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 Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. 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. Identifying the target NSCLC patient for maintenance therapy: an analysis from a placebo-controlled, phase III trial of maintenance pemetrexed (H3E-MC-JMEN)† PARAMOUNT: Descriptive Subgroup Analyses of Final Overall Survival for the Phase III Study of Maintenance Pemetrexed versus Placebo Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy. Randomized, phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined second-line treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. Efficacy and Safety of Pemetrexed Maintenance Therapy versus Best Supportive Care in Patients from East Asia with Advanced, Nonsquamous Non-small Cell Lung Cancer: An Exploratory Subgroup Analysis of a Global, Randomized, Phase 3 Clinical Trial The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). 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 as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non-small-cell lung cancer.
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 The phase III , r and omized , placebo-controlled Sequential Tarceva in Unresectable NSCLC ( SATURN ; BO18192 ) study found that erlotinib maintenance therapy extended progression-free survival ( PFS ) and overall survival in patients with advanced non-small-cell lung cancer ( NSCLC ) who had nonprogressive disease following first-line platinum-doublet chemotherapy .  This study included prospect i ve analysis of the prognostic and predictive value of several biomarkers . PATIENTS AND METHODS M and atory diagnostic tumor specimens were collected before initiating first-line chemotherapy and were tested for epidermal growth factor receptor ( EGFR ) protein expression by using immunohistochemistry ( IHC ) , EGFR gene copy number by using fluorescent in situ hybridization ( FISH ) , and EGFR and KRAS mutations by using DNA sequencing . An EGFR CA simple sequence repeat in intron 1 ( CA-SSR1 ) polymorphism was evaluated in blood . RESULTS All 889 r and omly assigned patients provided tumor sample s.  EGFR IHC , EGFR FISH , KRAS mutation , and EGFR CA-SSR1 repeat length status were not predictive for erlotinib efficacy . A profound predictive effect on PFS of erlotinib relative to placebo was observed in the EGFR mutation-positive subgroup ( hazard ratio [ HR ] , 0.10 ; P < .001 ) . Significant PFS benefits were also observed with erlotinib in the wild-type EGFR subgroup ( HR , 0.78 ; P = .0185 ) . KRAS mutation status was a significant negative prognostic factor for PFS . CONCLUSION This large prospect i ve biomarker study found that patients with activating EGFR mutations derive the greatest PFS benefit from erlotinib maintenance therapy . No other biomarkers were predictive for outcomes with erlotinib , although the study was not powered for clinical outcomes in biomarker subgroups other than EGFR IHC-positive [ corrected ] . KRAS mutations were prognostic for reduced PFS . The study demonstrated the feasibility of prospect i ve tissue collection for biomarker analyses in NSCLC 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 PURPOSE PointBreak ( A Study of Pemetrexed , Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer ) compared the efficacy and safety of pemetrexed ( Pem ) plus carboplatin ( C ) plus bevacizumab ( Bev ) followed by pemetrexed plus bevacizumab ( PemCBev ) with paclitaxel ( Pac ) plus carboplatin ( C ) plus bevacizumab ( Bev ) followed by bevacizumab ( PacCBev ) in patients with advanced nonsquamous non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were r and omly assigned to receive pemetrexed 500 mg/m(2 ) or paclitaxel 200 mg/m(2 ) combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles . Eligible patients received maintenance until disease progression : pemetrexed plus bevacizumab ( for the PemCBev group ) or bevacizumab ( for the PacCBev group ) . The primary end point of this superiority study was overall survival ( OS ) . RESULTS Patients were r and omly assigned to