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PRRT Moves Needle Forward in NETs, But Unmet Needs Remain

Kristi Rosa
Published: Tuesday, Mar 12, 2019

Michael Morse, MD, FACP, MHS

Michael Morse, MD, FACP, MHS

One of the most exciting options for the management of patients with neuroendocrine tumors (NETs) is peptide receptor radionuclide therapy (PRRT), said Michael Morse, MD, FACP, MHS, who added that the significant activity for this approach now raises important questions about sequencing of the growing list of therapies.

In January 2018, the FDA granted an approval to the radionuclide therapy Lutathera (lutetium (Lu)- 177 dotatate) for the treatment of patients with somatostatin receptor–positive gastroenteropancreatic NETs. The regulatory decision was based in part on results of the phase III NETTER-1 trial, which compared Lutathera with high-dose octreotide LAR (Sandostatin) in patients with metastatic or locally advanced, inoperable, well-differentiated midgut neuroendocrine tumors that progressed during treatment with standard dose octreotide LAR. They were required to have somatostatin receptors present on all target lesions. Initial results demonstrated a 79% reduction in the risk of progression or death with Lutathera.1

Updated data presented at the 2018 ASCO Annual Meeting demonstrated that the median overall survival (OS) for patients who received Lutathera had not been reached, while those who were given high-dose octreotide showed a median OS of 27.4 months.2

Further, at the time the data were presented, the progression-free survival (PFS) showed 30 events in the Lutathera cohort versus 78 events in the octreotide cohort (HR, 0.21; 95% CI, 0.14-0.33; P <.0001). Moreover, investigators reported a significantly longer time to decline in those who received Lutathera versus those given octreotide for global health status (HR, 0.406; P = .0006), physical functioning (HR, 0.518; P = .0147), role functioning (HR, 0.580; P = .0298), and fatigue (HR, 0.621; P = .0297).

“We're trying to understand where it fits in the entire paradigm of treating NETs,” said Morse. “A typical discussion that I've had several times today in my clinic is, if someone has had a somatostatin analog and they have progressed, there are several options for those patients. It might be local regional therapy, it might be a systemic therapy, it might be everolimus (Afinitor), or it might be Lutathera. It's great to know that we have another therapy that can prolong PFS, and, in an interim analysis lengthens overall survival.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Gastrointestinal Malignancies, Morse, a medical oncologist at Duke Cancer Institute, highlighted the importance of PRRT in the management of patients with NETs and identified significant unmet needs that will need to be addressed in order to continue advancement in the space.

OncLive®: What is some recent progress that has been made in NETs?

Morse: The big excitement for everyone, of course, is that the FDA, at the beginning of last year, approved Lutathera. Obviously, it took some time to get things up and running. Insurance companies have to get up to speed with realizing that this drug is out there and what its benefits are, but finally, toward the end of the year, we were starting to see more insurance approvals, and so, we're beginning to treat more patients with it. Patients have heard about it; they're clearly asking for it.

Could you expand on the use of PRRT in this space?

One of the big new areas in NETs is the use of PRRT. The concept is that there's a molecule called DOTA-TATE which is a peptide, that is very much like octreotide to which is bound a chelator. In the case of Lutathera, the chelator holds the beta-emitter Lu177. The DOTATATE binds to the somatostatin receptors on NETs and delivers the radioactivity. It’s a systemic therapy as opposed to another form of radiotherapy that is sometimes given to NET patients, such as yttrium-90 (Y-90) radioembolization, which is just directed at the liver. [Lutathera] is a systemic therapy, and so, it's ideal for patients who have multifocal disease even outside of the liver.

The big impact it clearly has had was demonstrated in the NETTER-1 trial, where patients who had progressed on octreotide LAR were randomized to receive Lutathera as 4 doses 8 weeks apart versus a higher dose of octreotide LAR 60 mg monthly, which is double the standard dose.

The main endpoint of the trial was PFS, and [Lutathera] clearly markedly improved PFS. There also looks like, when the data are mature, that there will be improvement in median OS. There has also been follow-up data in regard to quality of life (QoL), and clearly, QoL improves on [Lutathera]. Further, most metrics, whether you look at individual symptoms such as flushing or diarrhea, seem to improve over time. If you look at global metrics of QoL, those seem to improve over time as well.

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