***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: BACKGROUND Imatinib is st and ard therapy for advanced gastrointestinal stromal tumors ( GIST ) , but most patients develop resistance . This phase I-II study assessed the safety and efficacy of co-administering everolimus with imatinib in imatinib-resistant GIST . PATIENTS AND METHODS In phase I , patients received imatinib ( 600/800 mg/day ) combined with weekly ( 20 mg ) or daily ( 2.5/5.0 mg ) everolimus to determine the optimal dose . In phase II , patients were divided into two strata ( progression on imatinib only ; progression after imatinib and sunitinib/other tyrosine kinase inhibitor ) and received everolimus 2.5 mg plus imatinib 600 mg/day . Primary end point was 4-month progression-free survival ( PFS ) . RESULTS Combination treatment was well tolerated . Common adverse events were diarrhea , nausea , fatigue , and anemia . In phase II strata 1 and 2 , 4 of 23 ( 17 % ) and 13 of 35 ( 37 % ) assessable patients , respectively , were progression free at 4 months ; median PFS was 1.9 and 3.5 months , and median overall survival was 14.9 and 10.7 months , respectively . In stratum 1 , 36 % had stable disease ( SD ) and 54 % progressive disease ( PD ) , while in stratum 2 , 2 % had partial response , 43 % SD , and 32 % PD . CONCLUSION Predetermined efficacy criteria were met in both strata . The combination of everolimus and imatinib after failure on imatinib and sunitinib merits further investigation in GIST These findings may potentially influence future clinical practice , with encouraging long-term survival data and better safety of masitinib with respect to sunitinib indicating a positive benefit – risk ratio . Considered in the setting of effective subsequent therapies , data show that adding masitinib to the armaterium of drugs used to treat GIST generates a clinical ly relevant survival benefit Purpose Patients with advanced GIST following st and ard imatinib and sunitinib often have good performance status and need additional therapy . This study tested nilotinib , a second-generation tyrosine kinase inhibitor , in patients with advanced GIST refractory to st and ard therapies . Methods This single-center open-label phase II study has a primary objective to determine progression-free survival at 6 months . Using a novel statistical design , 17 patients were to be enrolled ; if ≥10 were progression free ( PF ) at 2 months , 19 additional patients would be enrolled . The therapy was considered of benefit if ≥13 of 36 patients were PF at 6 months . All patients signed informed consent and entry criteria included normal cardiac function . Exploratory analyses correlating genotype with response were also performed . Results Thirteen patients were treated ; 2 had received agents after imatinib and sunitinib . Treatment was well tolerated with one grade 4 anemia attributed to nilotinib . No measurable responses were observed ; median time to progression was 2 months . One patient remained on study with stable disease for 12 months . Mutation testing is available from 10 primary tumors with 7 exon 11 mutations , 1 exon 9 mutation , and 2 without KIT/PDGFR mutations . Two sample s from recurrent disease had 2 mutations , both primary exon 11 mutations with an additional exon 17 mutation , including the patient with prolonged stable disease . Conclusions Nilotinib was well tolerated in these patients with advanced GIST . Accrual was halted due to insufficient clinical benefit . However , nilotinib may provide benefit to specific subsets of advanced GIST with exon 17 mutations PURPOSE Most gastrointestinal stromal tumors ( GISTs ) harbor mutant KIT or platelet-derived growth factor receptor alpha ( PDGFRA ) kinases , which are imatinib targets . Sunitinib , which targets KIT , PDGFRs , and several other kinases , has demonstrated efficacy in patients with GIST after they experience imatinib failure . We evaluated the impact of primary and secondary kinase genotype on sunitinib activity . PATIENTS AND METHODS Tumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic , imatinib-resistant/intolerant GIST . KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy . Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity . RESULTS Clinical benefit ( partial response or stable disease for > or = 6 months ) with sunitinib was observed for the three most common primary GIST genotypes : KIT exon 9 ( 58 % ) , KIT exon 11 ( 34 % ) , and wild-type KIT/PDGFRA ( 56 % ) . Progression-free survival ( PFS ) was significantly longer for patients with primary KIT exon 9 mutations ( P = .0005 ) or with a wild-type genotype ( P = .0356 ) than for those with KIT exon 11 mutations . The same pattern was observed for overall survival ( OS ) . PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations ( which involve the KIT-adenosine triphosphate binding pocket ) than for those with exon 17 or 18 mutations ( which involve the KIT activation loop ) . Biochemical profiling studies confirmed the clinical results . CONCLUSION The clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases , which has implication s for optimization of the treatment of patients with GIST Purpose This multicenter phase 2 study assessed the tolerability and efficacy of motesanib , an oral inhibitor of Kit , platelet-derived growth factor receptor ( PDGFR ) , and vascular endothelial growth factor receptors ( VEGFR ) , in patients with imatinib-resistant gastrointestinal stromal tumors ( GIST ) . Methods Patients with advanced GIST who failed imatinib mesylate after ≥8 weeks of treatment with ≥600 mg daily received motesanib 125 mg orally once daily continuously for 48 weeks or until unacceptable toxicity or disease progression occurred . The primary endpoint was confirmed objective tumor response per RECIST and independent review . Secondary endpoints included progression-free survival ( PFS ) , time to progression ( TTP ) ; objective response by 18FDG-PET and by changes in tumor size and /or density ( Choi criteria ) ; pharmacokinetics and safety . Results In the patients evaluable for response ( N = 102 ) , the objective response rate was 3 % ; 59 % of patients achieved stable disease , with 14 % achieving durable stable disease ≥24 weeks ; 38 % had disease progression . Higher objective response rates were observed per 18FDG-PET ( N = 91 ) ( 30 % ) and Choi criteria ( 41 % ) . The median PFS was 16 weeks ( 95 % CI = 14–24 weeks ) ; the median TTP was 17 weeks ( 95 % CI = 15–24 weeks ) . The most common motesanib treatment-related grade 3 adverse events included hypertension ( 23 % ) , fatigue ( 9 % ) , and diarrhea ( 5 % ) . Motesanib did not accumulate with daily dosing . Conclusions In this study of patients with imatinib-resistant GIST  , motesanib treatment result ed in acceptable tolerability and modest tumor control as evident in the proportion of patients who achieved stable disease and durable stable disease AIMS To assess the antitumour activity , safety , pharmacokinetics and pharmacodynamics of continuous daily sunitinib dosing in patients with imatinib-resistant/intolerant gastrointestinal stromal tumour ( GIST ) and to assess morning dosing versus evening dosing . PATIENTS AND METHODS In this open-label phase II study , patients were r and omised to receive morning or evening dosing of sunitinib 37.5mg/day . The primary end-point was clinical benefit rate ( CBR ; percent complete responses+partial responses [PRs]+stable disease [ SD ] 24 weeks ) . Secondary end-points included progression-free survival ( PFS ) , overall survival ( OS ) , safety , pharmacokinetic parameters and plasma biomarker levels . RESULTS Sixty of 61 planned patients received treatment ( 30 per dosing group ) ; 26 completed the study . Overall , the CBR was 53 % ( 95 % exact CI , 40 - 66 ) : eight patients ( 13 % ) achieved objective PRs ; 24 ( 40 % ) achieved SD 24 weeks . Median PFS was 34 weeks ( 95 % CI , 24 - 49 ) ; median OS was 107 weeks ( 95 % CI , 72 - not yet calculable ) . Most adverse events ( AEs ) were of grade 1 or 2 in severity , and were manageable through dose modification or st and ard interventions . No new AEs were apparent compared with the approved intermittent dosing schedule . Antitumour activity and safety were generally similar with morning and evening dosing . Continuous daily sunitinib dosing achieved and sustained effective drug concentrations without additional accumulation across cycles . Decreases from baseline in plasma levels of soluble KIT after 20 and 24 weeks of dosing correlated with longer OS . CONCLUSION For patients with imatinib-resistant/intolerant GIST , continuous daily sunitinib dosing appears to be an active alternative dosing strategy with acceptable safety BACKGROUND HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors ( GIST ) .  BIIB021 is an oral non-ansamycin HSP90 inhibitor . We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib .  PATIENTS AND METHODS The primary end-point was metabolic partial response ( mPR ) as assessed by  fluorodeoxyglucose positron emission tomography ( FDG-PET ) .  The secondary end-points were pharmacokinetic assessment s of BIIB021 and pharmacodynamic assessment s of HSP70 .  Twenty-three patients were treated on two schedules : 12 pts received 600 mg twice a week ( BIW ) and 11 patients received 400 mg three times a week ( TIW ) . All had prior imatinib and sunitinib but stopped>14 days before starting BIIB021 . RESULTS The median age was 59 years ( 33 - 88 years ) , 61 % male , 44 % Eastern Cooperative Oncology Group 1 ( ECOG1 ) . The best response was PR by FDG-PET for five patients ( 3/12 at 600 mg BIW and 2/9 at 400 TIW ) for an overall response rate of 22 % . The response duration was 25 - 138 days . Adverse events ( AEs ) were mild to moderate . The mean Cmax was 1.5 µmol and the mean AUC was 2.9 µmol h. Cmax>1.5 µmol was associated with a decrease in st and ardized uptake value ( SUVmax ) . HSP70 increased substantially following treatment . CONCLUSIONS This study met its primary end-point . BIIB021 leads to objective responses in refractory GIST patients . Pharmacodynamic studies confirmed HSP90 inhibition . Further evaluation of BIIB021 in GIST is warranted BACKGROUND Advanced GISTs are incurable , but often treatable for years with tyrosine kinase inhibitors ( TKIs ) . The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA . Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients . However , almost all patients develop resistance to these TKIs , typically due to the development of secondary mutations , heralding the need for new therapeutic options . We conducted a phase II study evaluating the efficacy and toxicity of pazopanib , a broad spectrum TKI inhibiting KIT , VEGFRs ( -1 , -2 , and -3 ) , and PDGFR ( -α and -β ) in patients with advanced GIST following failure of at least imatinib and sunitinib . METHODS Patients received pazopanib 800 mg orally once daily . All patients were assessed for efficacy with CT scans every 8 weeks ( two cycles ) . Patients continued pazopanib until progression or unacceptable toxicity . The primary end point was the 24-week nonprogression [ complete response+partial response+stable disease ( SD ) ] rate ( NPR ) per RECIST 1.1 . Secondary end points included PFS , OS , and toxicity . RESULTS Between August 2011 and September 2012 , a total of 25 patients were treated at two institutions . Median number of prior therapy was 3 ( range 2 - 7 ) . A total of 90 cycles of pazopanib were administered , with a median of two cycles ( range 1 to 17 + ) per patient . Best response of SD at any time was observed in 12 ( 48 % ) patients . The NPR was 17 % [ 95 % confidence interval ( CI ) 4.5 - 37 ] . 
    Output:
    
The available data for the second-line suggest that sunitinib is the best option while in the third line , regorafenib is the best option