PemCBev ( n = 472 ) or PacCBev ( n = 467 ) . For PemCBev versus PacCBev , OS hazard ratio ( HR ) was 1.00 ( median OS , 12.6 v 13.4 months ; P = .949 ) ; progression-free survival ( PFS ) HR was 0.83 ( median PFS , 6.0 v 5.6 months ; P = .012 ) ; overall response rate was 34.1 % versus 33.0 % ; and disease control rate was 65.9 % versus 69.8 % . Significantly more study drug-related grade 3 or 4 anemia ( 14.5 % v 2.7 % ) , thrombocytopenia ( 23.3 % v 5.6 % ) , and fatigue ( 10.9 % v 5.0 % ) occurred with PemCBev ; significantly more grade 3 or 4 neutropenia ( 40.6 % v 25.8 % ) , febrile neutropenia ( 4.1 % v 1.4 % ) , sensory neuropathy ( 4.1 % v 0 % ) , and alopecia ( grade 1 or 2 ; 36.8 % v 6.6 % ) occurred with PacCBev . CONCLUSION OS did not improve with the PemCBev regimen compared with the PacCBev regimen , although PFS was significantly improved with PemCBev . Toxicity profiles differed ; both regimens demonstrated tolerability 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 This was a post hoc analysis of patients with non-squamous histology from a phase III maintenance pemetrexed study in advanced non-small cell lung cancer ( NSCLC ) . Patients and methods The six symptom items ' [ average symptom burden index ( ASBI ) ] mean at baseline was calculated using the lung cancer symptom scale ( LCSS ) . Low and high symptom burden ( LSB , ASBI < 25 ; HSB , ASBI ≥ 25 ) and performance status ( PS : 0 , 1 ) subgroups were analyzed for treatment effect on progression-free survival ( PFS ) and overall survival ( OS ) using the Cox proportional hazard models adjusted for demographic/ clinical factors . Results Significantly longer PFS and OS  for pemetrexed versus placebo occurred in LSB patients [ PFS : median 5.1 versus 2.4 months , hazard ratio ( HR ) 0.49 , P < 0.0001 ; OS : median 17.5 versus 11.0 months , HR 0.63 , P = 0.0012 ] and PS 0 patients ( PFS : median 5.5 versus 1.7 months , HR 0.36 , P < 0.0001 ; OS : median 17.7 versus 10.3 months , HR 0.54 , P = 0.0019 ) . Significantly longer PFS , but not OS , occurred in HSB patients ( median 3.7 versus 2.8 months , HR 0.50 , P = 0.0033 ) and PS 1 patients ( median 4.4 versus 2.8 months , HR 0.60 , P = 0.0002 ) . Conclusions ASBI and PS are associated with survival for non-squamous NSCLC patients , suggesting that maintenance pemetrexed is useful for LSB or PS 0 patients following induction Introduction : The PARAMOUNT phase III trial demonstrated that pemetrexed continuation maintenance significantly reduced the risk of disease progression ( hazard ratio = 0.62 ) and death ( hazard ratio = 0.78 ) versus placebo in patients with advanced nonsquamous non – small-cell lung cancer . To further underst and the survival data , descriptive subgroup analyses were undertaken . Methods : Nine hundred thirty-nine patients received induction therapy ( four 21-day cycles pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 ) , after which 539 nonprogressing patients with an Eastern Cooperative Oncology Group performance status ( PS ) of 0/1 were r and omized ( 2:1 ) to maintenance pemetrexed ( 500 mg/m2 ) cycles or placebo until disease progression . Results : Baseline characteristics of patients surviving for longer periods were comparable to patients surviving shorter periods , suggesting overall survival ( OS ) benefit for all subgroups of patients on maintenance therapy . An examination of type and severity of induction adverse events also found no association with survival duration . Response to induction ( tumor response versus stable disease ) was not determinate of pemetrexed maintenance OS outcome as assessed by waterfall plot and scattergrams and by the distribution of patients among various OS intervals . The length of the interval before beginning maintenance therapy ( < 7 days versus ≥7/⩽30 days ) also did not impact the survival results . PS , a known prognostic factor , was the only baseline characteristic associated with improved OS ; however , both PS 0 and PS 1 patients exhibited a survival benefit from pemetrexed maintenance . Conclusions : In PARAMOUNT , the OS