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Role of PRRT in the Management of NETs

Insights From: Heloisa P. Soares, MD, UNM Comprehensive Cancer Center; Jonathan R. Strosberg, MD, Moffitt Cancer Center; Timothy J. Hobday, MD, Mayo Clinic College of Medicine and Science
Published: Tuesday, Apr 03, 2018



Transcript: 

Timothy J. Hobday, MD: Peptide receptor radionuclide therapy consists of a high-energy radionuclide particle, lutetium-177, that is bound to DOTATATE, which binds metastatic receptors avidly. Thus, in our neuroendocrine tumors that generally have very high expression of somatostatin receptors, the drug is preferentially bound to tumor tissue and less to normal tissues in the body. This delivers the radiation directly to the tumor in a selective way throughout the body. Certainly, other tissues of the body have some somatostatin receptors on them, such as a pituitary gland, adrenal gland, ovaries, and testes. There will be some radiation delivered to these organs, as well as to the kidneys and the bone marrow. This therapy has generally been quite safe and well tolerated, and we hope that this will continue to significantly advance the care of our patients.

There’s a phase III randomized trial that demonstrated that PRRT significantly, and fairly dramatically, increased progression-free survival in patients with midgut carcinoid tumors who had progressed on a somatostatin analog. We’ll wait, over the next few years, to see if this translates to a benefit in overall survival. But it was clearly a significant advance in those patients.

It’s a little harder to know where it will fit into the treatment algorithm for patients with neuroendocrine tumors of pancreas primary, lung primary, or unknown primary sites. Depending on the approval decision by the FDA, it may be available for those patients. Physicians, in multidisciplinary centers, will have to compare it to other treatment modalities that might be available for each individual patient, such as systemic chemotherapy, surgical techniques, and other systemic therapies. This is based on what we know about peptide receptor radiotherapy from the large experience in Europe that has accumulated over the last decade or more—as it has been standard therapy there.

Patients should be selected for the use of peptide receptor radiotherapy by imaging techniques that are able to document that the tumors are very richly populated with somatostatin receptors. The Octreoscan that has been used for many years has generally been the standard of care for that treatment selection in Europe and on the NETTER-1 randomized clinical trial here in the United States. With Gallium-68 PET imaging, which is now more widely available in the United States and across the world, it is felt that this is an even better way of trying to define tumors that strongly express somatostatin receptors.

Jonathan R. Strosberg, MD: NETTER-1 was the first randomized phase III study of peptide receptor radiotherapy of a radiolabeled somatostatin analog. The population studied was patients with midgut neuroendocrine tumors—midgut means small intestine, jejunoileum, proximal colon, and cecum. This is the most common type of well-differentiated neuroendocrine tumor. All patients had to have disease progression on the standard doses of octreotide. That progression needed to be a resist progression at baseline, but it could have occurred over a period as long as 3 years. The experimental arm of the study was a standard course of lutetium-177 DOTATATE, 200 mCi, every 8 weeks, for 4 treatments. The control arm of the study was high-dose octreotide, 60 mg, every 4 weeks.

The primary endpoint of the study was progression-free survival by central blinded radiology review. The study showed a very substantial improvement in PFS. The hazard ratio for progression of deaths was 0.21, meaning that there was a 79% improvement in risk of progression. On the octreotide arm, the median progression-free survival was 8.4 months. It was not reached with lutetium-177, at the time of the primary endpoint analysis.

A secondary endpoint was response rate. The response rate with lutetium-177 DOTATATE was 18%. It was only 3% with high-dose octreotide, so there was a very significant improvement in objective response rate. Overall survival was also an important secondary endpoint. And at the time of this primary analysis, the hazard ratio for survival was 0.4. In other words, there was a 60% improvement in risk of death, with a P value of 0.004. However, it’s important to emphasize that this is a preliminary analysis to survival. So, the threshold to statistical significance was even higher; it was 0.000085. The mature analysis of overall survival will take place in several years. For now, all we can say about survival is that the early data are very encouraging.

Heloisa P. Soares, MD: The NETTER-1 study is a fascinating study because it has answered a question that was very important. In Europe, we have been using PRRT for many, many years. Now we finally have a randomized phase III trial that looked into the midgut, and the results are fascinating. You have a significant improvement in progression-free survival in that disease. In a recent publication and presentation, the study also showed that PRRT really improves the quality of life of patients, decreases the amount of diarrhea, and increases the physical function of patients and other aspects of quality of life. So, in addition to having tumor control, you have a substantial improvement in the quality of life of patients that received PRRT. It’s very important—how much patients are affected by this disease and by the carcinoid syndrome.

PRRT will have a significant impact on the treatment algorithm for patients with neuroendocrine tumors. There are little nuances in each patient, but in many patients, we are going to move it to be a second-line treatment. The first step is going to still be a somatostatin analog. But then, as your second-line, once the patient has progressed, PRRT could actually be on the top of your list. Obviously, there are nuances. If the patient has a lot of liver disease and no disease outside of the liver, you can argue that doing a liver embolization is probably very good—especially in patients with midgut tumors, which are the patients who we know tend to respond really well to liver embolization. For patients that have a lot of extrahepatic disease, PRRT will probably be a very good second-line treatment—assuming that your tumors are continuing to be positive on Octreoscan or Gallium-68. There is a study, I believe, going on right now in Europe that compares PRRT with everolimus. That will be helpful in answering that question, as well.

Jonathan R. Strosberg, MD: If you look at outcomes, the outcomes with PRRT look superior to most other treatments—both in terms of response rate and, even more importantly, perhaps as far as progression-free survival. That being said, we always have to be cautious, when comparing different trials, when 2 drugs haven’t been compared with each other directly. That’s why it’s going to be so important, in my opinion, to start testing drug A versus drug B in formal clinical trials.

