Outcomes in patients with metastatic midgut neuroendocrine tumors (NETs), which have traditionally been associated with poor survival, can significantly improve with a radiopharmaceutical drug, the results of a phase 3 trial confirm.
The product, 177Lu-Dotatate (Lutathera, under development by Advanced Accelerator Applications [AAA]), markedly improved progression-free survival (PFS) and objective responses compared with standard of care (high-dose octreotide), with a tolerable safety profile.
The data, which were published January 12 by the New England Journal of Medicine, are taken from the NETTER-1 study, the first phase 3 multicenter, randomized, controlled trial of 177Lu-Dotatate in patients with inoperable, progressive, somatostatin receptor–positive midgut NETs.
The results reaffirm interim data from the trial presented in 2015, which were described at the time as a "major advance," asreported by Medscape Medical News at the time.
This was followed by the presentation of early safety data at the start of 2016, which showed that 177Lu-Dotatate was well tolerated. The most common adverse events were gastrointestinal symptoms resulting from infusions of nephroprotective amino acids.
The final results, now reported by Jonathan R. Strosberg, MD, associate professor, Moffitt Cancer Center, Tampa, Florida, and colleagues, show that 177Lu-Dotatate achieved a clinically meaningful reduction in the risk for disease progression or death compared with standard care of almost 80%, and more than tripled the response rate compared with previous trials of other therapies.
"We believe these data show significant clinical benefit of Lutathera and are proud to have this study published in such a prestigious journal," commented Stefano Buono, chief executive officer of AAA, Saint-Genis-Pouilly, France.
Noting that more than 1500 patients in Europe and the United States have been treated with Lutathera so far, he added: "We believe Lutathera can offer patients with NETs a much-needed treatment option and enhance the current standard of care."
The drug has received an orphan drug designation by both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).
At present, it is administered on a compassionate-use and named-patient basis for NETs and other tumors overexpressing somatostatin receptors in 10 European countries, and is given in the United States at 14 sites under an Expanded Access Program for midgut NETs.
However, AAA recently announced that, with regard to the New Drug Application for 177Lu-Dotatate, the FDA raised issues over the "format, traceability, uniformity, and completeness of the NETTER-1 and Erasmus clinical datasets" and requested additional subgroup analyses and safety updates, as well as other stratification factors.
This came after a request by the EMA for "additional clarifications" of their application for marketing authorization, the "majority" of which have been provided, the company says, and also an inspection of one of their contract research organizations, which has been completed.
Citing the establishment of an "internal task force" to address the concerns raised by the FDA, the company said that it remains "steadfast in our efforts to resolve all of these outstanding issues as soon as possible."
For the current analysis, the researchers studied data on 229 patients with advanced, progressive, well-differentiated, somatostatin receptor–positive midgut NETs treated at 41 centers in 8 countries.
The patients were randomly assigned to 177Lu-Dotatate 7.4 GBq every 8 weeks plus best supportive care, including intramuscular octreotide long-acting repeatable (LAR) 30 mg (n = 116) or intramuscular octreotide LAR alone 60 mg every 4 weeks (n = 113).
At the data cutoff, 23 progression or death events had occurred in the 177Lu-Dotatate group compared with 68 in the control standard-of-care group. The estimated rate of PFS at month 20 was 65.2% with 177Lu-Dotatate vs 10.8% in the group.
Median PFS was not reached with 177Lu-Dotatate and was 8.4 months in the control group, giving a hazard ratio for disease progression or death of 0.21 (P < .001). This improvement was seen even after stratification and prognostic factors were taken into account.
Fourteen patients died in the 177Lu-Dotatate group compared with 26 controls, at a hazard ratio for death of 0.40 (P = .004). Median overall survival could not be determined because of the immaturity of the data.
The rate of complete and partial responses was 18% in the 177Lu-Dotatate compared with 3% among controls (P < .001).
Adverse events leading to premature withdrawal from the trial were seen in 7 (6%) of 177Lu-Dotatate patients and 10 (9%) patients in the control group. The rates of grade 3 or 4 adverse events were 41% and 33%, respectively, with no significant difference between the groups. However, the rate of any-grade adverse events was significantly higher with 177Lu-Dotatate than with standard-of-care therapy: 95% vs 84%, respectively (P = .01).
The most common adverse events in the 177Lu-Dotatate group were nausea (59%) and vomiting (47%), most cases of which were due to concurrent amino acid infusions, say the researchers. The most common adverse events in the control group were gastrointestinal disorders and fatigue or asthenia.
Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia were seen in 1%, 2%, and 9%, respectively, of the 177Lu-Dotatate patients compared with no patients in the control group. The researchers described these events as "transient," with no evidence of renal toxicity.
Dr Strosberg and colleagues write: "Data from non-randomized trials of 177Lu-Dotatate have consistently shown high response rates and long durations of median progression-free survival in heterogeneous patient populations with gastroenteropancreatic neuroendocrine tumors."
"The NETTER-1 trial validates these early-phase data in the context of a prospective, randomized trial," they add.
The study was funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239; EudraCT number 2011-005049-11. Dr Strosberg has disclosed no relevant financial relationships. Numerous other interests are reported by the many of the study authors, primarily the receipt of grant support and personal fees from AAA during the conduct of the study, as well as support and personal fees from, among others, Novartis, outside of the current research.
N Engl J Med. 2017;376:125-135. Abstract