benefit was seen across all subgroups . Other than PS , no baseline or clinical parameter clearly identified a subgroup more likely to benefit . Maintenance treatment decisions should be made on an individual basis 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 PURPOSE This phase III study investigated whether continuation maintenance with gemcitabine or switch maintenance with erlotinib improves clinical outcome compared with observation in patients with advanced non-small-cell lung cancer ( NSCLC ) whose disease was controlled after cisplatin-gemcitabine induction chemotherapy . PATIENTS AND METHODS Four hundred sixty-four patients with stage IIIB/IV NSCLC without tumor progression after four cycles of cisplatin-gemcitabine  were r and omly assigned to observation or to gemcitabine ( 1,250 mg/m(2 ) days 1 and 8 of a 3-week cycle ) or daily erlotinib ( 150 mg/day ) study arms . On disease progression , patients in all three arms received pemetrexed ( 500 mg/m(2 ) once every 21 days ) as predefined second-line therapy . The primary end point was progression-free survival ( PFS ) . RESULTS PFS was significantly prolonged by gemcitabine ( median , 3.8 v 1.9 months ; hazard ratio [ HR ] , 0.56 ; 95 % CI , 0.44 to 0.72 ; log-rank P < .001 ) and erlotinib ( median , 2.9 v 1.9 months ; HR , 0.69 ; 95 % CI , 0.54 to 0.88 ; log-rank P = .003 ) versus observation ; this benefit was consistent across all clinical subgroups . Both maintenance strategies result ed in a nonsignificant improvement in overall survival ( OS ) ; patients who received second-line pemetrexed or with a performance status of 0 appeared to derive greater benefit . Exploratory analysis showed that magnitude of response to induction chemotherapy may affect the OS benefit as a result of gemcitabine maintenance . Maintenance gemcitabine and erlotinib were well tolerated with no unexpected adverse events . CONCLUSION Gemcitabine continuation maintenance or erlotinib switch maintenance significantly reduces disease progression in patients with advanced NSCLC treated with cisplatin-gemcitabine as first-line chemotherapy . Response to induction chemotherapy may affect OS only for continuation maintenance Introduction : In a recent global phase 3 trial , patients with advanced non-small cell lung cancer ( NSCLC ) , who had not progressed after four cycles of platinum-based induction chemotherapy  , were r and omized to maintenance therapy with pemetrexed or placebo . The objective of this retrospective , exploratory , post hoc subgroup analysis was to compare outcomes of East Asian patients with non-East Asian patients treated with pemetrexed or placebo . Methods : Only patients with nonsquamous histology were analyzed . Patients were grouped by enrollment location ( East Asian = China , Korea , or Taiwan ; non-East Asian = all other countries ) . The Kaplan – Meier method was used to calculate median progression-free survival ( PFS ) and overall survival ( OS ) times . Hazard ratios ( HRs ) were calculated using unadjusted Cox proportional hazard models . Results : Of the 663 patients enrolled in the study , 481 patients had nonsquamous NSCLC : East Asian = 27 % and non-East Asian = 73 % . In the East Asian subgroup , there were more women , never smokers , and patients with adenocarcinoma .  PFS was similar between the subgroups and significantly prolonged in patients treated with pemetrexed than placebo ( median PFS : East Asian , 4.4 versus 1.6 months , HR = 0.42 , p < 0.001 ; non-East Asian , 4.5 versus 2.8 months , HR = 0.45 , p < 0.001 ) . OS was numerically prolonged in East Asians ( median OS : pemetrexed , 19.7 months ; placebo , 16.4 months ) compared with non-East Asians ( pemetrexed , 13.2 months ; placebo , 8.5 months ) . Pemetrexed was reasonably well tolerated with few severe adverse events reported . Conclusion : The results of this subgroup analysis support pemetrexed as maintenance therapy for East Asian patients with advanced , nonsquamous NSCLC BACKGROUND Recent studies of pemetrexed have identified a predictive role for non-small cell lung cancer ( NSCLC ) histology . We further review ed the differential efficacy of pemetrexed according to histology in two large , phase III NSCLC trials . METHODS One study tested pemetrexed versus docetaxel in previously treated patients ( n = 571 ) and the other tested cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients ( n = 1,725 ) with advanced NSCLC . Cox proportional hazard models were used to test for covariate-adjusted treatment-by-histology interactions ( THIs ) for overall survival ( OS ) and progression-free survival ( PFS ) . For each histologic subgroup , the Kaplan-Meier method was used to estimate unadjusted within-arm medians , and Cox models were used to estimate covariate-adjusted between-arm hazard ratios ( HRs ) . RESULTS In both studies , treatment arms were well balanced for histology . THIs were statistically significant ( p < .005 ) for both OS and PFS . Nonsquamous patients treated with pemetrexed-based therapy experienced longer survival than the comparators ( HR , 0.78 and 0.84 , respectively ) , whereas squamous patients had shorter survival ( HR , 1.56 and 1.23 , respectively ) . Whereas the efficacy of pemetrexed regimens differed according to histology , it did not differ for docetaxel or for cisplatin plus gemcitabine . Pemetrexed was well tolerated across histologic groups . CONCLUSIONS The consistency of these results across studies confirms the predictive effect of histology for pemetrexed and the survival advantage for pemetrexed in patients with nonsquamous histology . These analyses suggest pemetrexed should not be recommended for the treatment of squamous cell carcinoma , but , because of efficacy and safety advantages , pemetrexed may be preferable to other agents for treatment of patients with nonsquamous NSCLC PURPOSE Maintenance therapy is associated with improved survival in patients with non-small-cell lung cancer ( NSCLC ) , but few studies have compared active agents in this setting . AVAPERL evaluated the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment . PATIENTS AND METHODS Patients with advanced nonsquamous NSCLC received first-line  bevacizumab 7.5 mg/kg , cisplatin 75 mg/m(2 ) , and pemetrexed 500 mg/m(2 ) once every 3 weeks for four cycles . Those achieving response or stable disease were r and omly assigned at a ratio of 1:1 to maintenance bevacizumab 7.5 mg/kg or bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m(2 ) once every 3 weeks until disease progression or unacceptable toxicity . The primary end point was progression-free survival ( PFS ) after r and om assignment . RESULTS In total , 376 patients received induction treatment , 71.9 % achieved disease control , and 67.3 % were r and omly assigned to maintenance therapy , with 125 and 128 receiving single-agent bevacizumab and bevacizumab plus pemetrexed treatment , respectively . At a median follow-up of 8.1 months , PFS from r and om assignment was significantly improved in the bevacizumab plus pemetrexed arm ( median , 3.7 v 7.4 months ; hazard ratio , 0.48 ; 95 % CI , 0.35 to 0.66 ; P < .001 ) per a stratified model . The PFS benefit extended across age , performance status , smoking history , and induction response ( stable disease v partial response ) subgroups . Any grade , grade ≥ 3 , and serious adverse events occurred more often with bevacizumab plus pemetrexed maintenance . No new safety signals were observed . CONCLUSION In an unselected population of patients with nonsquamous NSCLC who had achieved  disease control  with platinum-based chemotherapy plus bevacizumab , bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone . The combination was well tolerated 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 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 In the phase III PARAMOUNT trial , pemetrexed continuation maintenance therapy reduced the risk of disease progression versus placebo ( hazard ratio [ HR ] , 0.62 ; 95 % CI , 0.49 to 0.79 ; P < .001 ) . Here we report final overall survival ( OS ) and up date d safety data . PATIENTS AND METHODS In all , 939 patients with advanced