During ESMO 2022 in beautiful but rainy Paris, we had the honour on Monday afternoon to present the first results from the COSMIC-313 study in advanced renal cell cancer. This is the first trial that uses a control arm, a modern control arm, contemporary control arm, not sunitinib. It’s actually nivolumab and ipilimumab so it’s double IO. The experimental arm was nivolumab, ipilimumab plus cabozantinib at 40mg/day, knowing this is a placebo controlled study. 

The primary endpoint was progression free survival by independent central review and the study actually met its primary endpoint – hazard ratio 0.73 corresponding to a clinically meaningful and statistically significant 27% decrease in the risk of death or progression. 

Some other elements to consider: the toxicity was higher so more steroid use in the triplet arm. There was also more diarrhoea all grade, more skin toxicity all grade, not high grade but there were more LFTs increase. We don’t know if these LFTs increase, transaminases increase, are immune related, are due to the TKI or a combination. But actually treatment discontinuation of the three study components occurred in 12% in the experimental arm and 5% in the control arm of nivolumab ipilimumab. 

What could be the clinical implications of this?

This is a great question. We still need to wait for overall survival but one interesting thing that emerged, despite all hazard ratios were less than 1.0 in the subgroups except in poor risk. When we look at poor risk, that are only 25% of patients, intermediate were 75%, we see the same response rate and same PFS; the hazard ratio is the same. This is a bit counterintuitive, you would think a triplet regimen would work more in poor risk. On the other hand, maybe these patients are very sick and don’t get enough of anything. So the intermediate risk patients faired actually better; this is a large chunk, 75% of the population. The hazard ratio from 0.73 in the total population of PITT to 0.63; the response rate difference became 10%. So we want to follow that signal but, the bottom line, this is a positive study with a control arm that is contemporary.

Are there any other renal studies that have stood out for you this year?

One of the things that stood out is the HIF2 inhibitor based studies. This is a very important and new target in renal cell cancer. That target and drug led in part to the 2019 Nobel Prize in Physiology or Medicine, including one of my close friends and colleagues, Dr Bill Kaelin from the Dana Farber Cancer Institute, in part investigating the basic level oxygen sensing. So HIF2 is part of the story, if you want, from an oncological but also cardiological perspective. 

So we knew there were two updates from studies, one with VHL syndrome. There the drug is approved – belzutifan, the HIF2 inhibitor, is approved in VHL syndrome. With more mature data the data looks stable, looks good, looks robust. We also have data with combination cabozantinib plus the HIF2 inhibitor belzutifan in previously treated patients. I had the honour to present this data previously; the update of the data looks good – patients are stable, patients do well. 

But what we presented here with Dr Merchan and myself, we presented data in untreated patients, first line, no IO, untreated patients. 35 patients, cabozantinib plus belzutifan, response rate 57%, PFS 30 months, although I would argue that it’s a bit unstable, the follow-up is shorter than 30 months, but no PD. This is interesting, we’re going to follow on that. This really favours the two ongoing phase III trials, one second line with the TKI lenvatinib plus belzutifan versus cabozantinib, the other one very promising with Dr Rini and myself is a triplet arm with pembrolizumab, lenvatinib, HIF2 versus pembrolizumab lenvatinib, and there’s a third arm containing CTLA-4. 

An exciting time in RCC. I want to remind you, 2005 when I started my Fellowship the median survival in metastatic RCC was one year; now five years. So I think this is great. We are not going to stop until every patient is cured, hopefully in this lifetime.

The third segment, there was a very interesting session, really, really we waited for this session on Saturday with two studies in the adjuvant setting – PROSPER with neoadjuvant and adjuvant nivolumab and IMmotion010 with adjuvant atezolizumab in high risk renal cell cancer. Unfortunately, and unlike KEYNOTE-564, these both studies were really negative, dead negative. The hazard ratio was 0.9. A lot of difference in study design, in drugs. Dr Tom Powles, I invite you to see his discussion, he did a masterful discussion putting it into context. A day later Dr Bob Motzer presented in the Presidential Session adjuvant nivolumab ipilimumab but for six months. That also showed quite interesting results but, at the end of the day, it was negative. 

So we have adjuvant atezolizumab a year, neoadjuvant adjuvant nivolumab, six months of nivolumab ipilimumab, high risk RCC, all negative, only pembrolizumab one year is positive at 24 and 30 months. No OS benefit, there’s a trend, we’re going to follow on that.

What’s the overall picture for renal oncologists at the moment?

I think renal cell, as a disease, is evolving very fast, massive by massive. People ask me every time if my practice is changing and I’m like, ‘My practice is evolving by every meeting. I can’t keep up my slides are getting old, meeting by meeting, I cannot update them.’ But, at the end of the day, this is great news for patients.