Toni K. Choueiri, MD

 Toni, you’re the leader of the COSMIC-313 study and also the belzutifan studies. Do you want to speak to those trials in terms of where they stand and what people should be watching for and anticipating with those studies? 

Thank you, Bob. COSMIC-313 is a study that asked the question, “Is 3 superior to 2?” We went through this lovely talk from 1 to 2, to perhaps a 3, where cabozantinib is going to be added to nivolumab and ipilimumab vs controlled nivolumab and ipilimumab and modern control finally, not sunitinib. The study just finished. Accrual about to wrap up was primary end point PFS [progression-free survival], secondary end point OS [overall survival] with over 800 patients. In intermediate and poor risk, it’s important to see if we can push survival more and push the CRs [complete responses] more. 

The second study you alluded to is a study with a totally new agent. Here, we’re not adding drugs that are already approved as single agent or combo. Belzutifan is an HIF2 inhibitor, and Tom in a very eloquent way discussed the biology of clear-cell RCC [renal cell carcinoma] initially. HIF2 is a transcription factor thought for a long time to be completely undruggable. HIF2 doesn’t have those small pockets where the drugs could go until recently, with elegant crystallographic work showing it could. We could have molecules and the second-generation molecule MK 6482 belzutifan showing a response rate and a refractory population of clear cell RCC of more than 50 patients. It’s mostly at 25% with quite tolerable adverse effects. You don’t have diarrhea, hypertension, and anemia, which is on target because you target downstream HIF2. 

Down regulating actually could be a pharmacodynamic biomarker with these drugs. Hypoxia was another, which is likely on target. Toxicity was HIF2 physiology. We’re taking this to a phase 3 trial post-VEGF inhibitor plus PD-1 inhibitor, belzutifan against everolimus later lines. And belzutifan is being introduced first line and second line with other studies that are being planned. The 1 thing about this treatment, as Tom mentioned, is that the time to respond seems to be not 2 to 3 months with single-agent TKI or less than 2 months with the combos, but it takes time—around 6, 6½ months with it. It doesn’t work quickly if you want an average. But it’s a nice set addition, and I hope this would be there. Data also in VHL [von Hippel–Lindau] syndrome associated clear-cell RCC, where we saw some image of blastoma is shrinking. Just yesterday or the day before, there was an FDA note about. VHL syndrome is scheduled, I believe in September. This is all good news for the renal cell cancer field.

This transcript has been edited for clarity.

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Toni Choueiri, MD, closes with promising new studies that will impact metastatic clear-cell renal cell carcinoma therapeutics in the years to come. 

Promising Studies for the Future of Frontline mRCC

 I use both in my practice. I try to keep nivolumab-ipilimumab in the approved indication: intermediate and poor. I don’t use it in good risk. I don’t think it’s a mistake, because of the CR [complete response] rate, but I do not. That’s 1. In patients with sarcomatoid histology, it is the combo that should be the best standard because of the complete responses of 19% from CheckMate 214. That’s the second 1. The third 1, in patient with tumors that are not progressing rapidly, it was significant disease volume. Although we’ve seen responses with nivolumab-ipilimumab, I lean toward VEGF–TKI [tyrosine kinase inhibitor] rather than nivolumab-ipilimumab.

That’s an area where you’re going to get different opinions from all our friends and colleagues. I still think there’s an advantage. Especially with CRh [CR with partial hematologic recovery] and I/O [immuno-oncology] TKIs, the degree of shrinkage and the clinical benefit rates are excellent. You can always carve out patients that could be treated with just a single-agent TKI. I do have some of these patients in my practice, but the standard should be the default, should be I/O–TKI vs the other way around. Go into a favorable-risk situation if you made the decision to treat and not just monitor. The majority of people will make the decision to go forward with treatment that an I/O–TKI should be your default. Then you can carve out from them a smaller group that may benefit with just the TKI.

For instance, patients I just saw 2 types of patients today in clinic. One was an organ transplant patient. Obviously with a favorable-risk patient, you’re going to avoid your checkpoint inhibitor. Giving a single-agent TKI is reasonable. Another group that I’m leaning on, that we have the most data in the setting, is patients whose disease is predominantly in the remaining kidney. They’ve had a renal cell. They’ve lost a kidney from that. They have 1 kidney remaining, and it has tumors. And you’re channeling them like a patient with VHL [von Hippel–Lindau], and you’re trying to be careful and preserve kidney function. But sometimes we end up having to put them on a systemic therapy with the hope of making tumors they have smaller to allow a percutaneous intervention or just to stabilize things.

