What is the mechanism of action of this treatment?

The most common treatments for Neuroendocrine Tumors (NETs) include radiolabeled somatostatin analogs, such as Lutathera (177Lu-Dotatate), and molecularly targeted therapies like everolimus. Radiolabeled somatostatin analogs work by binding to somatostatin receptors, which are often overexpressed on NET cells, and delivering targeted radiation to destroy these cells while sparing surrounding healthy tissue. This targeted approach is crucial for NET patients as it maximizes tumor cell eradication and minimizes side effects. Everolimus, on the other hand, inhibits the mTOR pathway, which is involved in cell growth and proliferation, thereby slowing tumor growth. These mechanisms are significant for NET patients because they offer effective treatment options that can control tumor progression and improve quality of life.

What side effects are associated with this type of intervention?

The most common side effects of treatments like Lutathera (177Lu-Dotatate) for Neuroendocrine Tumors include nausea, which is often related to the amino acid infusions used to protect the kidneys during therapy. Hematologic toxicities are also frequent, including mild thrombocytopenia, lymphopenia, anemia, and leukopenia, with nadir counts typically occurring four to six weeks post-infusion and resolving within eight weeks. Serious adverse events are rare but can include myelodysplastic syndrome and respiratory tract infections. Overall, these treatments are well-tolerated, with a significant improvement in progression-free survival and quality of life for many patients.

What prior FDA approvals exist?

The FDA has approved 177Lu-Dotatate (Lutathera) for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in adults. This radiolabeled somatostatin analog delivers targeted radiation to neuroendocrine tumor cells, providing a treatment option for patients with progressive metastatic gastrointestinal NETs. Another related drug is everolimus, which can be considered for patients with progression following somatostatin analog therapy who are not candidates for PRRT (Peptide Receptor Radionuclide Therapy).

What other types of research exist?

Promising novel alternatives to Lutathera for neuroendocrine tumor patients include selective RET inhibitors such as Selpercatinib and Pralsetinib, which have shown efficacy in RET-altered thyroid cancers and other RET-driven malignancies. Additionally, the combination of peptide receptor radionuclide therapy (PRRT) with checkpoint immunotherapy (e.g., PD-1 inhibitors like Nivolumab) is being explored and has shown potential in enhancing treatment response. These alternatives offer targeted approaches that may provide benefits for patients with specific genetic profiles or those who have not responded to traditional therapies.

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Somatostatin Analog

Lutathera for Neuroendocrine Tumors (NETTER-2 Trial)

Phase 3

Waitlist Available

Research Sponsored by Advanced Accelerator Applications

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Karnofsky Performance Score (KPS) ≥ 60

Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, assessed by any of the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization: [68Ga]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT (or MRI when applicable based on target lesions) imaging, [68Ga]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging (e.g. NETSPOT®), Somatostatin Receptor scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan® SPECT/CT), SRS with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging.

Must not have

Hyperkaleamia > 6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment

Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other systemic therapies for GEP-NET administered for more than 1 month or within 12 weeks prior to randomization in the study

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from fpfv until end of study (about 94 months)

Awards & highlights

Pivotal Trial

No Placebo-Only Group

Summary

This trial is testing if a combination of targeted radiation therapy and a hormone-like drug can slow down disease progression in patients with fast-growing gastroenteropancreatic neuroendocrine tumors. The treatment aims to deliver radiation directly to cancer cells while using the hormone-like drug to manage symptoms and slow tumor growth. The study includes patients who have not previously used similar treatments or have used them without their disease getting worse.

Who is the study for?

This trial is for adults and adolescents (15 years or older, over 40 kg) with advanced Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine tumors (GEP-NET), diagnosed within the last 6 months. Participants must have a certain level of tumor cell proliferation (Ki67 index ≥10 and ≤55%), express somatostatin receptors on all target lesions, and have a Karnofsky Performance Score of at least 60. Pregnant women, those unable to use effective contraception, or patients who've had certain prior treatments are excluded.

What is being tested?

The NETTER-2 study tests whether Lutathera combined with long-acting octreotide can extend the time without disease progression in GEP-NET patients compared to high-dose long-acting octreotide alone. It's designed for first-line treatment; some participants may cross over to Lutathera after progression or receive re-treatment.

