I want to talk about an abstract presented on the FRACTION renal cell carcinoma clinical trial. This is the first presentation of data from the FRACTION programme for renal cell carcinoma. This is a larger overall programme than the data presented at ASCO this year. It’s a signal seeking phase II platform testing multiple different combinations of nivolumab with a second agent and it has two tracks, both an untreated patient track and then a previously treated patient track. This year’s presentation was track 2 – previously treated patients and receiving a combination of nivolumab plus ipilimumab. So a very timely presentation looking at the issue of CTLA-4 blockade in this setting of patients that have had prior therapy including prior checkpoint blockade.

The patients in this cohort, it was a 46 patient study, they were required to participate in track 2 to have had prior PD-1 or PD-L1 therapy. They have all failed prior PD-1 pathway blockade. 80% had also had prior VEGF pathway TKI therapy. It was a heavily pre-treated cohort with 50% of patients having had three or more prior therapies.
The primary endpoint of the cohort was overall response rate. So in the 46 patients there was a 15% response rate. The disease control rate was 52%. The duration of response in the responding patients was not reached with greater than 20 months median follow-up. So it does appear to provide some durable effects in the minority of patients that are having a response.

That touches on a very relevant issue which is what do we do with patients that have failed a frontline regimen? In the last 2½ years we have three new frontline regimens for renal cell carcinoma, all superior to Sutent monotherapy as the comparator. So the field has moved off of monotherapy with targeted agents and most patients are being offered checkpoint blockade in some combination regimen. But when they fail that primary therapy what are our options?

FRACTION sits in the larger context of looking at anti-CTLA-4 in the refractory treatment setting. There were other presentations at ASCO this year: the Hoosier Co-operative Group study GU16-260 looked at frontline PD-1 monotherapy with anti-CTLA-4 ipilimumab as a salvage agent in patients that were failing PD-1 monotherapy and that study had a 13% response rate. The TITAN study was presented at ESMO 2019 which had a similar format of starting patients on frontline anti-PD1 and providing CTLA-4 blockade as a salvage manoeuver, also showing a 12% response rate. Interestingly, just recently in this past week a publication in The Journal of Clinical Oncology of a multicentre retrospective look at this exact same approach providing ipilimumab, anti-CTLA-4 blockade, in patients that are PD-1 refractory, reporting a 20% response rate. So these studies, whether prospective like FRACTION or the retrospective recent publication, do provide evidence that it’s meaningful to provide ipilimumab as a salvage agent in our patients.

In FRACTION we’re continuing PD-1 blockade plus anti-CTLA-4, so a two drug combination. The dosing schedule was typical for how you would dose ipilimumab in the frontline setting, corresponding to the CheckMate-214 data that is also the FDA approved label for using ipilimumab. So it’s familiar to providers about how you’re dosing and scheduling your ipilimumab.

So that’s, again, a very relevant observation that does provide help to providers. I myself in my own clinic population sometimes have provided ipilimumab as a salvage strategy, very often in patients that have had primary success with PD-1 but are beginning to fail therapy. So anecdotally I’ve seen observations very much like the recent retrospective report of patients stabilising or having new de novo regression in this setting and providing ipilimumab. So it encourages us to consider that as a reasonable option for our patients that are failing front-line regimen that includes PD-1.

Certainly the FRACTION renal cell carcinoma programme is ongoing and, as I said, this is the first presentation at ASCO 2020 of data from that programme. There are other combinations of nivolumab plus a second investigational compound and there is data in the frontline setting, both frontline and salvage setting. So it will be a programme that we come back to numerous times to provide novel data regarding combinations for our renal cell carcinoma patients. So that will be a source for future data for sure.