Peptide Receptor Radionuclide Therapy for NETs

Transcript:Simron Singh, MD: Jon, I want to talk to you a bit about what some people may consider a targeted therapy as well—PRRT [peptide receptor radionuclide therapy]. You were the first author on a very important paper, the NETTER-1 paper. Can you tell us a bit about that? Can you tell the audience a bit about the treatment and when you think it should be used?

Jonathan R. Strosberg, MD: Sure. Most patients with well-differentiated neuroendocrine tumors express somatostatin receptors, specifically somatostatin receptor subtype 2. And so, attaching a radioisotope to a somatostatin analog is a means of delivering radiation to the tumor. That’s the underlying principle of the radiolabeled somatostatin analogs. This is a treatment that has evolved over several decades. It first started with indium-111, which has a very weak cytotoxic effect; then yttrium-90, which has a relatively large particle range; and, most recently, lutetium-177, which is a beta-emitting isotope with a relatively intermediate particle range of about 2 mm and a good therapeutic index. The data, until recently, were almost exclusively from large institutional series. Sometimes the data included hundreds of patients. Results have shown fairly high response rates ranging from about 20% in midgut NETs to about 40% in pancreatic NETs. Of course, all patients had somatostatin receptor-expressing tumors.

NETTER-1 was a randomized phase III trial of a radiolabeled somatostatin analog, specifically lutetium-177 dotatate. The drug was administered intravenously once every 8 weeks for 4 treatments. The population included patients with progressive midgut neuroendocrine tumors and those whose tumors were progressing on first-line octreotide given at a standard dose. Patients were randomized to receive lutetium-177 dotatate versus high-dose octreotide on the comparator arm. The primary endpoint, as you know, was progression-free survival by blinded central radiology review. The study showed a very significant improvement in progression-free survival. It was 8 months with high-dose octreotide. It was not reached at the time of analysis with lutetium-177 dotatate. The hazard ratio was 0.21. This was obviously very statistically significant.

At the same time, we did a preliminary analysis of overall survival. This is not the main overall survival analysis, but on preliminary analysis there were nearly twice as many deaths on the octreotide arm versus the lutetium arm. So these are early indications that it probably improves overall survival, but we have to wait for the final results. The response rate was roughly 18% with lutetium. So there was clearly evidence of activity in the midgut NET population, and I think the combination of the NETTER-1 study as well as single-arm data, primarily from Erasmus hospital in Rotterdam [Netherlands], led to the approval of lutetium-177 dotatate not just in midgut NETs but in gastroenteropancreatic neuroendocrine tumors in the United States as well as in Europe.

Simron Singh, MD: Yes, it has obviously been a huge leap forward in our understanding of how we can treat these neuroendocrine tumors. The trial was done specifically in midgut neuroendocrine tumors. Do you think we need to do further trials for the other neuroendocrine tumors, specifically pancreatic neuroendocrine tumors and even bronchial neuroendocrine tumors? Or do you think we have enough data at this time to extrapolate to use PRRT in these tumors?

Jonathan R. Strosberg, MD: You know, that’s been a controversial question. I would say that there’s almost certainly enough evidence based on the very long history of single-arm data to say that PRRT almost certainly works in the whole variety of NETs that express somatostatin receptors regardless of primary site, although that activity may be different. But I’m glad that there is a randomized study being conducted. The COMPETE study is looking at a slightly different radiolabeled somatostatin analog versus everolimus in nonfunctioning enteropancreatic NETs. I think that this will be a good study to sort of give us early indications of how to potentially sequence treatments. We really haven’t had too many studies, if any, in the neuroendocrine field comparing 2 active drugs. And so, I think that will provide us with some important information.

As far as selecting patients, it’s really important to do good quality somatostatin receptor imaging and make sure that all of the tumors express somatostatin receptors. If you have heterogeneous uptake, the tumors that are not expressing somatostatin receptors will often be relatively aggressive. And so, those would not be appropriate patients for PRRT treatment. I think what we’re talking about is using PRRT as second-line and beyond treatment. Sometimes there’s temptation among patients or practitioners to move it to the first-line setting. I think that’s appropriate only in very rare circumstances. Even though it’s an effective treatment and is well tolerated, there are risks with PRRT. There’s a roughly 2% risk of long-term bone marrow damage, myelodysplastic syndrome, or leukemia. We need to be aware of that. So I don’t think PRRT is going to displace somatostatin analogs as a first-line treatment—at least not in the near future—unless there is a clinical trial that’s evaluating that. But, certainly, it can be used in the second-line and beyond settings.

Transcript edited for clarity.