Investigational 177Lu-Dotatate improves survival, response rates in patients with progressing midgut neuroendrocrine tumors

In patients with midgut neuroendocrine tumors that had progressed during previous octreotide treatment, lutetium-177 (¹⁷⁷Lu-Dotatate) improved progression-free survival (PFS) as well as response rates, compared with high-dose octreotide LAR, according to results from an international, phase 3 clinical trial, which are published in the January 12^th issue of the New England Journal of Medicine.

¹⁷⁷Lu-Dotatate is radioactive molecule attached to a somatostatin analog.

Lead author Jonathan R. Strosberg, MD, associate professor, Gastrointestinal Oncology, and head of the Neuroendocrine Tumor Program, Moffitt Cancer Center, Tampa, FL, explained the structure of this investigational agent further:

“¹⁷⁷Lu-Dotatate is a radiolabeled somatostatin analog, a form of treatment also known as peptide receptor therapy. It basically involves attachment of a radionuclide to a somatostatin analog, thereby enabling delivery of systemic radiotherapy to somatostatin receptor expressing neuroendocrine tumors. This treatment has been studied extensively in early phase studies and large institutional series. The NETTER-1 study was the first randomized phase III study to evaluate this drug,” he said.

Currently, standard treatment for these tumors is comprised of hormonal therapy with a somatostatin analog to block tumor cell growth as well as reduce hormone production. In patients in whom tumor progression occurs, few options are available.

 “We serve one of the largest populations of neuroendocrine tumor patients in the United States, and many of our patients have traveled long distances at great expense to receive this treatment in Europe where it has been available on an experimental and compassionate use basis. Results have been impressive. We were therefore eager to participate in a randomized prospective study of ¹⁷⁷Lu-Dotatate in order to generate high level data on progression-free and overall survival as well as safety, and hopefully contribute to the approval of the drug for NET patients in the United States and elsewhere,” explained Dr. Strosberg.

For this study, he and fellow researchers enrolled 229 patients with metastatic or locally advanced midgut neuroendocrine tumors that had progressed during previous octreotide treatment. In all, 116 patients were treated with ¹⁷⁷Lu-Dotatate (7.4 GBq every 8 weeks, four IV infusions, plus best supportive care including IM octreotide long-acting repeatable [LAR; 30 mg]). The control group was comprised of 113 patients treated with IM octreotide LAR alone (60 mg every 4 weeks).

PFS—as assessed by blinded, central radiology review—was the primary endpoint of the study, and secondary endpoints included objective response rate, overall survival (OS), safety, and side effects.

At 20 months, PFS was 65.2% in those treated with ¹⁷⁷Lu-Dotatate (95% CI: 50.0-76.8) compared to 10.8% in the control group (95% CI: 3.5-23.0); corresponding response rates were 18% vs 3%, respectively (P < 0.001).

In a planned, prespecified interim analysis of OS, 14 patients treated with ¹⁷⁷Lu-Dotatate died, compared with 26 in the control group (P=0.004). In addition, treatment with ¹⁷⁷Lu-Dotatate conferred a 79% lower risk of disease progression or death compared to control treatment during follow-up. Finally, 18% of patients treated with ¹⁷⁷Lu-Dotatate had a radiographic response, compared with only 3% in the control group.

Adverse events were more common in patients treated with ¹⁷⁷Lu-Dotatate compared to controls (86% vs 31%, respectively), but all toxicities were reversible and manageable. The most common adverse events included nausea and vomiting.

“Side effects were relatively tolerable,” noted Dr. Strosberg. “Nausea/vomiting was a side effect that occurred primarily during amino acid infusions, which are given concurrently with ¹⁷⁷Lu-Dotatate for nephroprotection. This typically resolved after completion of the infusion. Grade 3 neutropenia and thrombocytopenia was very rare (1% and 2%, respectively) and tended to be transient. There was no evidence of drug-related nephrotoxicity during the observed time frame,” he added.

Which patients are ideal candidates for this potential treatment, and which are not?

“Based on the study, ideal patients are those with clinically significant progressive midgut NETs on somatostatin analog therapy,” Dr. Strosberg told MDLinx.

“Although amino acid infusions appear to be highly protective of renal function, the drug has not been well studied in patients with underlying renal dysfunction. Patients with impaired bone marrow function are also not ideal candidates. Patients who have very extensive liver disease may be at risk of radiation hepatitis, particularly if they have been previously treated with radioembolization, but this is somewhat speculative.  For patients with liver-only metastases, ¹⁷⁷Lu-Dotatate has not been compared to liver-directed approaches. Future studies should investigate the relative merits of this systemic treatment with various embolization therapies,” he added.

The FDA is currently reviewing a new drug application for ¹⁷⁷Lu-Dotatate.

“If FDA approved, clinicians should be aware of the availability of this treatment in the United States. It is anticipated that, at least initially, it will be offered in large academic hospitals. Because treatment is only administered four times over 8 months, it is not generally a major inconvenience for patients who may have to travel some distance to receive this treatment,” concluded Dr. Strosberg.

This study was supported by Advanced Accelerator Applications, the developer of ¹⁷⁷Lu-Dotatate.