Promise of Lenvatinib Excites in the RCC Landscape

Nicolas J. Vogelzang, MD

The treatment landscape for renal cell carcinoma (RCC) has expanded significantly over the past decade in the frontline setting with several new combinations becoming available for patients with clear cell histology. Most recently was the FDA approval of the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) based on the findings of the phase 3 CLEAR trial (NCT02811861).¹

Since the approval of the multikinase inhibitor lenvatinib in RCC, the agent is being investigated in various large trials to determine if further combinations can expand upon the benefit seen in the CLEAR trial. Some of these trials in progress were mentioned during the 2021 International Kidney Cancer Symposium, including the phase 3 MK-6482- 012 trial (NCT04736706) of the HIF-2α inhibitor belzutifan (Welireg) with lenvatinib vs pembrolizumab and quavonlimab a CTLA-4 inhibitor, vs pembrolizumab and lenvatinib in patients with advanced clear cell RCC with no prior treatment. MK-6482-011 (NCT04586231) is another phase 3 trial looking at the use of belzutifan plus lenvatinib vs cabozantinib (Cabometyx) in patients with RCC.

In an interview with Targeted Oncology™, Nicholas J. Vogelzang, MD, the chairman of medical oncology at Comprehensive Cancer Centers and a clinical professor of medicine at University of Nevada, Reno School of Medicine and University of Nevada, Las Vegas School of Medicine, discussed how the treatment landscape has changed for RCC and the continuing promise of lenvatinib.

Targeted Oncology™: Can you discuss some of the approvals that we’ve had and impressions of the different regimens?

VOGELZANG: The landscape is confusing to everyone, including treating doctors. The longest approval has been nivolumab [Opdivo]/ipilimumab [Yervoy]. Those data with Dr Motzer have been available for about 5 years, so we’ve gotten used to using nivolumab/ipilimumab. That was approved for poor- or intermediate-risk disease and had the best benefit in patients with sarcomatoid histology. It left good-risk patients more or less out of the picture. Then we got approval for pembrolizumab and axitinib [Inlyta], and a lot of doctors liked pembrolizumab/axitinib because it covered good-risk [patients] and we had both a phase 2 and a phase 3 [trial as evidence]. A lot of doctors got comfortable with pembrolizumab and axitinib. Then we had, if you will, the not very positive study of avelumab and axitinib and that did not reach a survival end point compared with sunitinib [Sutent]. And then this year, we got the nivolumab/cabozantinib and the CLEAR study of lenvatinib and pembrolizumab. And then lastly, of course, we still have the cabozantinib monotherapy approved as first line for patients.

It’s been a historical problem because nivolumab/ipilimumab has held sway for quite a while. And then pembrolizumab/axitinib came in, looked promising, and a lot of people switched to it. I’ve done a number of focus groups, and most doctors have been using pembrolizumab/axitinib, and some still like nivolumab/ipilimumab because of the long-term complete responses. I continue to see my patients who’ve been in long term complete response. It’s pretty remarkable; these are people who had lots of cancer and are [now] off all treatment, cancer free. And now we have these 2 new combinations, nivolumab/cabozantinib and lenvatinib/pembrolizumab, both of which are approved up front. And most people don’t have experience with lenvatinib and pembrolizumab. Most of us have experience with pembrolizumab and cabozantinib, but we use that as second line. So we know that lenvatinib and pembrolizumab have just recently been approved; very few doctors have used that combination. Aside from just being approved and not on pathway up until just recently, the dose of lenvatinib has been very high. And because the dose is high, there’s been some reticence on the part of oncologists to embrace lenvatinib at the 20-mg-per-day dose. Not that that’s the wrong dose. It’s just we were told that it was 18 mg, and that you can dose reduce; 20 mg is a big dose, and hypertension and diarrhea and other things are not necessarily easy to handle in the outpatient setting.

To summarize, there’s been a new kid on the block—that’s lenvatinib and pembrolizumab. And the uptake has been relatively slow because there are very good alternatives. However, the CLEAR study is very impressive. It’s got a 71% response rate with long [progression-free survival], 23.9 months.2 So all of us are going, “Geez, maybe we should try that.” And I for one am waiting for my next patient who’s willing to be treated [with this regimen], understanding that I’m going to have a learning curve. But I also got to realize that my nurses have to be ready to deal with the [adverse] effects and [that] I’m going to have to be careful.

Some of these regimens have led to real-world studies. Specifically, there was one from US Oncology of lenvatinib and everolimus (Afinitor) that you worked on.3 Can you speak to those results at all?

That is an interesting study, suggesting that lenvatinib and everolimus [are] better than sunitinib, but not better than lenvatinib and pembrolizumab. So I don’t think it’s going to get a lot of play because everolimus adds some toxicity to the lenvatinib. And I don’t see [it going] anywhere. If you’re going to use sunitinib, you should use lenvatinib and everolimus. And if you’re going to use lenvatinib and everolimus, you should use pembrolizumab and lenvatinib. It was a nice idea, but it doesn’t lead anywhere. It was more done for regulatory purposes, I think.

This year at IKCS, there were a bunch of studies exploring lenvatinib in other combinations, some doublets, some triplets. Can you speak to any of these trials in progress?

Yes, lenvatinib is a very effective drug in a number of conditions. Obviously, it’s already been approved in hepatocellular [carcinoma]. It’s been approved in combination with pembrolizumab in endometrial [carcinoma]. It’s going to be studied in non–small cell lung cancer. It’s underway in bladder cancer. It’s a very promising agent. And I expect it will become a multibillion-dollar drug in a variety of diseases. One of my friends happens to work for Eisai. They’re looking at about 10 different indications for the drug in a variety of malignancies.

_REFERENCES

_{1. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Updated August 11, 2021. Accessed December 13, 2021. https://bit.ly/31LwFU5}

_{2. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716}

_{3. Vogelzang NJ, Monnette AM, Wang Y, et al. Real-world clinical effectiveness of lenvatinib/everolimus in a heavily pretreated advanced/metastatic renal cell carcinoma population in the US community oncology setting. Clin Genitourin Cancer. 2021;19(6):P531-P539. doi:10.1016/j.clgc.2021.05.002}