Cabozantinib delays disease progression compared to sunitinib in metastatic renal cell carcinoma patients with a poor prognosis

Results of a multicenter phase II study demonstrated a superior progression-free survival (PFS) with cabozantinib over sunitinib in the first-line treatment of patients with metastatic clear-cell renal cell carcinoma (RCC). In this study, mainly including patients with a dismal prognosis, first-line cabozantinib reduced the risk of progression or death by 31% as compared to sunitinib with a similar adverse events profile. These data require validation in a phase III setting, but raise questions on whether cabozantinib should become the standard first-line treatment in this setting.

Both cabozantinib and sunitinib are tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptors (VEGFR). However, unlike sunitinib, cabozantinib also inhibits the action of MET and AXL, two proteins that were previously shown to be associated with tumor progression and the development of resistance to VEGFR inhibitors like sunitinib.

The CABOSUN study is a phase II, multicenter trial including 157 patients with untreated clear-cell metastatic RCC with an intermediate or poor risk according to the international metastatic RCC database consortium criteria (IMDC). Patients in the study were randomized to receive either oral cabozantinib (60mg once daily) or sunitinib (50mg once daily, 4 weeks on, 2 weeks off). The primary endpoint of the study was investigator-assessed PFS, with objective response rate (ORR), overall survival (OS) and safety as key secondary objectives. Overall, 81% of patients in this study had an intermediate IMDC risk score. Thirteen percent of patients had an ECOG performance status of 2 and in 36% of patients in the study bone metastases were found. This clearly reflects the dismal prognosis of patients included in this study. After a median follow-up of 20.8 months, 13 (16.5%) patients remained on therapy in the cabozantinib arm as compared to 2 (2.6%) patients in the sunitinib arm. The median PFS in the patients treated with cabozantinib was 8.2 months, which was significantly longer than the 5.6 months median PFS observed with sunitinib (HR[95%CI]: 0.69[0.48-0.99]; p=0.012). Also the ORR was significantly higher in the cabozantinib arm than in the sunitinib arm (46% vs.18%). The median OS was found to be 30.3 months for cabozantinib as compared to 21.8 months with sunitinib (HR[95%CI]: 0.80[0.50-1.26]).

With respect to safety, a similar rate of adverse events was observed in both study arms. The incidence of grade 3 or higher adverse events was 65% in the cabozantinib arm and 68% in the sunitinib arm. Dose reductions were needed in 58% of patients in the cabozantinib arm and in 49% of patients treated with sunitinib. The discontinuation rate due to adverse events was 20% with cabozantinib and 21% with sunitinib. The most common adverse events for both treatments included diarrhoea, fatigue, hypertension, palmar-plantar erythrodysesthesia, and ahematological events. This observation is in line with the classical safety profile observed in clinical trials with VEGFR inhibitors.

In this study, including metastatic RCC patients with a dismal prognosis, cabozantinib significantly delayed disease progression as compared to sunitinib. Cabozantinib is currently approved for second or later lines of therapies, after patients have progressed on a VEGFR tyrosine kinase inhibitor. This study will however raise questions on whether cabozantinib should become a first-line standard treatment. In order to answer this question we need to await the outcome of the ongoing phase III first-line studies which selected sunitinib as the control arm.

Reference

Choueiri T, Halabi S, Sanford B, et al. CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: Results from ALLIANCE A031203 trial. Presented at ESMO 2016; Abstract LBA30_PR.