Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Who Are Less Likely to Receive Subsequent Chemotherapy Beyond First-Line Therapy for Advanced Non-small Cell Lung Cancer?: Implications for Selection of Patients for Maintenance Therapy Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. Phase III randomized, double-blind study of maintenance CAI or placebo in patients with advanced non-small cell lung cancer (NSCLC) after completion of initial therapy (NCCTG 97-24-51). Randomized study of maintenance vinorelbine in responders with advanced non-small-cell lung cancer. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ILCP 01/03). A Brief Report on the Safety Study of Induction Chemotherapy Followed by Synchronous Radiotherapy and Cetuximab in Stage III Non-small Cell Lung Cancer (NSCLC): SCRATCH Study Multicenter Phase 2 Study of Interleukin-2 and 13-Cis Retinoic Acid as Maintenance Therapy in Advanced Non-Small-Cell Lung Cancer Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Erlotinib Monotherapy for the Maintenance Treatment of Non-Small Cell Lung Cancer after Previous Platinum-Containing Chemotherapy Maintenance therapy with gefitinib after first-line chemotherapy in patients affected by advanced non-small cell lung cancer. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Randomized phase III trial of platinum-doublet chemotherapy followed by gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a west Japan thoracic oncology group trial (WJTOG0203). FDG-PET as a Potential Tool for Selecting Patients with Advanced Non–Small Cell Lung Cancer Who May Be Spared Maintenance Therapy after First-Line Chemotherapy
BACKGROUND Several studies have shown the efficacy , tolerability , and ease of administration of pemetrexed-an antifolate antineoplastic agent-in  patients with advanced non-small-cell lung cancer . We assessed pemetrexed as maintenance therapy in patients with this disease . METHODS This r and omised double-blind study was undertaken in 83 centres in 20 countries . 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy  were r and omly assigned ( 2:1 ratio ) to receive pemetrexed ( 500 mg/m(2 ) , day 1 ) plus best supportive care ( n=441 ) or placebo plus best supportive care ( n=222 ) in 21-day cycles until disease progression . Treatment was r and omised with the Simon and Pocock minimisation method . Patients and investigators were masked to treatment . All patients received vitamin B(12 ) , folic acid , and dexamethasone . The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat . This study is registered with Clinical Trials.gov , number NCT00102804 . FINDINGS All r and omly assigned participants were analysed . Pemetrexed significantly improved progression-free survival ( 4.3 months [ 95 % CI 4.1 - 4.7 ] vs 2.6 months [ 1.7 - 2.8 ] ; hazard ratio [ HR ] 0.50 , 95 % CI 0.42 - 0.61 , p<0.0001 ) and overall survival ( 13.4 months [ 11.9 - 15.9 ] vs 10.6 months [ 8.7 - 12.0 ] ; HR 0.79 , 0.65 - 0.95 , p=0.012 ) compared with placebo . Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group ( 21 [ 5 % ] vs three [ 1 % ] ) . Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo ( 70 [ 16 % ] vs nine [ 4 % ] ; p<0.0001 ) , specifically fatigue ( 22 [ 5 % ] vs one [ 1 % ] , p=0.001 ) and neutropenia ( 13 [ 3 % ] vs 0 , p=0.006 ) . No  pemetrexed-related deaths occurred . Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy ( 227 [ 51 % ] vs 149 [ 67 % ] ; p=0.0001 ) . INTERPRETATION Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer . FUNDING Eli Lilly PURPOSE Gemcitabine plus carboplatin ( GC ) is active as front-line treatment for advanced non-small-cell lung cancer ( NSCLC ) . For patients without progression , timing of second-line chemotherapy for optimum clinical benefit remains uncertain . This phase III , r and omized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression . PATIENTS AND METHODS The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC .  Gemcitabine ( 1,000 mg/m(2 ) ) was administered on days 1 and 8 followed by carboplatin ( area under the curve = 5 ) on day 1 . After four 21-day cycles , patients who did not have progression were r and omly assigned either to an immediate docetaxel group ( docetaxel 75 mg/m(2 ) on day 1 every 21 days , with maximum of six cycles ) or to a delayed docetaxel group . The primary end point was overall survival ( OS ) measured from r and om assignment . Additional analyses included tumor response , toxicity , progression-free survival ( PFS ) , and quality of life ( QOL ) . RESULTS Enrollment totaled 566 patients ; 398 patients completed GC ; 309 patients were r and omly assigned equally to the two docetaxel treatment groups . Toxicity profiles were generally comparable for the docetaxel groups . Median PFS for immediate docetaxel ( 5.7 months ) was significantly greater ( P = .0001 ) than for delayed docetaxel ( 2.7 months ) . Median OS for immediate docetaxel ( 12.3 months ) was greater than for delayed docetaxel ( 9.7 months ) , but the difference was not statistically significant ( P = .0853 ) . QOL results were not statistically different ( P = .76 ) between docetaxel groups . CONCLUSION We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC , without increasing toxicity or decreasing QOL BACKGROUND Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor ( TKI ) therapy in non-small-cell lung cancer ( NSCLC ) . The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus st and ard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC . METHODS We undertook an open-label , r and omised , phase 3 trial at 22 centres in China . Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR ( exon 19 deletion or exon 21 L858R point mutation ) received either oral erlotinib ( 150 mg/day ) until disease progression or unacceptable toxic effects , or up to four cycles of gemcitabine plus carboplatin . Patients were r and omly assigned ( 1:1 ) with a minimisation procedure and were stratified according to EGFR mutation type , histological subtype ( adenocarcinoma vs non-adenocarcinoma ) , and smoking status . The primary outcome was progression-free survival , analysed in patients with confirmed disease who received at least one dose of study treatment . The trial is registered at Clinical Trials.gov , number NCT00874419 , and has completed enrolment ; patients are still in follow-up . FINDINGS 83 patients were r and omly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin ; 82 in the erlotinib  group and 72 in the  chemotherapy group were included in analysis of the primary endpoint . Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy ( 13.1 [ 95 % CI 10.58 - 16.53 ] vs 4.6 [ 4.21 - 5.42 ] months ; hazard ratio 0.16 , 95 % CI 0.10 - 0.26 ; p<0.0001 ) . Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib ( including neutropenia in 30 [ 42 % ] of 72 patients and thrombocytopenia in 29 [ 40 % ] patients on chemotherapy vs no patients with either event on erlotinib ) ; the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations ( three [ 4 % ] of 83 patients ) and skin rash ( two [ 2 % ] patients ) . Chemotherapy was also associated with increased treatment-related serious adverse events ( ten [ 14 % ] of 72 patients [ decreased platelet count , n=8 ; decreased neutrophil count , n=1 ; hepatic dysfunction , n=1 ] vs two [ 2 % ] of 83 patients [ both hepatic dysfunction ] ) . INTERPRETATION Compared with st and ard chemotherapy , erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability . These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC . FUNDING F Hoffmann-La Roche Ltd ( China ) ; Science and Technology Commission of Shanghai Municipality Background : Prospect i ve studies have implied that maintenance therapy for non-small cell lung cancer ( NSCLC ) has its effect by giving active drugs earlier to patients who otherwise die without receiving second-line therapy . The purpose of this study was to select patients with NSCLC who could most benefit from maintenance therapy  , by evaluating which patients would be less likely to receive second-line therapy . Methods : Clinicopathologic data of patients with advanced NSCLC who received four cycles of first-line chemotherapy followed by time-off therapy and eventual disease progression or death were review ed retrospectively . Patients were grouped into ones with first-line therapy only or ones with more than first-line therapy . Clinical characteristics between the two groups were compared . Results : A total of 271 patients were eligible for analysis , and 39 patients ( 14.4 % ) received only first-line therapy . Patients significantly more likely to receive only first-line therapy had performance status of two or three after first-line therapy , large volume of initial target lesions ( sum of long diameters ≥70 mm ) , or smaller decrease in target lesions ( decrease < 20 % ) after first-line therapy . Median overall survival of the 143 patients ( 52.8 % ) with at least one of these characteristics ( 16.3 months ) was significantly shorter than that of patients without any of these characteristics ( 23.5 months , p = 0.007 ) . Conclusion : Maintenance therapy may be of greater benefit to patients with NSCLC who have clinical characteristics including poor performance status after first-line therapy , large initial target lesions , or smaller decrease in target lesions after first-line therapy BACKGROUND Patients with advanced non-squamous non-small-cell lung cancer ( NSCLC ) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing , non-pemetrexed doublet . The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin . METHODS In this double-blind , multicentre , phase 3 , r and omised placebo-controlled trial , patients with advanced non-squamous NSCLC aged 18 years or older , with no previous systemic chemotherapy for lung cancer , with at least one measurable lesion , and an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 or 1 participated . Before r and omisation , patients entered an induction phase which consisted of four cycles of induction pemetrexed ( 500 mg/m(2 ) ) plus cisplatin ( 75 mg/m(2 ) ) on day 1 of a 21-day cycle . Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 were stratified according to disease stage ( IIIB or IV ) , ECOG performance status ( 0 or 1 ) , and induction response ( complete or partial response , or stable disease ) , and r and omly assigned ( 2:1 ratio ) to receive maintenance therapy with either pemetrexed ( 500 mg/m(2 ) every 21 days ) plus best supportive care or placebo plus best supportive care until disease progression . R and omisation was done with the Pocock and Simon minimisation method . Patients and investigators were masked to treatment assignment . The primary endpoint was progression-free survival in the intention-to-treat population . This study is registered with Clinical Trials.gov , NCT00789373 . FINDINGS Of the 1022 patients enrolled , 939 participated in the induction phase . Of these , 539 patients were r and omly assigned to receive continuation maintenance with pemetrexed plus best supportive care ( n=359 ) or with placebo plus best supportive care ( n=180 ) . Among the 359 patients r and omised to continuation maintenance with pemetrexed , there was a significant reduction in the risk of disease progression over the placebo group ( HR 0·62 , 95 % CI 0·49 - 0·79 ; p<0·0001 ) . The median progression-free survival , measured from r and omisation , was 4·1 months ( 95 % CI 3·2 - 4·6 ) for pemetrexed and 2·8 months ( 2·6 - 3·1 ) for placebo . Possibly treatment-related laboratory grade 3 - 4 adverse events were more common in the pemetrexed group ( 33 [ 9 % ] of 359 patients ) than in the placebo group ( one [ < 1 % ] of 180 patients ; p<0·0001 ) , as were non-laboratory grade 3 - 5 adverse events ( 32 [ 9 % ] of 359 patients in the pemetrexed group ; eight [ 4 % ] of 180 patients in the placebo group ; p=0·080 ) ; one possibly treatment-related death was reported in each group . The most common adverse events of grade 3 - 4 in the pemetrexed group were anaemia ( 16 [ 4 % ] of 359 patients ) , neutropenia ( 13 [ 4 % ] ) , and fatigue ( 15 [ 4 % ] ) . In the placebo group , these adverse events were less common : anaemia ( one [ < 1 % ] of 180 patients ) , neutropenia ( none ) , and fatigue ( one < 1 % ] ) . The most frequent serious adverse events were anaemia ( eight [ 2 % ] of 359 patients in the pemetrexed group vs none in the placebo group ) and febrile neutropenia ( five [ 1 % ] vs none ) . Discontinuations