Transcript Edited for Clarity 
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Transcript: 

Timothy J. Hobday, MD: Peptide receptor radionuclide therapy consists of a high-energy radionuclide particle, lutetium-177, that is bound to DOTATATE, which binds metastatic receptors avidly. Thus, in our neuroendocrine tumors that generally have very high expression of somatostatin receptors, the drug is preferentially bound to tumor tissue and less to normal tissues in the body. This delivers the radiation directly to the tumor in a selective way throughout the body. Certainly, other tissues of the body have some somatostatin receptors on them, such as a pituitary gland, adrenal gland, ovaries, and testes. There will be some radiation delivered to these organs, as well as to the kidneys and the bone marrow. This therapy has generally been quite safe and well tolerated, and we hope that this will continue to significantly advance the care of our patients.

There’s a phase III randomized trial that demonstrated that PRRT significantly, and fairly dramatically, increased progression-free survival in patients with midgut carcinoid tumors who had progressed on a somatostatin analog. We’ll wait, over the next few years, to see if this translates to a benefit in overall survival. But it was clearly a significant advance in those patients.

It’s a little harder to know where it will fit into the treatment algorithm for patients with neuroendocrine tumors of pancreas primary, lung primary, or unknown primary sites. Depending on the approval decision by the FDA, it may be available for those patients. Physicians, in multidisciplinary centers, will have to compare it to other treatment modalities that might be available for each individual patient, such as systemic chemotherapy, surgical techniques, and other systemic therapies. This is based on what we know about peptide receptor radiotherapy from the large experience in Europe that has accumulated over the last decade or more—as it has been standard therapy there.

Patients should be selected for the use of peptide receptor radiotherapy by imaging techniques that are able to document that the tumors are very richly populated with somatostatin receptors. The Octreoscan that has been used for many years has generally been the standard of care for that treatment selection in Europe and on the NETTER-1 randomized clinical trial here in the United States. With Gallium-68 PET imaging, which is now more widely available in the United States and across the world, it is felt that this is an even better way of trying to define tumors that strongly express somatostatin receptors.

Jonathan R. Strosberg, MD: NETTER-1 was the first randomized phase III study of peptide receptor radiotherapy of a radiolabeled somatostatin analog. The population studied was patients with midgut neuroendocrine tumors—midgut means small intestine, jejunoileum, proximal colon, and cecum. This is the most common type of well-differentiated neuroendocrine tumor. All patients had to have disease progression on the standard doses of octreotide. That progression needed to be a resist progression at baseline, but it could have occurred over a period as long as 3 years. The experimental arm of the study was a standard course of lutetium-177 DOTATATE, 200 mCi, every 8 weeks, for 4 treatments. The control arm of the study was high-dose octreotide, 60 mg, every 4 weeks.

The primary endpoint of the study was progression-free survival by central blinded radiology review. The study showed a very substantial improvement in PFS. The hazard ratio for progression of deaths was 0.21, meaning that there was a 79% improvement in risk of progression. On the octreotide arm, the median progression-free survival was 8.4 months. It was not reached with lutetium-177, at the time of the primary endpoint analysis.

A secondary endpoint was response rate. The response rate with lutetium-177 DOTATATE was 18%. It was only 3% with high-dose octreotide, so there was a very significant improvement in objective response rate. Overall survival was also an important secondary endpoint. And at the time of this primary analysis, the hazard ratio for survival was 0.4. In other words, there was a 60% improvement in risk of death, with a P value of 0.004. However, it’s important to emphasize that this is a preliminary analysis to survival. So, the threshold to statistical significance was even higher; it was 0.000085. The mature analysis of overall survival will take place in several years. For now, all we can say about survival is that the early data are very encouraging.

Heloisa P. Soares, MD: The NETTER-1 study is a fascinating study because it has answered a question that was very important. In Europe, we have been using PRRT for many, many years. Now we finally have a randomized phase III trial that looked into the midgut, and the results are fascinating. You have a significant improvement in progression-free survival in that disease. In a recent publication and presentation, the study also showed that PRRT really improves the quality of life of patients, decreases the amount of diarrhea, and increases the physical function of patients and other aspects of quality of life. So, in addition to having tumor control, you have a substantial improvement in the quality of life of patients that received PRRT. It’s very important—how much patients are affected by this disease and by the carcinoid syndrome.

PRRT will have a significant impact on the treatment algorithm for patients with neuroendocrine tumors. There are little nuances in each patient, but in many patients, we are going to move it to be a second-line treatment. The first step is going to still be a somatostatin analog. But then, as your second-line, once the patient has progressed, PRRT could actually be on the top of your list. Obviously, there are nuances. If the patient has a lot of liver disease and no disease outside of the liver, you can argue that doing a liver embolization is probably very good—especially in patients with midgut tumors, which are the patients who we know tend to respond really well to liver embolization. For patients that have a lot of extrahepatic disease, PRRT will probably be a very good second-line treatment—assuming that your tumors are continuing to be positive on Octreoscan or Gallium-68. There is a study, I believe, going on right now in Europe that compares PRRT with everolimus. That will be helpful in answering that question, as well.

Jonathan R. Strosberg, MD: If you look at outcomes, the outcomes with PRRT look superior to most other treatments—both in terms of response rate and, even more importantly, perhaps as far as progression-free survival. That being said, we always have to be cautious, when comparing different trials, when 2 drugs haven’t been compared with each other directly. That’s why it’s going to be so important, in my opinion, to start testing drug A versus drug B in formal clinical trials.

Transcript Edited for Clarity 
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