Robert Motzer, MD: So, one of the other questions that comes up is for these patients is, how do we best manage some of these sites that are problematic to address with regard to systemic therapy? And those include patients with brain metastasis or bone metastasis. And so, what is your approach to patients, Dr Ornstein, that have metastatic disease present, but at the same time they're presenting with active brain metastases?

Moshe Ornstein, MD: So, patients with brain metastases, I work extremely closely with the radiation oncology and neurosurgery colleagues. Especially if it's low volume brain metastases, we're going to work diligently to get them treated with Gamma Knife radiosurgery, some more definitive localized approach to the best of our abilities for the brain metastases. But in terms of which of the regimens has the best penetration or treatment of brain metastases, I'm not convinced that one is better than the other. So, in terms of systemic therapy in patients with brain metastases, I'm comfortable using any of the regimen. It's interesting as I talk to the radiation oncologists in terms of whether they're comfortable with patients being on TKIs, it is a bit of a mixed bag. Some of them say you can treat through the Gamma Knife, some of them are a little bit more concerned. So again, it's about collaborating with the radiation oncologists. The one thing I would say is patients with brain metastases are often treated with higher doses of steroids as they're leading into their definitive brain metastases surgery with Gamma Knife. And I generally don't like starting checkpoint inhibitors in patients who are on higher doses of steroids. So usually my approach will be, if it's somebody who definitively needs therapy, then obviously we have to do what's best and just treat them and manage accordingly, but I'll often hold the checkpoint inhibitor until they receive treatment for their brain metastases.

Robert Motzer, MD: Those are very good points that localized therapy is certainly key, and then systemic therapy may be of some assistance. Now, what about bone metastasis, Dr Rini? We've heard that cabozantinib is that drug of choice for patients with bone metastasis. Do you agree that cabozantinib is better than those? Do you think that's the drug that, say the combination of choice cabozantinib plus nivolumab for patients with predominant bone metastases?

Brian Rini, MD: Now, I think if you look at the data sets around cabozantinib, sometimes I believe it and sometimes not. Some are supportive, mostly those for METEOR against the mTOR inhibitor. I think the trials against the VEGF inhibitor didn't have quite that signal. So, I'm honestly not sure. A lot of that conversation was driven by cabozantinib or prostate cancer from years ago, and some dramatic bone scan changes. And it turns out that drug wasn't useful in prostate cancer, so I don't know if those were more anecdotes. So, I'm not sure. I think it's probably more important, and Moshe mentioned this, to just use a regimen you're comfortable with. And if you're a lenvatinib plus pembrolizumab user, I'm sure lenvatinib plus pembrolizumab works fine in bone mets, you know what I mean? So, I don't think you need to switch and take on a regimen you don't have familiarity with just because the patient has disease and bone. And I'd also emphasize local control of bone, just like we do for brain as well.