The radiolabeled somatostatin analog 177Lu-Dotatate is efficacious and safe in patients with previously treated advanced midgut neuroendocrine tumors, according to results of the randomized NETTER-1 trial.

Among the 230 patients studied in the phase III trial, compared with peers given high-dose octreotide LAR, patients given 177Lu-Dotatate had a 79% reduction in the risk of progression or death, lead study author Dr. Jonathan R. Strosberg reported in a presscast leading up to the Gastrointestinal Cancers Symposium.

In addition, 18% of patients had a complete or partial response to the radiolabeled analog, which is considered to be a type of peptide receptor radiotherapy. And there was a trend toward better survival with the radiolabeled analog in an interim analysis.

177Lu-Dotatate had a good safety profile, with somewhat higher rates of gastrointestinal adverse events (likely related to an amino acid infusion given along with the agent) and lymphopenia. Regarding leukemia and myelodysplastic syndrome, “the bottom line is that there were only two very questionable myelodysplastic symptom events seen so far. It’s not clear whether it’s true MDS or whether it’s related to therapy,” said Dr. Strosberg of the Moffitt Cancer Center, Tampa, Fla.

“While there have been few available systemic treatment options for patients progressing on first-line somatostatin analogs, [177Lu-Dotatate] appears to have a major therapeutic benefit in this patient population,” he said ahead of the symposium, which was sponsored by ASCO, ASTRO, the American Gastroenterological Association, and the Society of Surgical Oncology.

Everolimus is also likely to be increasingly used in this therapeutic space, given positive results of the RADIANT-4 trial, including a subgroup analysis being reported at the symposium, Dr. Strosberg acknowledged.

“I think there is going to be a lot of debate on whether 177Lu-Dotatate or everolimus should be used in the average patient that progresses on a first-line somatostatin analog,” he said. “I would argue if there is a predictive factor, it may be somatostatin receptor expression. Patients who express a lot of somatostatin receptors on their scans will probably have a high likelihood of doing well with peptide receptor radiotherapy.”

ASCO expert and presscast moderator Dr. Smitha Krishnamurthi of Case Western Reserve University, Cleveland, said, “177Lu-Dotatate showed impressive ability to slow the growth of midgut neuroendocrine tumors that have progressed on somatostatin analog therapy. Also notable was that the 177Lu-Dotatate resulted in a response rate of 18% in these tumors, which are typically unresponsive to systemic therapy. The trend toward improvement in overall survival was also encouraging.

“This tumor-targeted peptide receptor radionuclide therapy represents a new modality of anticancer treatment,” she maintained.

Patients were eligible for NETTER-1 – the first randomized trial of a radiolabeled somatostatin analog in this setting – if they had inoperable, somatostatin receptor–positive neuroendocrine tumors of the midgut (small intestine or proximal colon) that had progressed despite treatment with octreotide LAR at the standard dose of 30 mg.

They were randomized evenly to 177Lu-Dotatate (Lutathera), one treatment every 8 weeks for a total of four treatments, or to octreotide LAR (Sandostatin LAR) 60 mg every 4 weeks.

In results that Dr. Strosberg called “extremely impressive,” median estimated progression-free survival was not reached but expected to be about 40 months with 177Lu-Dotatate, compared with 8 months with high-dose octreotide. The difference corresponded to a sharply reduced risk of events with the radiolabeled analog (hazard ratio, 0.21; P less than .0001).

The objective response rate was 18% with 177Lu-Dotatate, compared with just 3% with high-dose octreotide (P = .0008).

“Most studies have shown response rates in the single digits,” he noted. “This is really the only large study that has shown a double-digit objective response rate in a population with midgut neuroendocrine tumors.”

An interim analysis of overall survival found that there were 13 deaths with 177Lu-Dotatate and 22 with high-dose octreotide, but longer follow-up is needed.

Grade 3 or 4 lymphopenia was more common with the radiolabeled analog (9% vs. 0%), as were grade 3 or 4 nausea (4% vs. 2%) and vomiting (7% vs. 0%).

“I would say most of the gastrointestinal side effects are related actually to the amino acid infusions that were used as nephroprotective drugs in combination with the [177Lu-Dotatate]. The trial mandated use of commercial formulations of the drugs, which are quite nauseating,” Dr. Strosberg said. “In Europe, they use modified amino acid formulations, which are much less nauseating.”

“The good thing is that the nausea and vomiting typically resolved when the amino acid infusion was discontinued,” he added.