Edotreotide 40microgram kit for radiopharmaceutical preparation

[177Lu]Lu-edotreotide is a radiopharmaceutical therapy (RPT) targeting somatostatin receptors, which are commonly overexpressed on neuroendocrine tumors (NETs). This systematic literature review and meta-analysis describes the efficacy and safety of [177Lu]Lu-edotreotide in patients with NETs. To date, there has been no meta-analysis of data for this specific RPT. PubMed, EMBASE, Cochrane databases, and abstracts from select congresses were searched for eligible studies (February/October 2024). Meta-analysis was performed using fixed and random-effects models. The primary objective was to evaluate the efficacy of [177Lu]Lu-edotreotide in terms of objective response rate (ORR; complete + partial response) in the subgroup of patients with gastro-enteropancreatic NETs (GEP-NETs) and those with any NETs, irrespective of origin (All-NETs). Secondary outcomes included disease control rate (DCR; best overall response of complete response + partial response + stable disease), median progression-free survival (mPFS), and median overall survival (mOS). Unpublished/updated data were requested from the investigators of the included publications where needed to provide missing information/enable evaluation of additional outcomes. Safety/tolerability data for [177Lu]Lu-edotreotide were also reviewed. Eight eligible studies were identified for inclusion in the meta-analysis, all in the advanced disease setting (5/8 included patients with progressive NETs). Most patients had grade 1/2 NETs (grade 1: 11%-63%; 2: 30%-79%; 3: 4%-11%). Updated data were provided for four of these studies. Overall, ORR and DCR were reported in six studies (GEP-NETs, n = 222; All-NETs, n = 423), mPFS in five studies (GEP-NETs, n = 294; All-NETs, n = 267), and mOS in six studies (GEP-NETs, n = 256; All-NETs, n = 408). Meta-analysis revealed consistently high heterogeneity (I2 >70%) across outcomes/patient populations. Patients with GEP-NETs appeared to have better outcomes than those with All-NETs in terms of ORR (34% vs. 19%), DCR (78% vs. 57%), mPFS (24.9 vs. 18.6 months), and mOS (44.8 vs. 39.1 months), respectively. Safety/tolerability data were inconsistently reported, but grade 3/4 toxicities were rarely noted during [177Lu]Lu-edotreotide treatment. These results support the effectiveness and safety of [177Lu]Lu-edotreotide as a treatment for patients with advanced NETs and suggest a potentially more favorable prognosis for those with GEP-NETs than for the broader All-NETs population. However, these results should be interpreted with caution due to the high level of heterogeneity. Encouraging ORRs and high DCRs were noted, indicating that [177Lu]Lu-edotreotide effectively stabilized disease in most patients. Although safety/tolerability data were inconsistently published across studies, [177Lu]Lu-edotreotide was generally well tolerated. Overall, these findings suggest that the efficacy and safety of [177Lu]Lu-edotreotide are in line with those reported for other RPTs in similar clinical settings. Clinical Trial Registration: PROSPERO 2024 CRD42024518028.

Abstract licence: CC BY 4.0

Everolimus is the only approved therapy for patients with advanced neuroendocrine tumors (NET) of lung and thymus and new treatment options are urgently needed. Expression of somatostatin receptor 2 (SSTR2) is frequently seen in functional imaging in lung-NETs opening the opportunity to treat SSTR2 positive patients with radioligand therapies (RLT). Retrospective data suggest a potential meaningful benefit of RLT directed to SSTR2 in lung-NET patients. The LEVEL trial is a randomized, open-label, phase III international trial of 177Lu-edotreotide versus everolimus in patients with progressive, locally advanced or metastatic, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment-naïve or have progressed (PD) on somatostatin analogues or ≤ 2 additional systemic treatments. Prior RLT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177Lu-edotreotide (total administered activity 7.5 ± 0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Only patients with positivity in somatostatin receptor imaging will be included. CT or MRI scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is progression-free survival (PFS) according to RECIST v1.1 based on local investigator assessment. Secondary endpoints include overall survival, overall response rate, safety, and quality of life (EORTC QLQ-C30). The expected sample size is 120 patients to demonstrate statistical significant risk reduction of 46.4% (HR = 0.536) in PFS with the experimental treatment using an overall 5% two-sided alpha error with 80% power. An interim PFS analysis was included using the Lan-DeMets with O’Brian-Fleming-like boundaries. The LEVEL trial will investigate if 177Lu-edotreotide has the potential to be incorporated as a standard treatment option for patients with NETs from the lung and Thymus. EU CT: 2022–502154-13–00 / www.clinicaltrials.gov : NCT05918302 (June 23rd, 2023).

Abstract licence: CC BY-NC-ND 4.0