The standard treatment for grade 1 or grade 2 non-functional and unresectable gastroenteropancreatic neuroendocrine tumour is monotherapy with somatostatin analogue or molecular target therapy like everolimus. However, there is a poor prognostic population of patients such as Ki-67 more than 5% or liver diffuse metastasis patients. For those aggressive indication patients the somatostatin analogue or molecular target monotherapy is not so good for PFS. For example, everolimus monotherapy provides a limited PFS of around 11 months. So that remains necessary for better therapeutic approaches. So that is why we evaluated the combination therapy of everolimus plus lanreotide for these poor prognostic GEP-NET patients.
What was the study design?
Our study is named STARTER-NET. The STARTER-NET trial was a randomised phase III trial to evaluate the efficacy of the combination of everolimus plus lanreotide for the first line setting. The main inclusion criteria was a histologically proven G1/G2 GEP-NET non-functioning and unresectable recurrent disease, Ki67 5-20% or diffuse liver metastatic patients and no prior treatment patients.
We randomised the patients to the everolimus arm and everolimus plus lanreotide arm 1:1. The primary endpoint was PFS and a key secondary endpoint was OS. The other secondary endpoints were ORR and DCR and safety.
What were the results of this study?
Our main findings were that the combination therapy of everolimus plus lanreotide significantly prolonged PFS. The median PFS of the everolimus arm was only 11.5 months, however the combination therapy median PFS was 29.7 months with a hazard ratio of 0.38. So our study was terminated early due to efficacy.
As for the overall survival, the median overall survival was not reached in both arms with a hazard ratio of 0.74. However, the combination therapy of everolimus plus lanreotide was a consistently better result in both PFS and OS. Also the overall objective response rate of the everolimus plus lanreotide arm was significantly greater at 23% compared with the everolimus arm at 8.3%.
As for the adverse events, slightly higher adverse events occurred in the everolimus plus lanreotide arm at 35.6% compared with the everolimus arm 14.9%. However, most adverse events were well tolerated and the most highly shown adverse event in the everolimus plus lanreotide arm was hyperglycaemia which is easily managed.
What is the clinical significance of these results?
From these results we could say this combination therapy, everolimus plus lanreotide, can be a new standard in the first-line setting for the patients with G1/G2 GEP-NET with poor prognostic factors. Especially from the subgroup analysis the combination therapy efficacy is higher in the Ki67 more than 10% group. So I would like to say that for the more aggressive G1/G2 GEP-NET it’s recommended to use combination therapy.
Is there anything else you would like to add?
In the future we would like to compare the PRRT study, PRRT is recently the good result from the NETTER-2 trial. Also from the NETTER-2 trial the median PFS of PRRT is around 30 months compared with our result. So we would like in the future to make a head-to-head clinical trial of everolimus plus lanreotide versus PRRT for the patients with Ki67 10-55%.