nonsquamous non-small-cell lung cancer ( NSCLC ) received four cycles of pemetrexed-cisplatin induction therapy ;  then , 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were r and omly assigned ( 2:1 ) to maintenance pemetrexed ( 500 mg/m(2 ) on day 1 of 21-day cycles ; n = 359 ) or placebo ( n = 180 ) . Log-rank test compared OS between arms as measured from r and om assignment ( α = .0498 ) . RESULTS The mean number of maintenance cycles was 7.9 ( range , one to 44 ) for pemetrexed and 5.0 ( range , one to 38 ) for placebo . After 397 deaths  ( pemetrexed , 71 % ; placebo , 78 % ) and a median follow-up of 24.3 months for alive patients ( 95 % CI , 23.2 to 25.1 months ) , pemetrexed therapy result ed in a statistically significant 22 % reduction in the risk of death ( HR , 0.78 ; 95 % CI , 0.64 to 0.96 ; P = .0195 ; median OS : pemetrexed , 13.9 months ; placebo , 11.0 months ) . Survival on pemetrexed was consistently improved for all patient subgroups , including induction response : complete/partial responders ( n = 234 ) OS HR , 0.81 ; 95 % CI , 0.59 to 1.11 and stable disease ( n = 285 ) OS HR , 0.76 ; 95 % CI , 0.57 to 1.01 ) . Postdiscontinuation therapy use was similar : pemetrexed , 64 % ; placebo , 72 % . No new safety findings emerged . Drug-related grade 3 to 4 anemia , fatigue , and neutropenia were significantly higher in pemetrexed-treated patients . CONCLUSION Pemetrexed continuation maintenance therapy is well-tolerated and offers superior OS compared with placebo , further demonstrating that it is an efficacious treatment strategy for patients with advanced nonsquamous NSCLC and good performance status who did not progress during pemetrexed-cisplatin induction therapy PURPOSE This phase III trial was performed to assess the potential benefit of adding maintenance erlotinib to bevacizumab after a first-line chemotherapy regimen with bevacizumab for advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS One thous and one hundred forty-five patients with histologically or cytologically confirmed NSCLC ( stage IIIB with malignant pleural effusion , stage IV , or recurrent ) received four cycles of chemotherapy plus bevacizumab .  Seven hundred forty-three patients without disease progression or significant toxicity  were then r and omly assigned ( 1:1 ) to bevacizumab ( 15 mg/kg , day 1 , 21-day cycle ) plus either placebo or erlotinib ( 150 mg per day ) . The primary end point was progression-free survival ( PFS ) . RESULTS Median PFS from time of r and om assignment was 3.7 months with bevacizumab/placebo and 4.8 months with bevacizumab/erlotinib ( hazard ratio [ HR ] , 0.71 ; 95 % CI , 0.58 to 0.86 ; P < .001 ) . Median overall survival ( OS ) times from r and om assignment were 13.3 and 14.4 months with bevacizumab/placebo and bevacizumab/erlotinib , respectively ( HR , 0.92 ; 95 % CI , 0.70 to 1.21 ; P = .5341 ) . During the postchemotherapy phase , there were more adverse events ( AEs ) overall , more grade 3 and 4 AEs ( mainly rash and diarrhea ) , more serious AEs , and more AEs leading to erlotinib/placebo discontinuation in the bevacizumab/erlotinib arm versus the bevacizumab/placebo arm . The incidence of AEs leading to bevacizumab discontinuation was similar in both treatment arms . CONCLUSION The addition of erlotinib to bevacizumab significantly improved PFS but not OS . Although generally well tolerated , the modest impact on survival and increased toxicity associated with the addition of erlotinib to bevacizumab maintenance mean that this two-drug maintenance regimen will not lead to a new postchemotherapy st and ard of care
INTRODUCTION Non-small cell lung cancer ( NSCLC ) is often diagnosed at later stages when treatment options are limited .
Maintenance therapy may prolong the time to disease progression and potentially increase overall survival .
Secondarily , it may increase the proportion of patients eligible for second-line therapy at the time of progression .
The objective of this systematic review was to examine the use of systemic treatment in the maintenance of patients with NSCLC .