ESMO 2016

Cabozantinib over sunitinib for metastatic renal cell carcinoma

Dr Toni Choueiri - Dana Farber Cancer Institute, Boston, USA

It’s my pleasure to present the result of the randomised phase II study of cabozantinib versus sunitinib in untreated metastatic RCC patients of poor and intermediate risk. As a way of introduction, cabozantinib, the experimental drug in question here, is an oral inhibitor of tyrosine kinases including not just the VEGF receptors but also MET and AXL. This drug was approved in the United States and in the EU for previously treated RCC.

So our question here was to evaluate cabozantinib compared to sunitinib in treatment naïve RCC patients of poor and intermediate risk groups. We felt that poor and intermediate risk groups are an unmet need and usually have inferior clinical outcomes relative to favourable risk patients. The primary endpoint in this CABOSUN trial was progression free survival as assessed by the investigators with the secondary endpoints being overall survival as well as overall response rate and safety. Just to put the study into perspective, especially that it deals with intermediate and poor risk patients which usually together represent the majority of RCC patients, so CABOSUN, the trial in question here, compared to two more so contemporary trials, so CABOSUN did not enrol any favourable risk patients, which is a study frontline of sunitinib versus everolimus, and which is also a contemporary study published in 2013 of sunitinib versus cabozantinib, both enrolled 25-30% favourable risk. CABOSUN enrolled 13% of ECOG performance 2 and 36%, the highest among the three trials, of patients with bone metastases. So that is to show you that this study really had many patients with negative adverse prognostic factors, even beyond these poor risk criteria - ECOG performance status 2 and prevalence of bone metastases, more than one-third of patients. So no patients with favourable prognosis, high rate of ECOG performance 2 and high rate of bone metastases all associated with poor prognosis and poor response in the metastatic setting to VEGF targeted therapy.

So overall these are the results. Treatment with cabozantinib resulted in a median progression free survival of 8.2 months compared to 5.6 months with the control arm of sunitinib. This was statistically significant, the hazard ratio was 0.69 corresponding to a one-sided p-value of 0.012. What about overall response rate assessed by investigators? In the CABOSUN trial overall response rate from cabozantinib was 46% by RECIST compared to 18% for sunitinib. As you can see, the confidence intervals do not cross, suggesting statistical significance.

Overall survival is very preliminary, the median follow-up is short and the numbers are the following: median OS with cabozantinib is 30.3 months, 21.8 versus sunitinib. The hazard ratio is 0.8. We intend to have in the next several months an update for the overall survival.

In terms of safety the median number of cycles, each cycle was defined on the study as six weeks, usually we followed sunitinib here because that’s the cycle for sunitinib that is given four weeks on two weeks off. With cabozantinib the median number of cycles is five with sunitinib two; grade 3/4 events were not different. Dose reduction was slightly higher with cabozantinib however discontinuation due to adverse events was 20% in both arms. There were no surprises in terms of side effects, these are side effects that do represent a class of agents, VEGF targeted therapy; hypertension, diarrhoea, PPE and fatigue are common side effects with both drugs. There was a greater exposure in the cabozantinib arm and a similar rate of adverse events and discontinuation between both arms.

So, what are the implications for the treatment of metastatic renal cell carcinoma after this study? We’ll go back and say that sunitinib is a standard of care and the most used agent in first line metastatic RCC. The median PFS is 8-11 months in a general unselected population of good, intermediate and poor risk. Patients with intermediate and poor risk, 70% on average, have worse prognosis. There is data from the International Metastatic Database Consortium that showed that these patients when you treat them with first line targeted therapy their PFS could be as short as 5.6 months which is exactly what we found in the control arm. So in CABOSUN cabozantinib did improve progression free survival and overall response compared to sunitinib, 8.2 versus 5.6 months, overall response rate 46% versus 18%. There was a similar safety profile. I do believe that cabozantinib represents a potential first line treatment option in patients with advanced renal cell carcinoma.