Minimizing Toxicity While Maintaining Efficacy in RCC - Episode 7

Second-Line Angiogenesis Inhibition in mRCC

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Evidence supports the frontline administration of bevacizumab for patients with metastatic renal cell carcinoma (mRCC); however, data on the second-line utilization of the VEGF inhibitor is sparse, Sumanta Kumar Pal, MD, notes. For patients who do not respond well to a frontline TKI, second-line treatment with bevacizumab may be a reasonable option, notes Brian I. Rini, MD. In this scenario, where side effects are a concern, Rini recommends omitting interferon alfa and using bevacizumab as a single-agent.

The START trial was formed to help answer questions regarding an optimal sequence for patients with clear cell mRCC following nephrectomy, Nizar M. Tannir, MD, says. This study will explore the mTOR inhibitor everolimus and the VEGF inhibitors bevacizumab and pazopanib in various 2-agent sequences. As part of this analysis, second-line monotherapy with bevacizumab will be analyzed, Tannir notes.

The angiogenesis inhibitor axitinib was recently approved as a second-line therapy for patients with mRCC based on results from the phase III AXIS trial. Treatment with this agent is generally started at 5 mg and eventually titrated upward, based on hypertension. In general, the hypertension associated with axitinib has a quick onset and occurs within the first 4 months following the initiation of therapy, notes Daniel J. George, MD. In addition to hypertension, other dose-limited factors may include GI toxicity, particularly diarrhea.

In order to determine the need for dose escalation, Rini utilizes imaging after 6 weeks of therapy. If tumor response is apparent, the dose size can remain the same. However, if signs of hypertension are not present and a response is not visible, Rini supports increasing the dose to 6 mg.

Axitinib dose titration was utilized in the AXIS trial to retain consistent pharmacokinetics across all patient populations. However, in a secondary analysis it was found that progression-free survival (PFS) was roughly equivalent in the titrated and nontitrated groups of axitinib-treated patients, suggesting the occurrence of hypertension is unrelated to outcomes.

As a result of this analysis, Tannir is hesitant to increase axitinib dosing to 7 or 10 mg. In addition to increasing toxicity, the higher dose also raises the cost of care. Until evidence is available that increasing the dose improves PFS or survival, Tannir plans to continue administering axitinib at the 5 mg dose without substantial dose increases.