Reviewing Data on Lenvatinib plus Pembrolizumab Combination Treatment for Advanced Renal Cell Carcinoma - Episode 17

The Exciting Future of Advanced Renal Cell Carcinoma Management

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A panel of oncologists look at what’s in the pipeline for advanced renal cell carcinoma, including trials and treatment options.

Brian Rini, MD: What trials are you excited about that are ongoing or maybe trials you’d like to see done in the advanced kidney cancer space?

Mehmet Asim Bilen, MD: Now, again, the future is bright, Brian. We have number of very important trials going to read out soon.

Brian Rini, MD: If a patient fails either an IO [immuno-oncology]/IO or an IO/TKI [tyrosine kinase inhibitor] regimen, do you have a way that you’re routinely treating those patients?

Mehmet Asim Bilen, MD: Yes, there is not Brian. And maybe another trial we can highlight in the same angle is [the] PDIGREE trial, starting off front IO/IO and depends on the response whether escalate or de-escalate. Those studies are going to help us [with] how to sequence. Overall, some of us felt like if this is a refractory from IO/IO, then there is no more IO. Then just go straight TKI. I still try to continue IO and maybe add TKI on top of it just to see whether there is some synergistic effect from VEGF in the immunotherapy component based on the biology we know on the CDA T cells and TREX and effect of the TKI on those. But hopefully, those trials will read out soon and we’re going to have more data in the SALVAGE setting. What do you think?

Brian Rini, MD: Yes. I agree. We’ve had a lot of data in the frontline setting over the last few years and not a whole lot in the refractory setting and that’s an important clinical arena. It’s all over the map. I tend to just give TKI monotherapy in the refractory setting, waiting for more data. But a whole lot of people will give IO/TKI regimens or continue the IO as you’ve said and it’s just a very large clinical need that we have because we want to balance benefit and risk. It’s sometimes tempting to just keep throwing drugs at patients, but obviously there’s toxicity limitations as well.

Moshe Ornstein, MD: We’ve spent the last 5 years excited about IO-based combinations in terms of doublets. With ipilimumab [Yervoy] and nivolumab [Opdivo] as the only IO/IO and then a host of IO/TKIs that we previously mentioned. And there’s this lingering question about if 2 are better than 1, are 3 better than 2? And that’s the COSMIC-313 trial. It’s looking at cabozantinib [Cabometyx] plus ipilimumab/nivolumab vs ipilimumab/nivolumab. And we didn’t talk a lot about the IO/IO regimens…but ipilimumab/nivolumab does have the longest follow-up data. We have the best sense of how patients are doing at 5 years and beyond, and those data are impressive in terms of long-term durability. The question is, does adding a TKI to that regimen, can that help give it a boost upfront as well? And the IO/TKI regimens are certainly better for the, that response rate upfront, that PFS [progression-free survival]. Can we get that upfront benefit with a triplet and also have that long-term durability of response that we see with ipilimumab and nivolumab? I would say that’s probably what the field as a whole is waiting to see most before moving forward with a lot of the other trials. And that has potentially practice changing implications depending on what the results look like. And 1 thing that we don’t talk about enough in this space, or we talk about enough but we get very frustrated about, are biomarkers. And we talked about a bunch of IO/TKI regimens, there might not be a biomarker to differentiate 1 IO/TKI from another IO/TKI. But 1 can hypothesize that there’s a biomarker to differentiate an IO/TKI regimen from an IO/IO regimen. I know the trial that you’ll lead, and we’re hopefully going to open here too, the OPTIC trial, which looks at these rinimotser, genomic cluster signatures. And basically, will decide treatment in the frontline setting based on a genomic signature for a patient, if a patient’s more likely, for instance, to respond to an IO/TKI vs an IO/IO. Those are the 2 main things: looking at triplets and then looking at biomarker driven studies.

Brian Rini, MD: I agree. Clearly triplets are where we’re headed. COSMIC will be the first data reported this calendar year. Merck has a large triplet trial. You can imagine there’s others planned. We’ll see. It’ll get more interesting because there will be some limits on how many drugs we can stick together in patients, both for toxicity reasons, financial reasons, practical reasons. COSMIC will be the first of that data, but certainly not the last. I agree with you about biomarkers. We talk about it, but we haven’t done anything about it. I’m hopeful before I retire that we’ll have a clinically useful biomarker in kidney cancer. I believe that’s the case, but we just haven’t done it so far. And then maybe the last thing I’ll mention to sign us off is frontline kidney cancer has had a ton of development over the last 5 to 10 years, but refractory kidney cancer not so much. As we move more drugs to the frontline that leaves less for the refractory lines. There are 2 trials randomizing IO-refractory patients to IO/TKIs versus TKIs. And that’s a main question in RCC [renal cell carcinoma] is do patients just get 1 shot at that immune-based regimen? One shot at cure, if you will? Or can we salvage some of those patients, potentially durably with these immune-based combinations? And it’s interesting, people have very strong feelings on either side whether those trials will be positive or negative. They’re accruing now I believe, and I’m assuming in a year or so, as those data come out, that’ll be an important building block of sequential therapy, which unfortunately is the reality for most patients. Even as we have better frontline and curative frontline regimens, the reality is the majority will require subsequent therapy.

Trancript edited for clarity.