Late Stage Trial Cements Lutetium Octreotate in Second-Line Setting

The randomized phase III NETTER-1 trial examined the efficacy of the peptide receptor radionuclide therapy (PRRT) Lu-Dotatate as a treatment for patients with midgut NETs, specifically in the small intestine and proximal colon.

The trial recruited 229 patients with inoperable, somatostatin receptor-positive NETs. All patients had progressed on standard-dose somatostatin analog therapy and were evenly randomized to either 4 administrations of 7.4 gigabecquerel of Lu-Dotatate every 8 weeks, or a control arm receiving high-dose octreotide LAR of 60 mg every 4 weeks.

In an interview with Targeted Oncology, Strosberg discusses the usefulness of Lu-Dotatate 177 and the future the treatment holds within the paradigm of midgut NETs.

TARGETED ONCOLOGY:

Can you tell us about the NETTER-1 trial?

STROSBERG:

The NETTER-1 trial was the first randomized trial of this form of therapy known as a radiolabeled somatostatin analog, or peptide receptor radiotherapy. The drug is called lutetium Octreotate, which is basically a combination of lutetium, a radioactive isotope, and Octreotate, a somatostatin analog. This combination enables the delivery of radiation to the somatostatin receptor-expressing tumor cells.

Patients with NETs of the midgut or the small intestine who had progressed on standard dose somastatin analog were randomized to receive either high-dose octreotide or lutetium Octreotate. The primary endpoint was progression-free survival determined by central radiology review, and the results were fairly striking.

There was a 79% improvement in progression-free survival. The median progression-free survival in the control arm was 8 months versus not reached yet with the lutetium after nearly 1.5 years median follow-up. In fact, it's anticipated that the median progression-free survival based on the Kaplan-Meier curve is going to be in excess of 3 years with lutetium.

We were expecting the trial to be positive, but I think the final outcome actually exceeded expectations.

TARGETED ONCOLOGY:

Can you tell us about 177 Lutetium Dotatate in neuroendocrine tumors?

STROSBERG:

So 177 Lutetium Dotatate, also known as lutetium Octreotate, commercially available as Lutathera, is a radiolabeled somatostatin analog. Lutetium 177 is a beta- and gamma-emitting isotope, which is attached via conjugator DOTA to Octreotate, which is a somatostatin analog with a slightly higher affinity to somatostatin receptor subtype 2 than octreotide. This allows delivery of the isotope directly to the tumor cells, and most neuroendocrine tumor cells express high levels of somatostatin receptors. So it's a very targeted form of radiation.

There has been a lot of data over the past decade or 15 years from Europe where more than 1000 patients have been treated with this form of therapy in either early-phase trials or in large institutional series. Many centers in Europe produce this compound on [an in-house] hospital basis. There are a lot of data showing high response rates and even longer durations of response. The average response rate from some large series is about 30%, and the average duration of response is about 2 to 3 years in the heterogeneous population of neuroendocrine tumors.

The data looked very promising from the outset, but finally we have a randomized phase III study to validate that.

TARGETED ONCOLOGY:

How would this treatment fit into the treatment sequencing for patients with neuroendocrine tumors?

STROSBERG:

This was a trial for patients who progress on a standard somatostatin analog. I would say for most patients with well-differentiated neuroendocrine tumors, somatostatin analogs are still the standard systemic first-line therapy for tumor growth as well as for hormonal syndromes, which many patients have. We measured somatostatin receptor expression using octreoscans.

I think that lutetium Octreotate is a very reasonable second-line therapy. In fact, lutetium Octreotate should be considered the standard second-line therapy in most of these patients.

TARGETED ONCOLOGY:

Have there been any toxicities or adverse events associated with this treatment in the trials?

STROSBERG:

The toxicity profile looks quite favorable. If we look at grades 3 and 4 toxicities, they have all been in the single digits. The most common was lymphopenia, which I would say is of less clinical significance than neutropenia. We only had one case of neutropenia, I believe, and that patient was taking immunosuppressive agents, so I'm not sure that is a significant toxicity.

We saw a fair amount of nausea and vomiting associated with amino acid infusions that are given to protect the kidneys during the lutetium infusion. The trial mandated the use of a commercial amino acid formulation, which includes 18 or 19 amino acids. When given at a high rate, that's quite nauseating. Once that infusion was stopped after 46 hours, the nausea went away immediately. In my experience, that was the most significant side effect.

The cytopenias tended to be relatively transient and there was very little in terms of chronic toxicities in the trial. The treatment is only given in 4 administrations — so patients receive 1 administration every 8 weeks. I would say that has many advantages as far as quality of life.

TARGETED ONCOLOGY:

How would physicians determine what patients to treat with this treatment?

STROSBERG:

This is one of the very few treatments that has a pretty good predictive marker, and that marker is somatostatin receptor expression. If you're doing an octreoscan, or a newer method like Ga-68 Dotatate PET/CT, these look at the degree of somatostatin receptor expression. If you have a tumor that is expressing a lot of somatostatin receptors and is progressing on somatostatin analog, then the patient would be a perfect candidate for this form of therapy.