***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: This subgroup analysis of ASCEND-5 study demonstrated better efficacy of ceritinib compared with the st and ard second-line chemotherapy in chemotherapy- and crizotinib-pretreated Japanese patients with ALK-rearranged NSCLC BACKGROUND The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer ( NSCLC ) is not known . We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients . METHODS This r and omised , open-label , phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries . Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ( [ cisplatin 75 mg/m2 or carboplatin AUC 5 - 6 plus pemetrexed 500 mg/m2 ] every 3 weeks for four cycles followed by maintenance pemetrexed ) ; r and omisation was stratified by World Health Organization performance status ( 0 vs 1 - 2 ) , previous neoadjuvant or adjuvant chemotherapy , and presence of brain metastases as per investigator 's assessment at screening . Investigators and patients were not masked to treatment assignment . The primary endpoint was blinded independent review committee assessed progression-free survival , based on all r and omly assigned patients ( the full analysis set ) . Efficacy analyses were done based on the full analysis set . All safety analyses were done based on the safety set , which included all patients who received at least one dose of study drug . This trial is registered with Clinical Trials.gov , number NCT01828099 . FINDINGS Between Aug 19 , 2013 , and May 11 , 2015 , 376 patients were r and omly assigned to ceritinib ( n=189 ) or chemotherapy ( n=187 ) . Median progression-free survival ( as assessed by blinded independent review committee ) was 16·6 months ( 95 % CI 12·6 - 27·2 ) in the ceritinib group and 8·1 months ( 5·8 - 11·1 ) in the chemotherapy group ( hazard ratio 0·55 [ 95 % CI 0·42 - 0·73 ] ; p<0·00001 ) . The most common adverse events were diarrhoea ( in 160 [ 85 % ] of 189 patients ) , nausea ( 130 [ 69 % ] ) , vomiting ( 125 [ 66 % ] ) , and an increase in alanine aminotransferase ( 114 [ 60 % ] ) in the ceritinib group and nausea ( in 97 [ 55 % ] of 175 patients ) , vomiting ( 63 [ 36 % ] ) , and anaemia ( 62 [ 35 % ] ) in the chemotherapy group . INTERPRETATION First-line ceritinib showed a statistically significant and clinical ly meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC . FUNDING Novartis Pharmaceuticals Corporation Over the past 15 years , targeted therapy has revolutionized the systemic treatment of cancer . In parallel , there has been a growing debate on the choice of end points in clinical trials in oncology . This debate basically hinges on the choice between overall survival ( OS ) and  progression-free survival ( PFS ) . PFS is advantageous because it is measured earlier than OS , requires a smaller sample size than OS to achieve the desired power , and is not influenced by cross-over . On the other h and , PFS is prone to measurement error and bias , and may not capture the entire treatment effect on the outcomes of most interest to patients with an incurable disease : a prolonged survival and improved quality of life . Therefore , how can we choose between two imperfect end points ? The answer to this question would certainly be made easier if PFS could be demonstrated to be a valid surrogate for OS . The validation of a surrogate end point is best made using  individual-patient data ( IPD ) from r and omized trials , which allows for st and ardized assessment s of the patient-level and the trial-level correlations between surrogate and final end points . Proper IPD meta-analytical evaluations for targeted agents have still been rare , and to our knowledge only three studies on this topic are currently available in the metastatic setting : one in breast cancer , one in colorectal cancer and one in lung cancer . Although these three studies suffer from limitations inherent to the availability of IPD and the design of the original clinical trials , they have not been able to vali date PFS as surrogate for OS , because only modest correlations were found between these two end points , both at the patient and at the trial level . Even if properly conducted surrogate-endpoint evaluations have thus far been unsuccessful , these evaluations are a step in the right direction and can be expected to be applied on a much larger scale in the era of data sharing of clinical trials Abstract Background This is the first trial to directly compare efficacy and safety of alectinib versus st and ard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer ( NSCLC ) patients who have progressed on , or were intolerant to , crizotinib . Patients and methods ALUR ( MO29750 ; NCT02604342 ) was a r and omized , multicenter , open-label , phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib . Patients were r and omized 2 : 1 to receive alectinib 600 mg twice daily or chemotherapy ( pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 , both every 3 weeks ) until disease progression , death , or withdrawal . Primary end point was investigator-assessed progression-free survival ( PFS ) . Results Altogether , 107 patients were r and omized ( alectinib , n = 72 ; chemotherapy , n = 35 ) in 13 countries across Europe and Asia . Median