In NETTER-2, phase III study, patients with newly diagnosed higher grade 2–3, somatostatin receptor-positive, metastatic, gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) had significant benefit from radioligand therapy. The study met its primary objective, with ¹⁷⁷Lu-Dotatate plus octreotide 30 mg long-acting repeatable (LAR) reducing the risk of disease progression or death by around 72% compared with high-dose octreotide 60 mg LAR. Consistent benefit was observed across all subgroups, including grade 2–3 NETs, and pancreatic as well as non-pancreatic primary origin. The objective response rate was one of the highest reported in the literature, 43.0% with ¹⁷⁷Lu-Dotatate plus octreotide 30 mg LAR compared with 9.3% for octreotide 60 mg LAR.
No new safety concerns were observed. One case of myelodysplastic syndrome was observed in the ¹⁷⁷Lu-Dotatate group. However, the follow-up time was limited at the time of primary analysis; long-term safety follow-up and data collection on secondary haematological malignancies are ongoing. The study findings are published by Dr. Simron Singh of the University of Toronto, Sunnybrook Odette Cancer Centre in Toronto, ON, Canada and colleagues on 5 June 2024 in The Lancet.
GEP NETs are classified by World Health Organization (WHO) into grades according to mitotic index, differentiation status and Ki67 proliferative index, which translates into aggressiveness. For patients with advanced disease, few treatment options exist, but include somatostatin analogues, targeted therapy, chemotherapy, and peptide receptor radionuclide therapy (PRRT). Furthermore, the change in the WHO grade 3 classification into well and poorly differentiated tumours makes the current optimal treatment for well differentiated grade 3 GEP NETs undefined.
Radioligand therapy delivers cytotoxic radiation directly to the tumour and, unlike most other systemic therapies, adverse events are generally minimal. ¹⁷⁷Lu-Dotatate is a ¹⁷⁷Lu-labelled somatostatin analogue that binds to somatostatin receptors, which are highly expressed in NETs. The groundbreaking phase III NETTER-1 study established the efficacy and safety of ¹⁷⁷Lu-Dotatate plus octreotide 30 mg LAR for the treatment of patients with advanced somatostatin receptor-positive grade 1 or grade 2 midgut NETs who had progressed on somatostatin analogues.
Although somatostatin analogues have been used as first-line treatment for advanced grade 1–2 GEP NETs (Ki67 <10%) following the phase III PROMID and CLARINET studies, such robust data do not exist for higher grade 2 tumours (Ki67 ≥10%) or grade 3 well-differentiated NETs. Historically, high-grade neuroendocrine neoplasms were universally described as poorly differentiated and often thought to be similar to small-cell malignancies. In 2017, grade 3 well-differentiated NETs were formally recognised by WHO as a distinct entity from the poorly differentiated neuroendocrine carcinomas. There is a paucity of high-quality evidence with respect to GEP NET treatments, especially for higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%) in the first-line setting.
The phase III NETTER-2 study aimed to investigate whether 177Lu-Dotatate plus octreotide 30 mg LAR, at the same dose and schedule as established in the NETTER-1 study, would prolong progression-free survival (PFS) compared with high-dose octreotide 60 mg LAR, in patients with newly diagnosed, advanced higher grade 2–3, well-differentiated GEP NETs.
NETTER-2 was an open-label, randomised, parallel-group, superiority, phase III study. The study investigators enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced GEP NETs from 45 centres across 9 countries in North America, Europe, and Asia. They used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg LAR then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by NET grade (2 versus 3) and origin (pancreas versus other).
Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was PFS by blinded, independent, central radiology assessment. The primary analysis was done at 101 PFS events as the final PFS analysis. NETTER-2 is active and not recruiting.
Between 22 January 2020 and 13 October 2022, the study investigators screened 261 patients, 35 (13%) of whom were excluded. They randomly assigned 226 patients, of whom 151 (67%) to the 177Lu-Dotatate group and 75 (33%) to the control group. Median PFS was 8.5 months (95% confidence interval [CI] 7.7–13.8) in the control group and 22.8 months (19.4–not estimated [NE]) in the 177Lu-Dotatate group (stratified hazard ratio 0.276 [0.182–0.418]; p < 0.0001).
