CheckMate-ER is a large randomised phase III trial that established the efficacy of cabozantinib and nivolumab in first-line advanced RCC, clear cell RCC. We know that giving neoadjuvant immunotherapy is superior to adjuvant immunotherapy in eradicating metastatic disease. Cytoreductive nephrectomy used to be the standard of care in the era of interferon and IL-2 and we don’t know yet the role of cytoreductive nephrectomy in our current standard of care.
So the thought was that because we know that having the primary tumour in place creates maximal immune response, peripherally and intratumourally, that giving cabozantinib and nivolumab prior to cytoreductive nephrectomy, the hypothesis was that we would be able to increase the complete response rate and have maximal response.
Can you summarise the patient population and design of the Cyto-KIK study?
These were patients with de novo metastatic clear cell kidney cancer. They had to have measurable disease, a great performance status, ECOG 0-1, and confirmed histologically clear cell RCC. They went on to receive standard of care, cabozantinib and nivolumab, for 12 weeks then cytoreductive nephrectomy and then they had a restaging scan between 1-3 months after the cytoreductive nephrectomy and resumed therapy.
What were the key efficacy and safety findings from this phase II trial?
The study established safety and feasibility of giving standard of care treatment and then doing a cytoreductive nephrectomy. One of the important findings was establishing that it is safe to actually give cabozantinib up to two weeks prior to surgery. We didn’t really have many adverse outcomes. We did a surgical Clavien-Dindo classification, we had two grade 2 anaemias in terms of the Clavien-Dindo scale and one grade 4 haemorrhage. So we did establish the safety interval of cabozantinib prior to surgery and I think that’s very important for the field.
In addition to that, this is a high-risk de novo metastatic population, the complete response rate was 9%. That’s not what we hoped for, it’s not better than the standard of care. There are large phase III studies such as PROBE and SWOG that are going to answer the question of whether or not cytoreductive nephrectomy is actually beneficial in this population.
Other endpoints that we’re looking at are median primary reduction of the primary tumour, we’re looking at PFS and overall survival and we haven’t got to those results as yet.
How might these results influence clinical decision-making for patients with advanced kidney cancer?
It’s safe, it’s feasible, but in terms of incorporating cytoreductive nephrectomy into the current standard of care, I think we have to wait on the PROBE trial and SWOG.
Is there anything else you would like to add?
I think it’s still an unanswered question whether or not it is beneficial to incorporate cytoreductive nephrectomy. Another goal of our study is the correlatives. We have a correlative rich study, we have pre-treatment and post-treatment biopsies and so we hope to also look at mechanisms of resistance to cabozantinib and nivolumab.
