Abstract
BackgroundIn 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.MethodsIn 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.ResultsHazard 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.ConclusionsPFS 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 registrationClinicalTrials.gov NCT01865747 (registered on 05/31/2013).
Highlights
In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy
The METEOR trial showed that cabozantinib improved PFS, OS, and objective response rate (ORR) compared with everolimus in patients with advanced RCC who received prior antiangiogenic therapy
In univariate analyses of the cabozantinib arm based on high vs low baseline biomarker levels, low hepatocyte growth factor (HGF), AXL, and VEGF were prognostic for improved PFS and low HGF, GAS6, AXL, VEGF, and IL-8 were prognostic for improved OS
Summary
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. VEGF-targeted therapies, mTOR inhibitors, immune checkpoint inhibitors and combination therapies are all standard treatments that have shown improvements in outcome in phase 3 clinical trials. Cabozantinib is a standard of care for the treatment of advanced RCC that has shown efficacy in previouslytreated patients and as a first-line therapy [3,4,5]. Cabozantinib inhibits multiple tyrosine kinases including MET, AXL, and VEGFR2 [6] that promote oncogenesis, angiogenesis, and resistance to antiangiogenic therapy in RCC. The VHL tumor suppressor gene is frequently inactivated in clear cell RCC, leading to hypoxia and upregulation of hypoxia-controlled genes including VEGF, MET, and AXL [7,8,9,10]. VEGF, MET, and AXL have been associated with poor prognosis in RCC [9, 11, 12], and MET and AXL have been implicated in resistance to VEGFR-targeted therapy [13]
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