Lenvatinib Regimen Setting Pace for Emerging Combos in Kidney Cancer

Thomas E. Hutson, DO, PharmD

The dual inhibitor combination of lenvatinib (Lenvima) and everolimus (Afinitor) is becoming an essential second-line treatment option in advanced renal cell carcinoma (RCC), and research to move the regimen into frontline settings is underway.

In May 2016, the FDA approved the 2-drug regimen as a treatment for patients with advanced RCC following prior antiangiogenic therapy. The pivotal phase II trial that resulted in regulatory approval for the combination, known as Study 205, demonstrated that lenvatinib plus everolimus reduced the risk of progression or death by 63% versus everolimus alone.

Additionally, the median progression-free survival (PFS) with lenvatinib plus everolimus was 14.6 months versus 5.5 months with everolimus (HR, 0.37; 95% CI, 0.22-0.62).

“The efficacy speaks for itself with this combination,” says Thomas E. Hutson, DO, PharmD, director of the Genitourinary Oncology Program, Texas Oncology-Charles A. Sammons Cancer Center at Baylor University Medical Center, of the Study 205 findings. “Combination therapy is here to stay for kidney cancer.”

With that advancement making an impact in clinical practice, researchers are also exploring the potential the combination could have in the frontline setting. The ongoing multicenter, randomized, open-label, phase III CLEAR trial, also known as Study 307, is comparing the efficacy and safety of lenvatinib in combination with either everolimus or pembrolizumab (Keytruda) versus sunitinib (Sutent) as first-line treatment in patients with advanced RCC (NCT02811861).

Hutson sat down for an interview with OncLive to discuss the power of this combination of lenvatinib and everolimus during the 15th International Kidney Cancer Symposium in Miami, Florida. The oncology expert also shared his insights on when and how the regimen should be used and on plans for the next steps for the practice-changing therapy.

OncLive: What impact has this combination had thus far on the field of RCC?

Hutson: It is a very unique combination; it is the only combination that targets the VEGF pathway and the mTOR pathway. Those are the 2 pathways that we believe to be the most important in tumorigenesis in RCC. It is those 2 pathways that we already have inhibitors of which have shown efficacy, and those pathway inhibitors have been approved around the world.

So this combination employs 2 strategies: Lenvatinib provides VEGF inhibition and it also has the ability to inhibit FGF, a pathway that we think is important in angiogenic escape. That is coupled with inhibition of mTOR with everolimus. That combination was the first combination approved in kidney cancer and it is the latest therapy for kidney cancer.

What was so compelling about the findings in Study 205?

The original randomized trial that resulted in regulatory approval in the United States was a phase II study. In that study, patients with clear cell RCC who had received 1 prior VEGF line of therapy were randomized to receive either the combination of lenvatinib and everolimus versus everolimus versus single-agent lenvatinib. There was a total of 50 patients per arm.

The trial reached its primary endpoint of a statistically significant prolongation in PFS, compared with the standard of care of the day, which was single-agent everolimus. It was roughly a median 14.6 months PFS in favor of the combination versus 5.5 months in favor of everolimus—a 3-fold improvement.

The combination also met 2 other efficacy endpoints. It had, if you will, the trifecta. It showed a benefit in response rate, with patients having greater than 40% tumor shrinkage over far less than 10% with everolimus. Also, there was a survival benefit. It proved a level of activity that places it among the best therapies for this cancer.

People will often ask, “Well, what are the side effects?” What I can share there is that this combination is tolerable. When you take 2 drugs, you expect that you are going to have more side effects than each of the agents as a single agent. That was the case.

However, the side effects that we saw with the combination were readily manageable by the physicians and the office staff, because we are familiar with how to manage VEGF and mTOR toxicities. Seventy percent of patients on the trial did require a dose reduction, and there are strategies to employ to do that.

Despite that, there was a level of efficacy that places the therapy among the best we have. It has resonated with the leadership and it has reached a category 1 NCCN recommendation for use as a second-line agent or beyond for kidney cancer.

There are several take-home points. Recently, we saw at the 2016 ESMO Congress that there are a variety of combinations that are going to be employed. With combination therapy, there is that toxicity concern that we will need to make judgments about. People often bring up cost of care when we bring up combination therapy. That is something that we, as a society, are going to have to address. Is the magnitude of improvement of efficacy worth the additional cost? I would say yes in this particular case.

What are the next steps for exploring this combination?

The combination is moving forward in a variety of settings. There is an important phase III frontline trial, the CLEAR trial, in which the combination will be studied and compared with lenvatinib and pembrolizumab, which is a PD-L1 inhibitor, and also versus sunitinib. It is going to be a 3-arm study to look in the frontline setting to see how this combination fairs.

We’re also going to be doing a phase II trial in the non—clear cell frontline setting to further assess that activity. That trial is slated to open very soon.

There is a third trial, which is going to be a dose-finding trial, to figure out what exactly is the best combination dose of lenvatinib. Its approval was at 18 mg with 5 mg of everolimus. This trial will compare that dose with a 14-mg dose of lenvatinib and everolimus.

What factors do you consider in choosing lenvatinib/everolimus over one of the other newer approved therapies in this setting, such as cabozantinib (Cabometyx) or nivolumab (Opdivo)?

The addition of lenvatinib/everolimus to the armamentarium for kidney cancer as one of the most powerful treatment combinations we have certainly places it in an area where one needs to make a treatment decision as to how to sequence agents.

First, you want to make sure it is given to your patients sometime early in the disease course. We recognize that our patients with kidney cancer oftentimes don’t make it past 3, 4, or 5 lines of therapy. We have 9 therapies. Therefore, clearly, this is one of the most active combinations that we have. We want to use that as one of the early lines of treatment.

You can make a strong case to use it second-line. If, for whatever reason, you position it not in second-line, you clearly want to make sure it's given in either the third- or fourth-line. There are other drugs out there that have similar levels of efficacy and I want to make sure that my patients get all of them at some point. The nuances as to what goes first are what we are still trying to figure out in the field.

For community oncologists, what are the most important factors to know when using this combination in clinical practice?

Community oncologists need to first know that the combination exists. This combination provides greater benefit—a 3-fold benefit over single-agent everolimus. In that setting, it’s kind of hard to find a patient where you would give just single-agent everolimus. Community oncologists are used to using everolimus. Therefore, now, anytime they think of everolimus, they should be thinking of the combination as the preferred mechanism.

Additionally, as I mentioned, one needs to position this early in the treatment schema of the patient. You need to be thinking about this in that second-, third- or fourth-line space.

Finally, don’t be afraid of the toxicity. The toxicity was not any different than what we would see with both single agents.

Motzer R, Hutson T, Glen H, et al. Randomized phase II three-arm trial of lenvatinib (LEN), everolimus (EVE), and LNE+EVE in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2015;33(suppl; abstr 4506).

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