Efficacy of 177Lu-Dotatate Induction and Maintenance Therapy of Various Types of Neuroendocrine Tumors: A Phase II Registry Study

Abstract

Peptide receptor radionuclide therapy (PRRT) has been recently established as a treatment option for progressive gastro-entero-pancreatic neuroendocrine tumors (NETs) including four 200 mCi induction cycles. The purpose of this phase 2 trial is to expand use of PRRT to different types of NETs with the application of dose adjustment and evaluate value of maintenance therapy in patients who had disease control on induction therapy. Forty-seven PRRT naïve NET patients with different primary origin received ¹⁷⁷Lu-DOTATATE induction therapy, ranging from 75 to 150 mCi per cycle, based on patients' clinical status such as liver and renal function, extent of metastases, and previous therapies. Thirty-four patients underwent additional maintenance therapy (50-100 mCi per cycle) following induction course until they developed disease progression. The estimated median progression-free survival (PFS) was 36.1 months. The median PFS in our MNET subgroup was 47.7 months, which is markedly longer than NETTER-1 trial with median PFS of 28.4 months. The median PFS was significantly longer in patients who received PRRT as first-line treatment after disease progression on somatostatin analogs compared to patients who received other therapies first (p-value = 0.04). The total disease response rate (DRR) and disease control rate (DCR) was 32% and 85% based on RECIST 1.1 and 45% and 83% based on Choi criteria. This trial demonstrates longer PFS with the addition of low dose maintenance therapy to induction therapy compared to NETTER-1 trial that only included induction therapy. Also, we observed considerable efficacy of PRRT in various types of advanced NETs.

Keywords: DOTATAE; Lu-177; NET; PRRT; neuroendocrine tumor; peptide receptor radionuclide therapy.

Figure 1

Swimmer plot representing the total number of cycles and cumulative dose for each patient. SD = stable disease. PR = partial response.

Figure 2

The overall survival did not reach median. The median progression free survival was 36.1 months.

Figure 3

Overall survival (OS) and Progression-free survival (PFS) based on tumor types. The median OS was significantly longer in patients with midgut neuroendocrine tumors (NETs) (p-value = 0.039). Estimated median PFS was 47.7 months in midgut NETs, 36.5 in pancreatic NETs, and 23.9 months in other types of NETs, which the difference was not statistically significant (p-value = 0.35).

Figure 4

The median PFS was markedly longer in patients who received peptide receptor radionuclide therapy (PRRT) as first therapy post disease progression/metastases, measuring 48.9 months compared to 25.5 months in the other group (p-value = 0.04).

Figure 5

Primary pancreatic neuroendocrine tumor with metastases to liver, lymph nodes and bones. (A). Selected axial ¹⁷⁷Lu-DOTATATE SPECT/CT image post first cycle of therapy shows multi-focal uptake in iliac bones. (B). Selected axial CT image before therapy shows no corresponding osseous lesion. (C). Selected axial ¹⁷⁷Lu-DOTATATE SPECT/CT post fourth cycle of therapy shows persistent uptake at the similar locations. (D). Selected axial CT image after fourth cycle of therapy demonstrates sclerotic changes in the right iliac bone posteriorly and pathologic fracture and underlying sclerotic changes in the wing of right iliac bone.