation study PURPOSE R1507 is a selective , fully human , recombinant monoclonal antibody ( immunoglobulin G1 subclass ) against insulin-like growth factor-1 receptor ( IGF-1R ) . The strong pre clinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor ( EGFR ) as anticancer therapy prompted this study . PATIENTS AND METHODS Patients with advanced-stage non-small-cell lung cancer ( NSCLC ) with progression following one or two prior regimens , Eastern Cooperative Oncology Group ( ECOG ) performance status 0 to 2 , and measurable disease were eligible . Patients were r and omly assigned to receive erlotinib ( 150 mg orally once a day ) in combination with either placebo , R1507 9 mg/kg weekly , or R1507 16 mg/kg intravenously once every 3 weeks . Treatment cycles were repeated every 3 weeks . The primary end point was comparison of the 12-week progression-free survival ( PFS ) rate . RESULTS In all , 172 patients were enrolled : median age , 61 years ; female , 33 % ; never-smokers , 12 % ; and performance status 0 or 1 , 88 % . The median number of R1507 doses was six for the weekly arm and 3.5 for the every-3-weeks arm . Grade s 3 to 4 adverse events occurred in 37 % , 44 % , and 48 % of patients with placebo , R1507 weekly , and R1507 every 3 weeks , respectively . The 12-week PFS rates were 39 % , 37 % , and 44 % , and the median overall survival was 8.1 , 8.1 , and 12.1 months for the three groups , respectively , with statistically nonsignificant hazard ratios . The 12-week PFS rate in patients with KRAS mutation was 36 % with R1507 compared with 0 % with placebo . CONCLUSION The combination of R1507 with erlotinib did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC . Predictive biomarkers are essential for further development of combined inhibition of IGF-1R and EGFR PURPOSE To investigate the efficacy of erlotinib versus docetaxel in previously treated patients with advanced non-small-cell lung cancer ( NSCLC ) in an epidermal growth factor receptor ( EGFR ) -unselected patient population . PATIENTS AND METHODS The primary end point was progression-free survival ( PFS ) . Secondary end points included overall survival ( OS ) , response rate , safety , and analyses on EGFR wild-type tumors . Patients with stage IIIB or IV NSCLC , previous treatment with one or two chemotherapy regimens , evaluable or measurable disease , and performance status of 0 to 2 were eligible . RESULTS From August 2009 to July 2012 , 150 and 151 patients were r and omly assigned to erlotinib ( 150 mg daily ) and docetaxel ( 60 mg/m(2 ) every 3 weeks ) , respectively . EGFR wild-type NSCLC was present in 109 and 90 patients in the erlotinib and docetaxel groups , respectively . Median PFS  for erlotinib versus docetaxel was 2.0 v 3.2 months ( hazard ratio [ HR ] , 1.22 ; 95 % CI , 0.97 to 1.55 ; P = .09 ) , and median OS was 14.8 v 12.2 months ( HR , 0.91 ; 95 % CI , 0.68 to 1.22 ; P = .53 ) , respectively . In a subset analysis of EGFR wild-type tumors , PFS  for erlotinib versus docetaxel was 1.3 v 2.9 months ( HR , 1.45 ; 95 % CI , 1.09 to 1.94 ; P = .01 ) , and OS was 9.0 v 10.1 months ( HR , 0.98 ; 95 % CI , 0.69 to 1.39 ; P = .91 ) , respectively . CONCLUSION Erlotinib failed to show an improvement in PFS or OS compared with docetaxel in an EGFR-unselected patient population BACKGROUND Despite recent advances in the treatment of advanced non-small-cell lung cancer , there remains a need for effective treatments for progressive disease . We assessed the efficacy of pembrolizumab for patients with previously treated , PD-L1-positive , advanced non-small-cell lung cancer . METHODS We did this r and omised , open-label , phase 2/3 study at 202 academic medical centres in 24 countries . Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1 % of tumour cells were r and omly assigned ( 1:1:1 ) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg , pembrolizumab 10 mg/kg , or docetaxel 75 mg/m(2 ) every 3 weeks . The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50 % of tumour cells . We used a threshold for significance of p<0.00825 ( one-sided ) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival . This trial is registered at Clinical Trials.gov , number NCT01905657 . FINDINGS Between Aug 28 , 2013 , and Feb 27 , 2015 , we enrolled 1034 patients : 345 allocated to pembrolizumab 2 mg/kg , 346 allocated to pembrolizumab 10 mg/kg , and 343 allocated to docetaxel . By Sept 30 , 2015 , 521 patients had died . In the total population , median overall survival was 10.4 months with pembrolizumab 2 mg/kg , 12.7 months with pembrolizumab 10 mg/kg , and 8.5 months with docetaxel .  Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel ( hazard ratio [ HR ] 0.71 , 95 % CI 0.58 - 0.88 ; p=0.0008 ) and for pembrolizumab 10 mg/kg versus docetaxel ( 0.61 , 0.49 - 0.75 ; p<0.0001 ) . Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg , 4.0 months with pembrolizumab 10 mg/kg , and 4.0 months with docetaxel , with no significant difference for pembrolizumab 2 mg/kg versus docetaxel ( 0.88 , 0.74 - 1.05 ; p=0.07 ) or for pembrolizumab 10 mg/kg versus docetaxel ( HR 0.79 , 95 % CI 0.66 - 0.94 ; p=0.004 ) . Among patients with at least 50 % of tumour cells expressing PD-L1 , overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel ( median 14.9 months vs 8.2 months ; HR 0.54 , 95 % CI 0.38 - 0.77 ; p=0.0002 ) and with pembrolizumab 10 mg/kg than with docetaxel ( 17.3 months vs 8.2 months ; 0.50 , 0.36 - 0.70 ; p<0.0001 ) . Likewise , for this patient population , progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel ( median 5.0 months vs 4.1 months ; HR 0.59 , 95 % CI 0.44 - 0.78 ; p=0.0001 ) and with pembrolizumab 10 mg/kg than with docetaxel ( 5.2 months vs 4.1 months ; 0.59 , 0.45 - 0.78 ; p<0.0001 ) . Grade 3 - 5 treatment-related adverse events were less common with pembrolizumab than with docetaxel ( 43 [ 13 % ] of 339 patients given 2 mg/kg , 55 [ 16 % ] of 343 given 10 mg/kg , and 109 [ 35 % ] of 309 given docetaxel ) . INTERPRETATION Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated , PD-L1-positive , advanced non-small-cell lung cancer . These data establish pembrolizumab as a new treatment option for this population and vali date the use of PD-L1 selection . FUNDING Merck & The purpose of this article is to provide up date d recommendations for the treatment of patients with stage IV non-small-cell lung cancer . A literature search identified relevant r and omized trials published since 2002 . The scope of the guideline was narrowed to chemotherapy and biologic therapy . An Up date Committee review ed the literature and made up date d recommendations . One hundred sixty-two publications met the inclusion criteria . Recommendations were based on treatment strategies that improve overall survival . Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life . For first-line therapy in patients with performance status of 0 or 1 , a platinum-based two-drug combination of cytotoxic drugs is recommended . Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy . For patients with performance status of 2 , a single cytotoxic drug is sufficient . Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment . Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy . The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor ( EGFR ) mutation ; for negative or unknown EGFR mutation status , cytotoxic chemotherapy is preferred . Bevacizumab is recommended with carboplatin-paclitaxel , except for patients with certain clinical characteristics . Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry . Docetaxel , erlotinib , gefitinib , or pemetrexed is recommended as second-line therapy . Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib . Data are insufficient to recommend the routine third-line use of cytotoxic drugs . Data are insufficient to recommend routine use of molecular markers to select chemotherapy Background : The interest of first- and second-line treatments in non-small cell lung cancer ( NSCLC ) has been demonstrated by successive r and omized trials . Improvements in lung cancer care have routinely allowed a significant proportion of patients to be considered for third-line treatment . Methods : A retrospective analysis was performed , including all consecutive patients with advanced NSCLC , who received at least three lines of systemic antineoplastic treatment at our institution . Results : From a population of 613 patients treated with first-line treatment , a total of 173 patients received  third-line treatment ( cytotoxic chemotherapy in 131 patients ; epidermal growth factor ( EGFR ) tyrosine kinase inhibitors in 42 patients ) . Only 13 patients ( 8 % ) received less than 75 % of the theoretical dose intensity ; 22 patients ( 13 % ) presented with severe toxicities . Symptom relief and performance status ( PS ) improvement were observed in 121 ( 92 % of the 131 patients with symptoms ) and 90 patients ( 52 % ) , respectively . Using multivariate analysis , survival after third-line treatment was significantly increased in patients younger than 70 years-old ( hazard ratio [ HR ] = 0.73 , 95 % confidence interval [ CI ] : 0.53–0.99 , p = 0.047 ) , who smoked less than 10 pack-years ( HR = 0.82 , 95 % CI : 0.57–0.93 , p = 0.036 ) , with no cancer-related symptoms ( HR = 0.75 , 95 % CI : 0.61–0.92 , p = 0.007 ) , a weight loss inferior to 5 kg since the beginning of second-line ( HR = 0.63 , 95 % CI : 0.52–0.75 , p = 0.013 ) , a PS 0 to 1 ( HR = 0.81 , 95 % CI : 0.76–0.86 , p = 0.008 ) , and no extrathoracic tumor spread at initiation of third-line treatment ( HR = 0.67 , 95 % CI : 0.47–0.94 , p = 0.042 ) . Disease control after both first- and second-line treatments was the strongest predictor of prolonged survival after third-line treatment ( HR = 0.47 , 95 % CI : 0.33–0.67 , p = 0.001 ) . Conclusions : Patients with advanced NSCLC may benefit from third-line treatment . The best c and i date s can be identified using st and ard prognostic factors , such as PS , and disease control after first- and second-line treatments PURPOSE Sunitinib plus erlotinib may enhance antitumor activity compared with either agent alone in non-small-cell lung cancer ( NSCLC ) , based on the importance of the signaling pathways involved in tumor growth , angiogenesis , and metastasis . This phase III trial investigated overall survival ( OS ) for sunitinib plus erlotinib versus placebo plus erlotinib in patients with refractory NSCLC . PATIENTS AND METHODS Patients previously treated with one to two chemotherapy regimens ( including one platinum-based regimen ) for recurrent NSCLC , and for whom erlotinib was indicated , were r and omly assigned ( 1:1 ) to sunitinib 37.5 mg/d plus erlotinib 150 mg/d or to placebo plus erlotinib 150 mg/d , stratified by prior bevacizumab use , smoking history , and epidermal growth factor receptor expression . The primary end point was OS . Key secondary end points included progression-free survival ( PFS ) , objective response rate ( ORR ) , and safety . RESULTS In all , 960 patients were r and omly assigned , and baseline characteristics were balanced . Median OS was 9.0 months for sunitinib plus erlotinib versus 8.5 months for erlotinib alone ( hazard ratio [ HR ] , 0.922 ; 95 % CI , 0.797 to 1.067 ; one-sided stratified log-rank P = .1388 ) . Median PFS was 3.6 months versus 2.0 months ( HR , 0.807 ; 95 % CI , 0.695 to 0.937 ; one-sided stratified log-rank P = .0023 ) , and ORR was 10.6 % versus 6.9 % ( two-sided stratified log-rank P = .0471 ) , respectively . Treatment-related toxicities of grade 3 or higher , including rash/dermatitis , diarrhea , and asthenia/fatigue were more frequent in the sunitinib plus erlotinib arm . CONCLUSION In patients with refractory NSCLC , sunitinib plus erlotinib did not improve OS compared with erlotinib alone , but the combination was associated with a statistically significantly longer PFS and greater ORR . The incidence of grade 3 or higher toxicities was greater with combination therapy BACKGROUND Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor . Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib . We aim ed to compare dacomitinib with erlotinib in a phase 3 study . METHODS In a r and omised , multicentre , double-blind phase 3 trial in 134 centres in 23 countries , we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer , progression after one or two previous regimens of chemotherapy , Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 - 2 , and presence of measurable disease . We r and omly assigned patients in a 1:1 ratio to dacomitinib ( 45 mg/day ) or erlotinib ( 150 mg/day ) with matching placebo . Treatment allocation was masked to the investigator , patient , and study funder . R and omisation was stratified by histology ( adenocarcinoma