Future Strategies in Kidney Cancer Treatment - Episode 5
James J. Hsieh, MD, PhD: The rationale to combine a different targeted therapy is really based on mechanism. We are not just combining drugs because they are the available drugs. We’re combining them rationally based on mechanism. Lenvatinib is good because it has 2 actions: It works on the VEGF receptor and also works on the FGF receptor. So, there are 2 mechanisms. mTOR inhibitors are the third mechanism.
When you want to combine drugs, you need to figure out whether you’re combining different mechanisms instead of combining the same mechanism. When you combine the same mechanism, a lot of time, you are increasing the toxicity; you’re not actually generating more. So, the key is to combine different mechanisms. This is why if you want to use mTOR inhibitors. mTOR is one pathway, and the VEGF is another pathway, and lenvatinib has VEGF plus FGF. FGF is important in kidney cancer because FGF has been shown to be involved in the bypass when a patient develops resistance to an anti-VEGF type of treatment.
Thomas Hutson, DO, PharmD, FACP: There is strong evidence in support of the combination of lenvatinib and everolimus. mTOR inhibition has been a main target with clinical efficacy proved in phase III trials of 2 agents: temsirolimus in the poor-risk frontline setting, and based upon the RECORD-1 study of several years ago, and everolimus as an agent with activity in the refractory patient population. Some of that clinical evidence in support of mTOR was based simply on observations, over the past several decades, that patients with poor-risk disease or those who develop refractory disease have increased P10 and increased mTOR activity. This could be observed in renal cell lungs.
Combining that pathway inhibition with VEGF inhibition has always been of interest. Unfortunately, a series of trials, reported at meetings such as ASCO and ESMO several years ago, showed that combinations with everolimus and temsirolimus were not viable—excess toxicity without much gained efficacy.
Lenvatinib is a novel agent that inhibits VEGF at very potent levels, almost as potently as any of the single VEGF-targeted agents, but also inhibits FGF. And FGF is a potential escape pathway—also known as angiogenic escape—that cancers utilize, especially when they’re becoming refractory. So, with the combination strategy of lenvatinib in the mTOR everolimus, one is targeting essentially 3 different pathways: their traditional VEGF pathway, which we know is associated with the VHL mutation, and it has strong rationale as a pathway for kidney cancer; mTOR inhibition, which we know is also important, especially in a subset of patients who may be P10 over-regulated or have an mTOR-dominated disease; as well as FGF, which may be an angiogenic escape pathway. That combination has proved to be efficacious at a level that we couldn’t even have imagined before we did the trial.
Martin H. Voss, MD: In considering lenvatinib and everolimus for our patients, the Eisai 205 study really has a few important take-home messages. It’s important to keep in mind that this is a randomized phase II study, so we have to take the results with a grain of salt, and these are not very big patient numbers. But what we did see for the combination of lenvatinib and everolimus were surprisingly high objective response rates on the RECIST assessment: over 40% objective response and a very low primary progression rate, meaning the likelihood of a patient having progressive disease at the best objective response was less than 10%, which is lower than other approved agents on the market.
The second take-home message for that study is that the toxicity was higher than what we’re used to seeing with monotherapy. About 25% of patients on the trial had to discontinue study treatment altogether due to toxicity, and about 70% of patients needed dose reductions at one point or another, had they been randomized to the combination.
So, for my own practice, I keep those 2 things in mind. The highly active combination is likely to yield tumor shrinkage, and it can be helpful in patients who are highly symptomatic from rapidly progressive disease. At the same time, we have to keep in mind that it can be quite toxic, and the patient has to have a good performance status to be considered for it, in my mind.
Thomas Hutson, DO, PharmD, FACP: The safety profile of lenvatinib and everolimus is not unsurprising, given the toxicities that we see with both agents as individuals. In the trial combination, I was surprised to see, and happy to report out as one of the study investigators, that the toxicity was just additive. There was no unexpected toxicity. The rationale is simple. When you take 2 agents that have toxicity and combine them at near full doses, you’re going to have additive toxicity. There was nothing surprising. And our physicians and the nursing staff taking care of patients will be readily able to care for the toxicity seen in patients receiving the combination.
In the clinical trial, the dosing strategy moving forward was to use lenvatinib at 18 mg per day combined with a single dose of everolimus at 5 mg per day. It’s packaged in a very simple manner, in a blister pack with a 10-mg pill of lenvatinib, a 4-mg pill of lenvatinib, and a third column with 4-mg pills of lenvatinib. So, the total dose is 18 mg. You would start your patient off at that dose level and then lower down to the 14-mg or the 10-mg, based on unacceptable toxicity.
Everolimus was supplied separately with a separate prescription at 5 mg per day, and generally, it’s a low enough dose of everolimus that your traditional mTOR-related toxicities—mouth sores hypercholesterolemia, etc—that one would see don’t appear as commonly in this regimen.
Transcript Edited for Clarity