First-Line Treatment Using Combination Therapy in Advanced RCC

Part 2: Managing Cabozantinib/Nivolumab and other First-Line RCC Regimens

During a live virtual event, Brian Rini, MD, discussed how the combination of cabozantinib plus nivolumab compares with lenvatinib plus pembrolizumab in terms of tolerability and management in patients with advanced renal cell carcinoma.


  • What are your reactions to the CheckMate 9ER (NCT03141177) data? ​
  • 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?

BRIAN RINI, MD: Does anybody want to talk about why they might choose cabozantinib [Cabometyx]/nivolumab [Opdivo] over lenvatinib [Lenvima]/pembrolizumab [Keytruda] and other regimens for frontline treatment of renal cell carcinoma [RCC], or any distinguishing features of this regimen that you find useful in practice?

ANUSHA MADADI, MD: I would choose it because I definitely find the 40 mg of cabozantinib to better tolerated with equal efficacy to axitinib [Inlyta]/pembrolizumab.

RINI: How about compared with the lenvatinib/pembrolizumab data?

MADADI: I find the tolerability of lenvatinib/pembrolizumab to consist of slightly more adverse events [AEs]. So, if there is a heavy burden of disease or I’m not too worried about progression, I find—especially in those 80 years and older—patients may tolerate nivolumab at the lower dose with cabozantinib over other agents.

RINI: OK, so based on just tolerability. That’s fair.

JIGARKUMAR PARIKH, MD: Is progression-free survival the end point we should be looking at? We have robust data with ipilimumab/nivolumab, seeing tremendous overall survival [OS] data. So, granted these immunotherapy [IO]/tyrosine kinase inhibitor [TKI] combinations are still new, can you just look at the OS curves, based on their favorable, intermediate, and poor risk categories to see what they look like?

RINI: I don’t have the breakdown by category. In general, the IO/TKIs have shown pretty consistent effects across patients with intermediate and poor risk, similar to ipilimumab/nivolumab, but now you’re starting to compare hazard ratios across subsets. [That comes] with all the normal caveats. In patients with favorable risk, there’s a response rate and PFS advantage, but not a proven OS advantage, in part because those patients do really well, in part because it’s a small subset.1-3 Ipilimumab/nivolumab in patients with favorable risk has a little less of an effect because there’s no anti-angiogenic agent, and that’s an angiogenic-driven subset. I don’t know that there are major differences across International Metastatic RCC Database Consortium subsets. I don’t have all the data in front of me, and the results have very wide confidence intervals.

PARIKH: I remember looking at the OS curve for 1 of the trials with the IO/TKI, and the OS curve for the favorable risk was very similar to sunitinib [Sutent].3 So the question is, should we even add IO to the favorable-risk group if there is no OS benefit?

RINI: Yes, it’s a good question. I’ll give you my opinion on it: what you get with a doublet versus single-agent TKI in favorable risk are 2 things. One is you do get response rate and PFS advantages. You could argue whether that’s important in individual patients, I’ll grant you that. To me, the biggest thing is that single-agent TKI does not cure patients, and I think a subset of patients are cured with IO/TKI.1-3 I don’t know what that subset is; we don’t really know the tail of the Kaplan-Meier curve, but I’m guessing it’s at least 10%, 15%, or 20%.

When you give single-agent TKI then IO, like single-agent nivolumab, very few of those patients are cured with single-agent nivolumab. So, I think there is something to the combination upfront, and you’re also not adding that much toxicity. Most of the toxicity is TKI-driven. The IO adds some but not unacceptable toxicity. So, I have a pretty strong bias that all patients, including those with favorable risk, should get doublets; but there are other physicians who feel as you suggested, that they could just get single-agent TKI.

If I were a patient with favorable risk metastatic RCC, I wouldn’t want sunitinib. Who wants sunitinib? Nobody. I want an immune-based doublet. I might even want ipilimumab/nivolumab. I want an immune-based doublet as opposed to single-agent TKI. If you’re talking about a very frail patient, or other circumstances, that’s a different discussion. But there are wildly different opinions on that.

In terms of survival, I think they all have a pretty consistent survival advantage for the intent-to-treat population.1-3 Again, breaking down into subsets gets a little tricky.

Does anyone have a different perspective on safety or tolerability of this regimen, or is anyone uncomfortable starting at 40 mg of cabozantinib?4

CHANDAR BHIMANI, MD: I have a very difficult time with cabozantinib even at the 40-mg daily dose. Most of my patients end up on getting the 20-mg dose. I have used this combination, and the cabozantinib is not as easy. I have patients with hand-foot syndrome, very bad mucositis, headache, abdominal pain, diarrhea, and 1 of my patients couldn’t even tolerate 20 mg, so I have to change the regimen to a single agent, in fact. It was a slightly different scenario. I’m glad that the direction is to start with 40 mg, not 60 mg; it would have been difficult challenge regardless.

RINI: Physicians have very different experiences, simply because TKI dosing is all over the map, and I have patients on 20 mg every other day that’s borderline too much for them, and other patients who tolerate 60 mg, and it just shows you the very different exposure even at the same strength across patients. But 2 people have very different perceptions of the tolerability of cabozantinib/nivolumab, and both are true; it’s just the spectrum of what you get with different regimens across different patients.


  • How do you mitigate, monitor, and manage toxicities associated with IO/TKI combination therapy?​
  • How do you decide which drug to modify when using a combination regimen?​
  • How often have you had to discontinue all systemic therapy for a patient due to AEs or immune-related AEs? ​

RINI: So, you have a patient on cabozantinib/nivolumab that comes in with diarrhea at 6 weeks. How do you decide what to do? What’s your decision-making in that patient? Do you stop both drugs, are you stopping one or the other, and when are you giving steroids? How do you approach potentially overlapping toxicity for any of the IO/TKI regimens?

GOVINDA BRAHMANDAY, MD: I think the TKIs have the shortest half-life, so if you stop them and the diarrhea gets better, I would probably be blaming it on the TKI.

RINI: Yes, I think that’s right.

NASFAT SHEHADEH, MD: If the patient has severe diarrhea, I will stop both and figure it out later on. But I agree that if it is mild to moderate, you can stop TKI, maybe use loperamide [Imodium], and they get better. I’m fine with that because I expect most likely this is coming from the TKI component, but if it’s severe I will hold both.

RINI: Yes, I think that’s right. I think if there’s any doubt, you certainly have to hold both. If it’s very severe, you may have to empirically give steroids. But TKI diarrhea tends to be more insidious in onset. People don’t look toxic, they just look annoyed, and they’re a little anorexic. It’s that kind of presentation, as opposed to a colitis which is much more acute and severe.

And [Dr Brahmanday] is absolutely right, the half-life of TKI is your friend, and for axitinib, for instance, the half-life is 4 to 6 hours. So, people are better in a day or 2, and it’s usually obvious what it’s from. Not always, and sometimes with AEs like liver function test abnormalities, they can linger. It’s always good on paper, but in real life it’s not quite that clean. But I think all those thoughts are correct.


1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500

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

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

4. Cabozantinib [Cabometyx]. Prescribing information. Exelixis Inc.; 2019. Accessed May 13, 2022.