Slowing the Growth of One Type of Advanced Neuroendocrine Tumor

GI oncologists are feeling quite optimistic about recently released data comparing two different treatments for patients with a specific type of neuroendocrine tumor.

While clinical trials of new drugs or drug combinations can sometimes show great improvements for patients, it’s rare for a trial to knock it out of the park. But that is what trial results show for the activity of a radiopharmaceutical therapy called Lutathera (lutetium Lu 177 dotatate) in patients newly diagnosed with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Data from the phase III NETTER-2 trial, released at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium in January 2024, compared Lutathera plus the long-acting somatostatin receptor agonist drug octreotide against high-dose octreotide alone in certain patients with newly diagnosed grade 2 and 3 GEP-NETs.

Patients who received the Lutathera plus octreotide lived a median 22.8 months without their cancers progressing. Patients who received high-dose octreotide lived a median 8.5 months without progression. That translates to a 72 percent reduction in the risk of disease progression or death with the first-line Lutathera combination. The overall response rate for patients treated with the radiopharmaceutical–octreotide combination was 65 percent, versus seven percent among patients on just high-dose octreotide.

“This study clearly provides really important information and shows durable control of this type of cancer,” says gastrointestinal oncologist Kelsey Klute, M.D., an investigator on the NETTER-2 trial. “Patients also tolerate it really well. So having a potential treatment that not only improves survival but also is good for quality of life is very important for our patients.”

Understanding NETs

Neuroendocrine tumors, or NETs, are a relatively rare type of cancer that can occur in different areas throughout the body. NETs form in neuroendocrine cells, which make hormones. Some of these tumors make extra amounts of hormones that may cause symptoms such as flushing and diarrhea. Not all NETs are the same. They can be different in size, and some types grow faster than others.

GEP-NETs are tumors that can grow in various areas of the gut, such as the stomach, small intestine, rectum, colon, appendix, or pancreas. “These cancers can often be slow growing, but not always,” explains Klute, a gastrointestinal oncologist at Nebraska Medicine and associate professor and researcher at the University of Nebraska Medical Center (Omaha). “Some patients may have some symptoms, but rarely jaundice, like many patients with pancreatic ductal adenocarcinoma. But many patients don’t have any symptoms and we may simply see something on an abdominal scan for another issue.”

Many GEP-NETs have a protein on their surface that binds to a hormone called somatostatin. Octreotide is a drug that mimics somatostatin and tricks the tumors into halting growth and hormone production. This is the standard initial treatment for people with advanced GEP-NETs that cannot be removed by surgery but are growing relatively slowly, which are classified as low and intermediate grade. 

Typically, treatment plans are tailored to each patient’s individual characteristics, taking into account factors like the level of hormones in the blood, tumor location, other health conditions, and the presence of somatostatin receptors on tumor cells.

Advanced GEP-NETs that grow at a faster rate, called high-grade tumors, are particularly tough to manage, with no standard initial treatment for these tumors. 

Treatment for GEP-NETs can be highly challenging and can span the range from a watch and wait approach for indolent tumors, low-grade disease, and other variables, to surgery, peptide receptor radionuclide therapy (PRRT) with a drug like Lutathera, targeted therapy, or radiation and chemotherapy, Klute explains.

About the NETTER-2 Trial

In early 2018, the FDA approved lutetium Lu 177 dotatate for the treatment of GEP-NETs in adults. Like octreotide, the drug mimics somatostatin. But it also sneaks something into the cell—a radioactive molecule that helps kill GEP-NETs by damaging the tumor cells’ DNA. 

The approval was based on findings from a trial called NETTER-1, which did not enroll people with the high-grade type of gastrointestinal neuroendocrine tumors. In addition, all participants in NETTER-1 had received at least one previous treatment.

In the NETTER-2 trial the researchers tested lutetium Lu 177 dotatate as the initial treatment of intermediate- and high-grade advanced GEP-NETs. The study was the first trial ever to test a radiopharmaceutical as initial therapy for a solid tumor.

More than 200 people with advanced GEP-NETs participated in the trial. For most of the patients, their tumors originated in the pancreas or small intestine, and about one-third of the patients had the highest-grade type of tumor, called grade 3 tumors.

All participants were randomly assigned to receive lutetium Lu 177 dotatate and octreotide every eight weeks or a larger dose of octreotide alone every four weeks, until their cancer started to get worse. The researchers tracked the patients for up to three years. 

In addition to the substantial improvements in progression-free survival among participants treated with the combination, there was an equally impressive improvement in the percentage of participants whose tumors shrank, or responded to the treatment: 43 percent versus nine percent.

The most common immediate side effects for both treatments were nausea, diarrhea, and abdominal pain, and both groups of participants reported a similar quality of life during treatment. However, in the NETTER-2 trial, one patient who received lutetium Lu 177 dotatate developed a blood cancer called myelodysplastic syndrome following treatment. 

When Lutathera was approved in 2018, there were many questions as to how best to treat patients in the first-line setting and those with well-differentiated tumors, Klute says. “To be clear, NETTER-1 focused on patients with midgut tumors and didn’t include patients with pancreas tumors or patients with grade 3 tumors,” she adds.

Although the new trial did include pancreatic tumors and higher-grade tumors, and the data was “compelling,” it’s still too soon to say that radiopharmaceuticals should immediately be given as first-line treatment for all of these patients, Klute notes. “We don’t know if using Lutathera earlier improves survival. For patients having a lot of symptoms from their cancer, Lutathera might be a better option since it’s more likely than octreotide to shrink tumors,” she says.

“We need to know if there is a better sequence of administration also. Do we use this combination early or maybe save it, especially in patients who aren’t having symptoms from their cancer?”

Despite still having some questions, Klute is hopeful. “Patients with this type of cancer (GEP-NETs) often hear, ‘Well at least it’s not that other type of pancreatic cancer,’” Klute says. “It’s still cancer and all cancer diagnoses are tough on patients. And each patient is different in terms of how aggressive this cancer can be. It’s not easy for anyone. The good news is we are making progress and trials like this spur more investigations and better answers on how we move forward.”