First-Line Treatment Using Combination Therapy in Advanced RCC

Part 1: Selecting Systemic IO and TKI Options for Clear Cell RCC

During a live virtual event, Brian Rini, MD, discussed the efficacy and tolerability of approved first-line tyrosine kinase inhibitor and immunotherapy combinations for patients with advanced renal cell carcinoma.


A 59-year-old Black woman received a diagnosis of clear cell renal cell carcinoma (RCC). She underwent left total nephrectomy in December 2019. Nine months later, she developed metastatic disease to bilateral lungs, mediastinum (35 × 38 mm), and retroperitoneal lymph nodes. She was diagnosed with stage IV RCC, clear-cell histology, with metastases to lung and retroperitoneum. Her Karnofsky performance status score was 90%. Her hemoglobin, neutrophils, and platelet levels were within normal limits. She had elevated corrected calcium above the upper limit of normal.

A decision was made to initiate systemic therapy. What frontline therapy are you most likely to choose for this patient?


  • Do you have experience using lenvatinib (Lenvima) in RCC with either everolimus or pembrolizumab (Keytruda)? ​
  • What are your reactions to the CLEAR trial (NCT02811861) data? ​
  • How will use of this combination in the frontline impact your second-line decision making?​
  • What is your impression of the safety/tolerability of this regimen?​
  • Are you familiar with the recommended dosages for this regimen? ​

BRIAN RINI, MD: There were 2 participants who chose lenvatinib/pembrolizumab for this frontline case, so I know there’s some experience. Could you say why you’re choosing lenvatinib/pembrolizumab in your practice, or do you have reactions from the other to these data, which you may be familiar with?

NASFAT SHEHADEH, MD: I said [I am using it because of the low progression-free survival hazard ratio], but I chose cabozantinib [Cabometyx]/nivolumab [Opdivo] to be honest with you. It’s 3 regimens very [close] to each other; it’s hard to pick one. I think lenvatinib/pembrolizumab came late. I don’t have experience with it in RCC. We have experience in using lenvatinib in other cancers, which makes drugs easier to use, sometimes.

ANUSHA MADADI, MD: I have used lenvatinib/pembrolizumab in the relapsed setting, post-axitinib [Inlyta] and pembrolizumab in a patient whom I was able to give and see a response for almost 6 months. So I think that is reassuring that lenvatinib/pembrolizumab is likely efficacious because of that phase 2 data, too, post-axitinib and pembrolizumab.1

RINI: There was a single-arm trial in approximately 100 patients who were immunotherapy-refractory, where it was impressive data in that setting, and I think it makes sense now that we see this frontline data that is an active regimen. There’s no level 1 evidence about giving immunotherapy after prior immunotherapy, but those trials are ongoing, as you may know, so we’ll see—hopefully in the next year or 2. But I agree, it’s active. How about toxicity?

CHUNZHI XIA, MD: I have used lenvatinib/pembrolizumab for endometrial cancer, and it’s hard to tolerate and has bad adverse events [AEs]. One of them had a very significant unhealed wound. So I found it’s very difficult to use this regimen, and I wonder what your other colleague experienced.

RINI: Can you remind me, in endometrial, is it 20 mg as well?

XIA: I used a very low dose, even down to 8 mg, and patients were still not able to tolerate it.

RINI: But the approved dose is 20 mg in endometrial cancer.2 What do other participants think? I agree, it’s a tough regimen. I’ve started using it more lately since approval, and some patients do OK at 20 mg, but most do not.

MADADI: Yes, I would agree, too. The majority of the times that I’ve used it, I had to dose reduce in patients with endometrial cancer, or even thyroid malignancies, in addition to RCC. Tolerating the full dose is extremely difficult with lenvatinib.

RINI: Does anybody start lower? I’ve used that. When I give cabozantinib in a refractory setting, I sometimes start at 40 mg just because patients are a little more frail, and I’m worried about toxicity. If physicians are giving this regimen, in this or any setting; is anybody starting lower and then going higher as needed?

JIGARKUMAR PARIKH, MD: Yes, so that’s my approach for most of these tyrosine kinase inhibitors [TKIs]. So, I have used pembrolizumab/lenvatinib in a frontline setting, and usually I start them at 8 mg. I would be very hesitant to start somebody at 20 mg.

RINI: I wasn’t part of this trial; I’m not sure of the decision-making. The trial of cabozantinib/nivolumab started at 40 mg, so they chose a little different approach that may have impacted efficacy data, but I think made it more tolerable. I’ve thought about TKI dosing for a long time now, and I’m still not sure how to do it. Whether it’s start high and go down or start low and go up. I don’t think the field has figured it out.

Does the impact of frontline therapy on second-line therapy impact your choice of frontline therapy? For example, do you say, “I’d really like to give cabozantinib second, so I’m not going to give cabozantinib/nivolumab up front.” Do you think about the sequence of therapies on day 1, or not? I tend not to do that, but I’m just curious if physicians give A so they can give B later, so to speak.

SHEHADEH: We do that from time to time, but we try to use the best therapy first. That’s what I like to use. Then we’ll figure it out, because sometimes they might have a good response that lasts for some time.

RINI: Agreed.

CHANDAR BHIMANI, MD: So, my take is that ipilimumab/nivolumab as a frontline treatment has the longest-term data compared with all these regimens, including lenvatinib and pembrolizumab, about 2 years follow-up, same as cabozantinib and nivolumab.3 So, I think by giving IO/IO, you have the longest data; 35% of patients are living beyond 5 years. And you have the advantage of being able to use the TKI in the second line.

But I see a disadvantage with ipilimumab/nivolumab, which is that when we are not seeing it up front, the overall response rate [ORR] is not that very high.

RINI: [The intent-to-treat population’s ORR is about] 40% with ipilimumab/nivolumab.3

BHIMANI: It’s not as high as the 71% [ORR for first-line lenvatinib/pembrolizumab in the CLEAR trial] of course, but I think that’s probably playing the role in the sense of the TKI.4 You are seeing the immediate shrinkage, a part of the TKI efficacy.

RINI: Yes, I think that’s right, and I agree. Ipilimumab/nivolumab will always have longer follow-up because it was started 2 years earlier, and it’s that durability that’s the most impressive. But you are sacrificing some upfront disease control, and this naturally leads into the triplet trials, the first of which should be reported this year, which is COSMIC [NCT03937219] of ipilimumab/nivolumab with or without cabozantinib, trying to get the best of both worlds; upfront disease control, and long-term durability.

Now whether that triplet will be tolerable, we’ll find out. If you’ve given ipilimumab/nivolumab and you’ve given cabozantinib, you know each of them independently can have AEs. So, combining them, you can imagine what might be difficult. But, we’ll see, it’s this kind of discussion that led to that triplet study, and there are other triplet studies going on now, too. But I agree with everything said.


1. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946-958. doi:10.1016/S1470-2045(21)00241-2

2. Lenvatinib (Lenvima). Prescribing instructions. Eisai Inc.; 2021. Accessed May 13, 2022.

3. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079

4. 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