Sumanta Pal, MD, an expert hematologist/oncologist, evaluates the combination of cabozantinib + nivolumab as first-line therapy for advanced clear cell renal cell carcinoma.
Brian Rini, MD: Give us a few minutes about cabozantinib-nivolumab and some of your salient features in this regimen. Why might you choose it in a frontline setting?
Sumanta Pal, MD, FASCO: Hans [Hammers], you brought up a lot of great points. As you point out, there’s a difficult choice that we face in the clinic overseeing the frontline patient. I certainly think it’s appropriate to put all the options on the table. I have a subset of patients who ultimately favor nivolumab-ipilimumab. Perhaps it would be because of the lack of more chronic toxicities associated with the TKI [tyrosine kinase inhibitor]. Really, it’s the ultimate demonstration of the equipoise that I have. We’re opening up a study, which Brian is running, that’s quite clever. It uses a schema in which you have biological allocation of patients to cabozantinib-nivolumab or nivolumab-ipilimumab. Hopefully, that’s the way we’re going to be doing things 10 years from now.
When it comes to cabozantinib-nivolumab, among the 3 options we have in the TKI–I/O space, I tend to side with it. It’s interesting; some of the reasons you cite sort of in support of lenvatinib-pembrolizumab might actually be justifications for using cabozantinib-nivolumab. For instance, as you mentioned with lenvatinib-pembrolizumab—and this is true for much of the program for this combination—they’re using that escalated dose of lenvatinib at 20 mg. It’s a little higher than what we in the renal cell community had gotten used to with 18 mg of lenvatinib in combination with 5 mg of everolimus. I certainly feel that that the extra 2 mg adds moderately to the toxicity, and we see that reflected in some of the discontinuation rates and rates of treatment interruption in the CLEAR trial vs some of the others.
In my hands it’s been challenging to administer higher doses of lenvatinib. We ran a trial in which we compared 18 mg with 14 mg of lenvatinib in combination with everolimus, not pembrolizumab. In broad terms, we didn’t see major differences in terms of toxicity. But there was some compromise, albeit very mild, in efficacy with the lower dose of lenvatinib vs a higher dose. For those reasons I’ve tended to slide away from using lenvatinib in the frontline setting. It’s always been curious to me that you have this marked benefit in progression-free survival, this hazard ratio of 0.39 that Brian showed in his slides, but an OS [overall survival] hazard ratio that’s identical across all those TKI–I/O [immunotherapy] studies. I haven’t wrapped my head around why that’s the case.
With cabozantinib-nivolumab, the dosing strategy is very different. With axitinib-pembrolizumab, we’re using the standard doses we’re used to in the frontline or second-line setting. With cabozantinib, we’re taking a step down. We’re going from 60 mg, which is the dose that we all know from the refractory or salvage setting, and we de-escalate to 40 mg. I don’t know necessarily if this was related to toxicities elicited by the combination in early studies. We were part of Andrea Apolo’s study looking at various dose levels of cabozantinib and nivolumab. I ran a study looking at cabozantinib and atezolizumab, and we were able to do 60 mg of cabozantinib with immunotherapy without a substantially increased toxicity signal. It was a surprising decision banking on the fact that patients would stay on this lower dose longer. I see that the rates of discontinuation and treatment interruption are lower with cabozantinib-nivolumab vs what’s seen with lenvatinib-pembrolizumab in broad terms. That toxicity issue pivoted me toward cabozantinib-nivolumab for the bulk of patients.
We see some manifestation of this, albeit imperfectly, in the quality-of-life data tethered to these studies. I’ll be the first to concede that the way we’re doing quality of life is by no means ideal. We’re probably not asking all the right questions that are relevant to a patient’s day to day even though we have them fill out dozens of pages of questionnaires. Having said that, with the data we have with cabozantinib-nivolumab vs sunitinib, we see the gradual trend toward improvement in quality of life with cabozantinib-nivolumab. It differentiates itself from sunitinib. I don’t see the same with axitinib-pembrolizumab or lenvatinib-pembrolizumab, so that’s another point in favor of using cabozantinib-nivolumab as my preferred frontline approach.
There are great logical arguments for each of these regimens. The 1 thing I’ve cautioned my colleagues in the community against is going rogue with these regimens and experimenting with initial dosing strategies. I’ve had a lot of folks call me who say, “I’m thinking about starting this patient on 8 mg of lenvatinib-pembrolizumab or 10 mg of lenvatinib-pembrolizumab.” I say, “Whoa, how do we know we’re getting the benefit you’re seeing in the CLEAR trial if we’re starting with these de-escalated regimens?” I’m encouraging folks to try to adhere to the data as much as possible and use the doses that have been established in these phase 3 trials.
Transcript edited for clarity.