due to drug-related adverse events occurred in 19 ( 5 % ) patients in the pemetrexed group and six ( 3 % ) patients in the placebo group . INTERPRETATION Continuation maintenance with pemetrexed is an effective and well tolerated treatment option for patients with advanced non-squamous NSCLC with good performance status who have not progressed after induction therapy with pemetrexed plus cisplatin . FUNDING Eli Lilly and Company BACKGROUND In the placebo-controlled phase III SATURN study , maintenance erlotinib after first-line chemotherapy demonstrated significantly prolonged progression-free survival ( PFS ) and overall survival ( OS ) in the overall study population of patients with advanced non-small-cell lung cancer ( NSCLC ) . METHODS After four cycles of platinum-based doublet chemotherapy , patients without progressive disease ( PD ) were r and omised to erlotinib ( 150 mg/day ) or placebo until PD or unacceptable toxicity . In this pre-planned analysis , data are assessed according to response to first-line chemotherapy ( complete/partial response [ CR/PR ] or stable disease [ SD ] ) . RESULTS Following first-line chemotherapy , 889 non-PD patients were included in the intention-to-treat population ( 55 % SD ; 44 % CR/PR ; < 1 % unknown response ) . Erlotinib maintenance therapy significantly prolonged PFS in both the SD ( hazard ratio [ HR ] = 0.68 ; P < 0.0001 ) and CR/PR ( HR = 0.74 ; P = 0.0059 ) groups , while OS was significantly prolonged in the SD group only ( HR = 0.72 ; P = 0.0019 ) . The erlotinib-related OS benefit in the SD group remained significant across subgroups , irrespective of tumour histology and /or EGFR mutation status . The incidence of adverse events was similar in the SD group and the overall population , and erlotinib treatment did not negatively impact quality of life . CONCLUSIONS Patients with advanced NSCLC and SD following first-line platinum-based doublet chemotherapy  derive a significant OS benefit from maintenance erlotinib therapy BACKGROUND Bevacizumab , a monoclonal antibody against vascular endothelial growth factor , has been shown to benefit patients with a variety of cancers . METHODS Between July 2001 and April 2004 , the Eastern Cooperative Oncology Group ( ECOG ) conducted a r and omized study in which 878 patients with recurrent or advanced non-small-cell lung cancer ( stage IIIB or IV ) were assigned to chemotherapy with paclitaxel and carboplatin alone ( 444 ) or paclitaxel and carboplatin plus bevacizumab ( 434 ) . Chemotherapy was administered every 3 weeks for six cycles , and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable . Patients with squamous-cell tumors , brain metastases , clinical ly significant hemoptysis , or inadequate organ function or performance status ( ECOG performance status , > 1 ) were excluded . The primary end point was overall survival . RESULTS The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab , as compared with 10.3 months in the chemotherapy-alone group ( hazard ratio for death , 0.79 ; P=0.003 ) . The median progression-free survival in the two groups was 6.2 and 4.5 months , respectively ( hazard ratio for disease progression , 0.66 ; P<0.001 ) , with corresponding response rates of 35 % and 15 % ( P<0.001 ) . Rates of clinical ly significant bleeding were 4.4 % and 0.7 % , respectively ( P<0.001 ) . There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group , including 5 from pulmonary hemorrhage . CONCLUSIONS The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths . ( Clinical Trials.gov number , NCT00021060 . BACKGROUND We conducted a r and omized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non-small-cell lung cancer . METHODS A total of 1207 patients with advanced non-small-cell lung cancer were r and omly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens : cisplatin and gemcitabine , cisplatin and docetaxel , or carboplatin and paclitaxel . RESULTS The response rate for all 1155 eligible patients was 19 percent , with a median survival of 7.9 months ( 95 percent confidence interval , 7.3 to 8.5 ) , a 1-year survival rate of 33 percent ( 95 percent confidence interval , 30 to 36 percent ) , and a 2-year survival rate of 11 percent ( 95 percent confidence interval , 8 to 12 percent ) . The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens . Treatment with cisplatin and gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more likely to cause grade 3 , 4 , or 5 renal toxicity ( in 9 percent of patients , vs. 3 percent of those treated with cisplatin plus paclitaxel ) . Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1 . CONCLUSIONS None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer BACKGROUND Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer ( NSCLC ) with activating EGFR mutations . We aim ed to assess the safety and efficacy of erlotinib compared with st and ard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC . METHODS We undertook the open-label , r and omised phase 3 EURTAC trial at 42 hospitals in France , Italy , and Spain . Eligible participants were adults ( > 18 years ) with NSCLC and EGFR mutations ( exon 19 deletion or L858R mutation in exon 21 ) with no history of chemotherapy for metastatic disease ( neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed ) . We r and omly allocated participants ( 1:1 ) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of st and ard intravenous chemotherapy of cisplatin 75 mg/m(2 ) on day 1 plus docetaxel ( 75 mg/m(2 ) on day 1 ) or gemcitabine ( 1250 mg/m(2 ) on days 1 and 8) . Carboplatin ( AUC 6 with docetaxel 75 mg/m(2 ) or AUC 5 with gemcitabine 1000 mg/m(2 ) ) was allowed in patients unable to have cisplatin . Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status ( 0 vs 1 vs 2 ) . The primary endpoint was progression-free survival ( PFS ) in the intention-to-treat population . We assessed safety in all patients who received study drug ( ≥ 1 dose ) . This study is registered with Clinical Trials.gov , number NCT00446225 . FINDINGS Between Feb 15 , 2007 , and Jan 4 , 2011 , 174 patients with EGFR mutations were enrolled . One patient received treatment before r and omisation and was thus withdrawn from the study ; of the remaining patients , 86 were r and omly assigned to receive erlotinib and 87 to receive st and ard chemotherapy . The preplanned interim analysis showed that the study met its primary endpoint ; enrolment was halted , and full evaluation of the results was recommended . At data cutoff ( Jan 26 , 2011 ) , median PFS was 9·7 months ( 95 % CI 8·4 - 12·3 ) in the erlotinib group , compared with 5·2 months ( 4·5 - 5·8 ) in the st and ard chemotherapy group ( hazard ratio 0·37 , 95 % CI 0·25 - 0·54 ; p < 0·0001 ) . Main grade 3 or 4 toxicities were rash ( 11 [ 13 % ] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group ) , neutropenia ( none vs 18 [ 22 % ] ) , anaemia ( one [ 1 % ] vs three [ 4 % ] ) , and increased amino-transferase concentrations ( two [ 2 % ] vs 0 ) . Five ( 6 % ) patients on erlotinib  had treatment-related severe adverse events compared with 16 patients ( 20 % ) on chemotherapy . One patient in the erlotinib group and two in the st and ard chemotherapy group died from treatment-related causes . INTERPRETATION Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors . FUNDING Spanish Lung Cancer Group , Roche Farma , Hoffmann-La Roche , and Red Temática de Investigacion Cooperativa en Cancer PURPOSE Early clinical studies with gefitinib showed promising efficacy and mild toxicity in patients with advanced non-small-cell lung cancer ( NSCLC ) . Thus , gefitinib was an ideal agent to evaluate in a maintenance setting in stage III disease . PATIENTS AND METHODS Untreated patients with stage III NSCLC , a performance score of 0 to 1 , and adequate organ function were eligible . All patients received cisplatin 50 mg/m(2 ) on days 1 and 8 plus etoposide 50 mg/m(2 ) on days 1 to 5 , every 28 days for two cycles with concurrent thoracic radiation ( 1.8- to 2-Gy fractions per day ; total dose , 61 Gy ) followed by three cycles of docetaxel 75 mg/m(2 ) . Patients whose disease did not progress were r and omly assigned to gefitinib 250 mg/d or placebo until disease progression , intolerable toxicity , or the end of 5 years . The planned sample size was 672 patients to confer power of 0.89 to detect a 33 % increase over the expected median survival time of 21 months ( one-sided P = .025 , log-rank test ) . R and om assignment was stratified by stage , histology , and measurable versus nonmeasurable disease . RESULTS Enrollment began in July 2001 . An unplanned interim analysis conducted in April 2005 rejected the alternative hypothesis of improved survival at the P = .0015 level for 243 r and omly assigned patients . The study closed , and preliminary results were reported . Now , with a median follow-up time of 27 months , median survival time was 23 months for gefitinib ( n = 118 ) and 35 months for placebo ( n = 125 ; two-sided P = .013 ) . The toxic death rate was 2 % with gefitinib compared with 0 % for placebo . CONCLUSION In this unselected population , gefitinib did not improve survival . Decreased survival was a result of tumor progression and not gefitinib toxicity PURPOSE This study assessed whether maintenance therapy with carboxyaminoimidazole ( CAI ) , compared to placebo , prolonged overall survival in stage IIIB/IV NSCLC patients who had tumour regression or stable disease after treatment with one chemotherapy regimen . METHODS After completion of chemotherapy , patients were r and omized to receive daily oral CAI at 250 mg or placebo . Treatment continued until patient refusal , disease progression or unacceptable adverse event ( AE ) . Quality of life ( QOL ) was assessed by UNISCALE and Functional Assessment of Cancer Therapy for Lung Cancer ( FACT-L ) . RESULTS Registration was halted early for slow accrual ( targeted 360 , r and omized 186 : 94 CAI , 92 placebo )  . All patients were off active treatment at time of analyses . Non-haematologic AEs ( primarily grade 1 , 2 ) observed significantly more often in the CAI group included fatigue ( 54.5 % versus 29.3 % ) , anorexia ( 31.1 % versus 13.0 % ) , nausea ( 62.2 % versus 30.4 % ) , vomiting ( 32.2 % versus 14.1 % ) , neurosensory ( 60.0 % versus 44.6 % ) and ataxia ( 33.3 % versus 16.3 % ) . Patients discontinued treatment for AEs , death on study or refusal more often in the CAI group ( 36.0 % versus 8.7 % , p<0.0001 ) . No significant differences in survival or time to progression were observed ( median : CAI versus placebo : 11.4 months versus 10.5 months , log rank p=0.54 ; 2.8 months versus 2.4 months , log rank p=0.50 ) . More patients receiving CAI reported a clinical ly significant ( 10-point ) decline in QOL particularly on the functional ( 58 % versus 37 % , p=0.05 ) construct of FACT-L and UNISCALE ( 72 % versus 51 % , p=0.04 ) . CONCLUSION The addition of CAI following chemotherapy does not provide clinical benefit or improvement in QOL over placebo in advanced NSCLC BACKGROUND Prolongation of chemotherapy duration , usually referred to as maintenance chemotherapy , has been considered as an approach to improve survival of patients with advanced non-small-cell lung cancer ( NSCLC ) . If the maintenance regimen differs from the induction regimen , patients will receive not only higher total doses of chemotherapy but also earlier delivery of non-cross-resistant agents . We conducted a r and omized trial to compare maintenance vinorelbine therapy with observation in previously untreated patients who responded to induction treatment with mitomycin-ifosfamide-cisplatin ( MIC ) .  METHODS Patients with stage IIIB NSCLC were treated with two monthly MIC cycles followed by radiotherapy ;  those with " wet " stage IIIB ( pleural or pericardial involvement ) , with stage IIIB with supraclavicular node involvement , or stage IV ( i.e. , metastatic ) NSCLC were treated with four monthly MIC cycles . Patients who responded to induction treatment were r and omly assigned to receive intravenous vinorelbine at a dose of 25 mg x m(-2 ) x wk(-1 ) for 6 months or no further treatment . Survival comparisons used the log-rank test and the Cox regression adjusted for stage . All statistical tests were two-sided . RESULTS A total of 573 patients were registered , of whom 227 responded to induction treatment and 181 were r and omly assigned ( 91 to maintenance vinorelbine and 90 to observation ) between January 1994 and March 2000 .  