I’ve had patients on a single-agent VEGF TKI, and most of us are aware of the data coming out of Houston, Texas, in the past where that was somewhat instrumental. They’ve done a lot of that work on looking at the degree of shrinkage in the tumor from the TKIs. I’m sure I/O–TKIs do that at some level too. I’m just not as familiar with that degree of shrinkage. I’ll have those patients on a single agent. But that’s the minority. The default for me, mostly is I/O–TKI. If a select group seems to be ideally suited for just a single-agent VEGF inhibitor, then I would consider using traditional sunitinib or pazopanib.

I see a role for that, especially for the follow-up, and we understand the CLEAR data better. Right now, the agent with the longest follow-up and the most attractive 1 is the durability of the response that exists with the I/O–I/O. What drives that, the ipilimumab or not, no one knows. There are triplet studies planned that add ipilimumab into an I/O–TKI regimen. It will be interesting to see the benefits. I completely agree with Toni. I usually agree with Toni on most things. But the way he unpacked that is a reasonable approach, where you are using both. You can look at the way that the patient is presenting. Do they have time? The difference is the I/O–I/O combination is going to work in less people.

The clinical benefit rate is less. Do you have a patient who can afford to have I/O–I/O not work? As the volume of disease sets, it would allow that. If you have someone on the other end of the spectrum, where you really need to have an insured a rapid response, we see the data, and we didn’t talk about it at the time to response for lenvatinib-pembrolizumab. The cabozantinib-nivolumab is probably pretty quick. You can get these really symptomatic patients under control quickly.

The other thing that we also didn’t mention is expanding understanding about stopping it. How do you go about stopping an I/O–TKI vs the I/O–I/O? Some people would say it’s a disadvantage to be on an I/O–TKI and try to stop. Other people would say it’s an advantage because you could go off the I/O or the TKI and do it that way. There’s a lot that we have to understand about these drugs. If I was predicting that CLEAR study on the CheckMate 9ER trials to continue to evolve, where there’s evidence of durability of response, the more durable those responses are, the less I’d be inclined to use an I/O–I/O in those setting. But we don’t know that yet.

Both nivolumab + ipilimumab and lenvatinib + pembrolizumab TKI/IO combinations are discussed, with patient selection and appropriate use being the focus. 

Using TKI/IO Combinations in Patients With mRCC 

 Tom, you’ve used lenvatinib for over a decade and are probably 1 of the heaviest users of lenvatinib in the United States. What has been your take on dosing of the lenvatinib and adverse effects within the class that you see as favorable or unfavorable for lenvatinib in combination, with everolimus and pembrolizumab?

 You all hit on things correctly. Diarrhea, hypertension, and fatigue are key ones. I’ve never run into a situation, thank goodness, where any type of renal proteinuria has resulted in an impairment and kidney function that impacted the ability of the patient to receive other therapy. Mind you, many of our patients have impaired kidney function with 1 kidney, and we insult them with IV [intravenous] contrast and other things that can precipitate worse things. 

As far as tolerability goes, some of the newer, more active agents have stepped up a little the degree of adverse effects that patients experience, whether that’s with the cabozantinib-type drug as a single agent or in combination. Same with lenvatinib-everolimus or lenvatinib-pembrolizumab. We go into those therapies starting with an idea that over 50% of patients require dose reductions. I’ve found that instructing the patient at the beginning and painting a picture for them that as a field, we try to start at the highest dose possible in most situations to get them to that first scan, to see maximum benefit. The expectation is that more than half of people will require fine-tuning of the dose or a dose reduction. 

To start with the lenvatinib, I understand that there may be a formulation difference in the tablets. But for the lenvatinib-everolimus combination, when you come with the blister pack, you have dose levels. It becomes a very easy way to lower from 18 to 14 and then 10. We’ll see how that gets packaged out there, but it’s ease of use from that perspective. It’s something I’ve noted in my patients. If you go into therapy with the right mindset, trying to optimize the efficacy by maintaining dose intensity but understanding and making sure the patient understands that if they are experiencing an adverse effect, to bring it to our attention. That is expected in some regard.

In the clinical trials, half of patients did require dose reduction. And as Toni mentioned, the discontinuation rate by doing so is low enough that it makes you feel that, “Hey, if someone runs into adverse effects, I can dose reduce. I can handle it with supportive care to the point that the majority of patients are able to stay on therapy.” The frequency of this happening in the clinical trials is high, and patients still get a benefit. You have a lot of evidence that when you talk to your patient, they shouldn’t be afraid. Sometimes patients are if lowering the dose means they’re not going to respond. You have evidence to say that that’s not the case. We need to make the therapy tolerable to you so you can stay on it for as long as possible. We shouldn’t worry as much that it’s somehow going to get a lower efficacy. It’s a doable regimen.

