Cabozantinib ( Cabometyx ) is an oral multitargeted tyrosine kinase inhibitor ( TKI ) that potently inhibits MET and AXL, both associated with poor prognosis in renal cell carcinoma ( RCC ), next to vascular endothelial growth factor receptor 2 ( VEGFR-2 ), KIT, FLT3 and RET.
Chronic treatment with vascular endothelial growth factor receptor ( VEGFR )-targeting Sunitinib ( Sutent ) upregulates MET and AXL in renal cell carcinoma, indicating that Cabozantinib may be particularly effective in patients with advanced renal cell carcinoma whose disease progressed on prior VEGFR-targeted treatment.
Cabozantinib ( 60 mg once daily ) has been investigated in comparison to Everolimus ( Afinitor ) ( 10 mg once daily ) in a phase III randomized controlled trial ( RCT ) in 658 patients with advanced renal cell carcinoma of whom 71% had received one prior and 29% had received at least two prior lines of VEGFR-targeted therapy.
The study demonstrated highly significant improved progression-free survival of 7.4 months versus 3.9 months with a hazard ratio ( HR ) of 0.51 [ 95% confidence interval ( CI ) 0.41–0.62 ] in favour of Cabozantinib.
Cabozantinib also showed a superior overall survival of 21.4 months versus 16.5 months ( HR 0.66; 95% CI 0.53–0.83 ).
Objective response rate was higher in Cabozantinib-treated patients, 17% versus 3%.
Clinical benefit was shown in all subgroups of patients, including in patients with bone or visceral metastases.
The safety profile was acceptable with manageable side effects.
Based on this study, Cabozantinib is a highly effective approved second-line treatment option for patients with advanced renal cell carcinoma with a manageable toxicity profile.
Other recently approved second-line agents include checkpoint inhibitor Nivolumab and VEGF-targeting agent Lenvatinib combined with Everolimus.
In the absence of predictive markers as well as head-to-head comparisons of these three approved treatments, the choice between these drugs in second-line treatment will probably be made based on comorbidities, tolerability of previous treatment and presence of high tumour burden with rapidly progressive disease.
Future pretreatment assessment of MET and AXL tumour aberration may aid clinicians to make a rational choice between currently approved second-line treatment options. ( Xagena )
Osanto S, van der Hulle T, Therapeutic Advances in Urology, 2018