Choueiri, et al. published on New England Journal of Medicine the results of the METEOR Trial (NCT01865747) (1). This randomized phase 3 trial evaluated the efficacy of Cabozantinib, a tyrosine kinase inhibitor that targets VEGFR, MET, RET and AXL, as compared with Everolimus, in 658 patients with aRCC previously treated with VEGFR-targeted therapy. Everolimus was considered standard therapy in this setting based on RECORD-1 trial (2). Primary end-point, progression-free survival (PFS), was achieved, with a gain of 3,6 months and a 42% reduction of the risk of progression with Cabozantinib compared to Everolimus [hazard ratio (HR) 0,58; P<0.001]. Cabozantinib was also associated with improved objective response rate (21% vs. 5%; P<0.001). Data on overall survival (OS) are pending, however a pre-planned interim analysis reveals improved survival for patients treated with Cabozantinib, with a 33% reduction of the risk death (HR 0.67; P=0.005), despite the fact that more patients in the Everolimus arm received subsequent systemic treatment (38% vs 47%). However, the trial also raised the issue of Cabozantinib's safety profile, since 60% of patients in the Cabozantinib arm required at least one-dose reduction, in contrast with 25% in the Everolimus arm, and grade 3-4 adverse events were also more common with Cabozantinib (68% vs 58%). Nevertheless, the authors underline that no more discontinuations due to adverse events with Cabozantinib were recorded.
Discussion of the METEOR Trial cannot be made without taking into account the results of CheckMate 025, published in the same New England Journal of Medicine issue (3). CheckMate 025 evaluated the efficacy of Nivolumab, a monoclonal antibody that inhibits T-cell checkpoint regulator programmed death 1 (PD-1), compared with Everolimus, in 821 patients with aRCC previously treated with VEGFR-targeted therapy. Nivolumab treated patients had an improved median OS of 25.0 months compared with 19.6 months for Everolimus, resulting in a HR of 0.73 (P = 0.002). Additionally, Nivolumab was associated with fewer grade 3-4 adverse events and improved ORR (25% vs. 5%; P<0.001). However Nivolumab had no impact on PFS. How does Cabozantinib compare with other second-line treatment options? Cabozantinib recorded a PFS of 7.4 months, which contrast with 3.8 months for Everolimus, consistent with what was seen in CheckMate 025 and RECORD-1 trials. Axitinib, also approved for the second line treatment of aRCC, recorded a PFS of 8.3 months (4). If we focus on the subgroup of patients pre-treated with Sunitinib in the METEOR and AXIS trials, patients treated with Cabozantinib had a PFS of 9,1 months in contrast with 6,5 months with Axitinib. To date, METEOR trial failed to show OS benefit, although there is a trend favoring Cabozantinib. However, the study was designed to provide adequate power to assess OS benefit, but at the time of the interim analysis the number of events needed to achieve appropriate statistical power had not yet occurred. Also, in the AXIS trial the PFS advantage did not translate to an OS benefit. Few agents proved to prolong OS in second-line aRCC treatment, with Nivolumab marking a new frontier on the treatment of aRCC. ORR with Cabozantinib (21%) overlaps that of Nivolumab (25%) and Axitinib (23%). In palliative treatment, safety profile is an important issue. Cabozantinib treated patients had more grade 3-4 adverse events compared with Everolimus, whereas Nivolumab treated patients experienced fewer grade 3-4 adverse events compared with Everolimus as well as suggesting an improved QoL. Adverse events profile is similar between Cabozantinib and Axitinib (common grade >3 adverse events: hypertension, diarrhea, fatigue).
What about the value of this new technology? ESMO's Magnitude of Clinical Benefit Scale (ESMO-MCBS v1.0 tool) is a validated tool to assess the magnitude of clinical benefit of a new cancer treatment (5). Applying form 2b to assess METEOR study a score of 2 is achieved (given absence of improvement on QoL or OS). Therefore, with the data currently available one cannot support a recommendation of high level of clinical benefit for Cabozantinib. In contrast, applying form 2a to CheckMate-025 one concludes that Nivolumab scores 3, which is further upgraded by 1 point due to improved QoL. As a result, a total score of 4 is obtained, which represents a high level of clinical benefit for Nivolumab. Such value in the setting of aRCC has only been seen in the first-line setting with Temsirolimus, Sunitinib and Pazopanib (5).
In conclusion, Cabozantinib, as assessed by METEOR trial, improves progression-free survival in aRCC following failure of VEGFR inhibitors, however Cabozantinib can hardly be considered, for now, a valuable second-line treatment option. For the future, trials looking for the best treatment sequence could provide some answers, as well performing comparative studies between Cabozantinib and other VEGF-targeted therapies.
Given these latest studies, what is the best treatment sequence for aRCC?
- Choueiri, T.K., et al.,Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.New England Journal of Medicine, 2015.373(19): p. 1814-1823.
- Motzer, R.J., et al.,Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial.Lancet, 2008.372(9637): p. 449-56.
- Motzer, R.J., et al.,Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma.N Engl J Med, 2015.373(19): p. 1803-13.
- Motzer, R.J., et al.,Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial.Lancet Oncol, 2013.14(6): p. 552-62.
- Cherny, N.I., et al.,A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).Ann Oncol, 2015.26(8): p. 1547-73.
Dr. Cátia Faustino declares no conflict of interests.
The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.