Clinical Trial Results

LUTATHERA® (Lutetium (177Lu) oxodotreotide)
Clinical Trial Results

For full LUTATHERA® safety information please refer to your local Summary of Product Characteristics or prescribing information via adacap.com/our-products/.

NETTER-1 study design

NETTER-1 is a Phase III, randomized, open-label, active-controlled trial with 231* midgut neuroendocrine tumor (NET) patients. It was carried out across 41 active centres in Europe and USA (27 European sites across Belgium, France, Germany, Italy, Portugal, Spain, and the UK; and 14 US sites).1,2

From 6 September 2012 to 14 January 2016, patients were enrolled and randomly assigned to receive either LUTATHERA® plus best supportive care (30mg octreotide long-acting repeatable [LAR]) or high-dose octreotide LAR 60mg. The prespecified final analysis occurred 5 years after the last patient was randomized, and the median duration of follow-up was over 6 years in each arm.2

All patients had failed previous treatment with 20-30mg octreotide LAR before randomization,1 but represented a well-functioning population, demonstrated by a mean Karnofsky performance-status (KPS) score of ~88.3,4

NETTER-1 study design1,2,5

Please note high-dose octreotide LAR 60mg is not the licensed dose.
GBq, gigabecquerels; IM, intramuscular; IV, intravenous;

Study objective and endpoints1

Objective:

Evaluate the efficacy and safety of LUTATHERA® (+ octreotide LAR 30mg) vs. high-dose octreotide LAR 60mg in patients with advanced, progressive, somatostatin receptor (SSTR)-positive midgut NETs

Primary endpoint:

Progression-free survival (PFS), defined as time from randomization to documented disease progression or death from any cause

Secondary endpoints:
  • Overall survival (OS), defined as time from randomization to death from any cause
  • Objective response rate
  • Safety and tolerability
Inclusion criteria:1
  • Inoperable midgut NETs that had metastasized or were locally advanced
  • Disease progression despite previous treatment with 20-30mg octreotide LAR every 3-4 weeks for a minimum of 12 weeks before randomization up to a maximum of 3 years
  • KPS score ≥60
  • SSTRs present on all target lesions
  • Ki67 ≤20%
Exclusion criteria:1
  • Serum creatinine level of >150µmol/L or creatinine clearance of <50mL/min
  • Hemoglobin level of <8.0g/dL
  • White-cell count of <2,000/mm3
  • Platelet count of <75,000/mm3
  • Total bilirubin level of >3 times the upper limit of normal range
  • Serum albumin level of >3.0g/dL
  • Treatment with >30mg octreotide LAR within 12 weeks of randomization
  • Radioligand therapy (RLT) at any time before randomization
  • Any surgery, liver-directed transarterial therapy or chemotherapy within 12 weeks of randomization
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*The total number of patients included in the NETTER-1 trial was 231, however the NETTER-1 primary analysis (cut-off date 24th July 2015) included 229 patients.
KPS, Karnofksy performance-status; LAR, long-acting repeatable; NET, neuroendocrine tumor; OS, overall survival; PFS, progression-free survival; RLT, radioligand therapy; SSTR, somatostatin receptor.
References: 1. Strosberg J, El-Haddad G, Wolin E et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017; 376(2): 125–135. 2. Strosberg J, Caplin M, Kunz P et al. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021; 22(12): 1752–1763. 3. Strosberg J, El-Haddad G, Wolin E et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017; 376(2): 125–135. Supplementary Appendix. 4. Péus D, Newcomb N, Hofer S. Appraisal of the Karnofksy Performance Status and proposal of a simple algorithmic system for its evaluation. BMC Med Inform Decis Mak. 2013; 13: 72. 5. Strosberg J, Kunz PL, Hendifar A et al. Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with (177)Lu-Dotatate: an analysis of the NETTER-1 study. Eur J Nucl Med Mol Imaging. 2020; 47(10): 2372–2382.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link adacap.com/pharmacovigilance/.

NETTER-1 efficacy

LUTATHERA® provided a significant 82% reduction in the risk of disease progression or death vs. control1

Median progression-free survival (PFS) was not reached at the time of the primary analysis* in the LUTATHERA® group vs. a median PFS of 8.5 months (95% CI: 5.8-9.1) in the control group (HR [95% CI], 0.18 [0.11-0.29]; P<0.0001).1

PFS (primary analysis, full analysis set [FAS]; cut-off date 24 July 2015)1

*High-dose octreotide LAR 60mg is not the licensed dose.
The total number of patients included in the NETTER-1 trial was 231, however the NETTER-1 primary analysis (cut-off date 24th July 2015) included 229 patients.
CI, confidence interval; FAS, full analysis set; HR, hazard ratio; PFS, progression-free survival.

LUTATHERA® consistently reduced the risk of disease progression or death vs. high-dose octreotide LAR,** regardless of patients’ prognostic factors.2

Prespecified subgroup analysis of PFS2

*SSTR expression was graded using the Krenning scale, which ranges from grade 0 (no tumor uptake) to grade 4 (very intense tumor uptake). Higher grades indicate a higher level of SSTR expression. All patients were required to have SSTRs present on all target lesions.2 **ENETS Grade 1 indicates a low-grade tumor. ENETS Grade 2 indicates an intermediate-grade tumor.2
CI, confidence interval; ENETS, European Neuroendocrine Tumor Society; 5-HIAA, 5-hydroxyindoleacetic acid; PFS, progression-free survival; SSTR, somatostatin receptor; ULN, upper limit of normal.

LUTATHERA® demonstrated an 11.7-month difference in overall survival (OS)3

NETTER-1 final analysis:3

At the time of the final OS analysis, which occurred 5 years after the last patient randomised (N=231, cut-off date 18 January 2021), the median follow-up duration was 76 months in each study arm. There were 73 deaths in the LUTATHERA® arm (62.4%) and 69 deaths in the high-dose octreotide LAR arm (60.5%).

Median OS in the LUTATHERA® group was 48.0 months (95% CI: 37.4-55.2) vs. 36.3 months (95% CI: 25.9-51.7) in the control arm. This difference was not statistically significant (HR [95% CI], 0.84 [0.60-1.17];† P=0.30‡).

The high rate of patient cross-over (36%) from control to radioligand therapy (RLT) during the follow-up may have contributed to the non-statistically significant difference in OS at the final analysis, among other factors.

OS in the intention-to-treat (ITT) population (final analysis)3

Kaplan–Meier curves were compared using an unstratified log-rank test.3
CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival.
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*Patients underwent randomization from 2012 to 2016; cut-off date for primary analysis was 24th July 2015.1,2 **High-dose octreotide LAR 60mg is not the licensed dose. †The HR and 95% CI were obtained using the unstratified Cox proportional-hazards regression model. The proportional-hazards assumption for the Cox analysis of OS was not fulfilled. ‡Unstratified log-rank test two-sided P-value.
CI, confidence interval; FAS, full analysis set; HR, hazard ratio; OS, overall survival; PFS, progression-free surviva; RLT, radioligand therapy.
References: 1. LUTATHERA® Summary of Product Characteristics. March 2022. 2. Strosberg J, El-Haddad G, Wolin E et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017; 376(2): 125–135. 3. Strosberg J, Caplin M, Kunz P et al. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021; 22(12): 1752–1763.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link adacap.com/pharmacovigilance/.

NETTER-1 Quality of Life (QoL)

The patient perspective complements the clinical evidence. QoL provides insight into the patient perspective.1 For patients with NETs it is of particular relevance that treatment does not compromise their QoL especially because their disease is mostly slow-growing in nature and characterised by a prolonged natural course. Pain, fatigue, diarrhoea and flushing are recognized as clinically relevant making up the core symptoms of the disease condition.2,3

QoL was assessed in NETTER-1 every 12 ± 1 weeks using the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C-30) and the accompanying NET-specific module (G.I.NET-21).2 A pre-specified analysis indicated an improvement in patients’ overall global health-related QoL up to week 84 with LUTATHERA® vs. high-dose octreotide LAR.*4

In an additional post-hoc analysis, Kaplan-Meier plots were produced showing time to first deterioration (TTD) by treatment arm, using a difference from baseline of at least 10 points as a criterion for deterioration.2 The median TTD for global health status was 28.8 months for LUTATHERA® vs. 6.1 months for high-dose octreotide LAR.* TTD analyses have been published in the Journal of Clinical Oncology by Strosberg et al. (2018) including those for the core symptoms.2

