Lu-177 Dotatate Improves Progression-Free Survival in Midgut Neuroendocrine Tumors
In a phase III trial (NETTER-1) reported in The New England Journal of Medicine, Strosberg et al found that the addition of the targeted radiotherapeutic agent lutetium Lu-177 dotatate to octreotide long-acting repeatable (LAR) (Sandostatin LAR) significantly improved progression-free survival vs high-dose octreotide LAR in patients with advanced progressive somatostatin receptor–positive midgut neuroendocrine tumors.
Study Details
In this open-label trial, 229 patients with well-differentiated, metastatic disease from 41 sites (27 in Europe, 14 in the United States) in 8 countries were randomized between September 2012 and January 2016 to receive a total of 4 intravenous (IV) infusions of Lu-177 dotatate (n = 116) given at 7.4 GBq every 8 weeks plus best supportive care including octreotide LAR given intramuscularly (IM) at 30 mg (n = 116) or octreotide LAR alone given IM at 60 mg every 4 weeks (n = 113 patients, control group); in the Lu-177 dotatate group, octreotide was given 24 hours after Lu-177 dotatate infusion and monthly after completion of the 4 infusions.
Patients had to exhibit disease progression on computed tomography or magnetic resonance imaging over the course of ≤ 3 years during treatment with octreotide LAR (20 to 30 mg every 3 to 4 weeks for at least 12 weeks before randomization). Randomization was stratified by the highest tumor uptake score on somatostatin receptor scintigraphy (grade 2, 3, or 4 on the Krenning score) and by the duration over which patients had received a constant dose of octreotide (≤ 6 months or > 6 months).
The primary endpoint was progression-free survival among all randomized patients. Analysis was planned after occurrence of ≥ 74 progression events. A total of 221 patients (111 in the Lu-177 dotatate group, 110 in the control group) received at least 1 dose of study treatment and constituted the safety population.
In the Lu-177 dotatate and control groups, 54% and 47% of patients were male, the mean age was 63 and 64 years, the median time since diagnosis was 3.8 and 4.8 years, the primary tumor site was the ileum in 74% and 73%, the most common sites of metastasis were the liver (84% and 83%) and lymph nodes (66% and 58%), and 61% and 59% had grade 4 somatostatin receptor scintigraphy.
Improved Progression-Free Survival
At the data-cutoff date for the primary analysis (23 events in the Lu-177 dotatate group, 68 in the control group), the estimated rate of progression-free survival at 20 months was 65.2% (95% confidence interval [CI] = 50.0%–76.8%) in the Lu-177 dotatate group vs 10.8% (95% CI = 3.5%–23.0%) in the control group. Median progression-free survival was not reached in the Lu-177 dotatate group vs 8.4 months (95% CI = 5.8–9.1 months) in the control group (hazard ratio [HR] = 0.21, P < 0.001).
The progression-free survival benefit of Lu-177 dotatate was consistent across all subgroups examined, including among patients with (HR = 0.20, 95% CI = 0.12–0.35) and without (HR = 0.15, 95% CI = 0.04–0.50) extrahepatic metastases, male (HR = 0.24, 95% CI = 0.12–0.45) and female patients (HR = 0.17, 95 % CI = 0.08–0.35), age > 65 years (HR = 0.24, 95% CI = 0.12–0.48) and ≤ 65 years (HR = 0.20, 95% CI = 0.10–0.38), somatostatin receptor expression of grade < 4 (HR = 0.23, 95% CI = 0.12–0.41) and grade 4 (HR = 0.18, 95% CI = 0.08–0.39), and European Neuroendocrine Tumor Society grade 2 (HR = 0.15, 95% CI = 0.07–0.34) and grade 1 tumors (HR = 0.24, 95% CI = 0.13–0.44).
Among 201 patients evaluable for tumor response, response was observed in 18% of the Lu-177 dotatate group vs 3% of the control group (P < .001). In a preplanned interim analysis of overall survival, there were 14 deaths in the Lu-177 dotatate group and 26 deaths in the control group (HR = 0.40, P = .004).
Toxicity
The most common adverse events of any grade in the Lu-177 dotatate group were nausea (59% vs 12% in the control group), vomiting (47% vs 10%), fatigue/asthenia (40% vs 25%), diarrhea (29% vs 19%), and musculoskeletal pain (29% vs 20%). Most cases of nausea and vomiting in the Lu-177 dotatate group were attributed to amino acid infusions given concurrently with drug infusion. Grade 3 or 4 adverse events occurred in 41% vs 33%; the most common in the Lu-177 dotatate group were lymphopenia (9% vs 0%), vomiting (7% vs 1%), and nausea (4% vs 2%). Grade 3 or 4 neutropenia and thrombocytopenia occurred in 1% and 2% of the Lu-177 dotatate group vs 0% of the control group.
Adverse events led to discontinuation of treatment in 6% vs 9% of patients. One patient in the Lu-177 dotatate group had histologic changes consistent with myelodysplastic syndrome that were considered possibly related to study treatment. No cases of renal toxicity were observed in patients receiving Lu-177 dotatate.
The investigators concluded: “Treatment with Lu-177 dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the Lu-177 dotatate group.”
The study was funded by Advanced Accelerator Applications.
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