***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: Lenvatinib is an oral , multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 ( VEGFR1‐VEGFR3 ) , fibroblast growth factor receptors 1 through 4 ( FGFR1‐FGFR4 ) , platelet‐derived growth factor receptor α ( PDGFRα ) , ret proto‐oncogene ( RET ) , and v‐kit Hardy‐Zuckerman 4 feline sarcoma viral oncogene homolog ( KIT ) signaling networks implicated in tumor angiogenesis . Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced , radioiodine‐refractory , differentiated thyroid cancer ( RR‐DTC ) . Lenvatinib significantly prolonged progression‐free survival ( PFS ) versus placebo in patients with radioiodine‐refractory differentiated thyroid cancer ( RR‐DTC ) in the phase 3 Study of ( E7080 )  Lenvatinib  in Differentiated Cancer of the Thyroid ( SELECT ) trial . This sub analysis evaluated the efficacy and safety of lenvatinib in Japanese patients who participated in SELECT . Outcomes for Japanese patients ( lenvatinib , n = 30 ; placebo , n = 10 ) were assessed in relationship to the SELECT population ( lenvatinib , n = 261 ; placebo , n = 131 ) . The primary endpoint was PFS ; secondary endpoints included overall survival , overall response rate , and safety . Lenvatinib PFS benefit was shown in Japanese patients ( median PFS : lenvatinib , 16.5 months ; placebo , 3.7 months ) , although significance was not reached , presumably due to sample size ( hazard ratio , 0.39 ; 95 % confidence interval , 0.10–1.57 ; P = 0.067 ) . Overall response rates were 63.3 % and 0 % for lenvatinib and placebo , respectively . No significant difference was found in overall survival . The lenvatinib safety profile was similar between the Japanese and overall SELECT population , except for higher incidences of hypertension ( any grade : Japanese , 87 % ; overall , 68 % ; grade ≥3 : Japanese , 80 % ; overall , 42 % ) , palmar – plantar erythrodysesthesia syndrome ( any grade : Japanese , 70 % ; overall , 32 % ; grade ≥3 : Japanese , 3 % ; overall , 3 % ) , and proteinuria ( any grade : Japanese , 63 % ; overall , 31 % ; grade ≥3 : Japanese , 20 % ; overall , 10 % ) . Japanese patients had more dose reductions ( Japanese , 90 % ; overall , 67.8 % ) , but fewer discontinuations due to adverse events ( Japanese , 3.3 % ; overall , 14.2 % ) . There was no difference  in lenvatinib exposure between the Japanese and overall SELECT population s after adjusting for body weight . In Japanese patients with radioiodine‐refractory differentiated thyroid cancer , lenvatinib showed similar clinical outcomes to the overall SELECT population . Some differences in adverse event frequencies and dose modifications were observed . Clinical trial registration no. : NCT01321554 Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor ( VEGFR ) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer ( DTC ) . However , there are no approved second- or third-line therapies . MET is implicated in resistance to VEGFR inhibitors . Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer . In a phase I study of cabozantinib , five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib . Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor ( RECIST ) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study . The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response . Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks . In this study , if at least five of 25 response-evaluable patients had an objective response , cabozantinib would be considered a promising agent in this patient population . Results Twenty-five patients were enrolled . The median age was 64 years , and 64 % of patients were men . Twenty-one patients had received only one prior VEGFR-targeted therapy ( sorafenib , pazopanib , or cediranib ) , and four patients had received two such therapies . The most common treatment-related adverse events were fatigue , weight loss , diarrhea , palmar-plantar erythrodysesthesia , and hypertension . One drug-related death was noted . Of the 25 patients , 10 ( 40 % ) had a partial response , 13 ( 52 % ) had stable disease , and two ( 8 % ) had nonevaluable disease . The median progression-free survival and overall survival were 12.7 months and 34.7 months , respectively . Conclusion Cabozantinib demonstrated clinical ly significant , durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy OBJECTIVE We conducted a prospect i ve phase II clinical trial to determine the efficacy of sorafenib in patients with advanced radio-iodine refractory differentiated thyroid cancer . In this article , the long-term results are presented . PATIENTS AND METHODS Thirty-one patients with progressive metastatic or locally advanced radioactive iodine refractory differentiated thyroid cancer received sorafenib 400 mg orally twice daily . The study end points included response rate , progression-free survival ( PFS ) , overall survival ( OS ) , best response by Response Evaluation Criteria in Solid Tumors criteria 1.0 , and toxicity . RESULTS Median PFS was 18 months ( 95 % confidence interval ( 95 % CI ) : 7 - 29 months ) and median OS was 34.5 months ( 95 % CI : 19 - 50 months ) . Eight patients ( 31 % ) achieved a partial response and 11 patients ( 42 % ) showed stable disease after a median follow-up of 25 months ( range 3.5 - 39 months ) . Toxicity mostly included h and foot syndrome , weight loss , diarrhea , and rash . CONCLUSION Sorafenib has clinical ly relevant antitumor activity in patients with progressive metastatic or locally advanced radio-iodine refractory differentiated thyroid cancer .  