First-Line Treatment Using Combination Therapy in Advanced RCC
During a live virtual event, Sandy Srinivas, MD, discussed results from the CLEAR trial of lenvatinib and pembrolizumab in renal cell carcinoma and the participants' experiences with the regimen including dose reductions needed by their patients across multiple cancer types.
SANDY SRINIVAS, MD: Were [any of your patients] participants of the CLEAR trial?1 Have you had any experience with lenvatinib/pembrolizumab?
HOMAYOON SHAHIDI, MD: I have not used it for RCC, but we use the exact same regimen for endometrial cancer.
SRINIVAS: What’s the dose of lenvatinib in endometrial cancer?
SHAHIDI: It’s 20 mg, and the dose of pembrolizumab is 200 mg.
SRINIVAS: What was your experience with the tolerability?
SHAHIDI: It caused a lot of fatigue, so I ended up reducing the dose to 10 mg. It wasn’t tolerated. I think 20 mg is a very strong dose for lenvatinib.
GIGI CHEN, MD: Yes, I also used it in uterine cancer and gynecologic cancer.
SRINIVAS: Wow, so many of you have had experience with this in other cancers. What was your experience with the dosing there, Dr Chen?
CHEN: When I used it for the uterine cancer, although the recommended dose is 20 mg, I find most of my patients are either receiving 12 mg or 10 mg of lenvatinib.
BRIAN VICUNA, MD: I’ve also used it in uterine cancer, and I also had to dose reduce; I went down to 14 mg. The patient had bad hypertension, mouth sores, mucositis. Those and the fatigue were the big issues.
SRINIVAS: You went from 20 mg to 14 mg?
VICUNA: Right. And she’s doing fine; she’s doing great at 14 mg.
SRINIVAS: Was the dose reduction needed immediately, or over the course of therapy?
VICUNA: It was within the first or second month, so it was early.
CHUNHUI FANG, MD: I have been using this combination for endometrial cancer on 2 patients, and I had a similar experience in the sense that fatigue is very common. I had one patient who had severe taste change, and she just couldn’t tolerate much in taste in the hospital because of dehydration. She was decreased to 14 mg and seemed to be doing better. The other patient is still on 20 mg so far, but it’s still early on the treatment, so I’m not sure she will be able to tolerate this combination.
The leg swelling is very severe. I’m not sure this is an adverse event from lenvatinib, but we have tried everything, including Lasix [furosemide], and it’s not improving.
SRINIVAS: When was the combination approved for endometrial cancer?
FANG: In 2019.2
SRINIVAS: So, you’re quite familiar with that. What’s your reaction to the CLEAR data?
FANG: I feel like all these new combinations are only adding to the confusion.
SRINIVAS: That’s true; when you have so many choices, how do you pick? But, based on what you have seen so far with the CLEAR data, what’s your overall take?
FANG: I think this combination can be offered if a patient’s very motivated, and otherwise doing well.
SRINIVAS: Is there any distinction that you find with the lenvatinib/pembrolizumab compared with axitinib [Inlyta] and pembrolizumab or cabozantinib [Cabometyx] and nivolumab [Opdivo]?
FANG: I think one of the advantages is that lenvatinib is a once-a-day medication, but axitinib is twice a day. That is potentially a benefit for compliance.
SRINIVAS: Does the overall response rate [ORR], or the progression-free survival, or the complete response rate stand out?
FANG: You’re not supposed to compare cross-trial, right?
SRINIVAS: That’s true. So, what’s your take? Do you feel that they’re all the same?
FANG: Unless they are being compared head-to-head, I will assume that they are similar, for sure.
CHEN: I think the ORR is very impressive for the lenvatinib/pembrolizumab combination, with an ORR of 71%, and over 90% of patients receiving a benefit. I think that’s very impressive.1 Looking at the sequencing of the patients, with all these different regimens that are approved, how would you sequence the treatments?
SRINIVAS: Yes, I think that’s really an important one, because for many of these patients who are not cured, we are clearly thinking about what happens in the second line. We shouldn’t think of the patient just in 1 snapshot, but we are clearly thinking about if we do lenvatinib/pembrolizumab as a front line, what’s going to be second line?
If a patient’s disease fails to respond to lenvatinib/pembrolizumab, we are probably using cabozantinib in the second line as a monotherapy. Those are all some good options that we have. If you use axitinib/pembrolizumab front line, are you using cabozantinib as second line, or would you consider using lenvatinib and everolimus? Clearly, that has good data in subsequent lines, as well.
SRINIVAS: What do you counsel your patients? Are you telling patients that they are likely to have a dose reduction?
CHEN: I tell my patients that they’ll likely have a dose reduction. I don’t think I have anybody who can tolerate the starting dose of 20 mg of lenvatinib. I have them keep a log of their blood pressure, and I also counsel them in terms of the fatigue, and some of the gastrointestinal symptoms.
SRINIVAS: Are you all starting at 20 mg in your patients with endometrial cancer? Are you starting at 20 mg and then going down? We have heard patients may start low and then escalate. Which category do you belong to? Do you start high and dose reduce?
CHEN: I start at 12 mg, because it’s 3 of the 4 mg tablets.
SHAHIDI: I started at 20 mg, thinking that the thyroid dose is 24 mg. A dose of 20 mg is probably tolerated, but it’s too high, in my opinion. I think 10 mg to 12 mg is the maximum tolerated dose.
SRINIVAS: Let’s talk about the dosing a little bit, because I think that’s something that I really wanted to point out. Because, in no other trial have we had this 20 mg dose of lenvatinib. In lenvatinib/everolimus, the starting dose is 14 mg. This is the first time in RCC that we have had a 20 mg starting dose. So, the recommended dose is 20 mg of lenvatinib plus pembrolizumab at 200 mg.3,4 This was how it was done in the CLEAR trial. They start at 20 mg, and the first reduction goes down to 14 mg, the second one down to 10 mg, and the third is down to 8 mg. In this trial, as well as in axitinib/pembrolizumab and in cabozantinib/nivolumab, the immunotherapy is given for 2 years, after which the tyrosine kinase inhibitor alone is continued. Most of you pointed out the lenvatinib dosage comes in 4 mg and 10 mg tablets for us to make the adjustments.
1. 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
2. Simultaneous review decisions for pembrolizumab plus lenvatinib in Australia, Canada and US. FDA. Published September 17, 2019. Accessed December 16, 2021. https://bit.ly/2mmwklD
3. Lenvima (lenvatinib). Prescribing information. Eisai Inc; 2021. Accessed December 16, 2021. https://bit.ly/3e2vx0w
4. Keytruda (pembrolizumab). Prescribing information. Merck & Co., Inc; 2021. Accessed December 16, 2021. https://bit.ly/3269nrG