The majority of patients with metastatic renal cell carcinoma (mRCC) are treated with a VEGF-targeted TKI in the first-line setting, believes moderator Daniel J. George, MD. Following progression on one of these agents, several treatments remain available as a second-line option, including the potent angiogenesis inhibitor axitinib.

The rationale to examine axitinib in the second-line setting stemmed from evidence suggesting that continued VEGF inhibition remains effective in later lines of treatment, explains Brian I. Rini, MD. As a result, the phase III AXIS trial evenly randomized 723 patients with clear-cell mRCC to receive second-line axitinib or sorafenib. Patient selection was carefully restricted to only one prior therapy; however, this treatment could have been a variety of agents, including cytokines, high-dose IL-2, temsirolimus, and a VEGF inhibitor.

This trial demonstrated a clinical advantage for axitinib with a hazard ratio of 0.67, notes Rini. The median progression-free survival (PFS) was 6.7 months in the axitinib arm compared to 4.7 months with sorafenib (P < .0001). Based on these findings, the FDA approved axitinib in early 2012.

A high-level of evidence exists for administering either everolimus or axitinib in the second-line setting, suggests Robert A. Figlin, MD. The challenge facing physicians is determining which treatment should be administered. In the absence of a head-to-head comparison, Rini recommends looking to the patient populations enrolled into each trial that examined these agents.

In the RECORD-1 trial exploring everolimus, approximately 21% of patients were truly in the second-line, points outs Rini. As a result, the trial was largely performed in the third- and fourth-lines of treatment. Inversely, the AXIS trial was conducted in a purely second-line setting. As a result, Rini believes the level of evidence for second-line use is in favor of axitinib over everolimus. However, Rini does not believe a characteristic is currently known that predicts a better response to a distinct second-line therapy. The one thing that does seems clear, notes George, is that the level of response to a VEGF TKI in the first-line seems to predict the overall prognosis.

If patients do not response well initially to a TKI, their prognosis is generally very poor. As a result, these patients should be treated aggressively or referred to a clinical trial. However, each of the VEGF inhibitors has unique characteristics, points out Thomas E. Hutson, DO, PharmD. As a result, a patient may not respond to one TKI in the frontline but have a long response to another in the second-line setting. Additionally, Rini notes, it is important to ensure that a patient is not responding to an agent, before moving on to a new treatment.