Jonathan Strosberg, MD
In December 2016, the FDA informed Advanced Accelerator Applications that its new drug application for Lutathera (177Lutetium DOTA-octreotate) as a treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) would need to be resubmitted.
The application was based on the phase III NETTER-1 trial, which randomized patients with advanced, progressive, somatostatin receptor-positive midgut NETS to receive either Lutathera (116 patients) plus best supportive care, including octreotide long-acting repeatable (LAR), or octreotide LAR alone (113 patients).
In an interview with OncLive
, lead NETTER-1 author Jonathan Strosberg, MD, medical oncologist, Department of Gastrointestinal Oncology, section head, Neuroendocrine Division, chair, Gastrointestinal Department Research Program, Moffitt Cancer Center, discussed the latest results from the NETTER-1 trial, which were published in January in The New England Journal of Medicine.
OncLive: Can you provide an overview of the trial and discuss the patient population for which this treatment is intended?
The NETTER-1 trial was performed in patients with metastatic NETs originating in the midgut, the midgut referring to the small intestine and proximal colon. Patients had to have evidence of progressive disease by RECIST at baseline. That progression could have occurred over a period of as long as 3 years and they had to have evidence of metastatic receptor expression on an octreotide scan. They had to be progressing on first-line somatostatin analog, such as a standard dose of octreotide LAR at 30 mg every 3 weeks.
Can you discuss the key efficacy findings of NETTER-1?
The primary endpoint was progression-free survival (PFS). At the time of data analysis, the median PFS was roughly 8 months on the high-dose octreotide arm, which is the control arm. The trial randomized patients to lutetium-177 dotatate versus high dose octreotide. The median PFS had not been reached in the investigational arm.
This translated to 79% improvement in PFS, which was both statistically and clinically significant. If you look at a particular time point, such as month 20, the PFS rate on the lutetium arm was 65% versus only 10% on the control arm.
Overall survival (OS) was a secondary endpoint, this was meant to be a preliminary analysis of OS, not a mature analysis. For OS, there was a hazard ratio of 0.4 and a P
value of .004. Very encouraging preliminary results for OS that needs to be confirmed on the true analysis.
How was the safety profile?
One of the side effects was nausea and vomiting that occurred predominantly during amino acids that are infused together with the lutetium to reduce toxicity to the kidneys. The drug is given 4 times, once every 8 weeks or 4 courses.
The trial mandated use of a commercial amino acid formulation, which was quite nauseating during the amino acid infusion. The nausea went away pretty quickly once the infusion was discontinued. That was 1 side effect that was observed. The grade 3/4 rate of nausea and vomiting was under 10%, but many patients experienced grade 1/2 nausea and vomiting during the amino acid infusion.
As far as hematic toxicity, which was a concern with this drug, grade 3/4 neutropenia and thrombocytopenia occurred in only 1% and 2% of patients, respectively.
There were discontinuations, but those were very few. As far as dose modifying toxicities, that occurred in only 5% of patients.
Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. doi: 10.1056/NEJMoa1607427.