Jonathan R. Strosberg, MD

In the phase III NETTER-1 trial reported in The New England Journal of Medicine, Jonathan R. Strosberg, MD, of the Moffitt Cancer Center in Tampa, Florida, and colleagues found that the addition of the targeted radiotherapeutic agent lutetium Lu-177 dotatate to the long-acting repeatable (LAR) formulation of octreotide (Sandostatin LAR) significantly improved progression-free survival vs high-dose octreotide in patients with advanced progressive somatostatin receptor–positive midgut neuroendocrine tumors.¹

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 highest tumor uptake score on somatostatin receptor scintigraphy (grade 2, 3, or 4 on the Krenning scale) 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 at least 74 progression events. A total of 221 patients (111 in the Lu-177 dotatate group, 110 in the control group) received ≥ 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, mean age was 63 and 64 years, median time since diagnosis was 3.8 and 4.8 years, 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 < .001). 

The progression-free survival benefit of Lu-177 dotatate was consistent across all subgroups examined, including among patients with extrahepatic metastases (HR = 0.20, 95% CI = 0.12–0.35) and those without extrahepatic metastases (HR = 0.15, 95% CI = 0.04–0.50), 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 ¹⁷⁷Lu-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.” ■

Disclosure: The study was funded by Advanced Accelerator Applications. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Strosberg J, El‑Haddad G, Wolin E, et al: Phase 3 trial of ¹⁷⁷Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med 376:125-135, 2017.