COMPETE Trial: [177Lu]Lu-Edotreotide Prolongs PFS vs Everolimus in Advanced GEP NETs

Peptide receptor radionuclide therapy and targeted molecular therapy are established treatment options for advanced gastroenteropancreatic neuroendocrine tumours. However, prospective evidence directly comparing these approaches has remained limited, leaving uncertainty regarding their optimal sequencing.

Results from the phase 3 COMPETE trial showed that [177Lu]Lu-edotreotide significantly prolonged progression-free survival compared with everolimus in patients with advanced, progressive, somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours. Treatment with [177Lu]Lu-edotreotide was also associated with a higher objective response rate and fewer treatment-related serious and grade 3–4 adverse events.

The article, titled “[177Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours (COMPETE): a phase 3, multicentre, randomised, open-label, superiority trial,” was published in The Lancet, Volume 408, Issue 10551, on July 18, 2026.

Authors: Thomas Walter, Henning Jann, Catherine Ansquer, Emmanuel Deshayes, Rocio Garcia-Carbonero, Alexandre Teulé, Richard P Baum, Hein J Verberne, Jarosław B Ćwikła, Rajaventhan Srirajaskanthan, Louis de Mestier, Chiara M Grana, Andreas Buck, Dieter Hörsch, Marianne Pavel, Lawrence O Dierickx, Michael Michael, Jonathan Strosberg, Attila Kollár, Paula Jimenez-Fonseca, Anja Rinke, Maribel del Olmo-García, Anthime Flaus, Jorge Hernando, Andreas Kluge, Monika Breuninger, Serhii Melnyk, Konstantin Zhernosekov, and Jaume Capdevila, for the COMPETE Investigator Team.

Read more about Neuroendocrine Tumors on OncoDaily.

Direct Comparison of PRRT With Everolimus

COMPETE was an international, multicentre, randomised, open-label, phase 3 superiority trial conducted at 49 specialist neuroendocrine tumour centres across 14 countries in Africa, Europe, North America, and Oceania.

The study enrolled adults with histologically confirmed, well-differentiated grade 1 or 2 gastroenteropancreatic neuroendocrine tumours, defined by a Ki-67 index of 20% or lower. Patients were required to have unresectable, metastatic, or both unresectable and metastatic disease that had progressed within the 36 months before randomisation.

All patients had somatostatin receptor-positive disease on functional imaging. Patients could be treatment-naive or previously treated, but all were required to have documented progressive disease. Previous therapy with peptide receptor radionuclide therapy or an mTOR inhibitor was not permitted.

Patients were randomly assigned in a 2:1 ratio to receive:

• Intravenous [177Lu]Lu-edotreotide at 7.5 ± 0.7 GBq every 3 months for a maximum of four cycles; or
• Oral everolimus at 10 mg per day for up to 30 months.

Concomitant somatostatin analogue therapy was not routinely required and was permitted only for symptom control in either treatment group.

The primary endpoint was progression-free survival assessed by blinded independent central review according to RECIST version 1.1. Key secondary endpoints included objective response rate and overall survival. Additional outcomes included disease control, safety, tolerability, and health-related quality of life.

The trial was registered with ClinicalTrials.gov as NCT03049189.

Study Population

Between April 13, 2017, and June 20, 2022, 324 patients were enrolled. Of these, 309 were randomly assigned: 207 to [177Lu]Lu-edotreotide and 102 to everolimus.

The median patient age was 65 years in the [177Lu]Lu-edotreotide group and 61 years in the everolimus group.

Pancreatic neuroendocrine tumours were the most common primary tumour type, accounting for 58% of the overall study population. Most patients had grade 2 disease, including 79% of patients assigned to [177Lu]Lu-edotreotide and 72% assigned to everolimus.

Overall, 91% of patients had non-functional tumours, and 85% were receiving the study treatment in the second-line setting. Most patients had previously received a somatostatin analogue.

Median follow-up for the overall study population was 40.6 months.

Significant Improvement in PFS

At the month 30 analysis, 152 progression-free survival events had occurred. The trial met its primary endpoint, with a statistically significant improvement in progression-free survival favouring [177Lu]Lu-edotreotide.

Median progression-free survival was:

• 23.9 months with [177Lu]Lu-edotreotide;
• 14.1 months with everolimus.

The stratified hazard ratio for disease progression or death was 0.67, corresponding to a 33% reduction in the hazard of progression or death with [177Lu]Lu-edotreotide compared with everolimus. The difference met the prespecified threshold for statistical significance, with a p value of 0.022.

Sensitivity analyses based on locally assessed progression-free survival were consistent with the blinded central review. Locally assessed median progression-free survival was 24.1 months with [177Lu]Lu-edotreotide and 17.6 months with everolimus.

Exploratory subgroup analyses generally favoured [177Lu]Lu-edotreotide. Among patients treated in the second-line setting, median progression-free survival was 23.9 months with [177Lu]Lu-edotreotide and 14.1 months with everolimus. Among patients with grade 2 tumours, median progression-free survival was 21.7 months and 9.2 months, respectively.

In the pancreatic neuroendocrine tumour subgroup, median progression-free survival was 24.5 months with [177Lu]Lu-edotreotide and 14.7 months with everolimus. However, these subgroup analyses were exploratory and were not powered to establish statistically significant differences within each subgroup.

Higher Objective Response Rate

The objective response rate assessed by blinded independent central review was significantly higher with [177Lu]Lu-edotreotide than with everolimus.

