Neuroendocrine tumors of the digestive system (GI-NETs) can arise in different parts of the digestive tract. GI-NETs originating in the ileum, duodenum, and appendix are known as midgut NETs, and tumors of the stomach, colon, and rectum are non-midgut NETs. Many of these tumors are functional; that is, they produce a variety of hormonal substances that cause serious, debilitating symptoms.
Aside from surgery and chemotherapy, somatostatin analogues (SSAs) such as octreotide are used to treat functional GI-NETs. Octreoide suppresses the hormone production commonly seen in GI-NETs, and is much more potent than the natural body hormone somatostatin. Octreotide also has direct anti-cancer activity in NETs, slowing the growth of these tumors.
Two new treatments for GI-NETs recently received much attention at the 2016 Gastrointestinal Cancers Symposium held in San Francisco in January. Researchers at the symposium presented clinical trial results that demonstrated the benefits of these new drugs.
The first drug, everolimus (Afinitor), which has already been approved by the U.S. Food and Drug Administration (FDA) for pancreatic NETs, produced promising results in the RADIANT-4 study. In the trial, 302 patients with advanced or metastatic GI-NETs were randomly selected to receive either Afinitor or a placebo. In both midgut and non-midgut NETs, treatment with Afinitor improved median progression-free survival (PFS) by more than 6 months. Improvement was observed in patients regardless of previous treatment with SSAs (that is, in both functional and non-functional cancers). However, there was practically no difference in overall survival between patients who received the placebo versus Afinitor. Moreover, almost one third of the patients who received Afinitor experienced severe toxicities, and dose reductions were necessary in 70% of patients treated with Afinitor.
Nevertheless, on February 26, the FDA approved Afinitor for treatment of GI-NETs, stipulating that treated tumors must be progressive, well-differentiated, and non-functional (that is, not amenable to treatment with SSAs).
The limitation of the FDA’s approval of Afinitor to non-functional tumors may be related to the other positive trial results reported at the Gastrointestinal Cancers Symposium. The phase III NETTER-1 study evaluated the efficacy of 177Lutetium-DOTATATE (Lutathera), an SSA attached to a radionuclide. Lutathera and similar drugs, collectively known as peptide receptor radionuclide therapy (PRRT), are already widely used in Europe to treat functional NETs, but PRRT is not available in the U.S. PRRT delivers radioactive SSAs directly to tumors that express somatostatin receptors, which results in selective killing of cancer cells.
NETTER-1 enrolled patients with advanced midgut NETs who had disease progression after SSA treatment. They were randomized to receive either four Lutathera treatments or the SSA octreotide. In the Lutathera group, the median PFS was not reached, but it is expected to last at least 3 years. In the octreotide group, the median PFS was 8 months. The most common side effects of Lutathera were nausea and vomiting. However, these were most likely due to amino acid infusions that were given to protect the kidneys of patients receiving Lutathera.
These results provide strong evidence of the efficacy of Lutathera and underscore the need to bring this drug to the U.S. In Europe, every clinic with a nuclear medicine center can produce and administer PRRT drugs, but this has not been implemented in U.S., mostly because FDA approval has not been forthcoming. With the results of NETTER-1 now available, this may soon change.
Clearly, PRRT has more value in functional GI-NETs than does Afinitor, and the time has come to enable GI-NET patients in U.S. to access PRRT. Perhaps the FDA’s approval of Afinitor for only non-functional NETs signals that PRRT is recognized by this all-powerful organization as a better option for functional NETs. Or perhaps it is wishful thinking on my part. Time will show. Additional Lutathera NETTER-1 Phase 3 study data will be presented on March 11, 2016, at the European Neuroendocrine Tumor Society (ENETS) Conference in Barcelona.