Clinical Trial Results

LUTATHERA® (Lutetium (177Lu) oxodotreotide)
Clinical Study

NETTER-1

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Clinical Study Results

Design

NETTER-1

The NETTER-1 trial began in 2012 with the first patient randomised on 6 September 2012. The study was carried out across 41 active centres in EU and USA (27 EU sites across Belgium, France, Germany, Italy, Portugal, Spain, and the UK; and 14 US sites).1

The NETTER-1 trial is an open-label multicentre, randomised, comparator-controlled clinical trial in patients with inoperable, somatostatin receptor (SSTR)-positive, histologically proven midgut carcinoid tumours, progressive under octreotide long-acting release (LAR).1

It compares progression-free survival (PFS) after treatment with LUTATHERA® plus best supportive care (30mg octreotide LAR) to treatment with high-dose (60mg) octreotide LAR.1 LUTATHERA® arm’s patients received 30mg octreotide LAR to ensure treatment uniformity as some were indeed expected to require this treatment for symptom management.1

Prior to randomisation in the study, patients were treated with 20mg or 30mg octreotide LAR every 3–4 weeks at a fixed dose for at least 12 weeks.1 Patients must have had progressive disease while receiving an uninterrupted fixed dose of octreotide LAR (20–30mg per 3–4 weeks).1

NETTER-1 study design1

GBq, gigabecquerels; IM, intramuscular; IV, intravenous.

Study objective and endpoints

The objective was to evaluate the efficacy and safety of LUTATHERA® (+ octreotide LAR 30mg) in comparison with high-dose (60mg) octreotide LAR in patients with advanced, progressive, SSTR-positive midgut neuroendocrine tumours (NETs).1

The primary endpoint was PFS, which was defined as the time from randomisation to documented disease progression (as evaluated by independent central review with radiologists unaware of treatment assignments) or death from any cause.1

Secondary endpoints included objective response rate, overall survival (OS) (defined as the time from randomisation to death from any cause), safety, and the side-effect profile.1

An objective tumour assessment on computed topography (CT) or magnetic resonance imaging (MRI) was performed every 12 weeks after the date of randomisation in both treatment groups.1 The treatment was considered to have failed if a patient had progressive disease on imaging, according to the central assessment with Response Evaluation Criteria in Solid Tumours (RECIST) criteria.1 Patients with treatment failure proceeded directly to the long-term follow-up (FU) phase.1

Demographic and Baseline Clinical Characteristics of the Patients at Enrollment*1

 

Key inclusion criteria:1

Eligible patients were adults who had midgut NETs:

  • That had metastasised or were locally advanced,
  • That were inoperable,
  • That were histologically confirmed and centrally verified,
  • That showed disease progression (according to RECIST, version 1.119) on either CT or MRI over the course of a maximum period of 3 years during treatment with octreotide LAR (20–30mg every 3–4 weeks for at least 12 weeks before randomisation).

Patients were required to have:1

  • A Karnofsky performance status score of at least 60 (on a scale from 0–100, with lower numbers indicating greater disability).
  • A tumour with well-differentiated histologic features. Well-differentiated histologic features were defined as a Ki67 index (the percentage of cells that are positive for Ki67 as determined by immunostaining of the primary tumour) of 20% or less; tumours were assessed as low-grade if they had a Ki67 index of 0–2%, intermediate-grade if they had a Ki67 index of 3–20%, or high-grade if they had a Ki67 index of greater than 20%, with a lower grade indicating a lower rate of proliferative activity.
  • And SSTRs present on all target lesions. Target lesions were selected from CT or MRI, and the degree of expression of SSTRs was determined on the basis of the lesion that had the highest uptake of radiotracer observed on planar SSTR scintigraphy (SRS) within 24 weeks before randomisation. All CT and MRI images were reviewed and evaluated for disease progression (according to RECIST criteria) and SSTR expression by independent central reviewers who were unaware of the treatment assignments.

Efficacy

82% reduction in the risk for a patient to progress or die under LUTATHERA® compared to high-dose (60mg) octreotide LAR (hazard ratio 0.18 [95% confidence CI: 0.11–0.29]).2

Median PFS:1

  • LUTATHERA®: Not reached (NR)
  • High-dose (60mg) octreotide LAR: 8.5 months (95% CI, 5.8–9.1)

PFS in patients with midgut NETs (NETTER-1)2

CI, confidence interval; HR, hazard ratio.
 

