Focused discussion on the selection of first-line therapy for advanced clear cell renal cell carcinoma based on sites of metastasis.
Brian Rini, MD: Let’s turn to some patient subsets. We haven’t talked about bone metastases, brain metastases, or liver metastases. We talked a little about high-volume symptomatic [patients] and how I/O [immuno-oncology]–TKI [tyrosine kinase inhibitor] regimens are preferred from a disease-control standpoint. Let’s take bone metastases. Cabozantinib has had this halo of having more of an effect in bone. Hans, we’ll start with you this time. Do you believe it? Does a metastasis in a particular organ drive your choice of therapy, bone or otherwise?
Hans Hammers, MD, PhD: I don’t think so, to be honest. I don’t see the data. For me, immunotherapy can work in any of these pieces. Immunotherapy for me is the most important component. If you see sclerosis and bone formation in these areas all of a sudden, it’s a very satisfying view because that means you have a nice treatment effect in these views.
The 1 advantage that cabozantinib has is the indirect effect on bone turnover. I don’t know how aggressive you guys are with bone-targeted therapy in terms of zoledronic acid—for example, bisphosphonates and others. This is obviously a widely debated topic in kidney cancer too. But the 1 advantage it has, if you will, is the suppression of bone turnover already built in. That’s 1 of the advantages it might have.
You have a higher rate of osteonecrosis of the jaw with cabozantinib than with some of the other agents, and it’s probably related to that. We all remember probably these mystery bone scans that became negative on cabozantinib in prostate cancer. If patients are worried about being on bone-targeted therapy, the advantage is you can probably have a 2 for 1.
Brian Rini, MD: Monty, how about you? Do you use the site of metastasis to drive your decision-making?
Sumanta Pal, MD, FASCO: The earlier discussion we had around the broader questions of dosing, quality of life, etc., probably come to the fore more often. They’re going to drive that initial treatment choice. Site of metastasis rarely comes into play these days because I can use those overriding clinical factors to tease apart the different regiments. It’s hard. Right, Brian? When you tease apart the different subsets within these trials of patients with bone metastases, you see activity with all the regimens. The regimen with cabozantinib with nivolumab is good, maybe not markedly distinct from what we see from the other regimens.
Having said that, I think there are some biologically compelling reasons to consider it in that context. Years ago, Bernard Escudier’s team presented some data at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] about metastases expression. It actually seems as though whereas in metastases expression primary tumors are robust, you see it to an even greater extent in brain metastatic sites and bone metastatic sites. It might lend some credibility to this hypothesis that cabozantinib might have this preferential activity in patients with those metastatic sites.
Brian Rini, MD: I tend not to pick a regimen based on site. As you said, Monty, there are bigger considerations rather than using regimen A for bone and B for liver. It gets too confusing. I’m not sure I’d be doing anything or helping anybody with that approach.
Let me ask both of you: would you give any TKI-based regimens to untreated brain metastases? My practice is that all brain metastases would get local therapy first, usually SBRT [stereotactic body radiation therapy]. Then I put them on whatever regimen is best. But I’ve heard of others. There are data out there about certain activity in untreated brain metastases. That makes me very uncomfortable. I’m wondering what you guys think.
Sumanta Pal, MD, FASCO: I always insist on primary treatment first for brain metastases. If I really feel a patient is super-symptomatic and needs to get on therapy right away, they’re getting nivolumab-ipilimumab first and their brain metastases treated simultaneously. But I always want to treat before using a TKI.
Hans Hammers, MD, PhD: Same here, certainly. SBRT has completely changed the way we approach brain metastases. I avoid whole-brain radiation. It should never be done in patients before stereotactic radiation. It’s probably safe to use a TKI. For some of these larger trials, even with sunitinib, with a phase 3 trial or with some of the excess trials, we didn’t necessarily screen for brain metastases. If you look back, they’re probably reasonably safe. But if I know that the patient has brain metastatic disease, I absolutely use local control first and start the TKI. Sometimes the problem in the brain is this almost-profound edema that you see. A lot of patients are on the non steroids, for example. In that setting, immunotherapy isn’t going to work because there are going to be multiples of prednisone equivalents way above the limit. I tend to radiate and then use a TKI. Sometimes I start a TKI before I start immunotherapy until they come down with the steroids, and then I go in with immunotherapy.
Brian Rini, MD: That’s fair. Talk about whether your consideration of what you might use second line affects your frontline consideration. I tend to use a lot of cabozantinib in the second-line setting, so I don’t use a lot of cabozantinib-nivolumab up front. That’s at least 1 of the reasons. Do you think about the whole sequence of therapies up front or no? Hans, you can go first.
Hans Hammers, MD, PhD: There was a time when I thought about it more, but we have so many pills at our disposal that that thinking is somewhat falling away. It’s much more important to make sure the initial treatment is well chosen for the patient to make sure they’re going to do well. I can see using both cabozantinib and lenvatinib in the first line without feeling guilty about it. I’m coming from the original salvage therapy thinking: I’d use up a salvage agent early on. I don’t have that feeling anymore. I’m like you. I love both agents; they’re both great. If somebody starts with cabozantinib, then I’d certainly go with lenvatinib [after] and vice versa. There are great opportunities for patients with both agents.
Brian Rini, MD: Monty, any thoughts on that?
Sumanta Pal, MD, FASCO: I don’t have a lot to add, but I still think we’re just notoriously bad at picking who those patients with primary PD are going to be. Sometimes you can try to tease that out from their clinical phenotype. If they’ve got big, raging, quickly-growing metastases, that might be that patient who’s going to quickly go on to second-line treatment. Having said that, I think it’s always best to put our best foot forward in this setting and use whatever regimen we feel is going to benefit the patient most, rather than saving stuff for later.
Brian Rini, MD: I have the same approach. I agree.
Transcript edited for clarity.