Philippe Ruszniewski, MD
Treatment with the novel peptide receptor radionuclide therapy (PRRT) Lutathera significantly increased progression-free survival (PFS) over octreotide LAR (Sandostatin) in patients with advanced midgut neuroendocrine tumors (NETs), according to findings from the phase III NETTER-1 trial presented at the 2015 European Cancer Congress.
Lutathera is a 177
Lu-DOTATATE PRRT that targets somatostatin receptors, which are overexpressed in about 80% of NETs, to deliver cytotoxic radiation directly to the tumor. After a median 30 months of follow-up of 229 patients in the intent-to-treat (ITT) population of the NETTER-1 trial, the median PFS with Lutathera was not reached compared with 8.4 months with octreotide LAR (HR, 0.209; 95% CI, 0.129-0.338), providing a risk reduction of 79.1% (P
“Our results confirmed data from phase I and II trials,” said lead investigator Philippe Ruszniewski, MD, head of gastroenterology and pancreatology at Beaujon Hospital, in Clichy, and professor at Paris Diderot University. “At the time we analyzed the data, median PFS for Lutathera had not been reached, whereas we could define it as 8.4 months in patients who received octreotide LAR alone. Results thus far show that patients on Lutathera are achieving extra time without their disease progressing. This kind of progression-free survival is rarely achieved in this type of cancer.”
The NETTER-1 trial is the first phase III multicentric, stratified, open, randomized, controlled trial to compare Lutathera with octreotide LAR, the current standard of care, in patients with inoperable, progressive, somatostatin receptor positive midgut NETs. The primary endpoint was PFS, according to RECIST 1.1 criteria. Secondary objectives included objective response rate (ORR), overall survival (OS), time to progression (TTP), safety, tolerability, and health-related quality of life.
Of the 230 patients with grade 1-2 metastatic midgut NETs randomized in a 1:1 ratio, 101 patients received Lutathera at 7.4 GBq administered intravenously in 4 doses given every 8 weeks together with renal protection consisting of an amino acid solution infusion. Another 100 patients received octreotide LAR at 60 mg by deep intragluteal injection every 4 weeks.
In the Lutathera cohort, ORR was 19%, (95% CI, 11-26) versus 3% with octreotide LAR (95% CI, 11-26; P
< .0004). One patient receiving Lutathera achieved complete response (CR), 18 showed partial response (PR) and 5 (4%) experienced progressive disease (PD) compared to no CR, 3 PR, and 27 PD (24%) with octreotide LAR. Stable disease was achieved by 77 (66%) and 70 (62%) patients in each respective cohort.
The interim analysis of the ITT population revealed a trend toward improved OS (P
< .0186) that did not reach statistical significance. Ruszniewski estimated the median PFS based on immature data at approximately 40 months with Lutathera.
This ongoing trial will continue to follow survival parameters until the data mature. At the time of the interim analysis, 13 patients receiving Lutathera and 22 octreotide LAR patients had died. The number of centrally confirmed disease progressions or deaths was 23 in the Lutathera group compared with 67 with octreotide LAR.
The safety profile demonstrated in NETTER-1 was consistent with the safety information generated in the phase I and II clinical trials. Serious adverse events (SAEs) with Lutathera included lymphocytopenia, reported in 3 patients, and thrombocytopenia, neutropenia, pancytopenia and bicytopenia, each of which occurred in 1 patient. There were 2 SAEs of acute kidney injury and 1 case of renal failure.
“We have also been able to see that Lutathera has a good safety profile and offers these patients a good quality of life,” Ruszniewski said, adding that there is a low risk of future DNA damage from the radionuclide, with the possibility of future mylodysplastic disease developing in about 3% to 4% of Lutathera-treated patients.
The NETTER-1 trial demonstrated that Lutathera was superior to octreotide LAR for the treatment of midgut NETS and may be practice-changing for the treatment of these patients, according to Ruszniewski. The incidence of NETs has been on the rise in Europe, which is probably due to improved diagnosis. Midgut NETs comprise 20% to 45% of overall NETs cases.
In April 2015, the FDA granted a fast track designation to Lutathera for the treatment of inoperable progressive midgut NETs. This designation is meant to facilitate the development of novel therapies. A diagnostic for identifying patients who are likely to respond to Lutathera, SomaKit-TATE, was granted a priority review designation in early September 2015. The kit is designed to facilitate 68Ga-DOTATATE for injection, which can be used to detect somatostatin receptor-positive NETs by PET scan.