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Background: In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced RCC after prior antiangiogenic therapy. Methods: In this exploratory analysis, plasma biomarkers from baseline and week 4 from 621 of 658 randomized patients were analyzed for CA9, HGF, MET, GAS6, AXL, VEGF, VEGFR2, and IL-8. PFS and OS were analyzed by baseline biomarker levels as both dichotomized and continuous variables using univariate and multivariable methods. For on-treatment changes, PFS and OS were analyzed using fold change in biomarker levels at week 4. Biomarkers were considered prognostic if p < 0.05 and predictive if pinteraction < 0.05 for the interaction between treatment and biomarker. Results: Hazard ratios for PFS and OS favored cabozantinib versus everolimus for both low and high baseline levels of all biomarkers (hazard ratios ≤0.78). In univariate analyses, low baseline HGF, AXL, and VEGF were prognostic for improvements in both PFS and OS with cabozantinib, and low HGF was prognostic for improvements in both PFS and OS with everolimus. Low AXL was predictive of relative improvement in PFS for cabozantinib versus everolimus. Results were generally consistent when baseline biomarkers were expressed as continuous variables, although none were predictive of benefit with treatment. In multivariable analysis, low baseline HGF was independently prognostic for improved PFS for both cabozantinib and everolimus; low HGF, GAS6, and VEGF were independently prognostic for improved OS with cabozantinib. No biomarkers were independently prognostic for OS with everolimus. On-treatment increases in some biomarkers appeared prognostic for PFS or OS with cabozantinib in univariate analyses; however, none were independently prognostic in multivariable analysis. Conclusions: PFS and OS were improved with cabozantinib versus everolimus at high and low baseline levels of all biomarkers. Low baseline HGF was consistently identified as a prognostic biomarker for improved PFS or OS with cabozantinib or everolimus, supporting further prospective evaluation of the prognostic significance of HGF in advanced RCC. Trial registration: ClinicalTrials.gov NCT01865747 (registered on 05/31/2013). [ABSTRACT FROM AUTHOR]

Background: In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced RCC after prior antiangiogenic therapy. Methods: In this exploratory analysis, plasma biomarkers from baseline and week 4 from 621 of 658 randomized patients were analyzed for CA9, HGF, MET, GAS6, AXL, VEGF, VEGFR2, and IL-8. PFS and OS were analyzed by baseline biomarker levels as both dichotomized and continuous variables using univariate and multivariable methods. For on-treatment changes, PFS and OS were analyzed using fold change in biomarker levels at week 4. Biomarkers were considered prognostic if p < 0.05 and predictive if pinteraction < 0.05 for the interaction between treatment and biomarker. Results: Hazard ratios for PFS and OS favored cabozantinib versus everolimus for both low and high baseline levels of all biomarkers (hazard ratios ≤0.78). In univariate analyses, low baseline HGF, AXL, and VEGF were prognostic for improvements in both PFS and OS with cabozantinib, and low HGF was prognostic for improvements in both PFS and OS with everolimus. Low AXL was predictive of relative improvement in PFS for cabozantinib versus everolimus. Results were generally consistent when baseline biomarkers were expressed as continuous variables, although none were predictive of benefit with treatment. In multivariable analysis, low baseline HGF was independently prognostic for improved PFS for both cabozantinib and everolimus; low HGF, GAS6, and VEGF were independently prognostic for improved OS with cabozantinib. No biomarkers were independently prognostic for OS with everolimus. On-treatment increases in some biomarkers appeared prognostic for PFS or OS with cabozantinib in univariate analyses; however, none were independently prognostic in multivariable analysis. Conclusions: PFS and OS were improved with cabozantinib versus everolimus at high and low baseline levels of all biomarkers. Low baseline HGF was consistently identified as a prognostic biomarker for improved PFS or OS with cabozantinib or everolimus, supporting further prospective evaluation of the prognostic significance of HGF in advanced RCC. Trial registration: ClinicalTrials.gov NCT01865747 (registered on 05/31/2013). [ABSTRACT FROM AUTHOR]

Background: In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced RCC after prior antiangiogenic therapy.Methods: In this exploratory analysis, plasma biomarkers from baseline and week 4 from 621 of 658 randomized patients were analyzed for CA9, HGF, MET, GAS6, AXL, VEGF, VEGFR2, and IL-8. PFS and OS were analyzed by baseline biomarker levels as both dichotomized and continuous variables using univariate and multivariable methods. For on-treatment changes, PFS and OS were analyzed using fold change in biomarker levels at week 4. Biomarkers were considered prognostic if p < 0.05 and predictive if pinteraction < 0.05 for the interaction between treatment and biomarker.Results: Hazard ratios for PFS and OS favored cabozantinib versus everolimus for both low and high baseline levels of all biomarkers (hazard ratios ≤0.78). In univariate analyses, low baseline HGF, AXL, and VEGF were prognostic for improvements in both PFS and OS with cabozantinib, and low HGF was prognostic for improvements in both PFS and OS with everolimus. Low AXL was predictive of relative improvement in PFS for cabozantinib versus everolimus. Results were generally consistent when baseline biomarkers were expressed as continuous variables, although none were predictive of benefit with treatment. In multivariable analysis, low baseline HGF was independently prognostic for improved PFS for both cabozantinib and everolimus; low HGF, GAS6, and VEGF were independently prognostic for improved OS with cabozantinib. No biomarkers were independently prognostic for OS with everolimus. On-treatment increases in some biomarkers appeared prognostic for PFS or OS with cabozantinib in univariate analyses; however, none were independently prognostic in multivariable analysis.Conclusions: PFS and OS were improved with cabozantinib versus everolimus at high and low baseline levels of all biomarkers. Low baseline HGF was consistently identified as a prognostic biomarker for improved PFS or OS with cabozantinib or everolimus, supporting further prospective evaluation of the prognostic significance of HGF in advanced RCC.Trial Registration: ClinicalTrials.gov NCT01865747 (registered on 05/31/2013). [ABSTRACT FROM AUTHOR]

Background: Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis.Methods: In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747.Findings: Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1-21·1) in the cabozantinib group and 18·8 months (16·0-21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7-not estimable) with cabozantinib and 16·5 months (14·7-18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53-0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41-0·62]; p<0·0001) and objective response (17% [13-22] with cabozantinib vs 3% [2-6] with everolimus; p<0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration).Interpretation: Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications.Funding: Exelixis Inc. [ABSTRACT FROM AUTHOR]

Wang is employed by Exelixis; and has stock/ownership interests with Exelixis.Dr. Powles has received honoraria from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; has a consulting or advisory role with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; has received research funding from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and has received travel/accommodation/other expenses from AstraZeneca, Ipsen, MSD, Pfizer, and Roche.Dr. Powles has received honoraria from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; has a consulting or advisory role with Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; has received research funding from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and has received travel/accommodation/other expenses from AstraZeneca, Ipsen, MSD, Pfizer, and Roche.Competing interestsDr. [Extracted from the article]