Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial.

By T. Choueiri, B. Escudier, T. Powles, N. Tannir, P. Mainwaring, B. Rini, H. Hammers, F. Donskov, B. Roth, K. Peltola and 13 more. The Lancet Oncology, 2016

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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.

Subfields: Immunology, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/a305e4704d7dedf97e12cbf99af9337e8f1b6f2d

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In Immunology

1. Pedro C. Barata
2. Charles Swanton
3. E. Small
4. B. Rini

In Molecular Biology

1. Charles Swanton
2. B. Rini

In Pulmonary and Respiratory Medicine

1. Pedro C. Barata
2. Charles Swanton
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Citations in the corpus

• Renal cell carcinoma (2017, background): “However, second-line treatment has been dramatically modified by the report of two large trials showing improvement in OS with nivolumab and cabozantinib [50-52] over everolimus.”
• Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. (2017, background): “Cabozantinib, an oral small-molecule inhibitor of tyrosine kinases, including VEGFRs, MET, and AXL,(19) was recently approved for the treatment of patients with RCC who have received prior antiangiogenic therapy on the basis of a phase III trial (METEOR; Metastatic Renal Cell Carcinoma Phase III Stu”
• Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2010, background): “However, second-line treatment has been dramatically modified by the report of two large trials showing improvement in OS with nivolumab and cabozantinib [50-52] over everolimus.”
• Treatment of renal cell carcinoma: Current status and future directions (2017, background): “83).(120) Dose reductions were almost 3 times more frequent with cabozantinib than with everolimus (60% vs 25%, respectively), but the incidence of grade 3 and 4 AEs was similar for both groups (68% vs 58%, respectively), and approximately 10% of patients in each group discontinued treatment because”
• Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma (2018, neutral): “Fatigue 212 (45) 49 (10) 0 70 (30) 10 (4) 0 Nausea 147 (31) 10 (2) 0 42 (18) 4 (2) 0 Hypertension 137 (29) 73 (16) 1 (<1) 14 (6) 4 (2) 0 Vomiting 121 (26) 2 (<1) 0 28 (12) 6 (3) 0 Increase in aspartate aminotransferase level 105 (22) 51 (11) 4 (1) 27 (11) 15 (6) 1 (<1)”
• Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. (2019, background): “However, second-line treatment has been dramatically modified by the report of two large trials showing improvement in OS with nivolumab and cabozantinib [50-52] over everolimus.”