LUTATHERA® demonstrated an Overall Response Rate (ORR) of 18% (vs. 3% with high-dose (60mg) octreotide LAR)1

The ORR of 18% in the LUTATHERA® arm (compared with 3% in the control arm) is notable given that response rates above 5% have not been observed in large randomised clinical trials of other systemic therapies in this patient population.1

ORR in patient with midgut NETs (NETTER-1)1

 

CR, complete response; ORR, objective response rate; PR, partial response.

LUTATHERA® demonstrated treatment benefit across stratification & prognostic factors1

Prespecified subgroup analysis of PFS (NETTER-1)1

CI, confidence interval; ENETS, European Neuroendocrine Tumor Society; LAR, long-acting release; ULN upper limits of normal.
 

LUTATHERA® shows estimated longer OS in planned interim analysis1,2

At the time of the per protocol interim analysis (24 July 2015)*, there were 17 deaths in the LUTATHERA® arm and 31 in the high-dose (60 mg) octreotide LAR arm. The hazard ratio was 0.459 in favour of LUTATHERA®, but did not reach the level of significance for interim analysis (HR 99.9915% CI: 0.140, 1.506).2 Per protocol interim analysis* results show estimated longer OS with LUTATHERA® than with high-dose (60mg) octreotide LAR.1

An update conducted about one year after (30 June 2016) showed a similar trend with 28 deaths in the LUTATHERA® arm and 43 in high-dose (60mg) octreotide LAR arm, an HR of 0.536, and a median OS of 27.4 months in high-dose (60mg) octreotide LAR arm and still not reached in LUTATHERA® arm.1

*Per protocol interim analysis was planned with a very high threshold for statistical significance (α = 0.0085%), interim analysis did not reach this prespecified level of significance.1 The final OS analysis is foreseen after 5 years or 158 cumulative deaths.1

28 OS events in the LUTHATHERA® arm vs. 43 in the long-acting octreotide arm1

 

NETTER-1 confirms phase 1, 2 study efficacy results in Midgut NETs2

Erasmus phase 1, 2 study was a monocentric single arm open label study to evaluate the efficacy of lutetium (177Lu) oxodotreotide (7.4 GBq administered for 4 times every 8 weeks) co-administered with amino acid solution in patients with SSTR-positive tumours.2

The mean age of patients enrolled in the study was 60 years.2

Most patients were Dutch (811) with the remaining (403) residents of various European and non-European countries.2

Tables beside display the results observed in the Erasmus phase I, II study for the FAS (full analysis set) Dutch population with gastroenteropancreatic (GEP) and bronchial NETs (360 patients).2

Best response, ORR and duration of response (DoR) (Erasmus phase I, II study)2

 

*Includes Foregut, Midgut and Hindgut; **Foregut NETs other than bronchial and pancreatic
CI, confidence interval; CR, complete response; GEP-NET, gastroenteropancreatic neuroendocrine tumour; PR, partial response; SD, stable disease; ORR, objective response (CR+PR); DoR, duration of response.

PFS and OS (Erasmus phase I, II study)2

*Includes Foregut, Midgut and Hindgut; **Foregut NETs other than bronchial and pancreatic
CI, confidence interval; PFS, progression-free survival; OS, overall survival.

 

Safety

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Summary of the safety profile2

The most common adverse reactions in patients receiving Lutathera treatment were nausea and vomiting which occurred at the beginning of the infusion in 58.9% and 45.5% of patients, respectively. The causality of nausea / vomiting is confounded by the emetic effect of the concomitant amino acids infusion administered for renal protection.

Due to the bone marrow toxicity of Lutathera, the most expected adverse reactions were related to haematological toxicity: thrombocytopenia (25%), lymphopenia (22.3%), anaemia (13.4%), pancytopenia (10.2%).

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

LUTATHERA® was associated with limited acute toxic effect1

When administered concomitantly with a renal protective agent, LUTATHERA® was associated with limited grade 3 or 4 haematologic toxic effects and showed no evidence of renal toxic effects over the trial time frame (median duration of FU, 14 months).1

Gastrointestinal disorders1

A majority of the cases of nausea (65%) and vomiting (73%) in patients were attributable to amino acid infusions that were performed concurrently with administration of LUTATHERA®, and the events resolved once the infusions were completed.

