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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.
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Daniel J. George, MD
Director of Genitourinary Oncology
Duke Cancer Institute
Durham, North Carolina
Robert A. Figlin, MD
Professor of Medicine and Biomedical Sciences
Chief, Division of Hematology/Oncology
Cedars-Sinai Comprehensive Cancer Center
Los Angeles, California
Thomas E. Hutson, DO, PharmD
Director of Genitourinary Oncology, Texas Oncology;
Professor Medicine, Texas A&M
Health Science Center, Dallas, Texas
Eric Jonasch, MD
Associate Professor of Medicine
University of Texas MD Anderson Cancer Center
Brian I. Rini, MD
Professor of Medicine, The Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio