PRRT Moves Needle Forward in NETs, But Unmet Needs Remain

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.”

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

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

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.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.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.

One of the things that I am telling patients is that, “Although this is a great new therapy, some of the benefits will take some time.” In fact, with the scan right after the end of therapy, sometimes there's stable disease but we'll see a response later. In fact, overall, about 19% of patients will have a partial response and about 1% will have a complete response [to the therapy], which is higher than our other FDA approved systemic therapies.

How did findings from the CLARINET trial impact the paradigm?

There are obviously many ways of trying to improve upon that data. There are ongoing studies in which investigators are combining other therapies with Lutathera. For example, one of the studies of interest gives us additional data on other somatostatin analogs. While octreotide LAR was the combination with Lutathera in the NETTER-1 trial, naturally, people might ask, "Well, I'm on lanreotide (Somatuline Depot). How does lanreotide perform?" The PRELUDE trial combined lanreotide with Lutathera and clearly showed that it was equally effective to do that, equally safe. So, patients now know that they can probably use either of the drugs along with their PRRT.The history of treating NETs with somatostatin analogs goes back to their use for [patients with] carcinoid syndrome. It took a few years before people realized that these drugs actually seemed to be able to control the tumor; they have antitumor activity.

Initially, there was the PROMID trial, which was not a study submitted for regulatory approval, but did show that octreotide LAR improved PFS compared with observation in patients with midgut NETs. Naturally, we want to offer these therapies to all of our patients with NETs, but we didn't have the data, and yet we were doing that with octreotide LAR. Therefore, if you had a pancreatic NET or a lower GI-tract NET, we were just making the assumption that there would be a better PFS in using octreotide LAR.

What is an unmet need that still needs to be addressed in this field?

The CLARINET trial was, first of all, a registration study done for regulatory approval. The trial included patients with well or moderately differentiated, nonfunctioning, somatostatin receptor—positive NETs of grade 1 or 2 originating in the pancreas midgut, or hindgut or were of unknown origin. They were randomized to receive lanreotide at 120 mg monthly versus placebo. There, [lanreotide] demonstrated an improvement in PFS not just in midgut NETs, but also in pancreatic NETs. Therefore, that trial led to an FDA indication for lanreotide for its anticancer activity.The big unmet need is in patients who have had resections of their disease, but don't have any obvious metastatic disease yet. We know that many people with NETs will relapse after their surgery, whether they have pancreatic or midgut NETs. Whether disease is found serendipitously or due to symptoms, the bottom line is that there’s a very high rate of lymph node involvement and high rate of recurrence, so we clearly need an adjuvant therapy. We don't have one right now, and there are no studies that have been able to address this yet, because people survive a long time. It’s going to be challenging to show that.

The other area, clearly, is that although people with metastatic NETs still can live a long time, and are living longer than they used to, there's still a high rate of progression. Therefore, what is that next drug? If you've already used a somatostatin analog, and you've used an mTOR inhibitor like everolimus, sunitinib (Sutent) for pancreatic NETs, and you've done PRRT—not necessarily in that order—and you’ve done chemotherapy in pancreatic NETs, what is next?

There are ongoing studies with other targeted therapies. There is a lot of interest in combining PRRT with targeted therapies or with chemotherapy, and we're just in the infancy of learning about the molecular biology of NETs. Unfortunately, very few [tumors] have easy-to-target mutations; some of them have abnormalities in chromatin remodeling. In terms of the drugs that target chromatin right now, it's hard to say what their efficacy is going to be in NETs, but it’s just an example. As we learn more about the molecular biology, we'll learn more about what drugs and what targets we need to be developing further.

References

1. Strosberg JR, Wolin EM, Chasen B, et al. NETTER-1 phase III: efficacy and safety results in patients with midgut neuroendocrine tumors treated with ¹⁷⁷Lu-DOTATATE. J Clin Oncol. 2016;34 (suppl 15; abstr 4005). doi: 10.1200/JCO.2016.34.15_suppl.4005.
2. Strosberg JR, Wolin EM, Chasen BA, et al. First update on overall survival, progression-free survival, and health-related time-to-deterioration quality of life from the NETTER-1 study: 177Lu-Dotatate vs. high dose octreotide in progressive midgut neuroendocrine tumors. J Clin Oncol. 2018;36 (suppl 15; abstr 4099). doi: 10.1200/JCO.2018.36.15_suppl.4099.