Expanding Therapy for Neuroendocrine Tumors

Results from two phase III studies indicate that the mTOR inhibitor everolimus (Afinitor; Novartis) and the radiopharmaceutical ¹⁷⁷Lutetium-DOTATATE (Lutathera; Advanced Accelerator Applications) both substantially delay disease progression in patients with advanced neuroendocrine tumors (NET) of the gastrointestinal (GI) tract. The data were presented by Simron Singh, MD, and Jonathan Strosberg, MD, respectively, during the American Society of Clinical Oncology's Gastrointestinal Cancers Symposium, held in San Francisco, CA, January 21–23.

NETs occur most commonly in the GI tract, pancreas, and lungs. Each year, about 8,000 people in the United States are diagnosed with GI NETs, a subset broadly divided into midgut and non-midgut categories. The former includes tumors originating in the ileum, duodenum, and appendix; the latter encompasses tumors of the stomach, colon, and rectum. Surgery, chemotherapy, or somatostatin analogs (SSA), a standard hormone therapy, are the main treatments.

Singh, a medical oncologist at the University of Toronto's Odette Cancer Center in Canada, reported results from a subgroup analysis of the RADIANT-4 study, in which 175 patients with advanced GI NETs were randomized to receive everolimus or placebo. Sixty of these patients had midgut NETs, and the rest had non-midgut tumors. In both categories, treatment with everolimus improved the median progression-free survival (PFS) by more than 6 months.

“This study enrolled both patients who had previously received SSAs, and those who hadn't,” Singh noted. “Interestingly, everolimus was effective across the board, regardless of pretreatment.” The drug was well tolerated, he added, with the main side effects being mouth inflammation, diarrhea, and fatigue.

Strosberg, a medical oncologist at Moffitt Cancer Center in Tampa, FL, reported results from the NETTER-1 study, which evaluated ¹⁷⁷Lutetium-DOTATATE, an SSA attached to a radiopharmaceutical. This is a type of peptide receptor radionuclide therapy (PRRT), Strosberg said, adding that it has been used to treat thousands of patients in Europe. “It enables the targeted delivery of radiation to tumors expressing somatostatin receptors, which many well-differentiated NETs do in high concentrations.”

The study's 230 patients, all with advanced midgut NETs, had progressed on first-line SSA therapy. They were randomized to receive four ¹⁷⁷Lutetium-DOTATATE treatments, or the SSA octreotide (Sandostatin; Novartis). The median PFS in the experimental arm has not been reached, Strosberg reported, “but it's expected to be longer than 3 years, which is extremely impressive for this population.” By contrast, the median PFS in the control arm was just 8 months. He also noted that ¹⁷⁷Lutetium-DOTATATE's main side effect, nausea, was “mostly related to the amino acid infusions used to protect the kidneys [from radiation].”

PRRT is readily available in Europe because “each hospital with a nuclear medicine center can produce and administer their own radiolabeled SSAs,” Strosberg explained, “while PRRT is less common in the U.S., because there's been some reluctance to invest in the large randomized studies needed for its regulatory approval, NETs being a rare cancer.”

“There's going to be some debate as to whether this therapy or everolimus should be used for the average patient who progresses on SSAs,” he added, “and I think somatostatin receptors should be considered'if they're present on a patient's PET scan, he or she will likely do well on [¹⁷⁷Lutetium-DOTATATE].”

¹⁷⁷Lutetium-DOTATATE “represents a new modality of anticancer treatment,” noted Smitha Krishnamurthi, MD, a medical oncologist at Case Comprehensive Cancer Center in Cleveland, OH, “and the positive data on everolimus, along with its good tolerability, are very welcome for a patient population with few therapeutic options.” –Alissa Poh

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