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Interim results from a phase 3 trial supported the use of the radioligand therapy ¹⁷⁷Lu-DOTATATE (Lutathera) as first-line therapy to treat high-grade gastroenteropancreatic neuroendocrine tumors.

The NETTER-2 trial, presented at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, found a significant progression-free survival (PFS) benefit among newly diagnosed patients who received upfront ¹⁷⁷Lu-DOTATATE plus octreotide vs high-dose octreotide alone.

Overall, the ¹⁷⁷Lu-DOTATATE group had PFS of 22.8 months vs 8.5 months in octreotide group, demonstrating a 72% reduction in the risk for death over 3 years of follow-up.

The overall response rate in the radioligand arm was also significantly higher: 43% vs 9.3% with octreotide alone.

The response rates are "some of the highest ever reported in neuroendocrine tumors," said lead investigator and presenter Simron Singh, MD, a medical oncologist at the University of Toronto, Toronto, Ontario, Canada.

The study has "clinical practice changing implications and supports the use of first-line" ¹⁷⁷Lu-DOTATATE in grades 2 and 3 well-differentiate gastroenteropancreatic neuroendocrine tumors, Singh added.

The earlier NETTER-1 trial established ¹⁷⁷Lu-DOTATATE in the second line. The current NETTER-2 trial evaluated the radioligand therapy in the first line among patients with advanced grade 2 or 3 well-differentiated tumors with a Ki-67 index of 10%-55%.

The trial randomized 226 patients 2:1 to ¹⁷⁷Lu-DOTATATE plus 30 mg octreotide vs 60 mg octreotide alone.

The two arms in the trial were well balanced. Most patients had liver metastases, and many had bone and peritoneal involvement. Over half of tumors originated in the pancreas and almost a third in the small intestine. Overall, 35% of patients had grade 3 disease. The median Ki-67 index was 17% in the ¹⁷⁷Lu-DOTATATE arm and 16% in the high-dose octreotide arm.

Patients received the radioligand once every 8 weeks along with 30 mg octreotide for four cycles and continued octreotide every 4 weeks. The 60 mg octreotide group received the agent every 4 weeks.

Overall, PFS was nearly threefold higher in the ¹⁷⁷Lu-DOTATATE arm — 22.8 months vs 8.5 months — with PFS advantage holding across tumor grade, site of origin, and various subgroups.

Among 43% of patients in the radioligand group who exhibited an overall response, eight had a complete response.

The overall survival data are pending, but researchers found no overall survival benefit with ¹⁷⁷Lu-DOTATATE in the NETTER-1 trial.

The time to deterioration in quality of life was similar between the two arms. Global health status scores were higher, but not significantly so, in the ¹⁷⁷Lu-DOTATATE arm.

However, the incidence of grade 3 and higher adverse events was generally higher among people who received the radioligand. The adverse events included decreased leukocyte counts (5.4% vs 0%), elevated gamma-glutamyl transferase (4.8% vs 2.7%), and small intestine obstruction (3.4% vs 0%). Grade 3 or higher abdominal pain, however, was more common with octreotide monotherapy (4.1% vs 2.7%).

Despite the promising overall findings, study discussant Jordan Berlin, MD, a medical oncologist and researcher at Vanderbilt University, Nashville, Tennessee expressed concerns about using ¹⁷⁷Lu-Dotate in the first line.

The radioligand, for instance, carries a small risk for myelodysplastic syndrome (MDS), with one case occurring in the trial. Grade 3 or higher hematotoxicities were much more common in the radioligand group: 13.6% vs 1.4%.

A lot of these patients have indolent disease, and "if you start early, you are potentially exposing them to MDS and other hematologic toxicity earlier," Berlin told Medscape Medical News.

Another caveat to using the radioligand in the first line, Berlin noted, was the lack of overall survival findings so far. "We don't have proof of a survival benefit," he said.

He added, however, that he would likely use the radioligand upfront for particularly bulky and aggressive disease.

Ana De Jesus-Acosta, MD, a medical oncologist at Johns Hopkins University, Baltimore, Maryland, who moderated the session, agreed with upfront use in aggressive cases but said she will struggle over the decision to use the radioligand in the first line for more intermediate cases, such as grade 2 disease with a Ki-67 index of 10%-20%.

Treatment decisions in these cases will require a one-on-one discussion with the patient to weigh risks and benefits, she said.

The trial was funded by ¹⁷⁷Lu-DOTATATE maker Novartis and included employees as investigators. Singh is an employee of Sanofi and disclosed honoraria and research funding form Novartis and advising the company. Berlin is involved with many companies, including being a consultant for Bristol-Myers Squibb/Celgene, Merck, and Bayer. Jesus-Acosta reported research funding from AstraZeneca and Merck and being a Merck consultant.

M. Alexander Otto is a physician assistant with a master's degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com