Nizar M. Tannir, MD, FACP: As effective as our therapies are in the first line and subsequent lines of treatment, there is still a large number of patients who do not respond at all. They have innate resistance, or they respond and then, unfortunately, have recurrence or progression of disease. Depending on what therapy they received in the first-line setting, we then make the decision of what to treat the patient with in the second-line setting. The scenario may be that the patient is receiving or has received a first-line therapy with an anti-VEGF agent such as pazopanib or sunitinib—those have been the 2 most frequently prescribed first-line anti-VEGF agents. When the patient progresses on one of these agents, the choice has been to go with an immune checkpoint inhibitor. So, you are going from a targeted therapy to an immune checkpoint inhibitor therapy. Nivolumab was FDA approved in that space in November 2015. The approval was based on the CheckMate-025 study that showed improved survival compared with everolimus, which had been an FDA-approved agent in the salvage setting post sorafenib or sunitinib. But there are other choices in that space.

After progressive disease with a first-line tyrosine kinase inhibitor, such as pazopanib or sunitinib, one can treat a patient with cabozantinib or lenvatinib and everolimus. These are the 3 FDA-approved therapies for second-line therapy after a first-line TKI. The FDA has recently approved the combination of nivolumab and ipilimumab as first-line therapy for patients with metastatic renal cell carcinoma who have intermediate- or poor-risk RCC factors by IMDC criteria. If a patient is now receiving or has received this combination and has progressive disease, I think the option is to go with a tyrosine kinase inhibitor. The choices here are axitinib or cabozantinib, based on previous data post immunotherapy. Axitinib was FDA approved, as mentioned, in 2012 post sunitinib, as well as post cytokine. By extrapolation, I think axitinib would be a good choice here.

At this ASCO Annual Meeting, a poster presented by the Cleveland Clinic group reported their prospective phase II trial with axitinib post immune checkpoint inhibitor therapy. That’s obviously an option. Another option is cabozantinib. This is a fertile area for investigation, where we are looking at, for example, testing 1 of these agents—axitinib, cabozantinib, or lenvatinib—and combining it with another agent in that second-line space, post immune checkpoint inhibitor therapy.

Chung-Han Lee, MD, PhD: The combination of lenvatinib plus everolimus is an FDA-approved combination in the second-line setting after progression on a prior TKI. Lenvatinib is the multi-TKI that inhibits VEGF receptors 1 to 3 and FGFR1 to 4, among other kinases, including PDGF. In this setting, it broadly targets multiple receptor tyrosine kinase inhibitors.

mTOR is a nexus to integrate growth factor and nutrient signaling. It takes information from the growth factor signaling from the receptor tyrosine kinases in order to control growth and proliferation. The combination of the 2 mechanisms likely provides some type of synergism, or additive effects, in order to improve outcomes.

In order to overcome resistance, mTOR inhibitors have been added to lenvatinib plus everolimus or have been used in combination with lenvatinib. mTOR mutations, or activating mutations within the mTOR pathway, are actually relatively few. I can’t fully explain the clinical responses that we see to mTOR inhibitors. Therefore, they also play a critical role in the problem with the resistance mechanisms that may be downstream of other growth factor signaling. Lenvatinib targets 2 key proangiogenic growth factors, including VEGF and FGF. Together, this seems to provide a mechanism to overcome resistance that can be seen with inhibition of VEGF signaling alone.

Transcript Edited for Clarity