As radiopharmaceutical therapy (RPT) expands beyond neuroendocrine tumors and prostate cancer, it is important to understand the U.S. Food and Drug Administration (FDA) approval process and to establish a shared vocabulary for effective communication. The 505(b)(2) New Drug Application is a well-established mechanism for FDA approval of nuclear medicine products. It is an application for drugs that are similar to an approved product, supported by published literature and studies conducted on similar drugs, and bridging studies demonstrating the scientific relevance of the data to the product. This streamlined approval pathway can encourage development of more treatment options, facilitating greater patient access and improved resilience to supply chain disruptions. The evolving RPT landscape necessitates new nomenclature. "Radioligand equivalent" refers to an RPT approved through the 505(b)(2) pathway, distinct from a generic RPT approved through an Abbreviated New Drug Application. Establishing shared terminology supports clear multidisciplinary communication and fosters informed treatment selection.

Neuroendocrine tumors (NETs) are rare, heterogeneous neoplasms with varying prognoses and management approaches. Peptide receptor radionuclide therapy (PRRT), targeting tumors expressing somatostatin receptors, delivers cytotoxic radiation to tumor cells. While PRRT has demonstrated efficacy in advanced, well-differentiated NETs, the optimal sequencing with other therapies remains an area of active research. This review explores PRRT’s role in NET management, focusing on its mechanisms, clinical efficacy, safety profile, and integration into a multi-modal treatment strategy. We also examine evidence on the sequencing of PRRT with surgery, liver-directed therapy, chemotherapy, and targeted therapies to optimize treatment outcomes. We conducted a comprehensive review of recent clinical trials, cohort studies, and expert consensus guidelines to assess PRRT’s place in the treatment paradigm. Factors influencing treatment sequencing, such as tumor type, receptor expression, disease burden, and patient-specific characteristics, are also discussed. PRRT has proven effective for patients with advanced, somatostatin receptor-positive NETs, especially for inoperable tumors or those progressing after other therapies. While PRRT plays a vital role in management, its sequencing with other treatments remains complex, with evidence supporting its use both early and late in treatment based on individual patient factors. Optimizing its sequencing with other treatments requires further research but offers potential for improved outcomes. A personalized, multidisciplinary approach is essential for maximizing PRRT’s benefits in NET management. This review article summarizes current evidence and describes patient-specific circumstances, enabling treatment provider to make informed PRRT sequencing decisions.

Purpose: The next generation of theranostics studies is looking at novel combinations with radiation sensitizers to enhance peptide receptor radionuclide therapy’s efficacy. In this study, we present safety and efficacy data from a multicenter phase I study of a [177Lu]lutetium-dotatate–triapine combination in patients with gastroenteropancreatic (GEP) neuroendocrine tumors (NET). Patients and Methods: The study consisted of 2 phases (part A: dose escalation; part B: dose expansion) administering the recommended phase II doses (RP2D) for the 2 agents. All patients received 200 mCi of [177Lu]lutetium-dotatate on day 1 of four 8-week cycles, in combination with oral triapine administered at assigned dose levels (100, 150, or 200 mg) from day 1 to day 14 of each cycle. Results: A total of 31 (A: 15; B: 16) patients received treatment. Across the study, 9 patients experienced dose-limiting toxicities: grade 3 anemia (n = 1), grade 5 cardiac arrest (unrelated to investigational product; n = 1), and grade 4 neutropenia (n = 7). Based on the overall safety and pharmacokinetics data, a [177Lu]lutetium-dotatate (200 mCi) plus triapine (150 mg) dose was selected as the RP2D for the expansion phase. Grade ≥3 treatment-related adverse events were observed in 77% of patients: anemia (23%), nausea and vomiting (3%), lymphopenia (58%), neutropenia (35%), and decreased white blood cell count (39%). The majority of cytopenias were transient and resolved within 2 weeks. Among the 28 evaluable patients, the objective response rate was 21.4%, and the median progression-free survival has not been reached (median follow-up period, 23.7 months). Conclusions: The combination of [177Lu]lutetium-dotatate (200 mCi) and oral triapine (150 mg D1-14) was well tolerated and demonstrated preliminary activity in patients with well-differentiated GEP-NET (NCT04234568).

Targeted radionuclide therapy (TRT) is an emerging modality in oncology that delivers internal radiation specifically to tumor sites. It typically consists of a particle-emitting radionuclide, a linking complex with a chelator for securely binding radionuclides to targeting molecules, and a binding moiety of targets expressed on tumor cells. Early clinical results have been promising, with several TRT agents approved for treating various cancers, including prostate cancer and gastroenteropancreatic neuroendocrine tumors, or their microenvironment. However, most patients eventually relapse following TRT monotherapy, leaving room to further improve patient outcomes. Combination strategies could be beneficial to improve therapeutic index, enhance cytotoxic effects, or modulate tumor target expression; promising preclinical data have led to early-phase clinical trials. This review provides a concise overview of physical and chemical properties of commonly used β- and α-emitting radionuclides and a forward-looking rationale for combination regimens of TRT and other therapeutic modalities, such as hormone therapy, DNA damage repair inhibitors, immunotherapy, chemotherapy, external beam radiotherapy, and other combinations. We discuss the preclinical rationale, available clinical data, and ongoing key clinical trials with TRT combination therapy. Additionally, we highlight future perspectives including emerging radionuclides and prognostic and predictive biomarkers to optimize TRT combination therapy.

Normalized exposure matrix from Sigminer

Representativeness of study participants