Kaplan-Meier plot for TTD in global health status, EORTC QLQ C-302

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*High-dose octreotide LAR 60mg is not the licensed dose.
CI, confidence interval; EORTC QLQ C-30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; LAR, long-acting repeatable; NET, neuroendocrine tumor; QoL, quality of life; TTD, time to deterioration.
References: 1. Khan S, Krenning EP, van Essen M et al. Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate. J Nucl Med. 2011;52(9): 1361–1368. 2. Strosberg J, Wolin E, Chasen B et al. Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial. J Clin Oncol. 2018;36(25): 2578–2584. 3. Singh S, Granberg D, Wolin E et al. Patient-Reported Burden of a Neuroendocrine Tumor (NET) Diagnosis: Results From the First Global Survey of Patients With NETs. J Glob Oncol. 2017;3(1): 43‒53. 4. LUTATHERA® Summary of Product Characteristics. March 2022.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link adacap.com/pharmacovigilance/.

NETTER-1 safety

Adverse events in NETTER-1

As of the final analysis, 76% of patients in NETTER-1 received all four LUTATHERA® infusions, with only 11% of patients discontinuing treatment due to adverse events.*1

The majority of grade 3/4 adverse reactions were comparable between the LUTATHERA® group and the active control group. The most common grade 3/4 adverse reactions were vomiting, nausea, diarrhea and abdominal pain, which occurred in 7% or less of patients taking LUTATHERA® plus octreotide LAR 30mg.2

NETTER-1 adverse events table2

Hematologic events in NETTER-1

More patients experienced grade 3 or 4 hematologic events in the LUTATHERA® group vs. the control group, however these events were transient.2

Change in hematological parameters over time:3

Leukocytes
View data
Lymphocytes
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Neutrophils
View data
Platelets
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Long-term safety1

The long-term safety profile of LUTATHERA® was investigated in the NETTER-1 long-term follow-up, with a focus on renal function and secondary hematological malignancies.

At the time of the NETTER-1 final analysis, after a median follow-up time of over 6 years for each study arm, the safety profile remained consistent with that previously reported at 24 months follow-up, with no new safety signals identified.

A total of 2/111 (2%) of LUTATHERA®-treated patients developed myelodysplastic syndrome, with no new cases reported in the long-term follow-up period. No cases of acute myeloid leukemia were reported throughout the entire study.

The rate of severe nephrotoxicity in the LUTATHERA® group was low (5%) and similar to that reported in the control group. LUTATHERA® treatment was also not associated with any long-term detrimental impact on kidney function.

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*Cut-off date 18 January 2021. Safety population n=231.1
References: 1. Strosberg J, Caplin M, Kunz P et al. 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021; 22(12): 1752–1763. 2. Strosberg J, El-Haddad G, Wolin E et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017; 376(2): 125–135. 3. Strosberg J, El-Haddad G, Wolin E et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017; 376(2): 125–135. Supplementary appendix.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link adacap.com/pharmacovigilance/.

ERASMUS study design1

ERASMUS is a monocentric, single arm, open-label, Phase I/II study, including 1,214 patients treated with lutetium (177Lu) oxodotreotide co-administered with amino acid solution. The main analysis was conducted on 811 Dutch patients with different somatostatin receptor (SSTR)-positive tumor types, including 360 patients with GEP-NETs and bronchial NETs (Dutch full analysis set).

Study objective and outcomes1

Objective:

Evaluate the efficacy of lutetium (177Lu) oxodotreotide co-administered with amino acid solution in patients with SSTR-positive tumors

Outcomes:
  • Objective response rate, including complete response and partial response according to RECIST criteria
  • Duration of response
  • Progression-free survival
  • Overall survival
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GEP-NET, gastroenteropancreatic neuroendocrine tumor; NET, neuroendocrine tumor; RECIST, Response Evaluation Criteria in Solid Tumors; SSTR, somatostatin receptor.
Reference: 1. LUTATHERA® Summary of Product Characteristics. March 2022.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link adacap.com/pharmacovigilance/.

