177Lu-Dotatate, a radionuclide related to octreotide, reduced the risk of disease progression or death by 79% in a phase III trial involving 229 adults with advanced, progressive midgut neuroendocrine tumors, investigators reported in the New England Journal of Medicine.

“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,” said Jonathan R. Strosberg, MD, of the Moffitt Cancer Center, Tampa, and his associates.

Midgut neuroendocrine tumors involve the jejunoileum and the proximal colon, and they frequently metastasize to the mesentery, peritoneum, and liver. No standard second-line systemic therapies are currently available. The investigators performed this open-label study at 41 medical centers in eight countries, randomizing patients to receive either four intravenous infusions of 177Lu-Dotatate over the course of 8 weeks plus best supportive care (116 patients in the intervention group), or high-dose octreotide long-acting repeatable (LAR) alone (113 patients in the control group). They have been followed for a median of 14 months in this ongoing trial.

All the study participants had metastatic disease that progressed despite first-line treatment using octreotide LAR; 80% had also undergone surgical resection, and nearly half had received some other form of systemic therapy before entering this study. The primary tumor site was the ileum in most patients, and most also had metastases in the liver, the lymph nodes, or both, “typically in the mesentery or retroperitoneum.”

The primary efficacy endpoint – the estimated rate of progression-free survival at month 20 – was 65.2% in the intervention group, compared with 10.8% in the control group. This represents a 79% lower risk of disease progression or death with 177Lu-Dotatate. An interim analysis of overall survival (an endpoint that cannot be determined definitively until more time has passed) showed a 60% lower risk of death in the intervention group than in the control group. Treatment response rates were 18% and 3%, respectively, Dr. Strosberg and his associates reported (New Engl J Med. 2017 Jan 12. doi:10.1056/NEJMoa1607427).

177Lu-Dotatate was administered together with a renal-protection agent, and there has been no evidence of renal toxic effects to date. Rates of low-grade hematologic toxicities were low. The most common adverse effects were nausea and vomiting, which were largely attributed to the renal-protection agent, as well as fatigue, asthenia, abdominal pain, and diarrhea. Adverse events leading to premature withdrawal from the trial developed in more of the control group (9%) than of the intervention group (6%).