Second-Line Treatment of Metastatic Renal Cell Carcinoma

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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. However, several second-line options are available following progression on one of these agents, including sorafenib, axitinib, and everolimus.

In the second-line setting, the superiority of axitinib over sorafenib was clearly demonstrated in the phase III AXIS trial, Sumanta Kumar Pal, MD, notes. In this trial, the median progression-free survival (PFS) was 6.7 months in the axitinib arm compared with 4.7 months with sorafenib (HR = 0.67; P < .0001). When examining patients in the AXIS study who received first-line cytokines rather than a VEGF inhibitor, the PFS advantage increases to around 5 months, Pal adds.

In the RECORD-1 study that explored everolimus for patients with mRCC, only 21% of patients were truly treated in the second-line setting. For true second-line patients, the PFS advantage was near 5 months, Pal notes. Based on these data, side effect profiles, and his personal experience, Pal generally switches to second-line everolimus following treatment with a frontline VEGF inhibitor.

The selection of a second-line therapy can be guided by the magnitude and duration of response to frontline treatment, Daniel J. George, MD, believes. If the response to a frontline VEGF inhibitor is favorable, this treatment approach can reasonably be continued in the second-line setting. However, if a patient rapidly progresses on a frontline VEGF TKI, switching to an mTOR inhibitor is warranted. Utilizing this approach results in approximately 75% of patients receiving a second-line VEGF inhibitor and 25% receiving an mTOR inhibitor, George notes.

Renal cell carcinoma is driven by VEGF, both in the first- and second-line setting, Brian I. Rini, MD, suggests. As a result of this mechanism, Rini believes continued VEGF inhibition in the second-line setting results in the most substantial improvement in survival. In general, retrospective data from clinical trials seems to support this theory, Rini notes.

The unavailability of concrete prospective data to support an optimal sequence illustrates an unmet need in the treatment of mRCC, Robert A. Figlin, MD, states. At this point, a head-to-head comparison is not available to explicitly answer treatment selection questions, leaving physicians to make qualitative decisions on an individual basis.