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
GBq, gigabecquerels; IM, intramuscular; IV, intravenous;
Study objective and endpoints1
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
Progression-free survival (PFS), defined as time from randomization to documented disease progression or death from any cause
- Overall survival (OS), defined as time from randomization to death from any cause
- Objective response rate
- Safety and tolerability
- 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%
- 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
KPS, Karnofksy performance-status; LAR, long-acting repeatable; NET, neuroendocrine tumor; OS, overall survival; PFS, progression-free survival; RLT, radioligand therapy; SSTR, somatostatin receptor.
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
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
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
CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival.
CI, confidence interval; FAS, full analysis set; HR, hazard ratio; OS, overall survival; PFS, progression-free surviva; RLT, radioligand therapy.
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
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
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.
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
Evaluate the efficacy of lutetium (177Lu) oxodotreotide co-administered with amino acid solution in patients with SSTR-positive tumors
- Objective response rate, including complete response and partial response according to RECIST criteria
- Duration of response
- Progression-free survival
- Overall survival
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
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
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
- Determine the efficacy, safety and tolerability of LUTATHERA® in patients with progressive, advanced pNETs based on retrospective real-world data from multiple sites
- Progression-free survival (PFS), based on local radiological assessment (RECIST v1.1 evaluation obtained where possible)
- 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
- LUTATHERA®-treated patients with pNETs that were:
- Unresectable or metastatic
- Well-differentiated (grade 1 or 2)
- Somatostatin receptor positive
- NETs of other or unknown origins, including those with pancreas involvement
- Tumors with mixed histology
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)
Median overall survival (OS) in the FAS (N=110) was 41.4 months (95% CI: 28.6-50.2).
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)
Effect of prior chemotherapy on OS with LUTATHERA® (sub-group analysis)
Effect of prior PKIs on OS with LUTATHERA® (sub-group analysis)
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.