Oncology · Medical Literature
[177Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours (COMPETE): a phase 3, multicentre, randomised, open-label, superiority trial.
Abstract
Peptide receptor radionuclide and targeted therapy are both approved treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs), but clinical evidence for preferred sequencing is scarce. The COMPETE trial evaluated the efficacy and harms of peptide receptor radionuclide therapy ([177Lu]Lu-edotreotide) versus targeted molecular therapy (everolimus) in patients with advanced, progressive, somatostatin receptor-positive GEP NETs. This phase 3, open-label, superiority trial included patients aged 18 years or older with treatment-naive or previously treated unresectable or metastatic (or both) grade 1-2 GEP NETs. Patients were enrolled from 49 specialist neuroendocrine tumour treatment centres across 14 countries in Africa, Europe, North America, and Oceania and randomised (2:1) to intravenous [177Lu]Lu-edotreotide (7·5 ± 0·7 GBq every 3 months, maximum four cycles) or oral everolimus (10 mg/day) for up to 30 months. Random assignment was via a central, web-based randomisation system (block size of 6) and stratified by primary tumour origin and previous therapy. The primary endpoint was progression-free survival, assessed via blinded independent central review in all randomly assigned patients at 30 months. Harms were assessed in all enrolled patients who received at least one dose of a study drug. This study was registered with ClinicalTrials.gov (NCT03049189) and is no longer recruiting. Between April 13, 2017, and June 20, 2022, 324 patients were enrolled and 309 patients (including 168 [54%] male patients and 141 [46%] female patients) were randomly assigned to treatment: 207 to the [177Lu]Lu-edotreotide group and 102 to the everolimus group. The median follow-up for progression-free survival was 27·5 months (IQR 19·6-30·4) for the [177Lu]Lu-edotreotide group and 21·2 months (8·9-29·4) for the everolimus group. Median progression-free survival was significantly longer with [177Lu]Lu-edotreotide versus everolimus (23·9 months [95% CI 18·7-30·0] vs 14·1 months [9·2-20·9]; stratified hazard ratio 0·67 [95% CI 0·48-0·95]; p=0·022). Treatment-related adverse events occurred in 178 (82%) of 217 patients in the [177Lu]Lu-edotreotide group and 96 (97%) of 99 patients in the everolimus group. 40 (18%) patients in the [177Lu]Lu-edotreotide group and 40 (40%) in the everolimus group had at least one treatment-related grade 3-4 adverse event. The most common treatment-related adverse events in the [177Lu]Lu-edotreotide group were diarrhoea and nausea (both 79 [36%] patients) and asthenia (66 [33%] patients), whereas those in the everolimus group were diarrhoea (45 [45%] patients), asthenia (36 [36%] patients), and anaemia (27 [27%] patients). No treatment-related deaths occurred in either study group. [177Lu]Lu-edotreotide led to statistically significant and clinically meaningful improvements in progression-free survival. Efficacy and harms results support the use of [177Lu]Lu-edotreotide in early lines of therapy in patients with advanced, progressive GEP NETs. ITM Solucin.
Clinical relevance
In patients with advanced, progressive, SSTR-positive grade 1–2 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), does peptide receptor radionuclide therapy with [177Lu]Lu-edotreotide result in superior progression-free survival compared to targeted molecular therapy with everolimus? __SNAPSHOT__ {"studyDesign":"Phase 3, multicenter, randomized, open-label, superiority trial (NCT03049189)","setting":"49 specialist neuroendocrine tumor treatment centers across 14 countries in Africa, Europe, North America, and Oceania","sampleSize":"n=309 (intervention: 207 [177Lu]Lu-edotreotide; control: 102 everolimus); 2:1 randomization","population":"Adults ≥18 years with treatment-naive or previously treated unresectable or metastatic grade 1–2 (Ki-67 ≤20%) SSTR-positive GEP-NETs. Majority had pancreatic primary (57.6%), grade 2 disease (~79% in PRRT arm, ~72% in everolimus arm), non-functional tumors (91%), and were receiving study treatment as second-line therapy (85%); most had prior somatostatin analogue exposure.","intervention":"Intravenous [177Lu]Lu-edotreotide 7.5 ± 0.7 GBq with nephroprotective amino acid solution every 3 months for a maximum of 4 cycles; SSAs permitted at investigator discretion for symptom control only (21% received concomitant SSA)","comparator":"Oral everolimus 10 mg/day for up to 30 months or until disease progression","primaryOutcome":"Progression-free survival (PFS), assessed at a 30-month analysis timepoint (152 PFS events had occurred at analysis)","followUp":"Median follow-up for the overall study population: 40.6 months; ongoing 5-year safety and OS follow-up planned","fundingSource":"Industry (ITM Isotope Technologies Munich SE, developer of [177Lu]Lu-edotreotide / ITM-11)"}
Key findings
PRIMARY OUTCOME: [177Lu]Lu-edotreotide statistically significantly improved median PFS versus everolimus (23.9 vs. 14.1 months; HR 0.67, 95% CI 0.48–0.95; p=0.022), representing a 33% relative reduction in the hazard of disease progression or death. The absolute PFS gain was 9.8 months (calculated). NNT for an additional 1-year PFS event prevented cannot be derived from median data alone and is not reported. SECONDARY OUTCOMES: Objective response rate (ORR) by central assessment was significantly higher with [177Lu]Lu-edotreotide vs. everolimus (21.9% vs. 4.2%; p<0.0001); by local assessment, ORR was 30.5% vs. 8.4% (p<0.0001). Interim median overall survival (OS) was 63.4 vs. 58.7 months (HR 0.78, 95% CI 0.5–1.1; p=0.206), numerically favoring [177Lu]Lu-edotreotide but not statistically significant and considered immature. SUBGROUP ANALYSES (pre-specified by tumor origin): Gastroenteric NETs — median PFS 23.9 vs. 12.0 months (HR 0.64, 95% CI 0.38–1.08; p=0.090); Pancreatic NETs — median PFS 24.5 vs. 14.7 months (HR 0.70, 95% CI 0.45–1.09; p=0.114); Grade 1 — median PFS 30.0 vs. 23.7 months (HR 0.89, 95% CI 0.42–1.87; p=0.753); Grade 2 — median PFS 21.7 vs. 9.2 months (HR 0.55, 95% CI 0.37–0.82; p=0.003); Second-line — median PFS 23.9 vs. 14.1 months (HR 0.68, 95% CI 0.47–0.98; p=0.039); First-line — median PFS not reached vs. 18.1 months (HR 0.60, 95% CI 0.25–1.45; p=0.249). SAFETY: Treatment-emergent adverse events (TEAEs) related to study medication occurred in 82.5% ([177Lu]Lu-edotreotide) vs. 97.0% (everolimus). Grade 3/4 treatment-related AEs were substantially lower with [177Lu]Lu-edotreotide (18% vs. 40%). Most common AEs with [177Lu]Lu-edotreotide: diarrhea and nausea (both 36%), asthenia (33%). Most common AEs with everolimus: diarrhea (45%), asthenia (36%), anemia (27%). One grade 2 serious TEAE of myelodysplastic syndrome was reported with [177Lu]Lu-edotreotide; no unforeseen TEAEs occurred.