One- and 2-year survival rates were 42.2 % and 20.1 % in the vinorelbine arm and 50.6 % and 20.2 % in the observation arm , respectively ( log-rank P = .48 ) . The hazard ratio of survival after adjustment on stage , in the vinorelbine arm relative to the observation arm , was 1.08 ( 95 % confidence interval = 0.79 to 1.47 ; P = .65 ) . There was also no difference between arms in progression-free survival ( log-rank P = .32 ) . CONCLUSION Maintenance vinorelbine did not improve survival of patients with advanced NSCLC who responded to induction MIC treatment . Nevertheless , other agents , including docetaxel and targeted agents , should be evaluated as maintenance agents before the concept is ab and oned BACKGROUND Findings from the phase 3 First-Line ErbituX in lung cancer ( FLEX ) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone ( hazard ratio [ HR ] 0·871 , 95 % CI 0·762 - 0·996 ; p=0·044 ) in patients with advanced non-small-cell lung cancer ( NSCLC ) . To define patients benefiting most from cetuximab , we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients . METHODS We used prospect ively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0 - 300 . We used response data to select an outcome -based discriminatory threshold immunohistochemistry score for EGFR expression of 200 . Treatment outcome was analysed in patients with low ( immunohistochemistry score < 200 ) and high ( ≥200 ) tumour EGFR expression . The primary endpoint in the FLEX study was overall survival . We analysed patients from the FLEX intention-to-treat ( ITT ) population . The FLEX study is registered with Clinical Trials.gov , number NCT00148798 . FINDINGS Tumour EGFR immunohistochemistry data were available for 1121 of 1125 ( 99·6 % ) patients from the FLEX study ITT population . High EGFR expression was scored for 345 ( 31 % ) evaluable patients and low for 776 ( 69 % ) patients . For patients in the high EGFR expression group , overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group ( median 12·0 months [ 95 % CI 10·2 - 15·2 ] vs 9·6 months [ 7·6 - 10·6 ] ; HR 0·73 , 0·58 - 0·93 ; p=0·011 ) , with no meaningful increase in side-effects . We recorded no corresponding survival benefit for patients in the low EGFR expression group ( median 9·8 months [ 8·9 - 12·2 ] vs 10·3 months [ 9·2 - 11·5 ] ; HR 0·99 , 0·84 - 1·16 ; p=0·88 ) . A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression ( p=0·044 ) . INTERPRETATION High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC . Assessment of EGFR expression could offer a personalised treatment approach in this setting . FUNDING Merck BACKGROUND Use of cetuximab , a monoclonal antibody targeting the epidermal growth factor receptor ( EGFR ) , has the potential to increase survival in patients with advanced non-small-cell lung cancer . We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer . METHODS In a multinational , multicentre , open-label , phase III trial , chemotherapy-naive patients ( > or=18 years ) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were r and omly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy . Chemotherapy was cisplatin 80 mg/m(2 ) intravenous infusion on day 1 , and vinorelbine 25 mg/m(2 ) intravenous infusion on days 1 and 8 of every 3-week cycle ) for up to six cycles . Cetuximab-at a starting dose of 400 mg/m(2 ) intravenous infusion over 2 h on day 1 , and from day 8 onwards at 250 mg/m(2 ) over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred . The primary endpoint was overall survival . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00148798 . FINDINGS Between October , 2004 , and January , 2006 , 1125 patients were r and omly assigned to chemotherapy plus cetuximab ( n=557 ) or chemotherapy alone ( n=568 ) . Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group ( median 11.3 months vs 10.1 months ; hazard ratio for death 0.871 [ 95 % CI 0.762 - 0.996 ] ; p=0.044 ) . The main cetuximab-related  adverse event was acne-like rash ( 57 [ 10 % ] of 548 , grade 3 ) . INTERPRETATION Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer . FUNDING Merck BACKGROUND EORTC study 08021/ILCP 01/03 evaluated the role of consolidation gefitinib , an oral tyrosine kinase inhibitor ( TKI ) , administered in patients with advanced non-small cell lung cancer ( NSCLC ) , not progressing following st and ard 1st-line chemotherapy . METHODS Patients with advanced NSCLC , not-progressing after four cycles of platinum-based chemotherapy  , were r and omised to receive either gefitinib 250mg/d or matched placebo until progression or unacceptable toxicity . The primary end-point was overall survival ( OS ) . Secondary end-points were progression-free survival ( PFS ) and toxicity . The study was powered to detect a 28 % increase in OS from a median of 11 - 14.1months ( HR=0.78 ) and planned to r and omise 598 patients to observe 514 deaths . RESULTS After inclusion of 173 patients , the trial was prematurely closed due to low accrual . Baseline characteristics for gefitinib ( n=86 ) and placebo ( n=87 ) arms were well balanced . After a median follow up of 41months , the difference in median OS in the gefitinib and placebo arms was not statistically significant ( 10.9 and 9.4months , HR 0.83 [ 95 % confidence interval ( 95 % CI ) 0.60 - 1.15 ] ; p=0.2 ) . The difference in median PFS significantly favoured gefitinib ( 4.1 and 2.9months , HR=0.61 , [ 95 % CI 0.45 , 0.83 ] ) , p=0.0015 ) . Adverse events reported in more than 10 % of patients were rash ( 47 % with gefitinib versus 13 % with placebo ) and diarrhoea ( 34 % with gefitinib versus13 % with placebo ) . CONCLUSIONS Despite its premature closure , this trial confirms previous evidence that consolidation gefitinib is safe and improves PFS . However , no difference in OS was observed in this study ( NCT00091156 ) Background : In patients with advanced ( stage IIIb/IV ) NSCLC , the addition of cetuximab to chemotherapy has demonstrated increased activity compared with chemotherapy alone . Furthermore , the additio of cetuximab to RT in patients with locally advanced squamous cell head & neck carcinoma significantly prolongs the duration of locoregional control and median overall survival compared