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Anti-Angiogenesis and mTOR Inhibition in Carcinoid Tumors

Insights From:Jennifer Eads, MD, Case Western Reserve University; Matthew H. Kulke, MD, Harvard Medical School; Diane Reidy Lagunes, MD, Memorial Sloan-Kettering Cancer Center; Eric H. Liu, MD, FACS, Rocky Mountain Cancer Center; James C. Yao, MD, The University of Texas MD Anderson Cancer Center
Published: Tuesday, Apr 05, 2016


Transcript:

Matthew H. Kulke, MD:
Unfortunately, there are many patients who have more widespread metastatic disease. We need to think about drugs. I’m going to turn to James. You’ve been a leader in this area. Let’s start with mTOR inhibition. You showed early on that treatment with everolimus is effective in pancreatic neuroendocrine tumors. A recent study shows it’s also active in other types of neuroendocrine tumors.

James C. Yao, MD: Yeah. That’s a great segue to discuss this. Everolimus was approved for pancreatic neuroendocrine tumors in 2011, based on the RADIANT-3 study. Still, there was a lot of unmet need in other neuroendocrine tumors of other sites. Among them, there’s little data for any sort of treatment, including somatostatin analogues in lung neuroendocrine tumors, and there is little data for therapy for any large bowel-like colorectal neuroendocrine tumors. RADIANT-4 was designed to address that. It’s a randomized phase III study. It was 2:1 randomization for everolimus versus placebo, stratified by primary site. Stratum A was mostly midgut tumors and unknown primary, and the stratum B was more badly behaved tumors.

We showed in the study, which we recently published, that there was a 2.8-fold improvement in median progression-free survival, so more than 50% reduction in risk of disease progression. At the time of the final progression-free survival analysis, a first interim overall survival analysis was also conducted, showing a trend to our benefit. We still have a lot more to learn from the study, with more maturing of the data following for overall survival and how the patient did in terms of quality of life. And hopefully these data will be coming soon.

Matthew H. Kulke, MD: In addition to mTOR inhibition, you’ve also been involved in another strategy. These tumors are known to be highly vascular. Sunitinib is approved for pancreatic neuroendocrine tumors. What about the role of antiangiogenic therapy in carcinoid tumors?

James C. Yao, MD: Yeah, that’s a really great question. At this point, we don’t have a definitive answer to that part yet. There are certainly great scientific rationale to look at antiangiogenic therapy in neuroendocrine tumors because these tumors are very vascular, and there are a lot of data in the literature showing that VEGF and so forth are prognostic in terms of outcome in these patients. So sunitinib was FDA-approved in 2011 for pancreatic neuroendocrine tumors, but the role of sunitinib in non-pancreatic primary is undefined at this time point.

There are other drugs being studied. One was bevacizumab, and that was looked at in a phase III study, SWOG 0518, where we compared octreotide plus bevacizumab to octreotide plus interferon. What we saw is that there was a higher response rate in the bevacizumab arm, but no difference in progression-free survival. There was a little bit of improvement also, in time, to treatment failure—probably more reflecting the adverse event profile than anything else. Unfortunately, the question for bevacizumab remains unclear. If you thought interferon was active and had a role, and the two arms look certainly nearly identical in PFS, then bevacizumab may have a role. But if interferon is just giving toxicity and has no benefit, then bevacizumab probably cannot be interpreted to be of benefit either.

There’s one other VEGF inhibitor that’s been looked at, which is pazopanib. I think you and I did a phase II together across Dana Farber and MD Anderson that showed promising activity, especially in the pancreatic NET group, but also, potentially, a PFS benefit in the carcinoid group. There’s a study ongoing in the Cooperative Groups with pazopanib in non-pancreatic NET, and that randomized phase II has completed accrual. And there’s thought whether or not we should expand it into more of a phase III study to answer the role of anti-VEGF therapy in a more definitive way.

Transcript Edited for Clarity
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Transcript:

Matthew H. Kulke, MD:
Unfortunately, there are many patients who have more widespread metastatic disease. We need to think about drugs. I’m going to turn to James. You’ve been a leader in this area. Let’s start with mTOR inhibition. You showed early on that treatment with everolimus is effective in pancreatic neuroendocrine tumors. A recent study shows it’s also active in other types of neuroendocrine tumors.

James C. Yao, MD: Yeah. That’s a great segue to discuss this. Everolimus was approved for pancreatic neuroendocrine tumors in 2011, based on the RADIANT-3 study. Still, there was a lot of unmet need in other neuroendocrine tumors of other sites. Among them, there’s little data for any sort of treatment, including somatostatin analogues in lung neuroendocrine tumors, and there is little data for therapy for any large bowel-like colorectal neuroendocrine tumors. RADIANT-4 was designed to address that. It’s a randomized phase III study. It was 2:1 randomization for everolimus versus placebo, stratified by primary site. Stratum A was mostly midgut tumors and unknown primary, and the stratum B was more badly behaved tumors.

We showed in the study, which we recently published, that there was a 2.8-fold improvement in median progression-free survival, so more than 50% reduction in risk of disease progression. At the time of the final progression-free survival analysis, a first interim overall survival analysis was also conducted, showing a trend to our benefit. We still have a lot more to learn from the study, with more maturing of the data following for overall survival and how the patient did in terms of quality of life. And hopefully these data will be coming soon.

Matthew H. Kulke, MD: In addition to mTOR inhibition, you’ve also been involved in another strategy. These tumors are known to be highly vascular. Sunitinib is approved for pancreatic neuroendocrine tumors. What about the role of antiangiogenic therapy in carcinoid tumors?

James C. Yao, MD: Yeah, that’s a really great question. At this point, we don’t have a definitive answer to that part yet. There are certainly great scientific rationale to look at antiangiogenic therapy in neuroendocrine tumors because these tumors are very vascular, and there are a lot of data in the literature showing that VEGF and so forth are prognostic in terms of outcome in these patients. So sunitinib was FDA-approved in 2011 for pancreatic neuroendocrine tumors, but the role of sunitinib in non-pancreatic primary is undefined at this time point.

There are other drugs being studied. One was bevacizumab, and that was looked at in a phase III study, SWOG 0518, where we compared octreotide plus bevacizumab to octreotide plus interferon. What we saw is that there was a higher response rate in the bevacizumab arm, but no difference in progression-free survival. There was a little bit of improvement also, in time, to treatment failure—probably more reflecting the adverse event profile than anything else. Unfortunately, the question for bevacizumab remains unclear. If you thought interferon was active and had a role, and the two arms look certainly nearly identical in PFS, then bevacizumab may have a role. But if interferon is just giving toxicity and has no benefit, then bevacizumab probably cannot be interpreted to be of benefit either.

There’s one other VEGF inhibitor that’s been looked at, which is pazopanib. I think you and I did a phase II together across Dana Farber and MD Anderson that showed promising activity, especially in the pancreatic NET group, but also, potentially, a PFS benefit in the carcinoid group. There’s a study ongoing in the Cooperative Groups with pazopanib in non-pancreatic NET, and that randomized phase II has completed accrual. And there’s thought whether or not we should expand it into more of a phase III study to answer the role of anti-VEGF therapy in a more definitive way.

Transcript Edited for Clarity
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