Selecting an Appropriate Combination Therapy for Patients with Advanced Clear Cell RCC


The panel discusses which of the four approved combination regimens in advanced clear cell RCC they would choose for higher-risk patients, and the factors that play into the decision.

Nizar Tannir, MD: There are a couple of questions I’d like to ask both of you. Let’s go through the first one. In patients with intermediate or poor risk, we have 4 approved regimens: nivolumab-ipilimumab and the 3 IO [immunotherapy]-TKIs [tyrosine kinase inhibitors]. Moshe, which of those 4 regimens do you choose for patients with intermediate or poor risk? How do you decide on these?

Moshe Ornstein, MD, MA: That’s a great challenge these days, and it’s a wonderful challenge to have because it means there are lots of options. Obviously, the first decision tree that we get to is deciding between IO-TKI and IO-IO. The way I think about it and describe it to patients is that IO-IO is always going to have the longest-term follow-up. It’s quite possibly going to have the best tail of the curve. But at the same time, it’s probably going to have the highest primary PD [progression of disease] rate, and we’re losing something up front. Whereas with patients treated with IO-TKIs, the upfront benefit of response rates, PFS [progression-free survival], and even complete response [CR] rates with lenvatinib and pembrolizumab, is superior. If I knew which patients would more likely be on the higher tail of the curve, it would make the job easier.

There are many patients who are concerned about the here and now rather than 5 years down the road. I find that when I’m treating patients with metastatic clear cell RCC [renal cell carcinoma], they tend to be symptomatic and have at least 2 IMDC [International Metastatic RCC Database Consortium] risk factors. I’m often concerned and they’re often concerned about the regimen they’re getting now. They want that regimen to work, and they don’t want to come back in 3 months and hear that their cancer has gotten worse. [We want] to provide them with a salvage therapy that can provide a sustained benefit.

I’ll generally choose an IO-TKI regimen. Within the IO-TKI options, for the patient who’s generally well, I lean toward lenvatinib and pembrolizumab. When there’s a little more concern about the ability to tolerate a TKI for the long term or even in the immediate future, I give axitinib and pembrolizumab more than cabozantinib and nivolumab, but I’d use either treatment option in a patient who’s a little less robust.

Nizar Tannir, MD: Scott, what about you? How do you choose for your patients? Because you’re an immunophile, is nivolumab-ipilimumab your first go-to? Or do you say, “OK, this patient should get nivolumab-ipilimumab, and this patient should get an IO-TKI?”

Scott Tykodi, MD, PhD: Definitely a lot of both. Full disclosure: I’ve done a lot of IL-2 [interleukin-2] therapy. IL-2 has no maintenance element to it; it’s an all-or-none drug. You’re hoping for a CR or a very good, sustained PR [partial response] off therapy. I use the same gestalt for patients with ipilimumab-nivolumab. With a younger patient with small-volume, asymptomatic disease, in whom I’m more worried about the long game and sustained disease control, if they have a bit of early progression, it’s no big deal. They aren’t going to get sick. I’m less worried about the higher incidence of refractory disease with that regimen.

With a patient with subjectively bulky disease, when I’m fearful that early progression is going to cause them a lot of grief, or if they’re already symptomatic from their disease burden, I’d start with an IO-TKI. Among the regimens, I’ve only been using nivolumab-cabozantinib or pembrolizumab-lenvatinib. I haven’t used pembrolizumab-axitinib at all in the last year, the rationale being the smaller primary refractory phenotype with those 2 regimens. The decision between them is based on sense of toxicity, the idea that nivolumab-cabozantinib may be better tolerated with a proportionally lower TKI dose.

With an older patient with comorbidities, I’d probably go with nivolumab-cabozantinib. With a patient who doesn’t have a reason to worry about dose reducing anything, I’d [choose] pembrolizumab-lenvatinib for the lovely response rate and PFS numbers. With heavily bone dominant disease, I often preferentially use a cabozantinib-based regimen: nivolumab-cabozantinib.

Nizar Tannir, MD: To add my input on this, I’m like you, Scott. For my patients, because we have nivolumab-cabozantinib data and the approval in January 2021, and the approval of lenvatinib-pembrolizumab in August 2021, when I’ve wanted to give an IO-TKI to any of my patients, I haven’t used pembrolizumab-axitinib. For the robust, healthy, fit patients, if I see that the patient is symptomatic and has bulky, high-volume disease, we need to debulk the metastatic disease medically quickly for the symptomatic patient. If I’m worried about the 18% or 20% progressive disease rate through induction with nivolumab-ipilimumab and I’m concerned that the patient may not get the opportunity to get to the second line with a TKI, if they progress through nivolumab-ipilimumab, I’ll use pembrolizumab-lenvatinib with a full dose of lenvatinib at 20 mg to quickly shrink that tumor and improve symptoms because of that 5.4% progressive disease rate.

For patients whom I’m not too worried about getting them to a second line, if they progress on nivolumab-ipilimumab, I’m going to still be able to get them to a TKI in the second line. For those patients who have intermediate or poor risk and sarcomatoid—10% of those patients will have sarcomatoid—the data are clear from the CCR [Clinical Cancer Research] publications of that subgroup. In CCR, we published CheckMate 214 [trial data] and presented further follow-up at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium], where we saw a 23% CR rate for that subgroup, 60% ORR [overall response rate], and a median OS [overall survival] exceeding 4 years.

Nivolumab-ipilimumab for sarcomatoid should be the standard of care. That’s where comorbidities influence which therapy I’d choose for patients. If a patient is a vasculopath, has hypertension, proteinuria, diabetes, or is on multiple antihypertensive therapies, any TKI is going to cause problems. For that patient, if I think I can get them through nivolumab-ipilimumab and they would be fine and still able to get to the second or even third line, I’ll choose nivolumab-ipilimumab.

Those are the 2 scenarios in which I would choose nivolumab-ipilimumab. Like Scott, I still use quite a bit of cabozantinib-nivolumab in patients with bone metastasis, especially if that’s the dominant site of disease. The MET blockade here with cabozantinib is important, as you pointed out at the outset of the program. I use cabozantinib-nivolumab for those patients.

We’ll have a chance to discuss this toward the end of the program and talk about the triplets. There was a recent press release about the COSMIC-313 trial, in which there were positive data—at least for PFS—in favor of the triplet of cabozantinib plus nivolumab-ipilimumab compared with placebo plus nivolumab-ipilimumab, with a hazard ratio of 0.72. In the near future, if this regimen is FDA approved, there may be a situation with patients with intermediate or poor risk where we can have the cake and eat it too, where we can give nivolumab-ipilimumab and a TKI. But we’ll have to see. There’s a large phase 3 trial with 2 triplets vs pembrolizumab-lenvatinib. We’ll see whether that will also have positive results and whether it’s deliverable.

Transcript edited for clarity.

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