Nephrotoxicity2

LUTATHERA® is excreted by the kidney.

The long-term trend of progressive glomerular filtration function deterioration demonstrated in the clinical studies confirms that LUTATHERA®-related nephropathy is a chronic kidney disease that develops progressively over months or years after exposure. An individual benefit-risk assessment is recommended prior to treatment with LUTATHERA® in patients with mild and moderate renal impairment. The use of LUTATHERA® is contraindicated in patients with severe kidney failure.

Adverse events in patients with midgut NETs (NETTER-1)*1

 

Bone marrow toxicity

Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia were reported in 1%, 2%, and 9% of patients, respectively, in the LUTATHERA® arm vs. no patients in the control group. These hematologic events were transient.1

Bone marrow toxicity (myelo-/haematotoxicity) manifested with reversible / transient reductions in blood counts affecting all lineages (cytopenias in all combinations, i.e., pancytopenia, bicytopenias, isolated monocytopenias – anaemia, neutropenia, lymphocytopenia, and thrombocytopenia). In spite of an observed significant selective B-cell depletion, no increase in the rate of infectious complications occurs after PRRT.2

Cases of irreversible haematological pathologies, i.e., premalignant and malignant blood neoplasms (i.e., myelodysplastic syndrome and acute myeloid leukaemia, respectively) have been reported following LUTATHERA® treatment.2

Hormonal crises

Hormonal crises related to bioactive substances release (probably due to lysis of the NET cells) have rarely been observed and resolved after appropriate medical treatment.2

Limited long-term toxicities have been observed following treatment in 610 patients (64 months median follow up) in phase I/II studies3

  • Renal tolerability:3 Renal failure occurred in 6 patients (1%), probably not related to LUTATHERA® treatment.
  • Haematologic tolerability:3 Acute Leukaemia (AL) occurred in 4 patients (0.7%) during follow-up (FU). The median FU was 55 months. Myelodysplastic Syndrome (MDS) occurred in 9 patients (1.5%). The median FU was 28 months.
  • Hepatic tolerability:3 No liver failure observed

Haematologic events in patients with midgut NETs (NETTER-1)4

 

Quality of Life

The patient perspective complements the clinical evidence. QoL provides insight into the patient perspective.5 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 recognised as clinically relevant making up the core symptoms of the disease condition.6,7

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).6 The results indicate an improvement in overall global health-related QoL up to week 84 for patients in the LUTATHERA® arm vs. those in the control arm.2

In a 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.6 The median TTD for global health status was 28.8 months for LUTATHERA® vs. 6.1 months for high-dose (60mg) octreotide LAR. TTD analyses have been published in the Journal of Clinical Oncology by Strosberg et al. (2018) including those for the core symptoms.6

Kaplan Meier plot for TTD in global health status, EORTC QLQ C-306

 

CI, confidence interval.

References: 1. Strosberg J, El-Haddad G, Wolin E et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. New Engl J Med. 2017;376(2): 127–135. 2. LUTATHERA® Summary of Product Characteristics. January 2021. Available at: https://www.ema.europa.eu/en/documents/product-information/lutathera-epar-product-information_en.pdf Accessed April 2021. 3. Brabander, T., van der Zwan, W.A., Teunissen, J.J.M., Kam, B.L.R., Feelders, R.A., de Herder, W.W., et al. (2017). Long-Term Efficacy, Survival, and Safety of [(177)Lu-DOTA(0),Tyr(3)]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors. Clinical cancer research: an official journal of the American Association for Cancer Research. 23 (16). p.pp. 4617–4624. 4. Strosberg J, El-Haddad G, Wolin E et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. New Engl J Med. 2017;376(2): 127–135. (Suppl Appendix) 5. Khan, S., Krenning, E.P., van Essen, M., Kam, B.L., Teunissen, J.J. and Kwekkeboom, D.J. (2011). Quality of life in 265 patients with gastroenteropancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA0,Tyr3]octreotate. Journal of nuclear medicine: official publication, Society of Nuclear Medicine. 52 (9). p.pp. 1361–8. 6. Strosberg et al. (2018). 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 36, Sept 2018. 7. 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.