First-Line Treatment Using Combination Therapy in Advanced RCC

Part 2: Tolerability of Immunotherapy plus TKI Inhibitors in RCC

During a live virtual event, Sandy Srinivas, MD, discussed the tolerability of the tyrosine kinase inhibitor/immunotherapy combinations cabozantinib plus nivolumab and lenvatinib plus pembrolizumab, compared with the dual immunotherapy ipilimumab plus nivolumab.


  • What are your reactions to the CheckMate 9ER (NCT03141177) data for renal cell carcinoma (RCC)? ​
  • How will you counsel patients regarding this regimen?​
  • What is your impression of the safety/tolerability of this regimen? ​
  • Are you familiar with the recommended dosages for this regimen? ​
  • How would use of this combination in the frontline impact your second-line decision making?

SANDY SRINIVAS, MD: I think cabozantinib [Cabometyx] plus nivolumab [Opdivo] has been around for a much longer time [than lenvatinib (Lenvima) plus pembrolizumab (Keytruda)], so I would love to hear any of your experience with the combination and what you think about the regimen.

HOLAVANAHALLI KESHAVA-PRASAD, MD: I think the data are good and the overall response rates are good and the progression-free survival is not as high as with the lenvatinib/pembrolizumab, but still, it is quite good.1 I think the dose of cabozantinib makes the difference with regard to tolerability.

SRINIVAS: Have you used this regimen much?

KESHAVA-PRASAD: I have used it in 1 patient. It was intermediate risk, and he’s doing fairly well. He had some fatigue and diarrhea, but when we backed off a little bit and then restarted, he’s OK. Overall, he’s responding as well.

KANWALDEEP RASILA, MD: I have 1 patient on it, and so far, nothing unexpected. I have not needed dose reduction…so far, so good.

SRINIVAS: What was your thought process in picking cabozantinib/nivolumab?

RASILA: When I had seen the patient, at that time it had just been recently approved, and the data were impressive; and as far as adverse events [AEs] with the dose of cabozantinib, they did not seem too bad. I think that was the reason that I ended up picking it at that point. And so far, the patient is tolerating it OK.

CHUNHUI FANG, MD: I tried using it in 1 patient, but unfortunately the patient died before treatment was arranged. I think 1 advantage for nivolumab and cabozantinib is that cabozantinib is a once-a-day medication, like lenvatinib. Also, single-agent wise, I think cabozantinib seems to be better tolerated in my limited experience, compared with axitinib [Inlyta]. So, I’m willing to try this combination when the next patient comes.

SRINIVAS: How do we decide between ipilimumab [Yervoy] plus nivolumab and any of these tyrosine kinase inhibitor [TKI]-containing regimens? We’ve mostly focused on the 2 TKI/immunotherapy [IO] regimens, but are any of you using ipilimumab/nivolumab?

FANG: I always calculate International Metastatic RCC Database Consortium [IMDC] score. It can classify a patient as intermediate or high risk. I usually offer ipilimumab/nivolumab because I have quite a few patients who are 3 or 4 years after starting treatment on ipilimumab/nivolumab, right now just on nivolumab maintenance, and still doing well. Another thing about ipilimumab/nivolumab is that you don’t have to worry too much about what if the patient progresses, because you can always use a TKI as a second-line treatment option.

SRINIVAS: Does anybody else favor ipilimumab/nivolumab over the TKI/IO regimen?

SANTHOSH AMBIKA, MD: I think the only time I’m using it is if they have more sarcomatoid component, I favor ipilimumab/nivolumab. Otherwise, I am moving away because the VEGF/TKI combination appears better overall, numbers-wise.

SRINIVAS: You like the higher response?

AMBIKA: Yes. Does having the intact primary make any difference with your choice? If they haven’t had any cytoreductive nephrectomy or something [like that].

SRINIVAS: I think that’s a great question. Many of these more contemporary trials now—the ones that have been published the last few years—a large majority of patients haven’t had a nephrectomy. Only 60% may have had a nephrectomy, and whether they have had nephrectomy or not, they appear to benefit from an IO/TKI.1 With the CARMENA [NCT00930033] data that came out, evaluating the role of nephrectomy, I think many people have decreased using upfront nephrectomy, and just go with systemic therapy first.2 And, if you have had a great response, then go on to getting a cytoreductive nephrectomy. But it would be a great question to see if any of you have changed your practice about the role of nephrectomy.

AMBIKA: Yes, I’m definitely doing it less often nowadays. I had a couple of patients where we took it out, and even though the mass was active, the final tests showed no viable tumor. This happened with a couple of patients on ipilimumab/nivolumab, so I stopped doing it, unless we really had to.

SRINIVAS: Pretty impressive, right? Even I’ve had a couple of my patients who received ipilimumab/nivolumab, and then after a great response elsewhere, taken the kidney out. The kidney was around 7.5 cm, and when they looked at it under the microscope, all dead tissue. So, that’s the great thing about ipilimumab/nivolumab, where you can stop everything and not have to continue additional therapy. But, Dr Rasila, how do you [choose] these IO/TKI combinations? Let’s say somebody has abnormal liver function tests [LFTs]. Do you have any trouble deciding if this is a TKI, or is it from the IO? Should we be starting steroids?

RASILA: I look at if they have other toxicities from the IO and get a sense of what may be going on. Sometimes, if I’m not sure, I will stop one; I will hold their TKI and see how things go. So far, most of the issues I’ve had have been with when they’re on IO alone. I have not had many elevated LFTs when they’re on both, luckily. But I have had some issues with IO, and IO combinations. I recently had a patient with myocarditis.

MERIN STEPHEN, MD: Yes, this is confusing because I’ve used pembrolizumab plus lenvatinib. So, [the patient] with uterine cancer had kidney insufficiency, and LFTs were going up at the same time, so we were working with a nephrologist. First, I had to dose reduce the lenvatinib right away; the 20 mg is really hard to sustain. Then we were doing one at a time for a while. Ultimately, she had a very impressive response, so we just stopped and monitored because of the durable responses that you can get from these combinations, and especially when you have the IO. So, we were able to stop it because of the kidney and liver damage for a while and just monitor off therapy, with a plan to reintroduce both at the lowest doses possible, if needed.

SRINIVAS: So, what was your starting dose of lenvatinib for that patient?

STEPHEN: She already had some renal insufficiency going in, so I think we started at 12 mg, and I had to go down to 8 mg, and then I may have had to lower it a little bit before holding it again.

MAY CHO, MD: In terms of AEs, lenvatinib usually has electrolyte abnormality and LFT abnormality. So, when they go together, then I will attribute that to TKI and the same thing with cabozantinib; if there is some other associated symptom, not just LFT alone, then I would dose reduce the TKI first. So, I don’t dose reduce the IO; we either stop or give a steroid. But I usually dose reduce the TKI, and that usually fixes most of the problems, especially if I see 2 of the symptoms together, that's usually from the TKI.


1. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

2. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675