Dual-tracer PET/CT and cocktail therapy with [¹⁷⁷Lu]Lu-FAP2286 and [¹⁷⁷Lu]Lu-DOTATATE in G3 Neuroendocrine Tumors (NET).

Abstract

BACKGROUND: There remains an unmet need for G3 neuroendocrine tumor (NET) treatment, and the therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) is suboptimal. PURPOSE: To investigate the feasibility and efficacy of cocktail therapy, combining co-administered [177Lu]Lu-Fibroblast activation protein (FAP) 2286 and [177Lu]Lu(lutetium)-(DOTA0, Tyr3) octreotide ([177Lu]Lu-DOTATATE), in eligible patients with G3 NET screened by dual-tracer PET/CT. METHODS: This single-center prospective study enrolled adults with histologically confirmed G3 NET (Ki67 ≥20%). Participants underwent dual-tracer PET/CT with [68Ga]Ga(gallium)-DOTATATE and [68Ga]Ga-FAP2286. Based on imaging findings, eligible participants received cocktail therapy combining co-administered [177Lu]Lu-FAP2286 and [177Lu]Lu-DOTATATE with a total dose of approximately 7.4 GBq per cycle. Imaging response was assessed by Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST1.0), clinical response by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), and adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE v5.0). RESULTS: Total 23 patients (15 males, aged 52 [37-66] median [IQR]) were enrolled and 7 received 2–6 cycles of cocktail therapy. For liver metastases, [68Ga]Ga-FAP2286 exhibited a higher sensitivity (82% vs 62%) and TBRliver (4.7±2.0 vs 2.9±2.3) compared to [68Ga]Ga-DOTATATE (P=0.036). According to PERCIST 1.0, 5 participants achieved a partial metabolic response, yielding an objective response rate of 71%. The 1-year survival rate was 86%, with median overall survival and progression-free survival both exceeding 15 months. Furthermore, 71% of participants experienced an improvement in global health status. The therapy was well-tolerated, with no treatment-related deaths or Grade 3/4 adverse events. CONCLUSION: In conclusion, this prospective study demonstrates that dual-tracer PET/CT effectively identifies G3 NET patients suitable for subsequent cocktail targeted radionuclide therapy. The subsequent cocktail therapy of [177Lu]Lu-FAP2286 and [177Lu]Lu-DOTATATE yielded promising efficacy and safety profile. This theranostic approach represents a promising strategy for treating G3 NET.