Lenvatinib Regimen Setting Pace for Emerging Combos in Kidney Cancer

Gina Columbus @ginacolumbusonc
Published: Saturday, Nov 05, 2016

Thomas E. Hutson, DO, PharmD

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. 


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