177Lu-Dotatate delays disease progression in gastrointestinal neuroendocrine tumors

Results of the phase III NETTER-1 trial, presented during the 2015 European Cancer Congress, demonstrate that lutetium (¹⁷⁷Lu)-Dotatate, combined with ocreotide LAR, significantly delays disease progression in patients with advanced gastrointestinal neuroendocrine tumors (NETs). In addition, the experimental therapy seems to lead to a longer overall survival (OS), although the latter needs confirmation in the final analysis of the trial.

NETs represent a rare group of tumors originating from neuroendocrine cells, which are predominantly found in the lungs, the pancreas and in the gastrointestinal system. From 1973 to 2004, the incidence of NETs increased dramatically with almost 500% from 1.09/100,000 to 5.24/100,000. The therapeutic options for patients with advanced NETs of the midgut, representing 20 to 45% of all NETs, who progress after first-line therapy with a somatostatin analogue (SSA), are limited. ¹⁷⁷Lu-Dotatate (Lutathera) is a member of a new family of therapeutics referred to as peptide receptor radionuclide therapies (PRRT). PRRT consists of the systemic administration of a specific radiopharmaceutical, allowing for targeted cytotoxic radiation at the tumor site. ¹⁷⁷Lu-Dotatate consists of the radionuclide lutetium and a protein designed to specifically bind to the somatostatin receptor, a protein that is overexpressed in approximately 80% of all NETs. Once bound to the somatostatin receptor, the lutetium can bomb the tumor cells with high-energetic electrons, ultimately leading to cell death. In the phase III NETTER-1 trial, a total of 229 patients with metastatic midgut NET from 36 European and 15 American centers, were randomly assigned to a treatment with either ¹⁷⁷Lu-Dotatate plus ocreotide LAR, or ocreotide LAR alone. The primary endpoint of the study was progression-free survival (PFS), with OS, safety and quality of life as key secondary objectives.

In the presented analysis ocreotide LAR was shown to be associated with a median PFS of 8.4 months, while the median PFS was not reached for the combination of ¹⁷⁷Lu-Dotatate and ocreotide LAR (HR[95%CI]: 0.209[0.129-0.338]; p 0.0001). This translates into a 79% reduction in the risk of isease progression or death with the experimental therapy. The objective response rate was also significantly higher with ¹⁷⁷Lu-Dotatate compared to ocreotide LAR: 19% and 3% respectively (p< 0.0004). In 4% of the ¹⁷⁷Lu-Dotatate treated patients disease progression was reported, as compared to 24% of patients with ocreotide LAR. In the interim analysis for OS, a total of 13 deaths were observed with the ¹⁷⁷Lu-Dotatate combination compared to 22 with the standard therapy of ocreotide LAR (p< 0.0186). With respect to toxicity, ¹⁷⁷Lu-Dotatate was shown to have a favorable safety profile and the treatment did not lead to a decreased quality of life.

In summary, treatment with ¹⁷⁷Lu-dotatate in combination with ocreotide LAR results in an unprecedented PFS in patients with recurrent, advanced NETs of the midgut. Moreover, the safety profile of this combination was found to be good and a trend towards a better OS was reported. Given the limited treatment options for these patients, these findings are likely to change the standard of care in this setting.

Reference

Ruszniewski P, et al. ¹⁷⁷-Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumours: Results of the phase III NETTER-1 trial. Presented at ECC 2015; Abstract #6LBA.