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Nivolumab Practice-Changing in RCC, But Biomarkers Still Critical for Progress

Laura Panjwani
Published: Wednesday, Mar 09, 2016

Jorge Garcia, MD

Jorge Garcia, MD

Since the approval of nivolumab (Opdivo) in renal cell carcinoma (RCC) in November 2015, the PD-1 inhibitor has virtually become the standard of care for patients in the second-line setting. However, many questions remain regarding the use of the drug, says Jorge Garcia, MD, Department of Hematology and Oncology, Cleveland Clinic.

“It has become the de facto second-line choice,” says Garcia. “The only concern I have is that people will use this agent in a very liberal manner. The reality of it is that this agent does not work for everyone.”

Biomarker development to determine which patients will respond is key, says Garcia. However, PD-1 testing—at least as it stands now—may not be the answer.

“There is a lot of controversy around PD-1 testing,” he says. “We need more information before it should become the standard biomarker in RCC.”

The CheckMate-025 study, which led to the nivolumab FDA approval for advanced RCC in the second-line setting, compared the efficacy of the agent with everolimus (Afinitor). In the study, patients who received nivolumab demonstrated a median overall survival (OS) of 25.0 months compared with 19.6 months in those who received everolimus (HR, 0.73; P = .002).

In an interview with OncLive, Garcia discusses CheckMate-025, the challenges with PD-1 as a biomarker, additional potential biomarkers, and why combination immunotherapy in RCC is still a work in progress.

OncLive: What impact has the approval of nivolumab had in RCC?

Garcia: The question really relates to what I define as the “hot and sexy” new treatments in cancer—checkpoint inhibitors. Nivolumab, a PD-1 inhibitor, has already been FDA approved in many diseases, including melanoma and lung cancer. In RCC, the CheckMate-025 trial led to the approval of nivolumab in the United States in November 2015.

What this agent does for us in kidney cancer is expand the horizon of available subsequent therapies. This agent was specifically approved for patients who failed primary therapy in advanced RCC. Nivolumab is an agent that works quite effectively. It is the first agent ever, in the history of RCC, which demonstrated survival improvement as a primary endpoint in that patient population. It will probably become one of the agents that most people will use in the second-line setting.

However, I do like to remind patients and physicians that there are many treatment options. In addition to nivolumab, there are oral tyrosine kinase inhibitors (TKIs), dual signaling VEGF inhibitors, and other new agents rapidly coming down the pipeline.

It doesn’t work for everyone, and there is data to suggest that some patients actually respond better than others to nivolumab. We just don’t know who these people are yet because the biomarker data is lacking. Therefore, we need to improve on that.

Are there other immunotherapies that you see potential for in RCC?

There are other PD-1 inhibitors to consider as well, including pembrolizumab (Keytruda), which is FDA approved in lung cancer and melanoma, and is moving quiet rapidly into bladder cancer and RCC.

There is also another compound, which is a ligand inhibitor but of the same pathway as nivolumab, called atezolizumab, which may also make it into bladder cancer. There are ongoing clinical trials with this agent in RCC, as well. There are many agents out there that target the immune system effectively.

Is PD-1 an effective biomarker for nivolumab in RCC?

The problem with PD-1 is that it depends on what antibody you use to do the test. It also depends on what you are testing—if you are testing the tumor specifically, the stroma, or the surrounding tissue.

There is a lot of controversy over what antibody will be used, and there are many antibodies available. Every trial for each different disease uses a different antibody. We need to unify the antibody methods and we need to unify the testing before we can define if this is the right biomarker for RCC.

If you look at the data for CheckMate-025, that data clearly indicates that people who over express the PD-1 ligand appear to have greater mathematical response in their tumor, based on the guidelines that we follow.

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