Weighing High Response Rates Versus Tolerability in Frontline RCC


During a live virtual event, Moshe Ornstein, MD, discussed the results of the CLEAR trial of lenvatinib and pembrolizumab in renal cell carcinoma and participants' experiences with these agents.

Moshe Ornstein, MD, MA (Moderator)

Genitourinary Medical Oncologist

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio

Moshe Ornstein, MD, MA (Moderator)

Genitourinary Medical Oncologist

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio


  • Do you have experience using lenvatinib (Lenvima) in RCC (with either everolimus or pembrolizumab [Keytruda])? ​
  • What are your reactions to the CLEAR (NCT02811861) data? ​
  • What is your impression of the safety/tolerability of this regimen?​
  • Are you familiar with the recommended dosages for this regimen? ​

MOSHE ORNSTEIN, MD, MA: I would love to hear some discussion about this combination which is now approved,1 and there certainly has been a shift at least within some practices to lenvatinib either in combination with everolimus in the refractory setting or in combination with pembrolizumab in the front-line setting.

What are some of your reactions to the CLEAR data? Do you have experience with it? And what do you think about this data? When you think about frontline treatment options, do you think about what is the best for the patient now or are you thinking, “I am giving the patient something in front line based on what I may be able or not be able to give them in the second line?”

SEEMA MISBAH, MD: I have not used it, but I did like the data. I was wondering, does it now take over as first line? Because I always think of axitinib [Inlyta] and pembrolizumab as first line in how I used to treat. Again, I have not used it as of yet, but I probably will consider using it as my first line based on this data. There is not a head-to-head trial yet, axitinib versus lenvatinib, correct?

ORNSTEIN: Yes. I think it is going to be challenging because no company is going to want to do that trial because there is not much to gain in it.

MISBAH: It sounds like they are both good drugs now. I would not have considered lenvatinib prior to this data because my go-to is axitinib. I will be honest, I will [still] use that first line. Most times, even when ipilimumab [Yervoy] and nivolumab [Opdivo] could be used, I prefer to use axitinib.

ORNSTEIN: So out of curiosity, because I used a lot of axitinib and pembrolizumab, what is your feeling about that combination, or what is more worrisome about using lenvatinib? I am curious is it more of a perception of lenvatinib, or is it just that you had not seen the data lined up like that in terms of overall response rates [ORR] and complete response [CR] rates, etc?

MISBAH: One is my familiarity with the axitinib. I am used to using it, [but] yes, seeing the data lined up has made it clearer that lenvatinib is a contender. The other thing is, I have had a run of bad luck with ipilimumab/nivolumab combinations with some of my patients. They have sky-high liver function test results, and I feel like they have been refractory. Again, this might just be my own bad luck but with the ipilimumab/nivolumab combination, I am sometimes reluctant to use it if I have other options.

ORNSTEIN: When this combination first came out, I mentioned that when I was talking to the company. I said there are these rates of adverse events [AEs] that are present with lenvatinib and pembrolizumab and there are times when clinicians will get a bad experience with a combination and then say they have 4 different combinations that have survival benefit and they do not want to take any chances. We get 1 best shot up front, and we do not want to take chances.

MISBAH: Exactly.

ORNSTEIN: What do others think about these data relative to axitinib/pembrolizumab?

ARUN SENDILNATHAN, MD: I am an oncologist at Kettering Health Cancer Center in Ohio, and I use axitinib and pembrolizumab all the time. I do have experience with lenvatinib, not in RCC, but in hepatocellular carcinoma [HCC] and thyroid cancer. Those patients had bad reactions and AEs. I remember 1 patient had severe hand-foot syndrome. We had to dose reduce and even dose interrupt, and another had bad diarrhea. I think that patient even had a fistula formation. So that is my experience in using lenvatinib, especially when you look at the dose that you use in RCC, the 20 mg, whereas in HCC you can even go down to 8 mg or 4 mg.2 I think the lowest dose in the CLEAR trial was 8 mg.3

So that is the main concern that I have with lenvatinib, but [seeing] the ORR and CR rates, I think it is about patient selection. If there is a very young patient who requires very quick response, I think I would definitely consider lenvatinib and pembrolizumab as a combination.

ORNSTEIN: I think it is interesting to hear the impact of lenvatinib in other settings, for instance that lenvatinib is used in much higher doses in thyroid cancer.2 Though in the CLEAR trial, they were able to go down as low as 8 mg, but I completely agree. I think [telling patients], “This might be more toxic. We do not know because we do not have head-to-head data, but there is experience from thyroid and liver cancers.” If I have a 50-year-old patient who is very symptomatic, very [sick], and is heading towards poor risk, that might sway me to use [lenvatinib] that has a response rate of over 70%.3


1. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. August 10, 2021. Accessed February 23, 2022. https://bit.ly/3BLLeEC

2. Lenvatinib (Lenvima). Prescribing information. Eisai Inc., 2021. Accessed February 23, 2022. https://bit.ly/3t30I35

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

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