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More than six times as many patients with advanced midgut neuroendocrine tumors remained alive and without disease progression at 20 months when treated with a radiolabeled peptide as compared with standard therapy, updated results of a randomized trial showed.

Patients treated with ¹⁷⁷Lutetium (Lu)-dotatate (Lutathera) had a 20-month progression-free survival (PFS) of 65.2% compared with 10.8% for patients who received the somatostatin analog octreotide LAR. When the trial ended after a planned interim analysis, almost twice as many patients in the octreotide arm had died as compared with the ¹⁷⁷Lu-dotatate arm (26 versus 14).

Treatment with the radiolabeled peptide was associated with more myelosuppression, but affected fewer than 10% of patients, reported , of Moffitt Cancer Center in Tampa, Fla., and colleagues.

"A subgroup analysis showed consistent benefit across major subgroups. The response rate of 18% in the ¹⁷⁷Lu-dotatate group (as compared with 3% in the control group) is also notable given that response rates above 5% have not been observed in large randomized clinical trials of other systemic therapies in this patient population," they wrote online in the .

"Although our trial has not yet reached the point at which the median overall survival can be calculated, the results of the interim analysis suggest longer survival with ¹⁷⁷Lu-dotatate than with high-dose octreotide LAR," they nosted.

The results confirmed findings reported last year at the Gastrointestinal Cancers Symposium and at the (ASCO) annual meeting.

Neuroendocrine tumors of the midgut (jejunoileum and proximal colon) constitute the most common malignant gastrointestinal neuroendocrine tumors. Often metastasizing to the mesentery, peritoneum, and liver, the tumors are associated with a 5-year survival of <50% in the metastatic state. Somatostatin analogs represent first-line therapy, and no standard second-line options exist except everolimus (Afinitor) for nonfunctional neuroendocrine tumors, the authors noted.

In studies dating back 25 years, radiolabeled somatostatin analog therapy (also known as peptide receptor radionuclide therapy, PRRT) has shown promise in the treatment of advanced, well-differentiated neuroendocrine tumors. In particular, ⁹⁰Y-DOTA⁰-Tyr³-octreotate (⁹⁰Y-DOTATOC) and ¹⁷⁷Lu-DOTA⁰-Tyr³-octreotate (¹⁷⁷Lu-dotatate) showed promise in early studies, the authors continued.

A of ¹⁷⁷Lu-dotatate showed a 30% overall response rate in 310 patients with gastropancreatic neuroendocrine tumors, including complete responses in 2%, and a median PFS of 33 months. The results supported continued evaluation of the agent in neuroendocrine tumors, including the phase III (Neuroendocrine Tumors Therapy) trial conducted by Strosberg's group.

NETTER-1 involved 229 with well-differentiated metastatic midgut neuroendocrine tumors. They were randomized to ¹⁷⁷Lu-dotatate plus best supportive care (including low-dose octreotide LAR) or to standard-dose octreotide LAR plus best supportive care. The primary endpoint was PFS.

At the cutoff date for the primary analysis (34 months after enrollment began) 23 PFS events had occurred in ¹⁷⁷Lu-dotatate arm versus 68 in the control arm. The different represented a 79% reduction in the hazard ratio for disease progression or death. The median PFS had yet to be reached with ¹⁷⁷Lu-dotatate versus 8.4 months in the control arm. The total events included 14 deaths in the ¹⁷⁷Lu-dotatate arm and 26 in the control arm.

Treatment-related adverse events occurred more often with ¹⁷⁷Lu-dotatate (86% versus 31%, P<0.001), but as did treatment-related serious adverse events (9% versus 1%, P=0.01). Overall, serious adverse events occurred in about 25% of patients in both arms. Five patients in the ¹⁷⁷Lu-dotatate group discontinued treatment because of adverse events related to treatment compared with none in the control group (P=0.06).

The most common adverse events (any grade) in the ¹⁷⁷Lu-dotatate group were nausea (59%), vomiting (47%), fatigue/asthenia (40%), diarrhea (29%), musculoskeletal pain (29%), and abdominal pain (26%). The most common grade 3/4 adverse events associated with ¹⁷⁷Lu-dotatate were lymphopenia (9%) and vomiting (7%).

Following Strosberg's presentation at the ASCO meeting, invited discussant , of the Chinese University of Hong Kong, noted that the trial, by any standard, must be considered "highly positive." Additionally, the investigational therapy was generally well tolerated as more than three-fourths of patients received the planned four cycles of PRRT.

Looking ahead, clinical practitioners and researchers must determine the most appropriate role for ¹⁷⁷Lu-dotatate, given the long natural history of midgut neuroendocrine tumors for many patients, Chan continued. Specifically, more work is needed to determine whether ¹⁷⁷Lu-dotatate will offer the most benefit when given before or after everolimus.

"We expect, on the basis of these results, that lutetium dotatate will be approved by the FDA or other regulatory authorities," Chan said.

An application for approval of ¹⁷⁷Lu-dotatate is .In December the FDA sent Advanced Accelerator Applications a letter requesting more information about the datasets from NETTER-1 and earlier clinical trials of the agent, including a safety update.

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