Examining TKI Combinations in Advanced RCC - Episode 3

Combining VEGF-TKIs + ICIs in mRCC

April 20, 2021
Robert J. Motzer, MD

Toni K. Choueiri, MD

Thomas E. Hutson, DO, PharmD

Toni Choueiri, MD, focuses on combining VEGF-tyrosine kinase inhibitors with immune checkpoint inhibitors in metastatic clear-cell renal cell carcinoma.

Toni K. Choueiri, MD: First, there is a clinical rationale that could trump the preclinical rationale that each drug, whether the new PD-1 inhibitor or the VEGF-targeted therapies, is active as a single agent. We are oncologists. If I see drug A work and drug B work, naturally, combining drug A and B could lead to better outcomes in circumventing tumor resistance. You’re working on different pathways. That’s clinical rationale. Luckily, we had VEGF TKIs [tyrosine kinase inhibitors] that were able to be combined with immune checkpoint blockers, because this did not pan out with sunitinib and pazopanib. But lenvatinib, cabozantinib, axitinib, and more recently tivozanib did pan out.

The preclinical rationale when targeting—let’s call these VEGF-targeted therapy plus or minus. Targeting VEGF seems to lead to immune favorability. VEGF leads to an increase overall in the signaling of Tregs [regulatory T cells], decreasing CD8, increasing myeloid-derived suppressor cells, and many other functions like in M2 macrophage signature. Imagine targeting VEGF—all this could be reversed, and there is a preclinical rationale for that. You add some of the VEGF TKIs that have other properties with cabozantinib, targeting MET and XL, and with lenvatinib targeting FGFR. You have potentially other functions that lead to an upregulation of the immune system. As an example, just off the top of my head, MET activation drives PD-L1 expression. The ligand for XL Gas6 is released by the tumor-associated macrophages and then pins the antigen-presenting cell function, and so on. That could also explain the cabozantinib effect. FGFR also plays a role in immunomodulation as the target of lenvatinib. It’s lovely to think about this preclinical rationale. How much it contributes to the efficacy of the combination remains unknown, but it’s not completely out of the realm.

This transcript was edited for clarity.