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Using Combination Therapies in Advanced pNETs

Insights From: Matthews H. Kulke, MD, Harvard Medical School; Jonathan R. Strosberg, MD, Moffitt Cancer Center; James C. Yao, MD, University of Texas MD Anderson Cancer Center
Published: Friday, Dec 18, 2015


The randomized phase II CALGB 80701 study evaluated the effects of combining mTOR inhibition with angiogenesis inhibition in patients with advanced pancreatic neuroendocrine tumors (pNETs). Participants were randomized to receive treatment with single agent everolimus, or a combination of everolimus and bevacizumab. Treatment with everolimus plus bevacizumab resulted in a superior progression-free survival and a higher response rate compared with everolimus alone. However, it was not a definitive study, says Matthew H. Kulke, MD. Although mTOR inhibition with angiogenesis inhibition is a potentially effective strategy, larger studies assessing this treatment are warranted, notes Kulke.

Temozolomide is an oral alkylating agent shown to be effective in shrinking advanced pNETs. An ongoing cooperative group study is assessing the efficacy of combining temozolomide with capecitabine compared with temozolomide alone in patients with advanced pNETs. The combination of temozolomide and capecitabine is based on preclinical data suggesting synergy between these two cytotoxic agents, states Jonathan R. Strosberg, MD, particularly if capecitabine is administered prior to temozolomide. Other ongoing studies are evaluating the doublet pairings of temozolomide with bevacizumab, everolimus, and a PARP inhibitor.

In the randomized phase II study COOPERATE-2, patients with advanced pNETs were randomized to receive everolimus with or without somatostatin analogue, pasireotide. There were reported differences in response rates but no significant difference observed in progression-free survival, says James C. Yao, MD.
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The randomized phase II CALGB 80701 study evaluated the effects of combining mTOR inhibition with angiogenesis inhibition in patients with advanced pancreatic neuroendocrine tumors (pNETs). Participants were randomized to receive treatment with single agent everolimus, or a combination of everolimus and bevacizumab. Treatment with everolimus plus bevacizumab resulted in a superior progression-free survival and a higher response rate compared with everolimus alone. However, it was not a definitive study, says Matthew H. Kulke, MD. Although mTOR inhibition with angiogenesis inhibition is a potentially effective strategy, larger studies assessing this treatment are warranted, notes Kulke.

Temozolomide is an oral alkylating agent shown to be effective in shrinking advanced pNETs. An ongoing cooperative group study is assessing the efficacy of combining temozolomide with capecitabine compared with temozolomide alone in patients with advanced pNETs. The combination of temozolomide and capecitabine is based on preclinical data suggesting synergy between these two cytotoxic agents, states Jonathan R. Strosberg, MD, particularly if capecitabine is administered prior to temozolomide. Other ongoing studies are evaluating the doublet pairings of temozolomide with bevacizumab, everolimus, and a PARP inhibitor.

In the randomized phase II study COOPERATE-2, patients with advanced pNETs were randomized to receive everolimus with or without somatostatin analogue, pasireotide. There were reported differences in response rates but no significant difference observed in progression-free survival, says James C. Yao, MD.
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