Strosberg Discusses Lutathera Approval, Remaining Challenges in NETs

Jonathan Strosberg, MD

Findings from the phase III NETTER-1 trial led to the January 2018 FDA approval of Lutathera (lutetium Lu 177 dotatate) for the treatment of patients with somatostatin receptor—positive gastroenteropancreatic tumors (GEP-NETs). The trial compared Lutathera with high-dose octreotide LAR for patients with 1 or 2 metastatic midgut NETs.

In NETTER-1, patients with midgut NETs who progressed on 30 mg of octreotide were randomized to Lutathera (n = 116) or high-dose octreotide (n = 113). Patients received 4 doses of Lutathera at 7.4 GBq every 8 weeks in combination with 30 mg of octreotide. The control arm received 60 mg of octreotide LAR every 4 weeks.

In the study, there was a 79% reduction in the risk of progression or death with Lutathera compared with octreotide. The median progression-free survival (PFS) had not been reached in the Lutathera arm compared with 8.5 months in the high-dose octreotide arm (HR, 0.21; 95% CI, 0.13-0.32; P <.0001).

The overall response rate with Lutathera was 13% versus 4% with octreotide (P <.0148). At the interim analysis of overall survival (OS) there was a 48% reduction in the risk of death seen with Lutathera versus octreotide (HR, 0.52; 95% CI, 0.32-0.84).

Following the Luthathera approval, Jonathan R. Strosberg, MD, notes that challenges remain and ongoing studies are exploring more novel regimens and combinations.

OncLive: How has treatment for patients with NETs and carcinoid syndrome evolved over the past couple years?

Can you explain the significance of the Lutathera approval?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Gastrointestinal Cancers, Jonathan R. Strosberg, MD, an associate professor of Moffitt Cancer Center, discussed ongoing advances and challenges in the treatment of patients with NETs.Strosberg: It has been a pretty exciting couple of years in the treatment of NETs and carcinoid syndrome. We've had the approval of everolimus (Afinitor) a few years ago for the treatment of progressive NETs of the gastrointestinal (GI) tract and lungs. Last year, we saw the approval of telotristat ethyl (Xermelo), a serotonin inhibitor, for the treatment of diarrhea related to carcinoid syndrome. [Recently] Lutathera, a radiolabeled somatostatin analog, was approved for the treatment of patients with progressive GEP-NETs. Radiolabeled somatostatin analogs have been developed for the past several decades, primarily in Europe. They have been manufactured in hospitals and have treated thousands of patients. The principle is delivery of a radioactive somatostatin analog to a somatostatin receptor—expressing NET.

The results have been quite good, with response rates ranging from about 20% to as high as 50% in pancreatic NETs. Significant median PFS durations have also been reported. Though it took time for the phase III NETTER-1 trial to get regulatory approval, the results showed substantial improvement in PFS as well as strong evidence that OS is improved. In a few years, this will be re-examined with a mature analysis.

What should physicians keep in mind with regard to Lutathera’s safety and dosing schedule?

The European Medicines Agency approved Lutathera in September 2017, and the FDA approved it at the end of January not only for midgut tumors, but also in NETs of the stomach, pancreas, colon and rectum.The standard regimen consists of 200 mCi of lutetium Lu 177 dotatate once every 8 weeks or so before treatment. It’s really 4 treatments over 8 months. The drug is often given combined with a somatostatin analog, either a long-acting octreotide or lanreotide, especially in patients with carcinoid syndrome.

Have there been any other developments other than the approval of Lutathera?

Other biological agents and new chemotherapy regimens are also under investigation. Can you elaborate on the potential benefit of these medications?

There is some debate over how long patients need to be off the long-acting somatostatin analog prior to each treatment. In the past, a delay of 6 weeks was often recommended, but there's increasing evidence that patients do not need to interrupt their every-4-week somatostatin analog treatment. Instead, it can be scheduled to coincide just before the next treatment. The big step forward was the Gallium-68 dotatate scan, which is a somatostatin receptor imaging study that is more accurate and sensitive than the prior somatostatin receptor imaging study, which is OctreoScan. A lot of institutions have switched from OctreoScan to Gallium-68 dotetate scans because they can show tumors as small as a few millimeters. There are several biological agents being evaluated. Pazopanib (Votrient) is a tyrosine kinase inhibitor primarily targeting the VEGF receptor. It is being compared with placebo in a large, randomized phase II study in metastatic NETs of the GI tract and lungs. Cabozantinib (Cabometyx), which targets many receptors, showed some promise in the phase II study, so it’s going to be studied in a cooperative phase III study—also in NETs of the GI tract and lungs.

What is the current state of treatment approaches in GEP-NETs?

With respect to chemotherapy agents, temozolomide-based regimens have been used quite a bit for the past decade or so, and they seem to work quite well primarily in pancreatic NETs and in tumors that are on the aggressive side. We are looking forward to the results of a large, randomized study comparing temozolomide plus capecitabine versus temozolomide monotherapy in pancreatic NETs. That is going to be a very exciting study that will tell us whether combination chemotherapy is better than single agents and also give us the first robust prospective data leading to temozolomide-based regimens.It’s important for community oncologists to be aware that there are new treatments. Some of them, such as Lutathera, will likely be available in specialized centers. It’s important to recognize that NETs can be particularly challenging. They're best treated in academic centers that have a multidisciplinary approach. It’s also important to recognize that not all patients require escalated and more aggressive treatment. In many cases, patients can be easily managed with somatostatin analogs. If their progression is relatively mild, you don't necessarily need to escalate their treatment. Trying to identify the appropriate patient for the treatment is one of the challenges of managing NETs.

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; abstr 4005).