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SAN FRANCISCO -- Patients with previously treated midgut neuroendocrine tumors (NETs) had a 79% reduction in the risk of disease progression or death when treated with a radiolabeled peptide, according to results of a randomized trial.

The median progression-free survival (PFS) had yet to be reached, but an estimate placed the median at about 40 months among patients treated with 177Lu-dotatate (Lutathera), versus 8.4 months with octreotide LAR. A preliminary survival analysis showed that almost 50% fewer patients in the 177Lu-dotatate group had died as compared with the octreotide LAR comparator group.

Both treatment groups had a low incidence of severe adverse events, reported , of Moffit Cancer Center in Tampa, Fla., and colleagues, at the Gastrointestinal Cancers Symposium.

"There have been few available systemic treatment options for patients who have progressive disease after a first-line somatostatin analog, and Lutathera appears to have a major therapeutic benefit in this population," Strosberg said during a press briefing prior to the symposium, which begins here Thursday.

The radiopharmaceutical agent demonstrated "impressive ability" to slow the growth rate of progressive midgut neuroendocrine tumors, said press briefing moderator , of University Hospitals Case Medical Center in Cleveland.

"It's also notable that lutetium-dotatate led to an overall response rate of 18% in these tumors, which are typically unresponsive to systemic therapy," said Krishnamurthi. "The trend toward improved survival is also encouraging.

"This tumor-targeted peptide receptor radionuclide therapy represents a new modality of anticancer treatment," she added.

Strosberg reported findings from the multicenter, phase III, international trial. Investigators in Europe and the U.S. enrolled patients who had inoperable advanced midgut NETs that had progressed on first-line treatment with a standard dose of a somatostatin analog (octreotide LAR 30 mg). Patients were randomized to 177Lu-dotatate or octreotide LAR 60 mg.

The primary endpoint was PFS, assessed every 12 weeks during treatment and follow-up. Data analysis included 230 randomized patients.

The intention-to-treat analysis (n=229) showed that 23 patients in the 177Lu-dotatate group had PFS events as compared with 67 patients in octreotide LAR arm. The difference translated into a 79% reduction in the hazard ratio for progression or death in favor of the radiopharmaceutical (HR 0.21, 95% CI 0.129-0.338, P<0.0001).

Significantly more patients in the 177Lu-dotatate arm had objective responses (18% versus 3%, P=0.0008), including one complete response and 17 partial responses with the radiopharmaceutical. Additionally, 66% of patients treated with 177Lu-dotatate and 62% treated with octreotide LAR had stable disease.

"This is the only large study that has shown a double-digit objective response rate in a population of patients with advanced midgut neuroendocrine tumors," Strosberg said.

The preliminary survival analysis suggests an early separation in the survival curves in favor of the 177Lu-dotatate group. The analysis showed that 13 patients in the 177Lu-dotatate arm had died, as compared with 22 in the Octreotide LAR arm (P=0.0186).

"This is a first interim look at overall survival," Strosberg said. "The threshold for statistical significance is 0.001, so strictly speaking, this is not a statistically significant improvement in survival at this point, although it is certainly suggestive of an improvement in overall survival."

Adverse events occurred more often in patients treated with the radiopharmaceutical, but no type of grade 3/4 adverse event occurred in as many as 10% of patients in the 177Lu-dotatate group. The most frequently reported adverse events (all grades) were nausea (59%), vomiting (47%), fatigue/asthenia (40%), diarrhea (29%), abdominal pain (26%), and thrombocytopenia (25%). The most common grade 3/4 adverse events were lymphopenia (9%) and vomiting (7%).

"Most of the gastrointestinal adverse events were related to the amino acids that were infused along with lutetium as nephroprotective drugs," Strosberg said. "The trial mandated use of commercial preparations of the amino acids, which are quite nauseating. In Europe, they use modified amino acid formulations that cause a lot less nausea."

The most frequent adverse events in the octreotide arm were abdominal pain (26%) and fatigue/asthenia (25%). Grade 3/4 abdominal pain occurred in 5% of patients, and no other type of event occurred in more than 2% of patients in the treatment arm.

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