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New Potent Treatments for Progressing Neuroendocrine Tumors

Susman, Ed

doi: 10.1097/01.COT.0000473586.65275.3f
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VIENNA, Austria—In the space of 30 minutes, an empty landscape for treating progressive neuroendocrine tumors of the lung and mid-gut remarkably now has two candidate therapies that exhibit potent efficacy, according to research presented here at the European Cancer Conference.

At a news conference, James Yao, MD, Professor of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center, demonstrated that treatment with everolimus in patients whose neuroendocrine tumors in the lungs and/or gut markedly improved progression-free survival when compared with placebo (Abstract 5LBA).

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“Treatment for patients diagnosed with non-functional, progressing neuroendocrine tumors of the lung and gut remain limited,” he explained in his presentation. “In fact, there are no agents that are approved or have demonstrated any activity in patients with lung neuroendocrine tumors.”

But his study, which he described as the first Phase III study to test the use of everolimus in this population, showed a remarkable improvement in progression-free survival, the primary endpoint of the RADIANT-4 trial, which was supported by Novartis. Patients treated with everolimus achieved a median 11.0 months of progression-free survival compared with 3.9 months among patients assigned to placebo.

That translates to a 52 percent reduction in the risk of progression or death, a highly statistically significant difference (p<0.00001), he said.

In the trial, 205 patients were treated with everolimus and 97 were assigned to the placebo arm. About 25 percent of the patients were diagnosed with gastrointestinal tumors, and the other 75 percent, with lung and other neuroendocrine tumors.

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Isotope Added to Octreotide

In another study, Philippe Ruszniewski, MD, Professor of Gastroenterology at Hospital Beaujon in France reported an improvement in progression-free survival achieved using the isotope 177Lu-Dotatate in addition to octreotide in patients with advanced, progressing mid-gut neuroendocrine tumors instead of just octreotide alone (Abstract 6LBA).

177Lu-Dotatate is a lutetium radionuclide chelated to a peptide, and the peptide targets somatostatin receptors, known to be overexpressed in about 80 percent of neuroendocrine tumors, he explained.

In the NETTER-1 study, the median progression-free survival of 8.4 months was achieved by patients who were treated with octreotide at 60 mg, but the median progression-free survival of the patients receiving the radionuclide had not been reached after a median of more than 40 months.

He calculated that the use of 177Lu-Dotatate reduced the risk of progression by 79.1 percent, also a highly statistically significant level (p<0.0001).

In addition, Ruszniewski said that of the 101 people assigned to 177Lu-Dotatate, one patient achieved a complete response; 13 had partial responses, and 77 maintained stable disease—a net clinical benefit of 95 percent.

That result compared with three partial responses and 70 instances of stable disease among the 100 patients taking octreotide—a 76 percent net clinical benefit. The difference in objective responses was significant (p=0.0004), he said.

“This shows that we were able to see tumor shrinkage in these patients.” A total of 90 percent of patients had tumor shrinkage, although in the majority of the cases the shrinkage did not meet RECIST criteria for a partial response designation, he said.

“I think we now have reasonable evidence that this represents a major advance in treatment of patients with progressing mid-gut endocrine tumors.”

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‘At Verge of Practice-Changing Trials’

Exactly how the new therapies will be used and in what sequence are details that will undoubtedly require more clinical trials, said Christoph Zielinski, MD, Professor of Medicine at the University of Vienna, the moderator of the news conference.

However, he did tell OT: “We are really at the verge of practice-changing trials. The question that always comes up is what would you rather use. The answer is: I don't know. This is something that would have to tested in a head-to-head comparison. The question again, though, is how would we ever perform this type of study.”

Zielinski said that he found the RADIANT-4 results compelling enough to change his practice. “I will be using everolimus with my neuroendocrine patients who are progressing.”

He suggested that the United States, through the National Cancer Institute, would be better positioned to do such a trial rather that in Europe, where researchers are more dependent on pharmaceutical support for these studies.

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Incidence on Rise

The researchers noted that while neuroendocrine tumors are relative rare, their incidence is on the rise. The incidence was 1.09 per 100,000 people in 1973 and by 2004 had risen to 5.25 per 100,000 people. Ruszniewski said that in the United States and Europe there are about 47,500 cases.

In both trials, the researchers performed interim analyses of overall survival, and in both cases the outcome favored treatment with the new drugs. The risk of death was reduced 36 percent among patients on everolimus in the RADIANT-4 trial (p=0.037), but did not achieve the pre-specified criteria for significance (p=0.0002), Yao said. The study has been ongoing for more than 27 months, and the next interim analysis for overall survival is expected in 2016.

Similarly, the number of deaths with 177Lu-Dotatate was 13 compared with 22 deaths of patients on octreotide alone (P<0.0186), but that was also an interim analysis and missed the criteria for significance (P<0.0001), Ruszniewski said, noting that median overall survival had not been reached for either arm of the study. The study has been ongoing for more than 25 months.

Both researchers said that they would have to wait for the results of the trials to mature to see if the treatments produce a significant survival advantage.

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Safety Profiles

Yao said that the safety profile for patients in the study reflected the known safety profile for everolimus in other studies; Ruszniewski also reported a favorable safety profile with 177Lu-Dotatate. He said seven patients were observed with serious blood and lymphatic system disorders, including three cases of lymphocytopenia; three patients were diagnosed with serious kidney disorders, and one patient had portal hypertension.

“We have conducted a sub-study in other patients to study the fate of the radionuclide,” Ruszniewski said in response to reporters' questions. “It does disappear from the blood. It is not entirely impossible that it could cause damage in the long run—this is radiation. From our Phase I and II studies we think that damage is possible but rare.

“The two organs that should be carefully watched are the bone marrow and the kidneys. To limit damage to the kidneys, amino acids are infused along with the radionuclide to compete with the radioactive agent and limit damage to those organs.” He said that in the long run there might be a risk of myelodysplastic syndromes in approximately three to four percent of patients.

Ruszniewski noted that in his study patients were eligible if they were progressing on octreotide, which meant that they were likely sensitive to somatostatin-targeted drugs at the onset of the trial. He said that patients with neuroendocrine tumors have generally better prognoses than patients diagnosed with other cancers: “This is not a case where patients will have to choose one treatment or another. Most of our patients receive all that we have. It is just a question of order.”

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Testing

He said that patients who are diagnosed with progressing neuroendocrine tumors of the mid-gut should undergo tests to make sure they have overexpressed somatostatin receptors. In 15 to 20 percent of the patients there is no overexpression, and, he said, success with the radionuclide would be limited in these patients.

“In this particular disease,” Yao said, “I think we will need both of these treatments. It may not be that important to know which one is better. I think a head-to-head study would be very unlikely even with support from the National Institutes of Health.”

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Abstracts

All the abstracts from the meeting are available at: http://bit.ly/ECC2015-search

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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