Lutathera Leads Therapeutic Advances in NETs

Daniel M. Halperin, MD

There have been several therapeutic and research advances made in the management of neuroendocrine tumors (NETs), said Daniel M. Halperin, MD, but perhaps the most exciting development has been the introduction of peptide receptor radionuclide therapy (PRRT).

In January 2018, the FDA approved the radionuclide therapy known as Lutathera (lutetium Lu 177 dotatate) for the treatment of patients with somatostatin receptor—positive gastroenteropancreatic NETs (GEP-NETs). The approval was based on positive results from the phase III NETTER-1 trial, which randomized patients with grade 1/2 metastatic midgut NETs to receive either Lutathera or high-dose octreotide LAR. Initial results revealed a 79% reduction in the risk of progression or death with Lutathera compared with octreotide.¹

An updated analysis from the 2018 ASCO Annual Meeting continued to demonstrate a higher proportion of progression-free survival (PFS) events in the octreotide arm compared with the Lutathera arm (HR, 0.21; 95% CI, 0.14-0.33; P <.0001).²

Although immunotherapy has yet to display the same benefit, recent findings from the 2019 Gastrointestinal Cancers Symposium are helping physicians narrow down the setting and population in which it may prove most beneficial. At the meeting, data were presented on pembrolizumab (Keytruda) in patients with advanced NETs. Of 107 patients enrolled in the phase II KEYNOTE-158 trial, only 4 responded.³ Despite these discouraging results, Halperin noted that pembrolizumab remains a point of interest in combination with other agents.

“A big part of moving the field forward is going to be proactively identifying the patients who are going to have the worst outcomes and then directing our therapies toward the underlying factors of that rapid pace of progression,” said Halperin. “We're still working on developing the right treatments to do that.”

OncLive: Could you discuss the use of PRRT and its benefit in patients with NETs?

What are some of the latest data to emerge in the field?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Halperin, medical oncologist, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, shed light on the latest research in NETs.Halperin: PRRT uses hormones to guide a nuclear “smart bomb” to kill the tumor wherever it lives. The therapy reduced the rate of progression or death by about 80% in the randomized NETTER-1 trial, where patients with midgut NETs were randomized to receive either the nuclear therapy or high-dose somatostatin analogue therapy.We have been very interested in immunotherapy. The KEYNOTE-158 study was presented by Jonathan Strosberg, MD, of Moffitt Cancer Center, at the 2019 Gastrointestinal Cancers Symposium; those data were a little discouraging. We saw around a 3% response rate and a PFS of about 4 months, which is essentially what we see with placebo.

What is the role of liver-directed therapy in NETs?

Have any surgical advances been made?

Many of us, myself included, will continue to do studies with immunotherapy. Time will tell whether pembrolizumab or another checkpoint inhibitor [will have a role in the treatment of this disease] and in what combination.Liver-directed therapy is fascinating in NETs. There have been several primarily retrospective series over the years using different liver-directed techniques. We have seen reasonable PFS and OS with them. Of course, these data came from retrospective studies of well-selected patients, but it’s certainly on the table as something we can do to help our patients.We consistently see that patients who are able to undergo surgery do better than patients who are not; that has been true for primary and metastatic resections. It's not always clear whether that's because the surgery itself offered benefit or because the patients were healthier and were able to tolerate the surgery.

Could you discuss the CLARINET trial? What were the key takeaways from this study?

What is your take-home message to your colleagues treating patients with NETs?

Within the last year or so, a paper was published in JAMA Oncology. In the study, investigators took a group of patients with metastatic disease who underwent primary resection and matched them with propensity analysis. They noticed that after matching patients based on how sick they were when they went to surgery, the benefit of resection went away. We're starting to wonder how benefit comes from surgical intervention and how much comes from patient selection. It still is certainly a component of our management.The CLARINET study was a randomized study of lanreotide (Somatuline Depot) in patients with nonfunctional GEP-NETs. This was based on the original investigator-initiated PROMID study with octreotide [in midgut NETs]. That study demonstrated that somatostatin analogues not only help with the symptoms of NETs, but also help to slow down the pace of progression. The study showed about a 65% reduction in the risk of progression or death with octreotide versus placebo, although the drug never moved forward after its registration. CLARINET looked more broadly across GEP-NETs to see if a similar benefit could be observed, and it was.The way we classify and name neuroendocrine neoplasms is critical in getting pathologists, medical oncologists, surgical oncologists, and everyone else on the team on the same page. The treatments are very different depending on how we classify the cancers, and the classifications keep changing. Staying on top of that and understanding the differences will allow us to treat our patients better.

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.
3. Strosberg JR, Mizuno N, Doi T, et al. Pembrolizumab treatment of advanced neuroendocrine tumors: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37(suppl 4;abstr 190). doi: 10.1200/JCO.2019.37.4_suppl.190.