Radiolabeled Somatostatin Analog May Represent A Paradigm Change in the Treatment of Neuroendocrine Tumors


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Jonathan R. Strosberg, MD

The study met its primary endpoint in an extremely impressive fashion. With roughly a year and a half of follow-up, the expected median progression-free survival is likely to be longer than 3 years.

—Jonathan R. Strosberg, MD

A radiolabeled somatostatin analog compound, 177Lu-DOTA0-Tyr3-Octreotate (177Lu-Dotatate), reduced the risk of disease progression or death by 79% in the international phase III NETTER-1 population of previously treated, advanced neuroendocrine tumors of midgut origin.1

177Lu-Dotatate belongs to a therapeutic class known as peptide receptor radionuclide therapy, which has been used far more commonly in Europe than in the United States. The agent is composed of a somatostatin analog linked to a radioactive molecule, which enables targeted delivery of radiation to tumors, according to Jonathan R. Strosberg, MD, of Moffitt Cancer Center, Tampa, Florida, who reported the NETTER-1 findings at the 2016 Gastrointestinal Cancers Symposium.

Dr. Strosberg explained that in Europe, hospitals’ nuclear medicine centers are allowed to produce their own radiolabeled somatostatin analogs for treatment, but this is not done in the United States. Advanced Accelerator Applications, which is marketing 177Lu-Dotatate as Lutathera, has now conducted the trials necessary to apply for regulatory approval in the United States.

“With neuroendocrine tumors being a rare disease, until recently there was not a pharmaceutical company willing to invest in a large randomized controlled trial that is required for regulatory approval here,” he told The ASCO Post.

177Lu-Dotatate is the latest of several generations of peptide receptor radionuclide therapies and has a therapeutic index that appears to be more favorable, compared with previous generations, according to Dr. Strosberg.

NETTER-1 Trial Results

NETTER-1 is the first trial to prospectively evaluate a peptide receptor radionuclide therapy in a randomized trial. It evaluated 230 patients progressing after somatostatin analog therapy, assigning them to 177Lu-Dotatate (7.4 GBq) once every 8 weeks (by 30-minute infusion) for four total treatments or high-dose octreotide LAR [long-acting repeatable] at 60 mg.

The main analysis of NETTER-1 was presented in the fall of 2015 at the European Cancer Congress, showing a reduction in disease progression of 79%.2 Median progression-free survival was not reached with 177Lu-Dotatate but was 8 months with octreotide LAR (P < .0001). “There was substantial separation of the curves,” noted Dr. Strosberg.

Response rates, typically very low in this disease, were 18% vs 3% (P < .0008), making this “the only large study showing double-digit response rates in midgut neuroendocrine tumors,” according to Dr. Strosberg. “Only 5% of patients had progressive disease as their best response,” he noted, emphasizing that outcomes were assessed by central radiology review, with reviewers completely blinded to treatment assignment.

“The study met its primary endpoint in an extremely impressive fashion,” Dr. Strosberg commented. “With roughly a year and a half of follow-up, the expected median progression-free survival is likely to be longer than 3 years.”

Radionuclide Therapy in Neuroendocrine Tumors

  • The phase III NETTER-1 trial of 177Lu-Dotatate, a radiolabeled somatostatin analog, reduced disease progression by 79% in patients with advanced neuroendocrine tumors of midgut origin.
  • The modality has been widely used in Europe and is undergoing U.S. Food and Drug Administration review for approval in the United States.
  • Tolerability of this therapy is good, except for transient nausea and vomiting during the infusion of adjunctive amino acids.

Thirteen patients have died in the experimental arm vs 22 patients in the control arm (P < .019), a numerical trend that “is suggestive of an improvement” in overall survival, he said.

It may be possible to predict response to this treatment via the level of expression of the somatostatin receptor. This can be measured with an Octreoscan or with more sophistication using a gallium-68-somatostatin analog–PET [positron emission tomography] scan, he added.

Serious Adverse Events

At the 2016 Gastrointestinal Cancers Symposium, Dr. Strosberg provided more details about the adverse events related to this novel therapy.1 Serious adverse events were reported in 26% of the experimental arm and 24% of the control arm, of which 9% and 1% were considered related to treatment. Only one opportunistic infection was documented, and it appeared to be unrelated to treatment.

The most common adverse event in the 177Lu-Dotatate arm was nausea, all grades of which were seen in 59% and 47%, respectively, and grades 3 and 4 in 4% and 7%. In the control arm, 12% reported nausea and 10% reported vomiting, and virtually no cases were severe.

The nausea and vomiting occurred primarily during the 4-hour infusion of amino acids, which protects against renal toxicity but causes this side effect, pointed out Dr. Strosberg. The study mandated the use of a certain formulation, but in clinical practice, this can be modified to be less nauseating.

Hematologic toxicities in the experimental arm included mostly mild degrees of thrombocytopenia (25%), lymphopenia (18%), anemia (14%), leukopenia (10%), and neutropenia (5%). Grade 3/4 lymphopenia was observed in 9%. Cytopenias, he added, “tended to be transient.”

Hepatotoxicity was rare, with increases in liver enzymes seen in 4% of the experimental arm. Renal function, as well, remained stable over the 2-year observation period. ■

Disclosure: Dr. Strosberg reported no potential conflicts of interest.

References

1. Strosberg JR, Wolin EM, Chasen B, et al: NETTER-1 phase III: Progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177-Lu-Dotatate. 2016 Gastrointestinal Cancers Symposium. Abstract 194. Presented January 23, 2016.

2. Strosberg J, Wolin E, Chasen B, et al: 177-Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumours: Results of the phase III NETTER-1 trial. 2015 European Cancer Congress. Abstract 6LBA. Presented September 27, 2015.


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