Addressing Unmet Needs in mRCC

Martin H. Voss, MD:There remains several unmet needs in the management of metastatic kidney cancer, and we have revisited rare kidney cancer variants several times now. And there’s little that we know with how effective indeed these newer drugs are in the non—clear cell setting. I do think it’s important to emphasize clinical trial enrollment for patients with rare histologies, and I do think it’s important for our pharmaceutical partners to show interest in conducting trials in that space rather than us only pursuing retrospective research in this setting.

I do think that all the optimism we have developed seeing what immunotherapy can do in untreated and pretreated patients points out a new unmet need, and that is to actually increase the number of complete remissions and the hope to achieve long-term disease control, possibly cure, for our patients. And I do think that that emphasizes the need for biomarker development, not only for the agents that we have on the market now, but also for drugs to come. It’s exciting to see that there are so many new therapies underway right now, and the emphasis certainly remains on combination therapy.

We have not talked yet about I-O/TKI combinations that now pair the old and the new and show that VEGF-directed kinase inhibitors can be paired safely with immuno-oncology drugs. That is certainly where the field is going in terms of the large registration trials that are ongoing right now. There are several combinations that are worth watching out for, and some of these, per their earlier development efforts, have now been presented in print. The combination of axitinib plus pembrolizumab seems to be highly active, and the phase Ib study was published in theLancet Oncologynot too long ago and demonstrated very high objective response rate, north of 70%, which is higher than what we have seen in untreated patients with ipilimumab/nivolumab. This is a small trial, it was only about 50 patients, but there was a notable CR rate included with that, and certainly it makes us interested to see if it might be even more effective. It is interesting to note also that on that trial, which granted brought on the more favorable risk type population, the benefit of the combination seems to extend to not only intermediate- and poor-risk but also favorable-risk patients who also had a response rate of about 75%. And that now has, of course, led to a large randomized study that has completed accrual, which compares the combination of axitinib/pembrolizumab with sunitinib in untreated patients, regardless of IMDC risk status.

There are various other TKI/I-O combinations that are showing similarly favorable early signals and are worth watching, another one being axitinib/avelumab, which has been very promising in the phase I setting and that’s also led to a randomized phase III study. And then thirdly, the combination of lenvatinib plus pembrolizumab. Again, this is the combination that in treatment-naïve patients has reported the highest objective response rate to date of over 80% in a very small sample size. Again, it is now being tested in a large randomized trial in comparison to sunitinib and on a third arm to lenvatinib plus everolimus. So, certainly, a lot to look forward to as we see these combinations mature and hopefully push the boundaries for our patients even further.

Transcript edited for clarity.