FDA Issues CRL to 177Lu-Edotreotide for GEP-NETs

The FDA has issued a complete response letter (CRL) to the new drug application (NDA) seeking the approval of the investigational radiotherapeutic agent ¹⁷⁷Lu-edotreotide (ITM-11) for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).¹

The CRL cited Chemistry, Manufacturing and Controls items, as well as issues related to third-party commercial facilities that should be addressed before the NDA can be approved. The regulatory agency did not cite any clinical safety or efficacy issues related to ¹⁷⁷Lu-edotreotide and did not request any additional clinical or nonclinical data. ITM, the developer of ¹⁷⁷Lu-edotreotide, is reviewing the FDA’s comments and will determine the appropriate next steps, including a future resubmission of the NDA.

The NDA was supported by data from the COMPETE trial (NCT03049189), which evaluated ¹⁷⁷Lu-edotreotide vs everolimus (Afinitor) in patients with unresectable, progressive grade 1 or 2 GEP-NETs. The trial met its primary end point of a clinically meaningful and statistically significant progression-free survival (PFS) improvement vs everolimus. Among patients in the ¹⁷⁷Lu-edotreotide arm (n = 207), the median PFS per blinded independent central review (BICR) was 23.9 months vs 14.1 months in the everolimus arm (n = 102; HR, 0.67; 95% CI, 0.48-0.95; P = .022).² 

“Our confidence in ITM-11’s therapeutic potential has not wavered, and we are committed to working closely with the FDA and our partners to address the items outlined in the CRL,” Dr Andrew Cavey, chief executive officer of ITM, stated in a news release.¹ “Our pivotal COMPETE trial data package stands, and our goal remains unchanged as we work toward bringing [¹⁷⁷Lu-edotreotide] to patients living with advanced GEP-NETs.”

What was the design of the COMPETE trial?

This prospective, controlled, open-label, multicenter trial enrolled adult patients with grade 1 or 2 unresectable or metastatic, progressive somatostatin receptor (SSTR)–positive disease who were treatment naive or had experienced disease progression following first-line therapy.² Patients also needed to have a glomerular filtration rate of at least 60 mL/min/1.73 m².

Patients were randomly assigned 2:1 to receive ¹⁷⁷Lu-edotreotide intravenously at 7.5 GBq ± 0.07 GBq every 3 months for 4 cycles, or oral everolimus at 10 mg daily for a maximum of 30 months, or until disease progression.

The primary end point was PFS per RECIST 1.1 criteria by BICR. ORR was a key secondary end point. Other secondary end points were overall survival (OS), disease control rate, duration of disease control, health-related quality of life, and safety and tolerability.

What additional findings from the COMPETE trial have been reported?

At a data cutoff of January 21, 2025, the interim median OS was numerically higher in the ¹⁷⁷Lu-edotreotide arm, at 63.4 months vs 58.7 months in the everolimus arm, although the statistical significance of this benefit was not yet conclusive (HR 0.78; 95% CI, 0.5, 1.1; P = .206).

Regarding safety, 82.5% of patients in the safety population of the investigational arm experienced any-grade treatment-emergent adverse effects (TEAEs) related to study drugs vs 97.0% of those in the safety population of the control arm.

What are the next steps for evaluating ¹⁷⁷Lu-edotreotide?

This agent is also under investigation vs best standard of care (SOC) in the first or second lines of treatment in the phase 3 COMPOSE study in patients with well-differentiated, aggressive grade 2 or 3, SSTR-positive GEP-NETs.^1,3 SOC comparator regimens in this trial include capecitabine plus temozolomide, everolimus, or FOLFOX.³ PFS serves as the primary end point, and OS is a secondary end point.

References

1. ITM receives complete response letter for ¹⁷⁷Lu-edotreotide (ITM-11). News release. ITM. August 10, 2026. Accessed August 10, 2026. https://www.itm-radiopharma.com/news/press-releases/press-releases-detail/itm-receives-complete-response-letter-for-177lu-edotreotide-itm-11-763/
2. ITM announces FDA acceptance of new drug application (NDA) and PDUFA date for n.c.a. 177Lu-edotreotide (ITM-11) in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). News release. ITM. November 13, 2025. Accessed August 10, 2026. https://www.itm-radiopharma.com/news/press-releases/press-releases-detail/itm-announces-fda-acceptance-of-new-drug-application-nda-and-pdufa-date-for-n-c-a-177lu-edotreotide-itm-11-in-gastroenteropancreatic-neuroendocrine-tumors-gep-nets-747/
3. Lutetium 177Lu-edotreotide versus best standard of care in well-differentiated aggressive grade-2 and grade-3 gastroEnteroPancreatic neuroEndocrine tumors (GEP-NETs) - COMPOSE (COMPOSE). ClinicalTrials.gov. Updated September 10, 2025. Accessed August 10, 2026. https://clinicaltrials.gov/study/NCT04919226