ERASMUS efficacy1

Lutetium (177Lu) oxodotreotide showed favorable efficacy in patients with GEP-NETs that expressed somatostatin receptors (SSTRs).

Efficacy outcomes in the full analysis set (FAS) (n=360):

  • Objective response rate (ORR) was 45% (95% CI: 40-50)
    • Stable disease (SD) was found in 51% of patients
  • Median progression-free survival (PFS) was 28.5 months (95% CI: 24.8-31.4)
  • Median overall survival (OS) was 61.2 months (95% CI: 54.8-67.4)
    • Patients with a primary pancreatic NET had the longest median OS (66.4 months [95% CI: 57.2-80.9])

Best response, ORR and duration of response (DoR) for the FAS Dutch population (n=360)*1

Moa diagram
*Please note, LUTATHERA® is not approved for the treatment of bronchial NETs. Data for bronchial NET patients (n=19) have been removed from the table. **Includes Foregut, Midgut and Hindgut. †Foregut NETs other than bronchial and pancreatic.
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CI, confidence interval; CR, complete response; DoR, duration of response; FAS, full analysis set; GEP-NET, gastroenteropancreatic neuroendocrine tumor; NET, neuroendocrine tumor; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease.
Reference: 1. LUTATHERA® Summary of Product Characteristics. March 2022.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link adacap.com/pharmacovigilance/.

Safety profile summary

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link: adacap.com/pharmacovigilance/.

Summary of the safety profile1

The overall safety profile is based on pooled data from clinical trials (NETTER-1 pivotal Phase III and ERASMUS long-term Phase I/II Dutch patients), and compassionate use programs.1

The most common adverse events observed were nausea (58.9%) and vomiting (45.5%).1 The causality of nausea and vomiting is confounded by the emetic effect of the concomitant amino acid infusion administered for renal protection.1 In NETTER-1, most cases of nausea and vomiting were low grade, and resolved once the amino acid infusions were completed.2

Due to the bone marrow toxicity of LUTATHERA®, the most expected adverse reactions were related to hematological toxicity: thrombocytopenia (25%), lymphopenia (22.3%), anemia (13.4%), pancytopenia (10.2%).1

Other very common adverse reactions reported include fatigue (27.7%) and decreased appetite (13.4%).1

Frequency of adverse reactions reported from clinical studies and post-marketing surveillance1

The adverse reactions are listed in this table according to the frequency and the MeDRA System Organ Class (SOC). The frequencies are categorized as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data).1

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SOC, System Organ Class.
Reference: 1. LUTATHERA® Summary of Product Characteristics. March 2022.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link adacap.com/pharmacovigilance/.

NETTER-R study design1

NETTER-R is an international, retrospective, non-interventional, post-authorization study of 110 pancreatic neuroendocrine tumor (pNET) patients treated with LUTATHERA®.

Data were collected retrospectively from eligible patients’ medical records from the baseline visit (prior to receiving the first dose of LUTATHERA®), during LUTATHERA® treatment, and during follow-up visits, either until the most recent contact available or the end of the study. The median duration of follow-up was over 2 years.

The full analysis set (N=110) consisted of all patients who received at least one cycle of LUTATHERA® and provided data for at least one efficacy endpoint.

Study objectives and endpoints

Objective:
  • Determine the efficacy, safety and tolerability of LUTATHERA® in patients with progressive, advanced pNETs based on retrospective real-world data from multiple sites
Primary endpoint:
  • Progression-free survival (PFS), based on local radiological assessment (RECIST v1.1 evaluation obtained where possible)
Secondary endpoints:
  • Overall survival
  • Objective response rate
  • Duration of response
  • Time to progression
  • PFS (as determined by available tumor assessments, including RECIST v1.1, radiological, biochemical, metabolic, and clinical assessments)
  • Incidence of treatment-emergent adverse events
Inclusion criteria:
  • LUTATHERA®-treated patients with pNETs that were:
    • Unresectable or metastatic
    • Well-differentiated (grade 1 or 2)
    • Somatostatin receptor positive
    • Progressive
Exclusion criteria:
  • NETs of other or unknown origins, including those with pancreas involvement
  • Tumors with mixed histology
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NET, neuroendocrine tumor; PFS, progression-free survival; pNET, pancreatic neuroendocrine tumor; RECIST, Response Evaluation Criteria in Solid Tumors.
Reference: 1. Clement D, Navalkissoor S, Srirajaskanthan R et al. Efficacy and safety of 177Lu-DOTATATE in patients with advanced pancreatic neuroendocrine tumours: data from the NETTER-R international, retrospective study. Eur J Nucl Med Mol Imaging. 2022; Epub ahead of print.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link adacap.com/pharmacovigilance/.

