Bladder Cancer Update & Renal Cell Cancer Update, 2017 (Video Program)Perspective on the efficacy and tolerability of lenvatinib and everolimus as single agents and in combination
3:54 minutes.
TRANSCRIPTION:
DR LOVE: When I asked you if you had anybody you could present who got lenvatinib/everolimus, you said you hadn’t given it. So I’m curious maybe what your take is on the data and on that combination. DR RINI: Yes. So that’s a tricky one. It’s also just a randomized Phase II with only 50 patients per arm. And I think what was surprising to me, and maybe somewhat unbelievable is, there had been other trials of VEGF plus mTOR inhibitors. So there were 2 trials of bevacizumab plus either temsirolimus or everolimus, 2 large randomized Phase IIIs that were both uniformly negative. There have been other attempts to combine VEGF and mTOR inhibitors that were uniformly toxic. So there may be something special about lenvatinib that allows it to be combinable and allows it to be more efficacious, if you will, although I’m not aware of any biochemical properties. The PFS in that trial was initially reported over 14 months, which is longer than any front-line data we have. So I worry that it suffers again from what we see in randomized Phase IIs, is a small, perhaps unrepresentative data set, hidden biases and imbalances that just aren’t accounted for. And again, the level of toxicity is exceedingly high. Cabozantinib, I think, can be more toxic. Lenvatinib/everolimus is in order of magnitude more toxic, at least from the data that I’ve seen. Again, not having personally given it. So to me, I’m waiting for more data. I don’t really feel comfortable in a node-negative curative setting, giving people an exceedingly toxic regimen like that. DR LOVE: What do we know about lenvatinib as a single agent in RCC? DR RINI: Not much, I guess, is the short answer. So there was a lenvatinib monotherapy arm in that len/everolimus randomized Phase II. And it performed how you would expect a VEGF agent to perform in terms of response rate and PFS and things like that. So it wasn’t surprisingly good or bad in that setting. I’m not aware of other data. There may be some Phase I data that preceded the Phase II with lenvatinib single agent, but there’s not a wealth of data. DR LOVE: I just know it’s pretty impressive data in thyroid. DR RINI: Yes. DR LOVE: Which I’m not sure exactly — obviously it’s a different disease. But on the other hand, I’m not sure why it’s so effective in thyroid. You mentioned the fact that your take on the lenvatinib/everolimus, there’s a lot of toxicity. Do you think it’s more the everolimus in quality or TKI in quality? And what do you see with everolimus? DR RINI: I think my sense and my recollection is, it’s more TKI in terms of toxicity. I mean, everolimus by itself is fatigue, asthenia, some mucositis, a little bit of cytopenias, rash, anemia. So reasonably well tolerated. Kind of like a TKI, although, obviously, mechanistically different. And the combination is, again, TKI like fatigue and diarrhea I think were the predominant ones. I don’t remember the exact percentages, but I believe the incidence of Grade III or higher toxicity was over 70% — it might have even been close to 80%. DR LOVE: With the new TKIs, and particularly with nivolumab now coming on board, where does everolimus fit in your cascade of treatment? DR RINI: Yes. I think it’s really being moved out of the algorithm, honestly. I was never a big everolimus fan. I didn’t really find it quite active. I really didn’t have any patients who were long-term responders to that drug, unlike the TKIs, where we have a clinic full of patients who have 2-, 3-, 4-, 5-year responses. Obviously, those are exceptions. But over time, you get a sense that there are a significant subset. With the TOR inhibitors, I don’t think that’s true. There’s some data about patients with TOR and TSC mutations who can have long responses. But that’s almost anecdotal. So I think with the nivolumab and cabozantinib beating up on everolimus in their randomized Phase IIIs, I think most people are moving that to very late lines, if not out altogether. |