to radiotherapy alone . Therefore , the SCRATCH study was design ed to assess the safety of synchronous cetuximab with radical RT in patients with Stage III NSCLC . The safety results of cohort 1 from this phase I study are presented below . Methods : Twelve patients with inoperable stage III NSCLC were enrolled into cohort I. Inclusion criteria were performance status 0–1 , adequate organ function , and disease encompassable within a radical RT volume . Exclusion criteria were previous malignancy , thoracic RT or treatment with EGFR ( epidermal growth factor receptor ) targeted therapy . Patients received platinum-based induction chemotherapy , followed by weekly intravenous cetuximab ( initial dose 400mg/m2 ; maintenance dose 250mg/m2 ) and concomitant Rt ( 64Gy/32fractions/45days ) . The primary end-point was toxicity . NCI Common Toxicity Criteria ( CTC ) V3.0 assessment s were preformed weekly during radiotherapy , and at regular follow-up visits . Results : 9 out of 12 patients coompleted the concomitant therapy as planned , with no dose reductions . 3 patients did not complete the full schedule . One died from bronchopneumonia mid-treatment ; one experienced grade 3 lethargy following the first cetuximab dose and declined further cetuximab ; one experienced a grade 2 skin reaction following the third dose of cetuximab and declined futher treatment . On follow-up only one patient has developed a grade III reaction – pneumonitis – which settled on steroids with intermittent oxygen . Three patients have died on follow-up ( 2 from disease progression and one from thromboembolic disease ) . Of the 12 patients entered ito the study , 8 have survived at least 1 year , measured from the first day of induction chemotherapy . Conclusion : The results suggest that the early and late toxicities of synchronous cetuximab and radical RT are acceptable High serum levels of vascular endothelial growth factor ( VEGF ) are a poor prognostic factor for patients with advanced non-small-cell lung cancer ( NSCLC ) . We have previously shown that low-dose interleukin (IL)-2 and 13-cis retinoic acid ( RA ) decreased VEGF and improved the immune function of patients with advanced tumors treated with chemotherapy . The primary end point of this study was to verify whether IL-2 and RA decreased serum VEGF in NSCLC patients showing a clinical benefit from chemotherapy .  The secondary end point was the evaluation of clinical outcome . We treated 38 patients with advanced NSCLC who had a complete or partial response or disease stability to chemotherapy and had a median serum VEGF level of 508 ng/mL ; as maintenance therapy , they received subcutaneous IL-2 ( 1.8 × 106 IU ) and oral RA .  Matched controls ( n = 87 ) were selected from a large cohort of patients with a similar disease status , including clinical benefit from chemotherapy . The most common adverse events were mild cutaneous skin rash and fever . Serum VEGF decreased to a mean level of 152 ng/mL ( P = 0.0002 ) . A statistically significant improvement in immune function was observed ( lymphocyte and natural killer cell numbers and CD4+/CD8 + ratio ) with respect to baseline values and controls . An improvement in the clinical outcome was also observed compared with controls . These data show that the administration of low-dose subcutaneous IL-2 and oral RA to patients with advanced NSCLC showing a clinical benefit from chemotherapy is feasible with a low-toxicity profile , decreases VEGF , and seems to improve progression-free and overall survival PURPOSE The primary objective of this r and omized phase III study was to show significant difference in median time to progression ( TTP ) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy . PATIENTS AND METHODS Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1,250 mg/m(2 ) ( days 1 and 8) plus cisplatin 80 mg/m(2 ) ( day 1 ) every 21 days . Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were r and omized ( 2:1 fashion ) to receive maintenance gemcitabine ( 1,250 mg/m(2 ) on days 1 and 8 every 21 days ) plus best supportive care ( GEM arm ) , or best supportive care only ( BSC arm ) . RESULTS Between November 1999 and November 2002 , we enrolled 352 patients ( median age : 57 years ; stage IV disease : 74 % ; Karnofsky performance status ( KPS ) > 80 : 41 % ) . Following initial therapy , 206 patients were r and omized and treated with gemcitabine ( 138 ) or best supportive care ( 68 ) . TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms , respectively , while values for the maintenance period were 3.6 and 2.0 months ( for p < 0.001 for both ) . Median overall survival ( OS ) throughout study was 13.0 months for GEM and 11.0 months for BSC arms ( p = 0.195 ) . The toxicity profile was mild , with neutropenia being most common grade 3/4 toxicities . CONCLUSION Maintenance therapy with gemcitabine , following initial therapy with gemcitabine plus cisplatin , was feasible , and produced significantly longer TTP compared to best supportive care alone . Further studies are warranted to establish the place of maintenance chemotherapy in patients with advanced NSCLC The UK National Institute for Health and Clinical Excellence ( NICE ) invited the manufacturer of erlotinib ( Roche ) to su bmi t evidence for the clinical and cost effectiveness of erlotinib as monotherapy for the maintenance treatment of patients with non-small cell lung cancer ( NSCLC ) and stable disease following previous treatment with four cycles of platinumcontaining therapy .  