An objective response was observed in 22% of evaluable patients receiving [177Lu]Lu-edotreotide and 4% of those receiving everolimus. Four patients treated with [177Lu]Lu-edotreotide achieved a complete response, while no complete responses were reported with everolimus. Partial responses occurred in 19% and 4% of patients, respectively.

The disease control rate was similar between the groups, at 83% with [177Lu]Lu-edotreotide and 82% with everolimus. However, the median duration of disease control was longer with [177Lu]Lu-edotreotide, at 27.3 months compared with 17.2 months with everolimus.

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OS Data Remain Immature

At the time of analysis, 115 deaths had occurred. Median overall survival was 63.4 months with [177Lu]Lu-edotreotide and 58.7 months with everolimus. The stratified hazard ratio was 0.78, and the difference was not statistically significant.

The investigators noted that the overall survival data remained immature. Interpretation could also be affected by subsequent treatment, particularly because 53 patients, representing 52% of the everolimus group, subsequently received peptide receptor radionuclide therapy. Long-term survival and late-toxicity follow-up will continue for 5 years after each patient’s end-of-study visit.

Health-Related Quality of Life

Global health status and quality-of-life scores remained generally stable in patients receiving [177Lu]Lu-edotreotide but declined in those receiving everolimus. The least-squares mean change from baseline was 0.89 points with [177Lu]Lu-edotreotide compared with a decrease of 9.94 points with everolimus.

Among patients who experienced a clinically meaningful improvement in global health status or quality of life, the median duration from improvement to subsequent deterioration was 22.0 months with [177Lu]Lu-edotreotide and 10.2 months with everolimus. The investigators stated that detailed health-related quality-of-life findings would be reported separately.

Safety Outcomes Favoured [177Lu]Lu-Edotreotide

The safety analysis included 217 patients treated with [177Lu]Lu-edotreotide and 99 treated with everolimus. The [177Lu]Lu-edotreotide safety population included patients from both the randomised and non-randomised study cohorts.

Treatment-related adverse events occurred in 82% of patients receiving [177Lu]Lu-edotreotide and 97% receiving everolimus. Treatment-related grade 3–4 adverse events were reported in 18% and 40% of patients, respectively. Treatment-related serious adverse events occurred in 3% of patients treated with [177Lu]Lu-edotreotide and 15% treated with everolimus. Treatment-emergent adverse events leading to study discontinuation occurred in 6% of patients receiving [177Lu]Lu-edotreotide and 23% receiving everolimus.

The most common treatment-related adverse events with [177Lu]Lu-edotreotide were diarrhoea, nausea, and asthenia. With everolimus, the most common treatment-related adverse events were diarrhoea, asthenia, and anaemia. No treatment-related deaths occurred in either group.

Lymphopenia was more frequent with [177Lu]Lu-edotreotide, whereas anaemia was more frequent with everolimus. Most haematological adverse events were transient, with recovery observed by month 30.

Two patients treated with [177Lu]Lu-edotreotide developed myelodysplastic syndrome, including one case considered related to treatment. One case occurred in the everolimus group and was not considered treatment-related. No cases of acute myeloid leukaemia were reported.

Renal adverse events were infrequent, and creatinine and estimated glomerular filtration rate remained close to baseline during the study. Longer follow-up is ongoing to evaluate late haematological and renal complications associated with peptide receptor radionuclide therapy.

Clinical Interpretation

The investigators described COMPETE as the first phase 3 trial to directly demonstrate superior efficacy and a more favourable harms profile with [177Lu]Lu-edotreotide monotherapy compared with everolimus in advanced, progressive gastroenteropancreatic neuroendocrine tumours.

The study also provides prospective evidence supporting peptide receptor radionuclide therapy without mandatory concomitant somatostatin analogue treatment. Somatostatin analogues were allowed only when needed for symptom control, and their use did not appear to explain the progression-free survival benefit.

The results support consideration of [177Lu]Lu-edotreotide in earlier treatment lines, particularly following progression during previous somatostatin analogue therapy.

However, the authors cautioned against direct comparisons with studies such as NETTER-1 and NETTER-2 because of differences in patient populations, study designs, treatment regimens, tumour grades, previous treatments, and the radiolabelled somatostatin analogue used.

Study Limitations

The study had an open-label design because of the different administration methods of intravenous radioactive therapy and oral everolimus. To reduce the potential for assessment bias, radiological outcomes were evaluated through blinded independent central review.

Patients with functional gastrointestinal neuroendocrine tumours were excluded, and more than 80% of enrolled patients were White, indicating a need for further research in more racially and ethnically diverse populations. Only a small proportion of patients received the study treatments as first-line therapy. Therefore, conclusions regarding the use of [177Lu]Lu-edotreotide in treatment-naive disease remain exploratory.

Overall survival data were immature, and their interpretation could be influenced by post-study treatments, including subsequent peptide receptor radionuclide therapy in the everolimus group.

Takeaway

The phase 3 COMPETE trial provides direct evidence that [177Lu]Lu-edotreotide offers greater clinical benefit than everolimus for patients with advanced, progressive, somatostatin receptor-positive grade 1–2 gastroenteropancreatic neuroendocrine tumours.

[177Lu]Lu-edotreotide significantly prolonged progression-free survival, produced a higher objective response rate, and demonstrated a more favourable safety profile. The benefit was achieved without mandatory concomitant somatostatin analogue therapy.

These findings support [177Lu]Lu-edotreotide as a preferred treatment option over everolimus, particularly in the second-line setting following progression on previous therapy. Longer follow-up will further clarify overall survival and the risk of late treatment-related toxicities.

The full article is available in The Lancet.