Evolving Treatment Paradigms for Renal Cell Carcinoma - Episode 7
Daniel George, MD: In this session, we’re going to cover some of the strategies for metastatic renal cell carcinoma that involve I-O therapies in combination with VEGF-targeted therapies. I want to talk a little bit about some of the trial designs and some of the endpoints and walk us through a series of ongoing studies now, both at phase I all the way to phase III levels. Toni, can you summarize this field where we are?
Toni Choueiri, MD: After CheckMate-214 with nivolumab/ipilimumab and, currently not published yet, IMmotion-151, a VEGF ligand inhibitor bevacizumab plus PD-L1 inhibitor atezolizumab versus sunitinib. Again, the primary endpoint was met. We are waiting for the overall survival endpoint, although there are some discrepancies whether you look at progression-free survival by independent review or investigator review. So that’s another 2 out of 2 that are now positive. What’s going to come in the next few years, and perhaps less, is other PD-1, PD-L1 inhibitors in combination with VEGF TKIs, rather than the VEGF ligand inhibitor bevacizumab and all against sunitinib. Pembrolizumab is being combined in 2 trials: one with lenvatinib and the other one with axitinib in the front line against sunitinib with different endpoints; sometimes progression-free survival, overall survival, co-primary endpoints. They’re all supposed to read in the next few months to a year. There’s another study that compares cabozantinib plus nivolumab, called CheckMate-9ER, versus sunitinib, same thing. And we have some studies planned in the Alliance.
Daniel George, MD: Yes. Walt, some of these I-Os plus VEGF or VEGF TKI studies are looking at progression-free survival as an endpoint. What do you think about that when you think about these patients that we anticipate treating with a series of sequential therapies? Is that going to be a strong enough endpoint? Are we going to need to see overall survival in these studies?
Walter Stadler, MD: I think that in the context of ipilimumab/nivolumab, showing a true survival advantage, these trials have to show a survival and an advantage in order to be practice changing, especially in the frontline setting where many of these trials are being done. When they were designed, progression-free survival was considered to be an appropriate intermediate endpoint, and there’s some data that are, but I think in the context of this new data, it’s just not good enough. Toni already brings up the fact that in the atezolizumab/bevacizumab trial, the primary endpoint of investigator assessed progression-free survival was positive but centrally reviewed progression-free survival was not positive. I think we’re going to have to see what the survival data show in order to try to interpret that. Likewise, with the other studies, we’re really going to have to see that. Since the control arm is sunitinib, and since we have this goofy FDA-mandated drug schedule of 4 on, 2 off, and not all patients can tolerate that, and then goofy drug modification and dose reductions in those trials, this really sort of leads to that control arm being everybody’s favorite whipping boy because it appears to be the easiest thing to beat as well as being the standard of care. Now in that context of all these issues, I do believe that survival has to be the endpoint.
Daniel George, MD: This was brought up earlier with ipilimumab/nivolumab, that there’s a concern about the balance in the efficacy versus the toxicity. Rich, do you have a sense of the toxicity that we’re seeing, at least from the IMmotion-151 trial and maybe from the early phase I studies with these combinations of I-O and VEGF TKI?
Richard W. Joseph, MD: Yes. It’s first important to comment on the overall grade 3/4 toxicities of checkpoints versus sunitinib. Sometimes the checkpoints get a worse rap. But when you look at the total grade 3, 4 AEs (adverse events), there’s really not much of a difference and perhaps even less in the total grade 3/4. But there is more of a need to stop I-Os. Treatment discontinuations is higher in that, so I think there is a lot about how you want to think about AEs, whether it’s grade 3/4 versus discontinuation. In regard to atezolizumab and bevacizumab, I think it is probably one of the most well tolerated combinations, and that’s being presented here as well with a quality of life. When you’re thinking about quality of life, and especially in a patient maybe with poor performance status who may be elderly and that’s a quality that’s more important, that might be one of the more ideal regimens.
Daniel George, MD: Toni, do you have thoughts on these combinations?
Toni Choueiri, MD: I do agree. I think overall survival is going to be driving a lot of these precision on what to use. I agree with Walt. But also, there are trials where the primary endpoint is powered in PD-L1—positive patients. I can tell you that’s actually very smart and very interesting. Why is that? Because we know, from some days that we worked on with COMPARZ and others, that PD-L1–positive patients do not do well at all with sunitinib. If you look at the median PFS, it’s similar to the CABOSUN study. So, could we have a significant PFS advantage that will translate with a certain combination, VEGF/I-O, to select patients?
Richard W. Joseph, MD: But how are you going to use the VEGF if their PD-L1 marker was very different than anyone else’s?
Toni Choueiri, MD: Absolutely.
Richard W. Joseph, MD: So now when you send your tumor, are you going to send it for 3 different PD-L1s?
Toni Choueiri, MD: Well, hopefully with the combination, the Compendium (NCCN Biomarkers Compendium) use of the biomarkers…
Richard W. Joseph, MD: But maybe you want to pick from all 3 different regimens?
Toni Choueiri, MD: Right. I assume with avelumab/axitinib, which is an active combination, if this proves in PD-L1—positive disease to be really significantly superior—and it could be that patients don’t do well with sunitinib here—then hopefully we’ll have the companion biomarker from that trial. But I want to add: One of the issues we’re going to have is how to manage is side effects, and I want to give one example that illustrates my challenges here when I have a patient on a VEGF TKI/I-O. It’s the diarrhea, because diarrhea is the side effects that could be from I-O with a colitis. The treatment is very different than a diarrhea, which is very common with all VEGF TKIs from something else, and sometimes you cannot tell and it’s really challenging. I usually start by stopping the TKI, observing the patient very closely. The other one that is less common is the hepatitis, grade 1/2 due to the TKI. Compared to a brewing immune-related autoimmune, hepatitis from checkpoint blockers is very different.
Daniel George, MD: I think that’s a great point, and it’s really important to recognize that there could be some synergy, not just on the efficacy side, but also on the toxicity side. The phase I studies may not show it, and we may be fooled a little bit by atezolizumab/bevacizumab because that’s a better tolerated VEGF strategy. With these TKIs, we may end up seeing a little bit more of this. So, I think it is an important issue to look for.
Transcript Edited for Clarity