Robert Motzer, MD: Let’s address some of the practical considerations and management of patients with lenvatinib-pembrolizumab. One of the points is the dosing of lenvatinib. There are different doses that we use in different regimens for RCC [renal cell carcinoma]. Tom, you’ve been involved in the development of lenvatinib-pembrolizumab and lenvatinib-everolimus. Can you speak to the dose of lenvatinib used in these programs and the rationale for it?

Tom Hutson, DO, PharmD: The company spent a lot of time trying, at least early in the days when it was being developed, to understand lenvatinib as a single agent. What makes lenvatinib special is that it does more than just inhibit VEGF receptor. One of the receptors, a putative receptor that potentially makes it a therapy for refractory disease or to help with angiogenic escape, is its ability to inhibit FGF, and there’s some early preclinical work that suggests that the higher dose levels were needed to appropriately inhibit FGF. You’ll see across a couple of cancer tumor types that it’s approved for, being given as high as 24 mg. The company has tried to take that understanding of higher doses needed to inhibit and try to find ways it can be combined with other agents and still maintain its efficacy but also be tolerable.

We saw with lenvatinib-everolimus in dose-finding studies—moving into the phase 2 trial that you led, Bob—the highest dose of 18 mg was the preferred starting dose. With concerns of wanting to hit the target, starting at the full dose is the recommendation, as it is for pretty much all the therapies, we’re utilizing for kidney cancer. But we go into this therapy with a conversation with the patients up front about what to expect. With this particular therapy, more than half of patients require a dose reduction, and that’s what we saw in the clinical trials. Patients going into it need to understand that we want to keep you at the full dose, but if we start having adverse effects that are affecting your quality of life, don’t fret; over half of patients were in that same situation. We were able to lower the dose, and they were able to stay on therapy with continued efficacy, and the discontinuation rate was 20% or less when 1 employs dose interruption and dose reduction. This carried over into the lenvatinib-pembrolizumab story, and the original dose-finding studies with that combination suggested that lenvatinib at 20 mg would be the go-to dose. Thus, it’s there.

Naturally, there’s a little confusion. It’s 18 mg for 1, 20 mg for another, and then 24 mg. But the concept has been trying to give as much lenvatinib as possible to inhibit the FGF, which is that extra receptor that we think is valuable to inhibit beyond VEGF. Studies that have been done trying to show that lower doses may be as efficacious haven’t been fruitful with lenvatinib, and I’m pointing to 1 of our colleagues,…, phase 3 trial of lenvatinib-everolimus, looking at 2 different dose levels. There were concerns that it wasn’t even more tolerable, but it definitely wasn’t as efficacious, so the decision is to stay at the full dose. As long as 1 has a conversation with patients going into the therapy, there’s an expectation that you’re going to have a dose reduction. Patients understand that and are willing to go on that journey with you.

Robert Motzer, MD: Bradley, in terms of the important adverse events with this program and the reasons for dose reduction for lenvatinib, in your experience what have been the adverse events with this particular combination, lenvatinib-pembrolizumab, that we need to make patients and treating physicians aware of? What adverse events stand out in your experience with this program, for this regimen?

Bradley McGregor, MD: In the short term, I’ve been quite impressed with the hypertension. The degree of hypertension seen with lenvatinib seems to be a little higher than I see with some of the other VEGF TKIs [tyrosine kinase inhibitors]. Being on top of that blood pressure early and monitoring that blood pressure, I tell patients to be aware of this, calling…with the values and trying to make sure you’re aggressively managing the blood pressure is important. The other thing the patients see early on is going to be some of the GI [gastrointestinal] symptoms, bloating, abdominal discomfort, diarrhea—that’s been pretty common—as well as just some general asthenia and fatigue. Those are the things that happen up front and that require some dose reduction simply from the lenvatinib standpoint.

One of the toxicities that we appreciated long term with lenvatinib has been the long-term risk for proteinuria and some renal damage. Just make sure you’re monitoring those urinalyses, getting that urine protein-creatinine ratio. When you have a median PFS [progression-free survival] of 24 months, these patients are on this therapy for a long time, so you’re going to be at risk of these long-term toxicities with VEGF therapy. That long-term management is important. The fatigue does seem to be something that can be OK—you may be great for 18 months, and at month 19, you hit that wall and get that fatigue. Always be aware of these things, and always think if the fatigue is from the TKI or if it could be something from the I/O [immuno-oncology] and adrenal insufficiency or thyroid, along those lines.

Robert Motzer, MD: Thanks very much. One of the new aspects of patient management has been that outpatients are on therapy for long time periods because that they’re enjoying long-standing responses, a mark of success. Eric, what do you see for TKI–I/O therapy? What do you see as the duration of therapy for patients with pembrolizumab and lenvatinib or with the other TKI–I/Os in terms of how long do they stay on the I/O and do you continue on with the TKI? What’s your take in terms of the duration of therapy with lenvatinib-pembrolizumab and the other TKI–I/O combinations?

Eric Jonasch, MD: A number of these studies have been designed to have discontinuation of the PD-1 blocking agent after 2 years, which is interesting. From a health economics perspective, it might make a certain amount of sense. That’s the way these trials have been designed. Whether or not that makes biological and mechanistic sense, whether you need the PD-1 blockade after a period of time—those are unanswered questions. Patients are obviously interested in optimizing their care and the continuation of the benefit. It ends up becoming an interesting conversation with the patient when you do reach that 2-year mark, about continuing or discontinuing the pembrolizumab.

For the TKIs, when we were only giving these, I have some patients who have been on sunitinib, for example, for over a decade. If you manage the toxicity and you find that sweet spot from a dosing and scheduling perspective, patients can manage these adverse effects for a long time. Unfortunately, there aren’t perfect therapies from an adverse-effect perspective, but if we manage them right, you can keep them on for a long time and still maintain quality of life.

Robert Motzer, MD: That’s great. Are there any patients for whom you would say, “They can’t be offered TKI–I/O combinations,” based on other medical conditions or any other factors. Is there a group of patients whom you would not offer this sort of therapy to?

Eric Jonasch, MD: A person who has refractory hypertension or very hard-to-manage hypertension de novo would have a hard time with this. As Brad mentioned, the proteinuria. If you have somebody who has other renal issues that you could rapidly anticipate are going to become bigger problems long term, that would be a person who I’d also steer away from this. We didn’t talk about ipilimumab-nivolumab much. There are other regimens, like ipilimumab-nivolumab, where you can get good, durable responses in this patient population. There are other paradigms you can think about in which you aren’t stuck giving a TKI. Although I have to be frank, Bob: it’s pretty rare that I come across a patient I can’t give an I/O–TKI combination to.

Transcript edited for clarity.