NETTER-R efficacy1

Median progression-free survival (PFS) was 24.8 months (95% CI: 17.5-34.5) in patients whose tumor response was assessed by RECIST v1.1 (n=62 patients from the full analysis set [FAS]).

PFS assessed by RECIST v1.1 (n=62 from the FAS)

CI, confidence interval; PFS, progression-free survival; pNET, pancreatic neuroendocrine tumor; RECIST, Response Evaluation Criteria in Solid Tumors.

Median overall survival (OS) in the FAS (N=110) was 41.4 months (95% CI: 28.6-50.2).

OS (FAS)

CI, confidence interval; FAS, full analysis set; OS, overall survival.

Subgroup analyses revealed that PFS, assessed by RECIST v1.1 (HR: 3.672; P=0.0009), and OS (HR: 3.360; P<0.0001) were longer in patients who had not received prior chemotherapy vs. those who had. OS was also longer in patients who had not been previously treated with protein kinase inhibitors (PKIs) vs. those who had (HR: 2.187; P=0.0128).

The improved survival in patients who had received fewer treatments prior to starting LUTATHERA® may indicate the potential benefit of initiating LUTATHERA® early.

Effect of prior chemotherapy on PFS with LUTATHERA® assessed by RECIST v1.1 (sub-group analysis)

HR, hazard ratio; PFS, progression-free survival; RECIST, Response Criteria in Solid Tumors.

Effect of prior chemotherapy on OS with LUTATHERA® (sub-group analysis)

HR, hazard ratio; OS, overall survival.

Effect of prior PKIs on OS with LUTATHERA® (sub-group analysis)

HR, hazard ratio; OS, overall survival; PKI, protein kinase inhibitor.
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CI, confidence interval; FAS, full analysis set; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.
Reference: 1. Clement D, Navalkissoor S, Srirajaskanthan R et al. Efficacy and safety of 177Lu-DOTATATE in patients with advanced pancreatic neuroendocrine tumours: data from the NETTER-R international, retrospective study. Eur J Nucl Med Mol Imaging. 2022; Epub ahead of print.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link adacap.com/pharmacovigilance/.

NETTER-R safety1

In the NETTER-R study:

  • At least one treatment emergent adverse event (TEAE) occurred in 71.8% of patients, but no TEAEs led to treatment discontinuation
  • The most common TEAEs were nausea (28.2%), fatigue (22.7%) and abdominal pain (16.4%), which were predominantly grade 1/2
  • Grade 3 anemia, lymphopenia and thrombocytopenia occurred in 0.9%, 5.4% and 0.9% of patients, respectively
  • Renal TEAEs occurred in 5.5% of patients
  • No secondary hematological malignancies, including MDS or acute leukemia, were reported during the follow-up period (median duration 24.5 months)

LUTATHERA® was well-tolerated in a real-world population of advanced pNET patients,* with a safety profile consistent with the NETTER-1 and ERASMUS trials.

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*Safety analysis set (N=110) consisted of all patients who received at least one cycle of LUTATHERA®.
MDS, myelodysplastic syndrome; pNET, pancreatic neuroendocrine tumor; TEAE, treatment emergent adverse event.
Reference: 1. Clement D, Navalkissoor S, Srirajaskanthan R et al. Efficacy and safety of 177Lu-DOTATATE in patients with advanced pancreatic neuroendocrine tumours: data from the NETTER-R international, retrospective study. Eur J Nucl Med Mol Imaging. 2022; Epub ahead of print.
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report upon local legislation or to use the pharmacovigilance link adacap.com/pharmacovigilance/.