***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 Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity , precluding further development . We hypothesised that axitinib , a more selective VEGF inhibitor than others previously tested , could be combined safely with pembrolizumab ( anti-PD-1 ) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma . METHODS In this ongoing , open-label , phase 1b study , which was done at ten centres in the USA , we enrolled patients aged 18 years or older who had advanced renal cell carcinoma ( predominantly clear cell subtype ) with their primary tumour resected , and at least one measureable lesion , Eastern Cooperative Oncology Group performance status 0 - 1 , controlled hypertension , and no previous systemic therapy for renal cell carcinoma . Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose , and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy . Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks . We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab ; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment . The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles ( 6 weeks ) to estimate the maximum tolerated dose and recommended phase 2 dose . This study is registered with Clinical Trials.gov , number NCT02133742 . FINDINGS Between Sept 23 , 2014 , and March 25 , 2015 , we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3 , 2015 , and Oct 13 , 2015 , we enrolled 41 patients to the dose-expansion phase . All 52 patients were analysed together .  No unexpected toxicities were observed . Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period ( dose-finding phase ) : one patient had a transient ischaemic attack and two patients were only able to complete less than 75 % of the planned axitinib dose because of treatment-related toxicity . At the data cutoff date ( March 31 , 2017 ) , 25 ( 48 % ) patients were still receiving study treatment . Grade 3 or worse treatment-related adverse events occurred in 34 ( 65 % ) patients ; the most common included hypertension ( n=12 [ 23 % ] ) , diarrhoea ( n=5 [ 10 % ] ) , fatigue ( n=5 [ 10 % ] ) , and increased alanine aminotransferase concentration ( n=4 [ 8 % ] ) . The most common potentially immune-related adverse events ( probably related to pembrolizumab ) included diarrhoea ( n=15 [ 29 % ] ) , increased alanine aminotransferase concentration ( n=9 [ 17 % ] ) or aspartate aminotransferase concentration ( n=7 [ 13 % ] ) , hypothyroidism ( n=7 [ 13 % ] ) , and fatigue ( n=6 [ 12 % ] ) . 28 ( 54 % ) patients had treatment-related serious adverse events . At data cutoff , 38 ( 73 % ; 95 % CI 59·0 - 84·4 ) patients achieved an objective response ( complete or partial response ) . INTERPRETATION The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma . Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy ( NCT02853331 ) . FUNDING Pfizer BACKGROUND The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone . Here , we report preliminary results for the combination of avelumab , an IgG1 monoclonal antibody against the programmed cell death protein lig and PD-L1 , and axitinib , a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma , in treatment-naive patients with advanced renal-cell carcinoma . METHODS The JAVELIN Renal 100 study is an ongoing open-label , multicentre , dose-finding , and dose-expansion , phase 1b study , done in 14 centres in the USA , UK , and Japan . Eligible patients were aged 18 years or older ( ≥20 years in Japan ) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component , life expectancy of at least 3 months , an Eastern Cooperative Oncology Group performance status of 1 or less , received no previous systemic treatment for advanced renal cell carcinoma , and had a resected primary tumour . Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days , followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily . Based on the pharmacokinetic data from the dose-finding phase , ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen . The other patients in the dose-expansion phase started taking combination therapy directly . The primary endpoint was dose-limiting toxicities in the first 4 weeks ( two cycles ) of treatment with avelumab plus axitinib . Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib . This trial is registered with Clinical Trials.gov , number NCT02493751 . FINDINGS Between Oct 30 , 2015 , and Sept 30 , 2016 , we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study .  One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase . At the cutoff date ( April 13 , 2017 ) , six ( 100 % , 95 % CI 54 - 100 ) of six patients in the dose-finding phase and 26 ( 53 % , 38 - 68 ) of 49 patients in the dose-expansion phase had confirmed objective responses ( 32 [ 58 % , 44 - 71 ] of all 55 patients ) . 32 ( 58 % ) of 55 patients had grade 3 or worse treatment-related adverse events , the most frequent being hypertension in 16 ( 29 % ) patients and increased concentrations of alanine aminotransferase , amylase , and lipase , and palmar-plantar erythrodysaesthesia syndrome in four ( 7 % ) patients each . Six ( 11 % ) of 55 patients died before data cutoff , five ( 9 % ) due to disease progression and one ( 2 % ) due to treatment-related autoimmune myocarditis . At the end of the dose-finding phase , the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily . INTERPRETATION The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone , and the preliminary data on antitumour activity are encouraging . A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy . FUNDING Pfizer and Merck 
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Additionally , combination therapy failed to show obvious safety in most immune-related adverse events , whatever in all- grade or high grade