Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma
Toni K Choueiri1, Bernard Escudier, Thomas Powles
1From the Dana-Farber Cancer Institute, Boston (T.K.C., P.W.K.); Institut Gustave Roussy, Villejuif, France (B.E.); Barts Cancer Institute, Cancer Research UK Experimental Cancer Medicine Centre, Queen Mary University of London, Royal Free NHS Trust, London (T.P.); Icon Cancer Care, South Brisbane, QLD, Australia (P.N.M.); Cleveland Clinic, Cleveland (B.I.R.); Aarhus University Hospital, Aarhus, Denmark (F.D.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (H.H.); Texas Oncology-Charles A. Sammons Cancer Center, Baylor University, Dallas (T.E.H.); University of Ulsan College of Medicine (J.-L.L.) and Seoul National University Hospital (B.K.) - both in Seoul, South Korea; Helsinki University Central Hospital Cancer Center, Helsinki (K.P.); Washington University in St. Louis, St. Louis (B.J.R.); Sunnybrook Odette Cancer Centre, Toronto (G.A.B.), and Tom Baker Cancer Centre, Calgary, AB (D.Y.C.H.) - both in Canada; National Institute of Oncology, Budapest, Hungary (L.G.); Hospital de la Santa Creu i Sant Pau, Barcelona (P.M.); Medical University of Vienna, Vienna (M.S.); Exelixis, South San Francisco, CA (A.B-H., C.H., C.S., G.M.S.); University of Texas M.D. Anderson Cancer Center, Houston (N.M.T.); and the Memorial Sloan Kettering Cancer Center, New York (R.J.M.).
Background:
Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy.
Methods:
We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate.
Results:
Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus.
Conclusions:
Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).
Insights
Cabozantinib significantly improved progression-free survival in patients with advanced renal cell carcinoma after VEGFR-targeted therapy compared to everolimus. This tyrosine kinase inhibitor offers a new treatment option for this patient population.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Metastatic renal cell carcinoma (mRCC) pathobiology involves VEGFR, MET, and AXL.
- Resistance to antiangiogenic drugs is a challenge in mRCC treatment.
- Cabozantinib targets VEGFR, MET, and AXL, addressing key pathways in mRCC.
Purpose of the Study:
- To evaluate the efficacy of cabozantinib versus everolimus in patients with mRCC.
- To compare progression-free survival (PFS) as the primary endpoint.
- To assess overall survival (OS) and objective response rate (ORR) as secondary endpoints.
Main Methods:
- A randomized, open-label, phase 3 trial (METEOR) was conducted.
- 658 patients with mRCC progressed after VEGFR-targeted therapy were enrolled.
- Patients received either cabozantinib (60 mg daily) or everolimus (10 mg daily).
Main Results:
- Cabozantinib demonstrated a median PFS of 7.4 months vs. 3.8 months for everolimus.
- The rate of progression or death was 42% lower with cabozantinib (HR, 0.58; P<0.001).
- Objective response rate was 21% for cabozantinib versus 5% for everolimus (P<0.001).
Conclusions:
- Cabozantinib significantly improved PFS in patients with previously treated mRCC.
- The study suggests cabozantinib as a superior treatment option over everolimus for this patient group.
- Adverse events were manageable with dose reductions, with similar discontinuation rates.
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