Sorafenib can nowadays be considered as the st and ard option in these patients Purpose : Differentiated thyroid cancer ( DTC ) accounts for approximately 95 % of thyroid carcinomas . In the metastatic RAI-refractory disease , chemotherapy has very limited efficacy and is associated with substantial toxicity . With increasing knowledge of the molecular pathogenesis of DTC , novel targeted therapies have been developed . Lenvatinib is a tyrosine kinase inhibitor ( TKI ) with promising clinical activity based on the r and omized phase III SELECT trial . In Switzerl and , a Named Patient Program ( NPP ) was installed to bridge the time gap to Swissmedic approval . Here , we report the results from the Swiss Lenvatinib NPP including patients with metastatic RAI-refractory DTC . Methods : Main inclusion criteria for the Swiss NPP were RAI-refractory DTC , documented disease progression , Eastern Cooperative Oncology Group ( ECOG ) performance status 0 - 3 . The number of previous therapies was not limited . The Swiss Lenvatinib NPP was initiated in June 2014 and was closed in October 2015 with the approval of the drug . Results : Between June 2014 and October 2015 , 13 patients with a median age of 72 years have been enrolled . Most patients ( 69 % ) had at least one prior systemic therapy , mainly sorafenib . 31 % of patients showed a PR and 31 % SD . Median progression free survival was 7.2 months and the median overall survival was 22.7 months . Dose reduction due to adverse events was necessary in 7 patients ( 53 % ) . At the time of analysis 6 patients ( 47 % ) were still on treatment with a median time on treatment of 9.98 months . Conclusions : Our results show that lenvatinib has reasonable clinical activity in unselected patients with RAI-refractory thyroid cancer with nearly two-third of patients showing clinical benefit . The toxicity profile of lenvatinib is manageable BACKGROUND Lenvatinib , an oral inhibitor of vascular endothelial growth factor receptors 1 , 2 , and 3 , fibroblast growth factor receptors 1 through 4 , platelet-derived growth factor receptor α , RET , and KIT , showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine ( iodine-131 ) . METHODS In our phase 3 , r and omized , double-blind , multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131  , we r and omly assigned 261 patients to receive lenvatinib ( at a daily dose of 24 mg per day in 28-day cycles ) and 131 patients to receive placebo .  At the time of disease progression , patients in the placebo group could receive open-label lenvatinib . The primary end point was progression-free survival . Secondary end points included the response rate , overall survival , and safety . RESULTS The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group ( hazard ratio for progression or death , 0.21 ; 99 % confidence interval , 0.14 to 0.31 ; P<0.001 ) . A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups . The response rate was 64.8 % in the lenvatinib group ( 4 complete responses and 165 partial responses ) and 1.5 % in the placebo group ( P<0.001 ) . The median overall survival was not reached in either group . Treatment-related adverse effects of any grade , which occurred in more than 40 % of patients in the lenvatinib group , were hypertension ( in 67.8 % of the patients ) , diarrhea ( in 59.4 % ) , fatigue or asthenia ( in 59.0 % ) , decreased appetite ( in 50.2 % ) , decreased weight ( in 46.4 % ) , and nausea ( in 41.0 % ) . Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib ( 14.2 % ) and 3 patients who received placebo ( 2.3 % ) . In the lenvatinib group , 6 of 20 deaths that occurred during the treatment period were considered to be drug-related . CONCLUSIONS Lenvatinib , as compared with placebo , was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer . Patients who received lenvatinib had more adverse effects . ( Funded by Eisai ; SELECT Clinical Trials.gov number , NCT01321554 . ) In a previous phase 2 trial , axitinib was active and well tolerated in patients with advanced thyroid cancer . In this second phase 2 trial , the efficacy and safety of axitinib were evaluated further in this population , and pharmacokinetic/pharmacodynamic relationships and patient‐reported outcomes were assessed 
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For grade ≥3 adverse effects , h and -foot syndrome , hypocalcemia , and elevated ALT were more frequent in sorafenib-treated patients .
Moreover , lenvatinib-treated patients had a significantly higher incidence of severe weight loss , hypertension , and nausea .
Conclusion Significant differences in common adverse effects , such as all- grade and severe AEs , were detected between sorafenib and lenvatinib in the current study .