The Liverpool Review s and Implementation Group(LRiG ) at the University of Liverpool was commissioned to act as the Evidence Review Group ( ERG ) for this appraisal .The ERG review ed the clinical - and cost-effectiveness evidence in two stages and in accordance with the decision problem defined by NICE . The analysis of the su bmi tted models assessed the appropriateness of the approach taken by the manufacturer in modelling the decision problem . Analysis also included reliability of model implementation and the extent of conformity to published st and ards and prevailing norms of practice within the health economics modelling community . Particular attention was paid to issues likely to have substantial impact on the base-case cost-effectiveness results . Clinical evidence was derived from a multi-centre , double-blind , r and omized , phase III study design ed to address the overall population of NSCLC patients . Outcomes included progression-free survival ( PFS ) and overall survival ( OS ) . The recruited population was mainly from outside of Western Europe and no patients in the pivotal trial had received pemetrexed as a firstline therapy , which is now accepted clinical practice in the UK . The evidence considered in this article includes only the population for whom marketing authorizations has been received – that is , patients with stable disease following first-line therapy . The trial reported a small but statistically significant increase in both PFS and OS in patients with stable disease receiving erlotinib compared with placebo . However , no significant difference was identified in OS when patients with non-squamous disease and stable disease were considered as a subgroup . The economic evidence was focussed on the ERG ’s assessment of three economic models that related to patients with stable disease and compared erlotinib with placebo in the squamous and non-squamous population s and erlotinib with pemetrexed in the non-squamous population . The incremental cost-effectiveness ratios ( ICERs ) reported by the manufacturer were £ 39 936 per QALY gained ( stable disease , all ) ; £ 35 491 per QALY gained ( stable disease , squamous ) ; and £ 40 020 per QALY gained ( stable disease , nonsquamous ) . In comparison with pemetrexed , in the cases where erlotinib was considered to be superior or equivalent , erlotinib dominated . In the cases where erlotinib was considered to be slightly inferior , then the ICERs ranged between £ 91 789 and £ 511 351 per QALY gained ; these ICERs appear in the south-west corner of a cost-effectiveness plane , i.e. erlotinib is cheaper but less effective than pemetrexed . The ERG recalculated the base-case cost-effectiveness results in the manufacturer ’s su bmi ssion , considering nine key areas where corrections and /or adjustments were required , related to time horizon , discounting logic , costs of  erlotinib and pemetrexed , cost of second-line chemotherapy , unit costs , utility values , PFS and OS . This result ed in ERG-revised ICERs for the stable disease squamous population of £ 44 812 per QALY gained , in the stable disease non-squamous population of £ 68 120 per QALY gained , and , when erlotinib was compared with pemetrexed , the result was £ 84 029 per QALY gained . All values were above NICE ’s perceived willingness-to-pay threshold . After the second Appraisal Committee meeting , the Committee did not recommend the use of erlotinib in this patient population BACKGROUND Chemotherapy extends life for patients with advanced non-small cell lung cancer ( NSCLC ) . Second-line treatment of NSCLC includes the use of cytotoxic drugs ; however , toxicity is of concern . One molecular target for lung cancer is the epidermal growth factor receptor ( EGFR ) . Gefitinib ( Iressa ) is an EGFR inhibitor . The aim of our study was to evaluate time to progression ( TTP ) , overall survival ( OS ) and toxicities in a population affected by NSCLC using Iressa as maintenance therapy after first-line chemotherapy . PATIENTS AND METHODS Thirty patients were enrolled with stable disease or partial response . Six cycles of a platinum-based first-line chemotherapy were administered . Iressa was administered at the dose of 250 mg/d . RESULTS Median TTP was 5 months ; median overall survival was 8 months . TTP for adenocarcinoma and non-adenocarcinoma patients was 10 months and 3.2 months , respectively . No toxic effects were seen in 80 % of the patients ; 17 % of the patients had grade 1 follicolitis . OS for adenocarcinoma and non-adenocarcinoma patients were 15 and 5.9 months , respectively . CONCLUSION Gefitinib could be an ideal second-line therapy for adenocarcinoma patients responding to first-line chemotherapy PURPOSE This study evaluated the efficacy and safety of pemetrexed , carboplatin , and bevacizumab followed by maintenance pemetrexed and bevacizumab in patients with chemotherapy-naive stage IIIB ( effusion ) or stage IV nonsquamous non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients received pemetrexed 500 mg/m(2 ) , carboplatin area under the concentration-time curve of 6 , and bevacizumab 15 mg/kg every 3 weeks for six cycles . For patients with response or stable disease , pemetrexed and bevacizumab were continued until disease progression or unacceptable toxicity . RESULTS Fifty patients were enrolled and received treatment . The median follow-up was 13.0 months , and the median number of treatment cycles was seven ( range , one to 51 ) . Thirty patients ( 60 % ) completed > or = six treatment cycles , and nine ( 18 % ) completed > or = 18 treatment cycles . Among the 49 patients assessable for response , the objective response rate was 55 % ( 95 % CI , 41 % to 69 % ) . Median progression-free and overall survival rates were 7.8 months ( 95 % CI , 5.2 to 11.5 months ) and 14.1 months ( 95 % CI , 10.8 to 19.6 months ) , respectively . Grade 3/4 hematologic toxicity was modest-anemia ( 6 % ; 0 ) , neutropenia ( 4 % ; 0 ) , and thrombocytopenia ( 0 ; 8 % ) . Grade 3/4 nonhematologic toxicities were proteinuria ( 2 % ; 0 ) , venous thrombosis ( 4 % ; 2 % ) , arterial thrombosis ( 2 % ; 0 ) , fatigue ( 8 % ; 0 ) , infection ( 8 % ; 2 % ) , nephrotoxicity ( 2 % ; 0 ) , and diverticulitis ( 6 % ; 2 % ) . There were no grade 3 or greater hemorrhagic events or hypertension cases . CONCLUSION This regimen , involving a maintenance component , was associated with acceptable toxicity and relatively long survival in patients with advanced nonsquamous NSCLC . These results justify a phase III comparison against the st and ard-of-care in this patient population BACKGROUND First-line chemotherapy for advanced non-small-cell lung cancer ( NSCLC ) is usually limited to four to six cycles . Maintenance therapy can delay progression and prolong survival . The oral epidermal growth factor receptor ( EGFR ) tyrosine-kinase inhibitor erlotinib has proven efficacy and tolerability in second-line NSCLC . We design ed the phase 3 , placebo-controlled Sequential Tarceva in Unresectable NSCLC ( SATURN ; BO18192 ) study to assess use of erlotinib as maintenance therapy in patients with non-progressive disease following first-line platinum-doublet chemotherapy .  