Physicians Discuss Potential of Frontline Triplet Regimens for RCC


During a Targeted Oncology case-based roundtable event, Alan Tan, MD, discussed with participants their experience with tyrosine kinase inhibitor/immunotherapy combinations and the most recent results of triplet trials.

Alan Tan, MD (Moderator)

Director of GU Medical Oncology

Assistant Professor, Department of Internal Medicine

Division of Hematology, Oncology and Cell Therapy

Rush Medical College

Chicago, IL

Alan Tan, MD (Moderator)

Director of GU Medical Oncology

Assistant Professor, Department of Internal Medicine

Division of Hematology, Oncology and Cell Therapy

Rush Medical College

Chicago, IL


  • What are your perspectives on the studies of frontline combination regimens for patients with advanced renal cell carcinoma (RCC)?​
  • When you think about the immunotherapy (IO) plus tyrosine kinase inhibitor (TKI) combination regimens for favorable-risk mRCC, what differentiators come to mind? Thinking about each combination, what patient profile comes to mind? ​
  • Please discuss your real-world experience with using IO and TKI combinations.

ALAN TAN, MD: What are your perspectives on the CheckMate 9ER [NCT03141177], KEYNOTE-426 [NCT02853331], and CLEAR [NCT02811861] trial data [in patients with RCC]?

STAN NABRINSKY, MD: We have all heard [about] the 4 trial comparisons which compared IOs [immunotherapies] plus TKIs [tyrosine kinase inhibitors] versus sunitinib [Sutent]. The last time anybody used sunitinib would have been years ago. [The trials are] pretty much equal. I think, at this point, we have to talk about the COSMIC-313 trial [NCT03937219] because that trial, reaches the new dimensions in the first-line treatment of RCC. I think the future will be in the triplet [regimens], especially because in COSMIC-313, the comparator arm is placebo, ipilimumab [Yervoy], and nivolumab [Opdivo]—not sunitinib—[versus nivolumab/ipilimumab/cabozantinib (Cabometyx)].

TAN: That’s a good point, Dr Nabrinsky. At this point, we need to see overall survival [OS] data, the reason being the toxicity profile. Not many patients were able to complete all 4 cycles of ipilimumab/nivolumab.1 For the time being, I agree, it’s the first trial that has ipilimumab/nivolumab as a comparator arm, so this is the most modern-day comparator arm. We now have another trial with Merck looking at a triplet [regimen] as well, so I’ll be interested in the next couple years to see what that reads out as as well. They’re looking at lenvatinib [Lenvima] plus pembrolizumab [Keytruda] as a control arm, and then they’re looking at HIF-2α inhibitors in combination with IO/TKI or IO/IO. Have you used triplet therapy?

NABRINSKY: I started the first patient on triplet 3 weeks ago. So far, no significant adverse events [AEs].

TAN: I was surprised at the readout for COSMIC-313 because I’ve had several patients on COSMIC-313 in the triplet arm and also on CheckMate 9ER when they had the lead-in with the triplet [that included ipilimumab in an arm that was discontinued]. My thought was, maybe I got lucky, but it was reasonably well tolerated. As a whole, the study did not favor using the combination in poor-risk patients.1 We’re still trying to tease out those data. Maybe a lot of the patients were very poor risk, [having 6 factors for International Metastatic RCC Database Consortium (IMDC) risk status], we don’t know, so we’ll have to see further. Right now, unfortunately, triple therapy is not ready for primetime yet. But I’m glad your patient is doing well and impressed that you got it covered.

NABRINSKY: I had no problem with that. As long as it’s listed in the compendia, Medicare does not police what kind of combination you use.

TAN: Anybody else have any thoughts or experiences with triplet therapy?

JOANNA STANKIEWICZ, MD: I don’t have experience with the triplet, but even on clinical trials, where there is a selected group of patients, the discontinuation rate was quite high.1 An average patient, [who is] older, is not going to tolerate these treatments well. In private practice, when you see frail patients, you don’t want to harm them. [When giving] them the combination therapy, when they start to have AEs, they will not be willing to continue. In real life, the discontinuation [rate] is much higher than in clinical trials because the clinical trial patients are very motivated.

TAN: Because of that concern, does anybody try to start with single-agent IO for that matter?

BETY CIOBANU, MD: I have a patient on axitinib [Inlyta] plus pembrolizumab and he developed hepatitis due to the pembrolizumab, so I held the pembrolizumab. The patient [received] steroids and he recovered, but he was so scared that he did not want to go back on any IO, so I had to continue with single-agent axitinib. And even that turned out to be too toxic for the patient, so eventually we had to switch him.

ISOKEN KOKO, MD: I have a patient who has been on sunitinib for 6 years with stable disease, and now he’s beginning to have progressive disease. He is on dialysis, has chronic anemia. Otherwise his performance status is good. Now he’s developed liver metastases and stable lung metastases, biopsy positive. Is this someone you would consider for TKI/IO or combination or combination of IO/IO?

TAN: We don’t have great data on patients that have progressed on sunitinib….You said he had anemia?

KOKO: He has chronic kidney disease and is now on dialysis, so I think that is the cause of his anemia.

TAN: Those are the ones where I don’t think IMDC is perfect. I think we’re looking into better ways to try to risk stratify these patients in more biological manners using gene expression profiling and biomarkers. But right now, we don’t have a good biomarker in kidney cancer and we base it on clinical factors and IMDC. I think for that particular patient, if he’s on dialysis, IO/IO may be an option for that patient or even something like cabozantinib [Cabometyx] plus or minus nivolumab may be reasonable.

YAN JI, MD: My to-go regimen normally is cabozantinib/nivolumab. One thing is that compared with CLEAR [using a full dose of lenvatinib], the dose [of cabozantinib] they chose is 40 mg daily [as opposed to the approved 60 mg dose]. I think that makes a whole lot of difference. Almost no one can tolerate 60 mg for over [a few] weeks. It’s a lot of gastrointestinal symptoms, hand-foot syndrome, and fatigue. Most people can tolerate 40 mg quite well. With the response rate and then duration of response, I think that’s pretty impressive.

For pembrolizumab/axitinib, normally I think it’s pretty well tolerated, but I have 1 patient with very bad hand-foot syndrome, and after I held the axitinib, it got better. We lowered the dose and the AE returned, we lowered the dose [again], and then we held axitinib, and it got better. He has a complete response with his lung metastases and lymph node metastases. For now, we have been holding the TKI, [just] continuing the pembrolizumab, and he’s doing fine.

TAN: Oh, great.

JI: For the CLEAR data though, I have a question. When you look at the OS for the favorable-risk patients, I think the hazard ratio [for Memorial Sloan Kettering Cancer Center favorable-risk patients] was 1.0 compared with sunitinib [HR, 1.00; 95% CI, 0.51-1.96].1 Does that mean you want to avoid using the lenvatinib/pembrolizumab in those patients?

TAN: As far as the CLEAR data for OS, the data are not as mature. Right now, I personally would restrict more to intermediate/poor risk for the CLEAR data.

JI: Although, the NCCN put [lenvatinib/pembrolizumab] as one of the category 1 options, right?2

TAN: Right. Maybe for favorable risk, in my opinion, the combination may be a bit too toxic when we look at the benefits-risk ratio. My preferred regimen would be cabozantinib/nivolumab for someone like that. But it depends also on the sites of disease, bone metastasis, liver metastasis, brain metastases, those kinds of things.


1. Choueiri TK, Powles TB, Albiges L, et al. Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089

2. NCCN. Clinical practice guidelines in oncology. Kidney cancer, version 4.2023. Accessed January 25, 2023.

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