investigator-assessed PFS was 9.6 months [ 95 % confidence interval ( CI ) : 6.9–12.2 ] with alectinib and 1.4 months ( 95 % CI : 1.3–1.6 ) with chemotherapy [ hazard ratio ( HR ) 0.15 ( 95 % CI : 0.08–0.29 ) ; P < 0.001 ] . Independent Review Committee-assessed PFS was also significantly longer with alectinib [ HR 0.32 ( 95 % CI : 0.17–0.59 ) ; median PFS was 7.1 months ( 95 % CI : 6.3–10.8 ) with alectinib and 1.6 months ( 95 % CI : 1.3–4.1 ) with chemotherapy ] . In patients with measurable baseline central nervous system ( CNS ) disease ( alectinib , n = 24 ; chemotherapy , n = 16 ) , CNS objective response rate was significantly higher with alectinib ( 54.2 % ) versus chemotherapy ( 0 % ; P < 0.001 ) . Grade ≥3 adverse events were more common with chemotherapy ( 41.2 % ) than alectinib ( 27.1 % ) . Incidence of AEs leading to study -drug discontinuation was lower with alectinib ( 5.7 % ) than chemotherapy ( 8.8 % ) , despite alectinib treatment duration being longer ( 20.1 weeks versus 6.0 weeks ) . Conclusion Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients , with a favorable safety profile . Trial registration Clinical Trials.gov NCT02604342 ; Roche study PURPOSE Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospect ively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer . PATIENTS AND METHODS Patients were r and omly assigned to receive crizotinib ( 250 mg twice daily ; n = 172 ) or chemotherapy ( pemetrexed 500 mg/m(2 ) plus cisplatin 75 mg/m(2 ) or carboplatin at area under the curve 5 to 6 , every 3 weeks for ≤ six cycles ; n = 171 ) . Patients with stable treated brain metastases ( tBM ) were eligible . Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases ( BM ) , respectively ; intracranial time to tumor progression ( IC-TTP ; per protocol ) and intracranial disease control rate ( IC-DCR ; post hoc ) were measured . The intent-to-treat population was also assessed . RESULTS Of 343 patients in the intent-to-treat population , 23 % had tBM at baseline . A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population ( hazard ratio [ HR ] , 0.60 ; P = .069 ) , patients with tBM ( HR , 0.45 ; P = .063 ) , and patients without BM ( HR , 0.69 ; P = .323 ) . Among patients with tBM , IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks ( 85 % v 45 % , respectively ; P < .001 ) and 24 weeks ( 56 % v 25 % , respectively ; P = .006 ) . Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups ( tBM present : HR , 0.40 ; P < .001 ; median , 9.0 v 4.0 months , respectively ; BM absent : HR , 0.51 ; P < .001 ; median , 11.1 v 7.2 months , respectively ) and in the intent-to-treat population ( HR , 0.45 ; P < .001 ; median , 10.9 v 7.0 months , respectively ) . CONCLUSION Compared with chemotherapy , crizotinib demonstrated a significantly higher IC-DCR in patients with tBM . Improvements in IC-TTP were not statistically significant in patients with or without tBM , although sensitivity to detect treatment differences in or between the two subgroups was low BACKGROUND The efficacy of the ALK inhibitor crizotinib as compared with st and ard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer ( NSCLC ) is unknown . METHODS We conducted an open-label , phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease . Patients were r and omly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy ( pemetrexed , 500 mg per square meter of body-surface area , plus either cisplatin , 75 mg per square meter , or carboplatin , target area under the curve of 5 to 6 mg per milliliter per minute ) every 3 weeks for up to six cycles . Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy . The primary end point was progression-free survival as assessed by independent radiologic review . RESULTS Progression-free survival was significantly longer with crizotinib than with chemotherapy ( median , 10.9 months vs. 7.0 months ; hazard ratio for progression or death with crizotinib , 0.45 ; 95 % confidence interval [ CI ] , 0.35 to 0.60 ; P<0.001 ) . Objective response rates were 74 % and 45 % , respectively ( P<0.001 ) . Median overall survival was not reached in either group ( hazard ratio for death with crizotinib , 0.82 ; 95 % CI , 0.54 to 1.26 ; P=0.36 ) ; the probability of 1-year survival was 84 % with crizotinib and 79 % with chemotherapy . The most common adverse events with crizotinib were vision disorders , diarrhea , nausea , and edema , and the most common events with chemotherapy were nausea , fatigue , vomiting , and decreased appetite . As compared with chemotherapy , crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life . CONCLUSIONS Crizotinib was superior to st and ard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC . ( Funded by Pfizer ; PROFILE 1014 Clinical Trials.gov number , NCT01154140 . ) Background Alectinib , a highly selective inhibitor of anaplastic lymphoma kinase ( ALK ) , has shown systemic and central nervous system ( CNS ) efficacy in the treatment of ALK‐positive non – small‐cell lung cancer ( NSCLC ) . We investigated alectinib as compared with crizotinib in patients with previously untreated , advanced ALK‐ 
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( S ) Treatment-related deaths were infrequent among ALK-positive NSCLC .