Safe and Sound (So Far): A Radiopharmaceutical for GI Tumors

Nick Mulcahy

January 21, 2016

Patients with metastatic midgut neuroendocrine tumors (NETs) typically do not respond to systemic therapies, but an investigational radiopharmaceutical is changing expectations in this setting.

The product, known as ¹⁷⁷Lu-dotatate (Lutathera, under development by Advanced Accelerator Applications), demonstrated unprecedented progression-free survival and objective responses in this patient population in its first phase 3 trial, for which the interim data were presented last year at the European Cancer Congress.

But a question was raised at the congress: Is the therapy, which consists of a radioactive isotope attached to a somatostatin analogue (a standard treatment for midgut NETs), safe?

Now that question has a more robust answer, although not a long-term one.

"Lutathera is exceptionally well tolerated," Jonathan Strosberg, MD, a medical oncologist at the H. Lee Moffitt Cancer Center in Tampa, Florida, told Medscape Medical News.

Dr Strosberg is an investigator with the phase 3 study, known as NETTER-1, which involves 230 patients with advanced midgut NET who progressed on treatment with somatostatin analogs alone.

He discussed some of the new interim — but still early — safety data from the 5-year trial with reporters during a press briefing held in advance of the Gastrointestinal Cancers Symposium 2016 in San Francisco.

"The safety profile of Lutathera appears to be quite favorable, with really very few clinically relevant findings, particularly with respect to the main concerns of hematologic, renal, and hepatic parameters," Dr Strosberg summarized.

¹⁷⁷Lu-dotatate is a peptide receptor radionuclide therapy, which means it can "deliver the radiation in a targeted fashion to tumors that express the metastatic receptors," he explained. The approach is likely effective in this setting because "the very large majority of well-differentiated neuroendocrine tumors express very high concentrations of somatostatin receptors."

In NETTER-1, all 230 patients received the standard of care — long-acting release (LAR) octreotide (but at a higher dose than usual) — and half the patients were randomized to receive the radiopharmaceutical (7.4 GBq administered intravenously every 8 weeks for four doses).

Gastrointestinal symptoms were the most common adverse events in the trial, and were mostly caused by the amino acid infusions that are used nephro-protectively when patients receive ¹⁷⁷Lu-dotatate, Dr Strosberg reported. "The good thing is that the nausea and vomiting typically resolve once the amino acid infusion is discontinued," he said.

Table. Adverse Effects

  ¹⁷⁷Lu-dotatate, % (n=111) Octreotide, % (n=110)
Adverse Effect All grades Grade 3/4 All grades Grade 3/4
   Nausea 59 4 12 2
   Vomiting 47 7 10 0
   Diarrhea 29 3 19 2
   Abdominal pain 26 3 26 5
   Abdominal distention 13 0 14 0
   Thrombocytopenia 25 2 1 0
   Lymphopenia 18 9 2 0
   Anemia 14 0 5 0
   Leukopenia 10 1 1 0
   Neutropenia 5 1 1 0
   Fatigue 40 2 25 2
   Edema peripheral 14 0 7 0


The most common grade 3/4 adverse event was lymphopenia (reported in 9% of patients). However, Dr Strosberg noted that the "clinical significance" of the lymphopenia is unclear because there was just one case of an opportunistic infection, and this patient was also on chronic steroids and immunosuppressive drugs. Therefore, the infection was "very likely" not caused by the radiopharmaceutical, he said.

There were also two possible cases of myelodysplastic syndromes, but whether or not the syndromes are related to ¹⁷⁷Lu-dotatate is "very questionable," Dr Strosberg said.

General disorders were highlighted by fatigue, he reported.

In speaking with Medscape Medical News, Dr Strosberg contrasted the adverse-event profile of ¹⁷⁷Lu-dotatate with that of everolimus (Afinitor, Novartis), which has also shown efficacy, albeit less dramatically, in this patient population, and is under review by the US Food and Drug Administration for the treatment of NETs, including those of the midgut.

The adverse effects of the radiopharmaceutical are mostly limited to the period of administration, which is short. In contrast, everolimus is taken daily and, as a result, will produce chronic adverse effects in some patients, he said.

Another expert is impressed with ¹⁷⁷Lu-dotatate.

The experimental treatment "showed impressive ability to slow the growth of midgut neuroendocrine tumors that had progressed on somatostatin analog therapy," said press briefing moderator Smitha Krishnamurthi, MD, a medical oncologist at Case Western Reserve University in Cleveland, and an American Society of Clinical Oncology expert.

"This tumor-targeting peptide receptor radionuclide therapy represents a new modality of anticancer treatment," she summarized.

It is, however, a modality that has been in development for a while, Dr Strosberg pointed out. There have been several generations of radiolabeled somatostatin analogs; ¹⁷⁷Lu-dotatate is a "next-generation" version of this approach.

Progression-free survival was significantly longer in patients who received the radiopharmaceutical in addition to octreotide LAR. The hazard ratio of 0.2 (P < .0001) translates to a 79% reduction in the risk for disease progression or death. Median progression-free survival is "about 8 months" in patients who received octreotide alone, but the median has not yet been reached in the radiopharmaceutical group. Dr Strosberg said that the median progression-free survival is expected to be about 40 months for the experimental treatment.

In the radiopharmaceutical group, the there was one complete response and 17 partial responses, whereas in the octreotide-only group, there were no complete responses and three partial responses. So the overall response rate was much better in the radiopharmaceutical group than in the octreotide-only group (18% vs 3%; P = .0008).

"This is really the only study to have shown a double-digit response rate in a population of midgut neuroendocrine tumors," said Dr Strosberg.

Overall survival data are not mature, but so far there have been 13 deaths in the radiopharmaceutical group and 22 in the octreotide group (P = .0186), he noted.

Another radiopharmaceutical used in oncology — radium-223 (Xofigo, Algeta/Bayer) — is approved for prostate cancer, and has some very impressive data. However, the product is not used as much as other agents that are given orally that were approved at around the same time.

This study received funding from Advanced Accelerator Applications. Multiple NETTER-1 investigators report financial ties to industry, including Advanced Accelerator Applications. Dr Krishnamurthi has disclosed no relevant financial relationships.

Gastrointestinal Cancers Symposium (GICS) 2016: Abstract 194. To be presented January 22, 2016.


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