First-Line Treatment Using Combination Therapy in Advanced RCC

Discussing Real-World Experience Using Lenvatinib in Advanced RCC

During a Targeted Oncology case-based roundtable event, Robert J. Motzer, MD, discussed with participants their experiences using lenvatinib in treatment of advanced renal cell carcinoma. This is the second of 2 articles based on this event.


  • Do you have experience using lenvatinib (Lenvima) in RCC (with either everolimus [Afinitor] or pembrolizumab [Keytruda])? ​
  • How do you counsel patients regarding this regimen?​
  • What is your impression of the safety/tolerability of this regimen?​

DAYA SHARMA, MD: [If a patient has] diarrhea, how do you figure it out if it is coming from lenvatinib or coming from pembrolizumab?

ROBERT J. MOTZER, MD: There are some overlapping toxicities, and they are gastrointestinal [GI] toxicity, liver toxicity, and endocrine toxicity. For the most part, because the TKIs [tyrosine kinase inhibitors] have a short half-life, the toxicities related to the TKIs generally resolve very quickly when you hold the TKI. So, if you hold the TKI and the liver toxicity goes away or the diarrhea goes away, you can be pretty much assured it’s related to the TKI. And that goes for all the TKIs. The IO [immunotherapy]-related toxicity is slower to resolve, and it doesn’t resolve when you hold the TKI, so if you’re holding the TKI and the liver toxicity is persisting or getting worse, then it’s more likely an IO-related toxicity.

You can also do biopsies. We rarely do liver biopsies but with colonoscopy and sigmoidoscopy, the findings are strikingly different between TKI GI toxicity and colitis. So that’s another way to distinguish between the 2. Obviously, you can’t in all cases but that’s been what we’ve recommended. As far as the endocrine toxicity goes, the overlapping endocrine toxicity is primarily hypothyroidism, which is generally irreversible with either TKI or IO therapy. So, in either case, we treat with levothyroxine [Synthroid] replacement.

QAMAR ZAMAN, MD: Whenever I use lenvatinib, there was mostly GI toxicity and I have to dose reduce.

HARISH MADALA, MD: I’ve used lenvatinib, both in combination with everolimus and with pembrolizumab. The biggest challenge has been diarrhea. I think I scared one patient with the amount of diarrhea she experienced. I think it’s a great combination. Trying to figure out the right dose for the patient is the tricky part. I’ve been debating whether starting at the full dose and then titrating down, which is what most of us do, is the right way or maybe starting at an intermediate dose like 14 mg and going up would be a safer option. I just don’t know.

MOTZER: I would say if it’s a fit patient, it’s better to start with the full dose. If it’s somebody who’s debilitated or has comorbidities and you’re afraid you’re going to injure that patient, then I would not use the full dose or maybe not use this regimen. But I think if it’s a fit patient, you should go with the full dose and dose reduce because that’s what the efficacy data have been based on. The other thing is, generally, if you start at a lower dose with the idea that you’re going to go up, you generally don’t go up because everybody has some degree of toxicity. It makes you concerned about increasing the dose that it’s going to get it worse. Is the diarrhea something that happened right away in your patient or is that something that happened down the road with chronic dosing?

MADALA: It was right away. It did get better after we held lenvatinib within 10 days. It was lenvatinib-related and not IO-related.

ARIF HUSSAIN, MD: My experience with lenvatinib and pembrolizumab is a little different because we always have a clinical trial up front. We did not participate in [the CLEAR] study [NCT02811861], but I’ve used lenvatinib in the third or fourth line. The patient progressed. She had prior nivolumab [Opdivo], but, when I added pembrolizumab [to lenvatinib], it was remarkable the extent of response she had. In other words, we were able to resensitize her to lenvatinib by adding pembrolizumab after she had failed other therapies. And she’s still on that combination.

Secondly, I have a patient who progressed on ipilimumab [Yervoy] plus nivolumab then cabozantinib [Cabometyx], then I put him on lenvatinib with everolimus. He had massive [tumors] in the abdomen and in the lungs, and he’s had a remarkable response. The longer you [treat patients], the experience you gain is how you can’t [treat patients with] these broad brushes. They’re individual patients, how they respond [is unique]. But it’s amazing how some of these patients can get these responses. I think it becomes more of an art after first-line therapy. Now we have 6 different options and it’s confusing what you [should] do next, but it [comes from] experience. I never cease to be amazed that patients respond with some of these permutations.

MOTZER: I had a similar experience. Not in a large number of patients, but somebody who progressed through 5 or 6 lines of therapy and then talked me into giving him axitinib/pembrolizumab, and he’s had a great response. He’s been on it for a year. I’ve also had similar success with lenvatinib/everolimus. I think our opinion on lenvatinib/everolimus has been jaded partially because it’s usually fourth line in our lines of therapy, and so we see more toxicities. But I think it’s also a very effective regimen, although from the CLEAR data, lenvatinib plus pembrolizumab is the winner in the first line compared with lenvatinib/everolimus.1


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