This is a first-line study for patients with metastatic kidney cancer and in this study patients were randomised to receive either the old standard treatment that was sunitinib monotherapy, that is an antiangiogenic agent, or a combination of nivolumab plus cabozantinib, that is a combination of one immune checkpoint inhibitor, nivolumab, and one tyrosine kinase inhibitor with mainly antiangiogenic properties such as cabozantinib.

What was the study design?

It is a randomised controlled phase III study in which patients were stratified according to disease characteristics, especially the IMDC prognostic score, and randomised 1:1 to receive either sunitinib, standard dosing schedule, that is 50mg/day, four weeks on, two weeks off, or nivolumab 240mg every two weeks plus cabozantinib at 40mg/day orally.

The primary endpoint of the study was progression free survival and among the secondary endpoints there was also overall survival which remains the most important endpoint for every oncological trial.

What were the results of this study?

The study was already presented and published in the New England Journal of Medicine. At ASCO GU we had an update of the trial, the final survival analysis, which showed a significant improvement in terms of progression free survival in favour of the combination with a median progression free survival of more than 15 months as compared to something like 8 point something for sunitinib.  That was an advantage that proved to be statistically significant and, more importantly, was also a statistically significant overall survival benefit was achieved with more than 45 months overall survival for the combination as compared to less than 36 months for sunitinib monotherapy.

Both differences were statistically significant and on top of these results we were also able to demonstrate the high anti-tumour activity of the combination which proved able to induce a complete response, that all evidence of disease on a CT scan disappeared, in as many as 14% of patients, which is a very high percentage of patients experiencing a complete response. Even more importantly, another 20% of patients had a major response, which is not a complete response but a response that was very close to complete response.

What is the clinical significance of these results?

For sure the nivo/cabo combination is one of those combinations which in the past few years proved able to significantly prolong the overall survival of metastatic kidney cancer patients.  We should take into account that only in 2005 the expected overall survival for metastatic kidney cancer patients was around one year and now we are speaking about a much higher survival rate.

More importantly, we now have a huge amount of patients, again almost 50% of patients, experiencing complete response, which we still do not know because the overall follow-up of this trial is not so long. But still we start speaking about the possibility of curing even metastatic patients. Probably a small percentage of these patients but this is something that is unprecedented in the field of kidney cancer.

Is there anything else you would like to add?

Well, we now have four different combinations available for the first-line treatment of metastatic kidney cancer patients. Beyond the absolute values of overall survival, which are slightly different depending also on the different follow-up and the different composition of patients in terms of prognostic factors, but if we take a look at the hazard ratio for overall survival the benefit achieved is similar across the different trials.

So what is important, as has been clearly highlighted by my good friend, Professor Tom Powles from London, is that you have to pick your combination, taking into account the familiarity you have with the agents, the safety profile of the agents, convincing results, but you have to administer the combination in the best possible way which means an adequate management of adverse events. Unless we can do so, we cannot expect the benefit that has been shown by CheckMate-9ER and honestly also by the other studies.

For sure, we can conclude that the combination of nivolumab plus cabozantinib is one of the standard treatments today and should be proposed, or at least considered, to any given patient with metastatic kidney cancer.