METHODS Between December , 2005 , and May , 2008 , 1949 patients were included in the run-in phase ( four cycles of platinum-based chemotherapy ) . At the end of the run-in phase , 889 patients who did not have progressive disease were entered into the main study , and were r and omly allocated using a 1:1 adaptive r and omisation method through a third-party interactive voice response system to receive erlotinib ( 150 mg/day ; n=438 ) or placebo ( n=451 ) until progression or unacceptable toxicity . Patients were stratified by EGFR immunohistochemistry status , stage , Eastern Cooperative Oncology Group performance status , chemotherapy regimen , smoking history , and region . Co- primary endpoints were progression-free survival ( PFS ) in all analysable patients irrespective of EGFR status , and PFS in patients whose tumours had EGFR protein overexpression , as determined by immunohistochemistry . This study is registered with www . Clinical Trials.gov , number NCT00556712 . FINDINGS 884 patients were analysable for PFS ; 437 in the erlotinib group and 447 in the placebo group . After a median follow-up of 11.4 months for the erlotinib group and 11.5 months for the placebo group , median PFS was significantly longer with erlotinib than with placebo : 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for those in the placebo group ( HR 0.71 , 95 % CI 0.62 - 0.82 ; p<0.0001 ) . PFS was also significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib ( n=307 ) compared with EGFR-positive patients given placebo ( n=311 ; median PFS 12.3 weeks in the erlotinib group vs 11.1 weeks in the placebo group ; HR 0.69 , 0.58 - 0.82 ; p<0.0001 ) . The most common grade 3 or higher adverse events were rash ( 37 [ 9 % ] of 443 patients in the erlotinib group vs none of 445 in the placebo group ) and diarrhoea ( seven [ 2 % ] of 443 patients vs none of 445 ) . Serious adverse events were reported in 47 patients ( 11 % ) on erlotinib compared with 34 patients ( 8 % ) on placebo . The most common serious adverse event was pneumonia ( seven cases [ 2 % ] with erlotinib and four [ < 1 % ] with placebo ) . INTERPRETATION Maintenance therapy with erlotinib for patients with NSCLC is well tolerated and significantly prolongs PFS compared with placebo . First-line maintenance with erlotinib could be considered in patients who do not progress after four cycles of chemotherapy . FUNDING F Hoffmann-La Roche PURPOSE Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase . We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Chemotherapy-naïve patients with advanced stage ( IIIB/IV ) NSCLC , Eastern Cooperative Oncology Group performance status of 0 to 1 , and adequate organ function were r and omly assigned to either platinum-doublet chemotherapy up to six cycles ( arm A ) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily , until disease progression ( arm B ) . Patients were stratified by disease stage , sex , histology , and chemotherapy regimens . The primary end point was overall survival ; secondary end points included progression-free survival , tumor response , safety , and quality of life . Results Between March 2003 and May 2005 , 604 patients were r and omly assigned . There was a statistically significant improvement in progression-free survival in arm B ( hazard ratio [ HR ] , 0.68 ; 95 % CI , 0.57 to 0.80 ; P < .001 ) ; however , overall survival results did not reach statistical significance ( HR , 0.86 ; 95 % CI , 0.72 to 1.03 ; P = .11 ) . In an exploratory subset analysis of overall survival by histologic group , patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma ( n = 467 ; HR , 0.79 ; 95 % CI , 0.65 to 0.98 ; P = .03 ) . CONCLUSION This trial failed to meet the primary end point of OS in patients with NSCLC . The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib , especially for patients with adenocarcinoma Purpose : To investigate whether 18F-fluoro-2-deoxy-glucose positron emission tomography ( FDG-PET ) may be a potential tool to select a subgroup of patients who might be spared maintenance treatment , if the metabolic response after first-line chemotherapy could predict time-to-progression ( TTP ) . Experimental Design : A total of 43 patients who underwent baseline FDG-PET scan and did not show disease progression ( DP ) after 4 cycles of first-line chemotherapy were enrolled and underwent second FDG-PET 3 weeks after completion of the first-line chemotherapy . The primary endpoint was to compare percent decrease in maximum st and ard uptake value ( SUVmax ) between early ( TTP after second PET examination < 8 weeks ) and late ( TTP ≥8 weeks ) DP subgroups . Secondary endpoints were to determine whether fractional decrease in SUVmax could predict TTP and overall survival ( OS ) , both calculated from the date of the second FDG-PET . Results : Percent decreases in SUVmax in late DP subgroup were greater than those in early DP subgroup ( mean reduction , 54.7 % ± 27.2 % vs. 27.8 % ± 46.8 % , P = 0.021 ) . Receiver operating characteristic curves identified a 50.0 % decrease in SUVmax as the optimal threshold to distinguish these subgroups . Using this value as the cutoff result ed in a positive predictive value of 82.6 % and negative predictive value of 60.0 % in predicting TTP ≥8 weeks . Patients with SUVmax decrease < 50 % had significantly longer median TTP ( 3.0 vs. 1.5 months , P = 0.001 ) and OS ( not reached vs. 14.2 months , P = 0.003 ) . Conclusions : Fractional decrease in SUVmax of the main lesion after completion of 4 cycles of chemotherapy may discriminate patients with TTP ≥8 weeks and predict TTP and OS in patients with advanced NSCLC . Clin Cancer Res ; 17(15 ) ; 5093–100 . © 2011 AACR
A meta- analysis of all relevant r and omized controlled trials ( RCTs ) was performed to assess the role of maintenance therapy with either a continuation or a switch strategy in the treatment of non-small-cell lung cancer and to investigate improvement in overall survival ( OS ) and progression-free survival ( PFS ) .