vs non-adenocarcinoma ) , ethnic origin ( Asian vs non-Asian and Indian sub-continent ) , performance status ( 0 - 1 vs 2 ) , and smoking status ( never-smoker vs ever-smoker ) . The co primary endpoints were progression-free survival per independent review for all r and omly assigned patients , and for all r and omly assigned patients with KRAS wild-type tumours . The study has completed accrual and is registered with Clinical Trials.gov , number NCT01360554 . FINDINGS Between June 22 , 2011 , and March 12 , 2013 , we enrolled 878 patients and r and omly assigned 439 to dacomitinib ( 256 KRAS wild type ) and 439 ( 263 KRAS wild type ) to erlotinib . Median progression-free survival was 2·6 months ( 95 % CI 1·9 - 2·8 ) in both the dacomitinib group and the erlotinib group ( stratified hazard ratio [ HR ] 0·941 , 95 % CI 0·802 - 1·104 , one-sided log-rank p=0·229 ) . For patients with wild-type KRAS , median progression-free survival was 2·6 months for dacomitinib ( 95 % CI 1·9 - 2·9 ) and erlotinib ( 95 % CI 1·9 - 3·0 ; stratified HR 1·022 , 95 % CI 0·834 - 1·253 , one-sided p=0·587 ) . In patients  who received at least one dose of study drug , the most frequent grade 3 - 4 adverse events were diarrhoea ( 47 [ 11 % ] patients in the dacomitinib group vs ten [ 2 % ] patients in the erlotinib group ) , rash ( 29 [ 7 % ] vs 12 [ 3 % ] ) , and stomatitis ( 15 [ 3 % ] vs two [ < 1 % ] ) . Serious adverse events were reported in 52 ( 12 % ) patients receiving dacomitinib and 40 ( 9 % ) patients receiving erlotinib . INTERPRETATION Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours . Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations . FUNDING Pfizer PURPOSE c-MET ( MET ) receptor activation is associated with poor prognosis and epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor ( TKI ) resistance in non-small-cell lung cancer ( NSCLC ) . This global , r and omized phase II trial examined erlotinib plus tivantinib ( ARQ 197 ; ArQule , Woburn , MA ) , a novel MET inhibitor . METHODS Previously treated patients with EGFR TKI-naive advanced NSCLC were r and omly assigned to receive oral erlotinib ( 150 mg daily ) plus oral tivantinib ( 360 mg twice daily ) or erlotinib plus placebo ( EP ) . The primary end point was progression-free survival ( PFS ) . At the time of progression , cross-over from EP to erlotinib plus tivantinib ( ET ) was permitted . Archival tumor tissue specimens were required . RESULTS One hundred sixty-seven patients were r and omly assigned to ET ( n = 84 ) and to EP ( n = 83 ) . Median PFS was 3.8 months for ET and 2.3 months for EP ( hazard ratio [ HR ] , 0.81 ; 95 % CI , 0.57 to 1.16 ; P = .24 ) . Exploratory analysis revealed that the small cohort with KRAS mutations achieved a PFS HR of 0.18 ( 95 % CI , 0.05 to 0.70 ; interaction P = .006 ) . Objective responses were seen in 10 % of patients on ET , 7 % of patients on EP , and in two patients who crossed over from EP to ET , including one with EGFR mutation and MET gene copy number greater than 5 . There were no significant differences in adverse events between study arms . CONCLUSION The combination of the MET inhibitor tivantinib and erlotinib is well-tolerated . Although the study did not meet its primary end point , evidence of activity was demonstrated , especially among patients with KRAS mutations . Additional study of tivantinib and erlotinib in patients with NSCLC is planned PURPOSE Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor ( EGFR ) -targeted drugs in patients with non-small-cell lung cancer ( NSCLC ) . We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC . PATIENTS AND METHODS Patients with recurrent NSCLC were r and omly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib ; crossover was allowed at progression . Tumor tissue was required to assess MET status by immunohistochemistry ( IHC ) . Co primary end points were progression-free survival ( PFS ) in the intent-to-treat ( ITT ) and MET-positive ( MET IHC diagnostic positive ) population s ; additional end points included overall survival ( OS ) , objective response rate , and safety . RESULTS There was no improvement in PFS or OS in the ITT population ( n = 137 ; PFS hazard ratio [ HR ] , 1.09 ; P = .69 ; OS HR , 0.80 ; P = .34 ) . MET-positive