ASCO GU 2020: Updates in renal cancer

Dr Toni Choueiri - Dana-Farber Cancer Institute, Boston, USA

I presented Saturday morning results from a phase I/II study of a novel first in human oral HIF-2 inhibitor by the name MK-6482 which was a proof of principle that we can target that transcription factor. So 55 patients previously treated with clear cell RCC, I would say heavily pre-treated – median number of prior lines of therapy three – were started on 120mg once a day of this oral drug MK-6482.

The first thing, the drug was found largely to be safe, most of the toxicities were grade 1 and 2. Anaemia was the most common toxicity which is on-target toxicity due to the fact that this HIF-2 inhibitor lowers erythropoietin levels. We found also some hypoxia but we did not find these common side effects we see from VEGF inhibitors such as cardiovascular toxicity with hypertension or significant fatigue or hand food skin reaction.

Now, for efficacy, 24% of patients had responses, so it was a single agent in the refractory setting, which is quite encouraging. Progression free survival was 11 months. Most of the responses were durable and were beyond 6 months.

What we also presented during this GU ASCO 2020 is the activity of MK-6482 based on IMDC risk groups. We saw actually responses in not just the favourable risk but also the intermediate and the poor risk. So this is quite encouraging and led to the development of a phase III trial, registrational pivotal trial, with MK-6482 versus everolimus in patients with refractory clear cell RCC who progressed on prior VEGF TKI and checkpoint blockade.

Next, besides the phase III trial, we are trying to combine MK-6482 with other assets such as VEGF TKI, checkpoint inhibitor and others, hopefully for the next generation of trial, and do some elegant, hopefully, biomarker work to try to understand mechanisms of response and resistance because not every patient responds to this treatment.
You have to watch for HIF-2 inhibition and HIF-2 as a target in RCC. We thought for a long time that this is undruggable but now, luckily, we have a first in class drug that works and hopefully more drugs in the future.

There are some other interesting renal studies, one in particular combines a VEGF tyrosine kinase inhibitor, sitravatinib, with nivolumab in patients who had a prior TKI. Encouraging clinical activity and safety presented by the group at MD Anderson. There have been also multiple abstracts, one from the IMDC, really from Dr Bakouny and Heng [?], looking at the role of cytoreductive nephrectomy in the era of checkpoint blockers. Again, a very controversial topic, especially with the CARMENA showing no benefit much in the era of sunitinib. But really some elegant work from Dr Bakouny showing that there are some patients that may benefit in terms of overall survival from taking the kidney out. We have to be very careful how to interpret these retrospective studies and at least this, hopefully, will be the impetus to do a randomised trial in the cytoreductive nephrectomy space with checkpoint blockers like the one with Dr Young [?] and Dr Vaishampayan, the PROBE trial.

So, again, very exciting things and hopefully it will keep this meeting high level with a lot of new findings and new research.