What are the potential side effects?

Lutathera could cause nausea, vomiting, fatigue, low blood counts leading to increased infection risk or bleeding problems. Kidney damage and liver toxicity are also possible side effects. Long-term risks include secondary cancers due to radiation exposure.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I can care for myself but may need occasional help.

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My scans show my cancer has somatostatin receptors.

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My scans show my cancer has somatostatin receptors.

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I have at least one tumor that can be measured.

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I am 15 years or older and weigh more than 40 kg.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My potassium levels are high and not corrected before joining the study.

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I haven't taken Interferons, Everolimus, chemotherapy, or other systemic therapies for my GEP-NET in the last 3 months.

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My current tumor has grown despite previous treatments.

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I have undergone PRRT treatment before joining this study.

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My kidney function is reduced, with a creatinine clearance below 40 mL/min.

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I have not had any surgery in the last 12 weeks.

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I experience involuntary urine leakage.

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I've had radiation therapy to over a quarter of my bone marrow.

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I have had treatments like radioembolization for my neuroendocrine tumor.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ from fpfv until end of study (about 94 months)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~from fpfv until end of study (about 94 months)

This trial's timeline: 3 weeks for screening, Varies for treatment, and from fpfv until end of study (about 94 months) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Progression Free Survival (PFS) Per Central Assessment

Secondary study objectives

Disease Control Rate (DCR) Per Central Assessment

Duration of Response (DOR) Per Central Assessment

Overall Response Rate (ORR) Per Central Assessment (Key Secondary)

+4 more

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

5Treatment groups

Experimental Treatment

Active Control

Group I: Optional post-progression re-treatment with LutatheraExperimental Treatment1 Intervention

Participants who received Lutathera in experimental arm and who progressed and met re-treatment eligibility criteria received additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles)

Group II: Lutathera® plus Octreotide LAR 30 mg (Investigational arm)Experimental Treatment3 Interventions

Lutathera treatment consisted of a cumulative administered radioactivity of 29.6 GBq (800mCi) (7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 week). Participants in the Lutathera arm were concomitantly administered with octreotide LAR 30 mg (Sandostatin LAR Depot) the day after each administration of Lutathera and no earlier than 4 hours after completion of the Lutathera infusion. Once Lutathera treatment completed, participants continued the 4-week interval administrations of 30 mg octreotide LAR until the completion of the Treatment Phase. Concomitantly with Lutathera, sterile amino acid solution was administered to minimize renal radiation exposure during Lutathera treatment.

Group III: Octreotide LAR 60 mg (Control arm)Active Control1 Intervention

Participants were administered with octreotide LAR 60 mg (Sandostatin LAR Depot) at 4-week intervals until the completion of the Treatment Phase.

Group IV: Optional post-progression cross-over to LutatheraActive Control1 Intervention

Participants who received Octreotide LAR in Active comparator arm and who progressed and met cross-over eligibility criteria received maximum 4 cycles of Lutaathera (7.4 GBq/200 mCi x 4 cycles) plus octreotide long-acting (30 mg every 8 weeks).

Group V: Optional post-progression re-treatment with Lutathera after cross-overActive Control2 Interventions

Participants who received Octreotide LAR in Active comparator arm subsequently entered cross-over, received Lutathera in cross-over, progressed for the second time and met re-treatment eligibility criteria could receive additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles).

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Lutathera

2022

N/A

~90

0 / 14Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Neuroendocrine Tumors (NETs) include radiolabeled somatostatin analogs, such as Lutathera (177Lu-Dotatate), and molecularly targeted therapies like everolimus. Radiolabeled somatostatin analogs work by binding to somatostatin receptors, which are often overexpressed on NET cells, and delivering targeted radiation to destroy these cells while sparing surrounding healthy tissue. This targeted approach is crucial for NET patients as it maximizes tumor cell eradication and minimizes side effects. Everolimus, on the other hand, inhibits the mTOR pathway, which is involved in cell growth and proliferation, thereby slowing tumor growth. These mechanisms are significant for NET patients because they offer effective treatment options that can control tumor progression and improve quality of life.

Neuroendocrine tumor theranostics.