patients ( n = 66 ) treated with erlotinib plus onartuzumab showed improvement in both PFS ( HR , .53 ; P = .04 ) and OS ( HR , .37 ; P = .002 ) . Conversely , clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib ( n = 62 ; PFS HR , 1.82 ; P = .05 ; OS HR , 1.78 ; P = .16 ) . MET-positive control patients had worse outcomes versus MET-negative control patients ( n = 62 ; PFS HR , 1.71 ; P = .06 ; OS HR , 2.61 ; P = .004 ) . Incidence of peripheral edema was increased in onartuzumab-treated patients . CONCLUSION Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population . These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development BACKGROUND The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer ( NSCLC ) . METHODS Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy , stratified by ECOG performance status , previous bevacizumab treatment , histology , and presence of brain metastases , were allocated ( by computer-generated sequence through an interactive third-party system , in 1:1 ratio ) , to receive docetaxel 75 mg/m(2 ) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2 - 21 , every 3 weeks until unacceptable adverse events or disease progression . Investigators and patients were masked to assignment . The primary endpoint was progression-free survival ( PFS ) by independent central review , analysed by intention to treat after 714 events in all patients . The key secondary endpoint was overall survival , analysed by intention to treat after 1121 events had occurred , in a prespecified stepwise order : first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy , then in all patients with adenocarcinoma , then in all patients . This trial is registered with Clinical Trials.gov , number NCT00805194 . FINDINGS Between Dec 23 , 2008 , and Feb 9 , 2011 , 655 patients were r and omly assigned to  receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo . The primary analysis was done after a median follow-up of 7·1 months ( IQR 3·8 - 11·0 ) . PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group ( median 3·4 months [ 95 % CI 2·9 - 3·9 ] vs 2·7 months [ 2·6 - 2·8 ] ; hazard ratio [ HR ] 0·79 [ 95 % CI 0·68 - 0·92 ] , p=0·0019 ) . After a median follow-up of 31·7 months ( IQR 27·8 - 36·1 ) , overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group ( 206 patients ) compared with those in the docetaxel plus placebo group ( 199 patients ; median 10·9 months [ 95 % CI 8·5 - 12·6 ] vs 7·9 months [ 6·7 - 9·1 ] ; HR 0·75 [ 95 % CI 0·60 - 0·92 ] , p=0·0073 ) . Similar results were noted for all patients with adenocarcinoma histology ( 322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group ; median overall survival 12·6 months [ 95 % CI 10·6 - 15·1 ] vs 10·3 months [ 95 % CI 8·6 - 12·2 ] ; HR 0·83 [ 95 % CI 0·70 - 0·99 ] , p=0·0359 ) , but not in the total study population ( median 10·1 months [ 95 % CI 8·8 - 11·2 ] vs 9·1 months [ 8·4 - 10·4 ] ; HR 0·94 , 95 % CI 0·83 - 1·05 , p=0·2720 ) . Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea ( 43 [ 6·6 % ] of 652 vs 17 [ 2·6 % ] of 655 ) , reversible increases in alanine aminotransferase ( 51 [ 7·8 % ] vs six [ 0·9 % ] ) , and reversible increases in aspartate aminotransferase ( 22 [ 3·4 % ] vs three [ 0·5 % ] ) . 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression ; the most common of these events were sepsis ( five with docetaxel plus nintedanib vs one with docetaxel plus  placebo ) , pneumonia ( two vs seven ) , respiratory failure ( four vs none ) , and pulmonary embolism ( none vs three ) . INTERPRETATION Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy , especially for patients with adenocarcinoma . FUNDING Boehringer Ingelheim PURPOSE To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer ( NSCLC ) previously treated with chemotherapy . PATIENTS AND METHODS Eligible patients had a performance status 0 to 2 , previous treatment with one prior chemotherapy regimen for advanced NSCLC , and adequate organ function . Patients received pemetrexed 500 mg/m(2 ) intravenously ( i.v . ) day 1 with vitamin B(12 ) , folic acid , and dexamethasone or docetaxel 75 mg/m(2 ) i.v . day 1 with dexamethasone every 21 days . The primary end point was overall survival . RESULTS Five hundred seventy-one patients were r and omly assigned . Overall response rates were 9.1 % and 8.8 % ( analysis of variance P = .105 ) for pemetrexed and docetaxel , respectively . Median progression-free survival was 2.9 months for each arm , and median survival time was 8.3 versus 7.9 months ( P = not significant ) for pemetrexed and docetaxel , respectively . The 1-year survival rate for each arm was 29.7 % . Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia ( 40.2 % v 5.3 % ; P < .001 ) , febrile neutropenia ( 12.7 % v 1.9 % ; P < .001 ) , neutropenia with infections ( 3.3 % v 0.0 % ; P = .004 ) , hospitalizations for neutropenic fever ( 13.4 % v 1.5 % ; P < .001 ) , hospitalizations due to other drug related adverse events ( 10.5 % v 6.4 % ; P = .092 ) , use of granulocyte colony-stimulating factor support ( 19.2 % v 2.6 % , P < .001 ) and all grade alopecia ( 37.7 % v 6.4 % ; P < .001 ) compared with patients receiving pemetrexed . CONCLUSION Treatment with pemetrexed result ed in clinical ly equivalent efficacy outcomes , but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a st and ard treatment option for second-line NSCLC when available The EGFR gene is a major therapeutic target in advanced Non-small cell lung cancer ( NSCLC ) . Two reversible tyrosine kinase inhibitors , Erlotinib and Gefitinib , have been vali date d and registered for the treatment of NSCLC . Gefitinib has a label that is limited to NSCLC carrying mutations in the kinase domain of the EGFR gene , while the label of Erlotinib also includes second line treatment of patients with undefined EGFR status in their tumor , based on an early r and omized study that showed a small benefit in such unselected population ( 1 ) Purpose Provide evidence -based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer ( NSCLC ) . Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of r and omized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence -Based Care 's up date of a previous ASCO search . Results This guideline up date reflects changes in evidence since the previous guideline up date . Fourteen r and omized controlled trials provide the evidence base ; earlier phase trials also informed recommendation development . Recommendations New or revised recommendations include the following . Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma ( without positive markers , eg , EGFR/ALK /ROS1 ) , if the patient has high programmed death lig and 1 ( PD-L1 ) expression , pembrolizumab should be used alone ; if the patient has low PD-L1 expression , clinicians should offer st and ard chemotherapy . All other clinical scenarios follow 2015 recommendations . Regarding second-line treatment in patients who received first-line chemotherapy  , without prior immune checkpoint therapy , if NSCLC tumor is positive for PD-L1 expression , clinicians should use single-agent nivolumab , pembrolizumab , or atezolizumab ; if tumor has negative or unknown PD-L1 expression , clinicians should use nivolumab or atezolizumab . All immune checkpoint therapy is recommended alone plus in the absence of contraindications . For patients who received a prior first-line immune checkpoint inhibitor , clinicians should offer st and ard chemotherapy . For patients who can not receive immune checkpoint inhibitor after chemotherapy , docetaxel is recommended ; in patients with nonsquamous NSCLC , pemetrexed is recommended . In patients with a sensitizing EGFR mutation , disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy , and T790 M mutation , osimertinib is recommended ; if NSCLC lacks the T790 M mutation , then chemotherapy is recommended . Patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib , or if they previously received crizotinib , they may be offered chemotherapy In this superiority study , pemetrexed was compared with erlotinib in pre‐treated patients with metastatic non – small cell lung cancer ( NSCLC ) BACKGROUND Two phase II trials in patients with previously-treated advanced non-small-cell lung cancer suggested that gefitinib was efficacious and less toxic than was chemotherapy . We compared gefitinib with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer who had been pretreated with platinum-based chemotherapy . METHODS We undertook an open-label phase III study with recruitment between March 1 , 2004 , and Feb 17 , 2006 , at 149 centres in 24 countries . 