To be honest, 1 of the drivers is something we haven’t mentioned: the experience of the prescriber. The newer drugs aren’t necessarily out there as long. Many of the prescribers aren’t as familiar with them. As we learn with sunitinib, sorafenib, and pazopanib that some of the adverse effects that were most troubling at the beginning of the approvals when they were first used have become less and less. We see adverse-effect profiles reduce as we’ve done later trials with these agents as comparators. There’s a learning curve when it comes to these agents. But the lenvatinib, although there are toxicity concerns, isn’t so far out there that it couldn’t be used in our patients.

Dosing strategies to achieve strong efficacy and ameliorate adverse events with the combination of lenvatinib + pembrolizumab in metastatic clear-cell renal cell carcinoma.

Dosing Strategies for Maximum Efficacy With Len + Pembro

 In terms of toxicity overall and adverse events, there are TKI [tyrosine kinase inhibitor]–driven toxicities but also some immune-related adverse events. You have to use some of the art because some toxicities are overlapping between I/O [immuno-oncology] and TKI. Nothing really much different that diarrhea and liver function test elevation could be due to pembrolizumab or lenvatinib, while hypertension is due to lenvatinib. Treatment-related AEs [adverse events] were higher in all these trials of VEGF–I/O. It’s hard to compare them because the reporting is different.

I look at the treatment-related AEs leading to discontinuation of either drug or both drugs. Overall, these tend to be less than 10% for both drugs. The question that is important is the doses, which are different from the TKI. You start at 20 mg when you combine with pembrolizumab. When you combine with everolimus, it’s 18 mg. When we combine cabozantinib with nivolumab, it’s 40 mg. Which dose is right? Is it the pembrolizumab combination with lenvatinib—with lenvatinib at 20 mg—the right dose because a significant number of patients needed dose reduction?

In my book, I start at the FDA and what the trial did and I go down. It definitely needs folks who are well versed in managing the adverse effects of I/O but also the TKI, because with the TKI it’s always about the exposure. It’s not just the dose but the exposure. There’s a lot of trial and error. Today, 15 years after sunitinib, we don’t know what the right dose of sunitinib. We haven’t solved that. So we have to be very careful because the goal is to keep the patients on the regimen for the longest period of time—let’s say first line with a manageable adverse-effect profile and an acceptable quality of life. That’s the goal.

 In your own experience, for people on this program, what adverse events for the community oncologists did you find to be prominent? People have talked about the proteinuria as being a standout with lenvatinib.

 I have seen the typical TKI overall adverse effects: diarrhea, hypertension, stomatitis. I agree with you. I’ve seen also dysphonia, which I’ve also seen with axitinib. I have seen proteinuria to be higher than I would expect with sunitinib or cabozantinib, for example. I have followed the protocol because of our experience from the CLEAR trial on what to do. But I would argue—maybe not first line for proteinuria, which is what I would do, but for later line—that the proteinuria in use by VEGF-TKI is not the same proteinuria from chronic diabetes, etc. Although there are some reports with bevacizumab of proteinuria in a setting if you want of TTP [thrombotic thrombocytopenic purpura] and HUS [hemolytic uremic syndrome], which is a totally different ballgame. But I’ve seen a lot of patients on TKI in general at the later line who are responding and have tolerated 3 or 4 g without major effects on the kidney function or others.

So it’s manageable. We probably need to be a bit more careful if it’s a first line, because first-line patients’ median survival is quite prolonged, luckily. But I would not have a knee-jerk reflex to completely stop the drug and move on if there is a gram of protein. I would make sure first to do a 24-hour and work with the nephrosis. Sometimes, because their blood pressure is hanging in the 160-to-170-mmHg range, they’re not appropriately treated or diabetes is not well controlled. You have several contributing factors. That’s my approach.

 The hypertension occurs early with this combination. Physicians need to be particularly vigilant about hypertension early. But from my own experience, the trial results reflected this very low incidence of liver toxicity with lenvatinib and also with lenvatinib and pembrolizumab, as well as the lack of high-grade hand-foot syndrome. I rarely see that with this combination of myelosuppression. Some of the standouts in terms of the favorable parts of this combination were those particular aspects of the toxicity.

Hutson and Choueiri compare the safety profiles of lenvatinib + pembrolizumab against other TKI/IO combinations for patients with metastatic clear-cell renal cell carcinoma.

Toni K. Choueiri, MD | Authors

Articles

Promising Studies for the Future of Frontline mRCC

Using TKI/IO Combinations in Patients With mRCC

Dosing Strategies for Maximum Efficacy With Len + Pembro

Safety Profile of Len + Pembro From CLEAR in mRCC