For responders to ¹⁷⁷Lu-Dotatate group, the median duration of response was 23.3 months (18.4–NE). The disease control rate also favoured the ¹⁷⁷Lu-Dotatate group (90.7% versus 66.7%). Time to deterioration in quality-of-life showed no significant difference between groups. At the time of the primary analysis, the median overall survival (OS) had not yet been reached for either group, but no difference in OS was observed between the treatment groups at follow-up. The authors noted that by the cut-off date, 36 of 75 patients (48%) in the high-dose octreotide group had crossed over to the ¹⁷⁷Lu-Dotatate group. This finding is likely to confound the OS results, but will be reported in a future analysis.
During the treatment period, adverse events (AEs) of any grade occurred in 136 of 147 treated patients (93%) in the 177Lu-Dotatate group and in 69 of 73 treated patients (95%) in the control group. The most common (≥20%) AEs in both groups were nausea, diarrhoea, and abdominal pain. More patients in the ¹⁷⁷Lu-Dotatate group had AEs of grade 3 or worse (35% versus 27%). There were no study drug-related deaths during the treatment period.
First-line 177Lu-Dotatate plus octreotide LAR significantly extended median PFS by 14 months in patients with grade 2 or 3 advanced GEP NETs. 177Lu-Dotatate should be considered a new standard-of-care in first-line treatment in this population. The significant improvement in PFS and response with 177Lu-Dotatate plus octreotide LAR compared with somatostatin analogues alone was observed across tumour site and grade and will have clinical practice changing implications in support of first-line radioligand therapy as standard of care for advanced higher grade 2 and grade 3, well-differentiated, GEP NETs.
In an accompanied comment, Drs. Robert A. Ramirez and Cathy Eng of the Division of Hematology and Oncology, Vanderbilt University Medical Center in Nashville, TN, US wrote that although the results of NETTER-2 are impressive, many questions remain as to how to sequence subsequent therapy and if all patients with high grade 2–3 tumours should be treated with ¹⁷⁷Lu-Dotatate in the first-line setting. This especially holds true for patients with grade 2 disease as there are several other prospective trials with agents that also show efficacy.
Additionally, patients with grade 2 disease with relatively asymptomatic low volume of disease might choose an alternative option that does not increase risk for myelodysplastic syndrome as is seen with ¹⁷⁷Lu-Dotatate. For patients with grade 3 NETs, the choice of upfront ¹⁷⁷Lu-Dotatate might be clearer given the studies using aforementioned agents excluded patients with grade 3 disease.
Other questions arise as to whether octreotide LAR was the best comparator. The phase II OCLURANDOM study used a control group of patients who received sunitinib, which does have prospective data in grade 1–2 pancreatic NETs. The ongoing phase III COMPOSE study is using ¹⁷⁷Lu-Edotreotide in patients with well-differentiated NETs that are either aggressive grade 2 (Ki67 15–20%) or grade 3 (Ki67 >20% to ≤55%) with a control group of either folinic acid, fluorouracil, plus oxaliplatin; capecitabine and temozolomide; or everolimus. The results of COMPOSE might help clarify whether chemotherapy or PRRT should be used in this setting.
To date, the NETTER-2 study demonstrates the best evidence for the consideration of ¹⁷⁷Lu-Dotatate with octreotide LAR in patients with higher grade 2–3, inoperable, well-differentiated NETs. The data from NETTER-2 add to evidence that early molecular imaging could help optimise treatment selection and sequencing for patients with somatostatin receptor-positive primary tumours of GEP origin. NETTER-2 is the first phase III study to report results for radioligand therapy administered first-line to patients in any cancer population. It is also the first randomised study of any therapy for patients with grade 3 well-differentiated GEP NETs.
The study was funded by Advanced Accelerator Applications, a Novartis Company.
References
- Singh S, Halperin D, Myrehaug S, et al. on behalf of all the NETTER-2 Trial Investigators. [¹⁷⁷Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2–3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. The Lancet; Published online 5 June 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00701-3
- Ramirez RA, Eng C. The developing role of theranostics in NETs. The Lancet; Published online 5 June 2024. DOI: https://doi.org/10.1016/S0140-6736(24)00851-1