1. Carlson, Robert H.

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Radioisotope 177Lu-DOTATATE (Lutathera) has a favorable safety profile with no clinically relevant adverse effects in treatment of patients with midgut neuroendocrine tumors (NETs) who have progressed on somatostatin analogue treatment, according to new data from the Phase III NETTER-1 trial.

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The data were discussed at a presscast here in advance of the Gastrointestinal Cancers Symposium 2016 (Abstract 194).


NETTER-1 Trial

NETTER-1 is a multicenter, randomized, placebo-controlled trial that compared Lutathera with Ocreotide LAR in patients with inoperable, progressive, somatostatin-receptor positive midgut NETs.


In the first report from NETTER-1, presented at the 2015 European Cancer Congress (ECC) meeting in Vienna, Austria, patients treated with the experimental drug had a 79 percent lower risk of disease progression or death compared with those treated with Octreotide LAR.


"Currently, there are limited therapeutic options for patients with advanced midgut neuroendocrine tumors progressing on first-line somatostatin analog therapy," said study author Jonathan R. Strosberg, MD, Associate Professor at the H. Lee Moffitt Cancer Center, in the presscast previewing the symposium. "Midgut NET is highly resistant to systemic therapy and Lutathera has a major therapeutic benefit for this patient population."

Figure. Radioisotope... - Click to enlarge in new windowFigure. Radioisotope

Lutathera is a peptide receptor radionuclide that targets somatostatin receptors, which are overexpressed in approximately 80 percent of NETs, to deliver cytotoxic radiation directly to the tumor, Strosberg said.


At this meeting, Strosberg reported in greater detail on adverse events in NETTER-1. Overall, he said, the numbers of adverse events, including serious side effects, were similar between the two treatment groups (see Table).


The NETTER-1 data are on 230 patients with Grade 1-2 metastatic midgut NETs who were randomly assigned to receive treatment with Lutathera every eight weeks for four cycles (115 patients), or the somatostatin analogue Octreotide LAR 60 mg every four weeks (115 patients). Octreotide LAR is the current standard of care for GI NETs.


Patients in the control arm had progressed on Ocreotide LAR 30 mg, the label use.


Each Lutathera treatment dose was 7.4 GBq (gigabecquerels), equal to 200 millicurie.


At the time of statistical analysis, the number of confirmed disease progressions or deaths was 23 in the Lutathera group and 67 in the Octreotide LAR 60 mg group, Strosberg said. The study also suggested that Lutathera may extend patient survival: there were 13 deaths in the Lutathera group versus 22 with standard care.


"This is the first interim look at overall survival and not statistically significant at this point, but it does suggest an overall survival advantage for Lutathera," Strosberg said.


At the time of the report, median progression-free survival had not been reached for Lutathera, and was 8.4 months with Octreotide LAR.



Among 201 patients currently evaluable for tumor response, there were 19 (18.8%) complete and partial responses in the Lutathera group-1 complete response and 17 partial responses-versus three (3.0%, 3 partial responses) in the Octreotide LAR 60 mg group.


This study received funding from Advanced Accelerator Applications (AAA), the maker of Lutetium.


'Impressive Ability'

In April 2015, the FDA granted Fast Track designation to Lutathera for the treatment of patients with inoperable, progressive, well-differentiated, somatostatin-positive carcinoid tumors of the midgut.


Smitha Krishnamurthi, MD, an ASCO spokesperson and moderator of the presscast, said Lutathera showed impressive ability to slow the growth of midgut NETs that have progressed on somatostatin analogue therapy.


"Also notable was the Lutathera response rate of 18 percent, which in these tumors are typically unresponsive to systemic therapy," said Krishnamurthi, Associate Professor in the Department of Medicine-Hematology and Oncology at Case Western Reserve University School of Medicine and leader of the Gastrointestinal Oncology Disease team.


Adverse Events

(with Lutathera versus Ocreotide LAR, respectively)


* nausea all grades: 59 percent versus 12 percent;


* nausea grade-3/4: 4 percent versus 2 percent;


* vomiting all grades: 47 percent versus 10 percent;


* vomiting grade-3/4: 7 percent versus 0 percent;


* diarrhea all grades: 29 percent versus 19 percent;


* diarrhea grade-3/4: 3 percent versus 2 percent;


* thrombocytopenia all grades: 25 percent versus 1 percent;


* thrombocytopenia grade-3/4: 2 percent versus 0 percent;


* anemia all grades: 14 percent versus 5 percent;


* anemia grade-3/4: 0 percent versus 0 percent;


* lymphopenia all grades: 18 percent versus 2 percent; and


* lymphopenia grade-3/4: 9 percent versus 0 percent.