Practice implications
WHAT WAS ESTABLISHED: COMPETE provides the first head-to-head, randomized phase 3 evidence directly comparing PRRT with an active systemic standard-of-care (everolimus) in advanced GEP-NETs. [177Lu]Lu-edotreotide achieved a statistically significant and clinically meaningful improvement in median PFS (~9.8 months absolute gain) with a markedly more favorable grade 3/4 toxicity profile (18% vs. 40%). The ORR advantage is substantial and supports true tumor response rather than mere stabilization. WHAT WAS NOT ESTABLISHED: Overall survival superiority was not demonstrated; OS data remain immature and will require longer follow-up. PFS benefit in pre-specified subgroups by tumor origin (GE-NETs, P-NETs) and by grade 1 disease did not reach statistical significance individually, likely due to underpowering of subgroups; the grade 2 subgroup (p=0.003) and second-line setting (p=0.039) showed the clearest benefit. The optimal sequencing of PRRT relative to somatostatin analogues and the role of [177Lu]Lu-edotreotide versus the already-approved [177Lu]Lu-dotatate (NETTER-1/NETTER-2) are not resolved by this trial. WHICH PATIENTS: Predominantly second-line (85%), mostly grade 2 (majority), non-functional (91%), SSTR-positive GEP-NETs, with ~58% pancreatic primaries. UNDERREPRESENTED POPULATIONS: Grade 3 NETs, functional tumors requiring cytoreduction, and patients previously treated with PRRT (excluded). REGULATORY STATUS: [177Lu]Lu-edotreotide (ITM-11) is under FDA review with a PDUFA date of August 28, 2026; it is not yet approved. This summary is based on the published Lancet abstract and manufacturer press releases; full trial data and supplementary analyses in the publication should be consulted for complete clinical decision-making. Industry sponsorship (ITM) warrants standard vigilance regarding publication emphasis. __LIMITATIONS__ Open-label design: No blinding of patients or investigators; PFS assessment subject to performance bias, though central radiological review was employed for ORR.,Moderate sample size (n=309) with 2:1 randomization: Pre-specified subgroups (GE-NET, P-NET, grade 1) were individually underpowered, limiting confidence in subgroup-level effect estimates.,PFS as surrogate endpoint: OS benefit was not demonstrated at interim analysis (HR 0.78, p=0.206); OS data remain immature with continued follow-up required.,Industry sponsorship: Trial designed and funded by ITM Isotope Technologies Munich SE, the developer of [177Lu]Lu-edotreotide; introduces risk of favorable publication framing.,Comparator choice: Everolimus is one of several standard-of-care options; the trial does not address PRRT versus somatostatin analogues alone, chemotherapy, or sunitinib, nor does it address sequencing strategies.,No direct comparison to approved [177Lu]Lu-dotatate (Lutathera): Edotreotide uses non-carrier-added lutetium (higher isotopic purity), but relative efficacy and safety versus dotatate-based PRRT remains unknown.,Permitted concomitant SSA use (21% of patients): Differential SSA use across arms, even if balanced, introduces a potential confounding variable.,Crossover and post-progression therapy not fully reported in available summary: Confounding of OS outcomes by post-study treatments cannot be excluded.,Restricted generalizability: Grade 3 NETs, functional syndromes requiring immediate cytoreduction, and patients with prior PRRT were excluded; findings should not be extrapolated to these populations.,Late radiation toxicity, including secondary malignancies (e.g., MDS): Only one grade 2 MDS was reported, but follow-up duration may be insufficient to capture the full long-term myelotoxicity signal from lutetium-based PRRT. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ In the COMPETE trial, [177Lu]Lu-edotreotide demonstrated statistically significant and clinically meaningful superiority over everolimus in PFS (23.9 vs. 14.1 months; HR 0.67; p=0.022) with a markedly lower grade 3/4 toxicity burden (18% vs. 40%) in patients with advanced, progressive grade 1–2 SSTR-positive GEP-NETs, predominantly in the second-line setting. OS benefit was not yet established at interim analysis and requires mature follow-up. Pending FDA approval, these data support [177Lu]Lu-edotreotide as a preferred alternative to everolimus in appropriately selected SSTR-positive GEP-NET patients, particularly those with grade 2 disease progressing after somatostatin analogue therapy.