Let me start by some of the studies I’ve been involved in. SAVOIR was a randomised phase III trial of a MET tyrosine kinase inhibitor savolitinib versus standard sunitinib. 180 patients were supposed to be randomised, unfortunately the study closed after 60 patients but provided some evidence that targeting MET with savolitinib was a very reasonable approach in papillary renal cell carcinoma patients that have MET alterations and that’s 38-40% of all papillary RCC. They have a chromosome 7 duplication MET mutation or amplification. So the response rate was 27% versus less than 10% in savolitinib versus sunitinib treated patients respectively. The hazard ratio for progression free survival was 0.7 and for overall survival 0.5, all favouring savolitinib. The side effect profile favours savolitinib. Obviously you cannot draw a conclusion from a 60 patient trial but hopefully there will be another attempt to introduce savolitinib in papillary RCC patients that have MET alterations.
Another study I have been involved with is FRACTION-RCC. FRACTION-RCC actually is an innovative design where it’s part of a very large protocol where we build on a backbone the studies with Bristol Myers Squibb, we build on a backbone of nivolumab and then you add all these potentially very promising checkpoint blockers and immuno-oncology drugs. You have two tracks in each protocol: track one is patients who have not experienced checkpoint inhibitors before, previously untreated with checkpoint inhibitors, and track two is patients who progressed on prior checkpoint inhibitors. We built in a strategy to report now on the second cohort, on the second track. So we have 46 patients who progressed on prior immune checkpoint inhibitor that received nivolumab in combination with a CTLA-4 inhibitor ipilimumab. What we saw was no complete responses and a partial response rate of 16% and the combination was tolerated.
So this is interesting, in a way, to [?? 3:02] the combination even in prior immune checkpoint inhibitors to have responses. But this is not at all near the combination, the same combination, in patients with RCC, clear cell RCC, that are untreated that stayed, after many data cut-off and follow up, stayed at 42% and the complete responses at 10-11%. At the same time there are in relation two studies reported, one by Dr Atkins and McKay that ask the question in untreated patients whether we could add ipilimumab after nivolumab based on responses. If you have a response to nivolumab you do not need maybe ipilimumab but if you don’t, you have a stable disease or progression, you add ipilimumab. Dr Atkin’s study, the HCRN study, uses four doses of ipilimumab and Dr McKay’s study uses two doses of ipilimumab. In both situations the complete responses with the salvage approach was very low and no complete responses seen, again suggesting that if you really want to use nivolumab and ipilimumab, the PD-1 and the CTLA-4 inhibitor, you should use them together, preferably in untreated patients. So I think these are powerful studies.
There’s also one study presented by Dr Plimack which is a KEYNOTE-426 update. This regimen was now approved in renal cell cancer front line, the hazard ratio for overall survival from the first publication was 0.53. So a very powerful combination and at ASCO 2020 the update was done for 23 months and showed a similar result. The PFS was maintained and the OS was maintained, also the hazard ratio, probably due to subsequent lines of therapy, went up from 0.53 to 0.68. The interesting thing about that combination of VEGF-IO, pembrolizumab-axitinib, as well as nivolumab-ipilimumab, is that if you look at those 20% of patients that have IMDC favourable risk and you look at the overall survival hazard ratio, despite that these studies were not built specifically in the favourable risk, the hazard ratio with more follow-up is more than 1, begging the question do patients with favourable IMDC risk group need both drugs? Do they need VEGF-A or IO-IO? Maybe they need one modality, the TKI or even the IO single agent. We know less side effects with one drug than two drugs. An open question, no doubt.
So a very exciting ASCO 2020. I think the organisers in the ASCO staff did a very good job knowing that everyone was scrambling for this virtual, there was a huge social media presence. Hopefully the result will be disseminated and ASCO 2020 will continue with the education programme that is planned in August.