In cancer treatment, first-line therapies refer to the initial treatment for a cancer. Second-line therapies are treatments used when a cancer has not responded or has stopped responding to a first-line therapy. Third-line therapies are treatment options if both first- and second-line therapies have not worked or have stopped working.
Advanced renal cell carcinoma (RCC) is cancer that began in a kidney but has spread beyond that kidney. It includes locally advanced cancers that have spread to nearby tissues and lymph nodes as well as cancer that has spread to distant sites in the body.
Second- and third-line therapies are a common part of treatment for advanced RCC.
First-line treatments for advanced RCC
Before looking at second-line therapies, it’s important to take a look at first-line therapies. First-line treatment for RCC has evolved significantly in recent years and typically involves a combination of immunotherapies and/or targeted therapies. This includes first-line treatment for advanced RCC.
Immunotherapy combinations
Immune checkpoint inhibitors have become a mainstay of first-line treatment. These drugs work by helping the immune system recognize and destroy cancer cells. Common approaches include:
- Two immunotherapy drugs. Combining two immune checkpoint inhibitors to help the immune system's ability to recognize and destroy cancer cells.
- Immunotherapy plus targeted therapy: Pairing an immune checkpoint inhibitor with a targeted therapy, a drug that targets specific proteins or pathways that cancer cells need to grow and survive.
Targeted therapy
A targeted therapy used on its own may be the initial treatment approach.
Second- and third-line therapies for advanced RCC
There are several important factors that you and your healthcare team will consider when deciding how to approach second- and third-line therapy.
What medications were used in previous treatments is an important consideration. If you received immunotherapy, your healthcare team may recommend switching to targeted therapies. If you started with targeted therapy, your healthcare team may recommend immunotherapy, or in some cases, a different type of targeted therapy.
Your healthcare team will also consider how the cancer has responded to previous treatments, and how you responded to previous treatments. Was there a good initial response or no response at all? Did the therapy cause significant side effects?
Other factors that will be considered are treatment needs, prognosis, symptoms, the urgency for a rapid treatment response, and characteristics of the cancer. The priorities and preferences of the person being treated are also important.
What treatments are used for second- and third-line therapy?
Immunotherapy
Immune checkpoint inhibitors may be an option for second-line therapy, especially if they weren't used in first-line therapy.
Targeted therapy
Multiple targeted therapies can be used on their own as a second-line therapy. A healthcare team may recommend targeted drugs that weren't used in first-line treatment.
Surgery, radiation therapy, ablation
Though not common, these therapies may be recommended in some cases. Surgery, radiation, and ablation (procedures to destroy tumors) may be used with the goal of shrinking or removing a tumor and relieving symptoms caused by that tumor. This is a form of palliative care, treatment to reduce symptoms and improve quality of life.
New and emerging therapies
New cancer treatments are in development. Your healthcare team may recommend a new and emerging therapy for advanced RCC or possibly a clinical trial.
Remember, advanced RCC is a different experience for different people, and your healthcare team will be your best source of information about your diagnosis and your treatment options.
Sources: NCI Dictionary of Cancer Terms. First-li... + 16
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- NCI Dictionary of Cancer Terms. Second-line therapy. Accessed November 26, 2025.
- NCI Dictionary of Cancer Terms. Third-line therapy. Accessed November 26, 2025.
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