First-Line Treatment for Advanced RCC: Lenvatinib + Pembrolizumab


Centering discussion around the combination of lenvatinib + pembrolizumab in advanced clear cell RCC, Hans Hammers, MD, considers the role of this combination regimen in the first-line treatment setting.

Brian Rini, MD:
I’m going to turn it over to Dr Hammers, who’s going to take us through some of his arguments on why he would use lenvatinib-pembrolizumab in a frontline setting.

Hans Hammers, MD, PhD: Thank you, Brian. That was great. The discussion of the better immunotherapy backbone is going to continue until we have long-term follow-up data. It’s also going to be important in the context of the potentially more toxic triplet therapies, because 1 reason to pursue them is to keep a PD-1–CTLA4 backbone and then see how we can get away with the additional TKI [tyrosine kinase inhibitor]. This debate will continue for some time.

I was asked to talk about lenvatinib and pembrolizumab as a first-line setting. Before I start, I want to say that I like cabozantinib very much. Just because I’m not talking about it doesn’t mean I don’t use it. In fact, I’m a very avid user of that agent. It’s a very potent VEGF TKI in the salvage setting. This is 1 of the go-to drugs. Virtually all my patients who don’t respond to immunotherapy will eventually be treated with cabozantinib. I probably use nivolumab-ipilimumab more frequently than my colleagues here. But there’s a reason to go to PD-1–TKI combinations, particularly in patients with high tumor burden. In patients for whom disease progression early on is the highest risk for not doing well, I can certainly compromise the outcome if I don’t control that disease. The high response rate would attract me in this setting.

The lenvatinib-pembrolizumab regimen is the youngest of them. We don’t have as much follow-up as we do with some of the other agents. What attracts me is the highest response rate of 70%. The progressive disease is best response at 5%. The doubling of the progression-free survival, up to 2 years, is unprecedented. [This is compared with] a few months for cabozantinib over its control arm. It’s quite impressive in that regard. One reason is that at least among the 2 salvage agents that have been combined with immunotherapy, here you can combine it with full dosage—in fact, a higher [dose] than we use for lenvatinib in combination with everolimus. This is an agent where we don’t have to go in with a careful dose simply because it’s combinable. It combines well with immunotherapy. Most other TKIs, when you look at the AE [adverse event] tables, have an increased risk for liver toxicity. For example, when cabozantinib was combined with immunotherapy, they had to be careful with the dosing. There was some work to be done, and we still see an increase in liver toxicity. We don’t see that with lenvatinib, so it’s a bit of an outlier in that regard. In fact, they could increase the dose. This is a regimen in which the hallmark is to go in with in almost escalated anti-VEGF dosing schema. That’s what drives some of the adverse effects: higher risk for hypertension, dose reduction, etc. It’s a more intense regimen when you start. But from my perspective of using the agent in a setting of needing to control disease, it’s the perfect regimen.

We’ve learned a lot about TKIs. They’re very comfortable with a relatively quickly adjusting dosing and schedule to tolerability and quality of life in our patients. It’s important to keep a very close eye on blood pressure when you start with lenvatinib. In fact, optimize blood pressure before you start. That’s something that most of us aren’t scared of. We can adjust blood pressure medications, the schedules, and the dosing relatively quickly. It’s a very good agent. The half-life is another advantage of this agent. Compared with cabozantinib, which has a half-life of 5 to 7 days, the half-life of lenvatinib is roughly 24 hours. It washes out faster, so it’s easier to discriminate between the potential adverse effects—overlapping adverse effects between immunotherapy and the TKI-related adverse effects. For example, diarrhea is 1 of the more notorious adverse effects with lenvatinib. If you hold lenvatinib, the diarrhea goes away faster than if it was caused by the TKI. These are, in general, quite favorable properties of the TKI. Personally, I don’t think there’s much of a difference between nivolumab and pembrolizumab as the backbone. It’s mostly driven by the TKI and some of those properties. For those reasons, in my practice, if I go in the direction of the PD-1–TKI combination, I tend to prefer lenvatinib-pembrolizumab. We have to see how things are going to go. We’re going to touch on that with triplet therapies, but that’s my rationale to pursue that particular regimen.

Transcript edited for clarity.

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