Dr. Reed: The last aspect that I wanted to talk about with you this morning is the issue of brain metastasis in renal cell carcinoma. Brain metastases represent a problem in this disease that is often under appreciated. What is the scope of this issue?
Dr. Gong: This is a very prudent and often overlooked question, Dr. Reed, so I'm glad you're bringing this up. Brain metastasis in patients with renal cell carcinoma is actually a fairly uncommon population. The actual prevalence has been shown to be about 8% to 10% of all patients with metastatic RCC. The problem is, it's been poorly characterized in the literature, especially given that these patients sometimes have a very poor prognosis. Often a median overall survival as low as 3 months in those with multiple brain metastases. The other important point to cover in this population, is that the majority of clinical trials that have been conducted to date actually exclude patients with metastatic renal cell carcinoma with brain metastasis. As you can see, it's a poorly under characterized population in need of further investigation.
Dr. Reed: What are the standard treatment options for patients with brain metastases and renal cell carcinoma?
Dr. Gong: In the current era, the standard therapies for patients with brain metastases include surgical resection and radiation therapy. However, for the most part, majority of patients and those who are not amenable to those local regional therapies, the standard is still systemic therapy.
Dr. Reed: Your group, I understand has some experience using tyrosine kinase inhibitors in patients with brain metastasis. What sort of activity do we know for these agents in the setting of brain metastasis?
Dr. Gong: There has been a body of evidence that has investigated, but very limited, the activity of VEGF-TKIs. We know that agents such as sorafenib, sunitinib and pazopanib, which are also other VEGF-TKIs that are FDA approved in metastatic RCC have poor penetration to the CNS and this has been demonstrated in preclinical models, as well. The activity is not impressive. It can actually use a little bit more improvement and can be as low as in the single digit percentages for overall response rate. However, one unique VEGF-TKI that we've published on is cabozantinib, which is another VEGF-TKI that also hits MET and AXL targets in metastatic renal cell carcinoma. This is of interest because there has been studies that have shown brain metastasis specimens actually express MET at a much higher percentage in primary renal cell carcinoma tumors. This has been thought to be one reason why cabozantinib has a greater ability to penetrate the CNS and have some activity and we have published on that. The other thing to note is that the conventional trials of cabozantinib, including METEOR and CABOSUN actually was one of the few trials that did not exclude patients with brain metastasis. So this is another point to highlight that this agent may be an ideal agent to target brain metastases in patients with metastatic renal cell carcinoma.
Dr. Reed: Are there any other agents that have shown efficacy in brain metastases or other types of therapies?
Dr. Gong: You have experience in this arena as well, Dr. Reed, given your publication in Journal of Clinical Oncology. You highlighted that in the phase II NIVOREN trial, which investigated nivolumab in patients with metastatic renal cell carcinoma who had been pretreated with at least one prior line of anti angiogenic was another interesting study that included patients with brain metastasis. Although the response rate was not as high as other tumor types, for example, the overall response rate was about 12%. It did show some initial insight that nivolumab can have some activity in patients with brain metastasis. This correlates with the fact that in other studies preclinical studies and as well as human studies, that brain metastases from metastatic renal cell carcinoma do express PD-L1 as one of its markers as well. I think there's an active body of investigators that are trying to investigate either single or dual agent IOs in patients with metastatic RCC to the brain.
Dr. Reed: Yes, this is a clearly an unmet need and further research is needed and I hope these patients are included on trials in the future.
Dr. Gong: I agree, Dr. Reed. Thank you.