1466 patients with pretreated ( > /=one platinum-based regimen ) advanced non-small-cell lung cancer were r and omly assigned with dynamic balancing to receive gefitinib ( 250 mg per day orally ; n=733 ) or docetaxel ( 75 mg/m(2 ) intravenously in 1-h infusion every 3 weeks ; n=733 ) . The primary objective was to compare overall survival between the groups with co- primary analyses to assess non-inferiority in the overall per- protocol population and superiority in patients with high epidermal growth factor receptor (EGFR)-gene-copy number in the intention-to-treat population . This study is registered with Clinical Trials.gov , number NCT00076388 . FINDINGS 1433 patients were analysed per protocol ( 723 in gefitinib group and 710 in docetaxel group ) . Non-inferiority of gefitinib compared with docetaxel was confirmed for overall survival ( 593 vs 576 events ; hazard ratio [ HR ] 1.020 , 96 % CI 0.905 - 1.150 , meeting the predefined non-inferiority criterion ; median survival 7.6 vs 8.0 months ) . Superiority of gefitinib in patients with high EGFR-gene-copy number ( 85 vs 89 patients ) was not proven ( 72 vs 71 events ; HR 1.09 , 95 % CI 0.78 - 1.51 ; p=0.62 ; median survival 8.4 vs 7.5 months ) . In the gefitinib group , the most common adverse events were rash or acne ( 360 [ 49 % ] vs 73 [ 10 % ] ) and diarrhoea ( 255 [ 35 % ] vs 177 [ 25 % ] ) ; whereas in the docetaxel group , neutropenia ( 35 [ 5 % ] vs 514 [ 74 % ] ) , asthenic disorders ( 182 [ 25 % ] vs 334 [ 47 % ] ) , and alopecia ( 23 [ 3 % ] vs 254 [ 36 % ] ) were most common . INTERPRETATION INTEREST established non-inferior survival of gefitinib compared with docetaxel , suggesting that gefitinib is a valid treatment for pretreated patients with advanced non-small-cell lung cancer PURPOSE Sorafenib , an oral multikinase inhibitor , has shown preliminary activity in non-small-cell lung cancer ( NSCLC ) . Patients with advanced NSCLC were treated with erlotinib with or without sorafenib in this multicenter phase II trial . PATIENTS AND METHODS Key eligibility criteria included the following : stage IIIB or IV NSCLC ; one to two prior regimens ; Eastern Cooperative Oncology Group performance status of 0 to 2 ; and measurable disease . Patients were r and omly assigned 2:1 to sorafenib ( 400 mg orally twice a day ) plus erlotinib ( 150 mg orally daily ) or placebo plus erlotinib and stratified by squamous/nonsquamous histology and prior bevacizumab .  Treatment efficacy , measured by progression-free survival ( PFS ) and overall response rate ( ORR ) , was compared . Treatment of 168 patients allowed detection of 40 % improvement in the historical PFS of 2.2 months with single-agent erlotinib . RESULTS One hundred sixty-eight patients enrolled from February 2008 to February 2009 . Clinical characteristics of the two groups were similar . ORRs for sorafenib/erlotinib and placebo/erlotinib were 8 % and 11 % , respectively ( P = .56 ) ; disease control rates were 54 % and 38 % , respectively ( P = .056 ) . Median PFS was 3.38 months for sorafenib/erlotinib versus 1.94 months for placebo/erlotinib ( hazard ratio , 0.86 ; 95 % CI , 0.60 to 1.22 ; P = .196 ) . Seventy-two patients consented to analyses of tumor epidermal growth factor receptor ( EGFR ) . In 67 patients with EGFR wild-type ( WT ) tumors , median PFS was 3.38 months for sorafenib/erlotinib versus 1.77 months for placebo/erlotinib ( P = .018 ) ; median overall survival ( OS ) was 8 months for sorafenib/erlotinib versus 4.5 months for placebo/erlotinib ( P = .019 ) . An OS advantage for sorafenib/erlotinib was suggested among 43 patients with fluorescent in situ hybridization ( FISH ) EGFR-negative tumors ( P = .064 ) . Both regimens were tolerable , with modest toxicity increase with sorafenib . CONCLUSION Although there was little difference in ORR or PFS , subset analyses in EGFR WT and EGFR FISH-negative patients suggest a benefit for the combination of erlotinib/sorafenib compared with single-agent erlotinib with respect to PFS and OS
Purpose We performed a systematic review and meta- analysis to investigate the efficacy of third-line treatment for advanced non-small-cell lung cancer ( NSCLC ) .