PD-1 Inhibition in Advanced Renal Cell Carcinoma

Immune checkpoints are involved in pathways that disable activated T-cells so they do not overreact against the body, states David F. McDermott, MD. Inhibition of targets on the surface of T-cells, such as CTLA-4 and PD-1, can reactivate T-cells and allow them to eliminate cancers more effectively, explains McDermott.

Studies have shown encouraging improvements in response, progression-free survival (PFS), and overall survival (OS) with the use of CTLA-4 and PD-1 blocking antibodies compared with standard therapies across a variety of tumor types, including in renal cell carcinoma (RCC). Not only are these novel agents more effective than standard therapies they are also more tolerable, even when compared with older forms of immunotherapy like iinterleukin-2, adds McDermott.

Individuals with tumors that express high levels of PD-L1 may have a greater response to anti-PD-1 therapy, comments Thomas Hutson, DO, PharmD, noting that there may not be a direct correlation between PD-L1 expression and response to therapy. PD-L1 is an inducible marker that appears when T-cells recognize the tumor and may, therefore, not be present on every tumor, observes McDermott. It is also not a stable marker and may be affected by several variables, such as remaining in storage for a long period of time.

The PD-1 inhibitor nivolumab has been evaluated in clinical trials for patients with advanced RCC. Phase I data showed that nivolumab is well tolerated, although patients need to be monitored for pneumonitis, states Eric Jonasch, MD. Phase II results revealed that some patients had prolonged and persistent responses to nivolumab. Additionally, top-line findings from the pivotal phase III CheckMate-025 study revealed that nivolumab improved OS compared with everolimus for patients with metastatic RCC. Following this initial analysis, the study is being unblinded and patients in the everolimus arm will be allowed to cross over to receive nivolumab.