Radioligand Theranostics in the Management of Neuroendocrine Tumors

Radioligand theranostics (RT) in nuclear oncology and cancer therapy embodies the concept of an evolving individualized therapeutic approach with a focus more on molecular features rather than the organ of tumor origin. This precision therapeutic approach also focuses on the use of cancer-type specific biomarkers and molecular imaging—using PET-CT (positron emission tomography-computed tomography), SPECT (single photon emission computed tomography), MRI (magnetic resonance imaging), and gamma camera—for patient selection and directing appropriate radionuclide therapy. This editorial provides a brief history of diagnostics and therapies to the present time, a discussion on current modalities, and proposes new future regimens, involving the use of RT in combination with immunotherapies. It also suggests a multidisciplinary team approach to optimize access and delivery of care to patients with NETs, as well as providing more comprehensive treatment and less morbidity and improved outcomes.

Neuroendocrine tumors (NETs), also previously referred to as APUDomas (amine precursor uptake and decarboxylation), represent a constellation of diverse neoplasms most commonly, but by no means exclusively, arising in the gastrointestinal (GI) tract and lungs.^1,2 We as endocrinologists and oncologists recognize the challenge of early, accurate diagnosis of patients with NETs because of the wide spectrum of non-specific symptoms exhibited by patients.³ Thus, definitive diagnosis and appropriate treatment of NET may take 5–7 years from the time of initial symptom presentation, by which time the primary neoplasm likely has reached an advanced stage and multiple distant metastases are evident.⁴ As noted in a practical guidance article by these authors and other international experts, treatment of these generally indolent NETs varies according to primary tumor site, tumor differentiation and grade, and stage.⁵

Surgical extirpation or cytoreduction of NETs, if feasible, continues to be the treatment of choice and is associated with the best long-term overall survival and control of symptoms.^5,6 However, we typically find that recurrence after resection is common and additional therapeutic modalities are therefore indispensable. Furthermore, widely dispersed metastatic disease necessitates the utilization of systemic therapies such as peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogues.⁵

As readers may recall, somatostatin was first described by Paul Brazeau, Wylie Vale, Roger Burgus, Nicholas Ling, Madalyn Butcher, Jean Rivier, and Roger Guillemin in 1973⁷ and, over the past half century, this hormone/neurotransmitter has played a seminal role in the management of NETs.^8,9 Somatostatin binds to all five identified specific somatostatin receptors (SSTR 1—5) and mediates a plethora of inhibitory physiologic actions in the GI tract, pancreas, and pituitary. Somatostatin itself is short-lived in the circulation, but this limitation of clinical usefulness was obviated by the synthesis of biologically stable, long-acting somatostatin analogues with high affinity for the most important SSTR-2. The first somatostatin analogue was octreotide, whose clinical development was shepherded by these authors and many other investigators.

As many as 90% of gastroenteropancreatic neuroendocrine tumors (GEP NETs) display membrane receptors for somatostatin (primarily SSTR-2).^{10, 11} Unlabeled somatostatin analogues like octreotide represent an effective and integral treatment modality to inhibit hormone secretion of functional and non-functional NETs as well as attenuating tumor growth.^12,13 The clinical development of octreotide laid the foundation for the subsequent development of PRRT with LUTATHERA®, as discussed in detail below. We believe, and have discussed here, that one of the most impactful developments in NET diagnosis and treatment involves the amalgamation of molecular imaging and targeted treatment using radioisotope-labelled octreotide, a general concept broadly referred to as RT, as initially coined by Rosch and Baum in 2011.¹⁴

We should point out, however, that the fundamental principle of theranostics is not new; indeed, the oldest application dates back to Saul Hertz in the 1940s, who pioneered the use of iodine 131 (I 131) combined with I 130 to diagnose and treat patients with Graves’ disease and papillary/follicular thyroid cancer.¹⁵ More recently, a renaissance in radiopharmaceutical development has occurred. The use of a single compound as both a diagnostic and therapeutic agent is now slowly emerging in the United States (US) as a new paradigm of NET therapy with the potential to achieve impressive tumor control with minimal toxicity as well as improve quality of life and prolong survival. The RT paradigm focusses on an individual’s specific disease subtype and genetic profile to enable optimization of drug efficacy and safety. In contrast, the “hit and miss” and “one medicine fits all” approaches of cytotoxic chemotherapy and other therapies (immunotherapy, antibody drug conjugate therapy), expose the patient to potentially severe toxic side effects (both reversible and irreversible) regardless of whether these agents achieve meaningful therapeutic benefit in individual patients.

It is clear to us that RT represents a major step forward in personalized cancer therapy and ensures only patients whose tumors (primary and often unknown metastases) have the desired marker (identified by the diagnostic compound) will subsequently receive the corresponding targeted therapeutic agent.¹⁶ RT essentially involves the use of nanoscience to coalesce diagnostic and therapeutic applications to create a single agent for the diagnosis, drug delivery, and treatment-response monitoring of NETs. A linker molecule such as a somatostatin analogue is conjugated to appropriate chelators, including DTPA (diethylene-triamine-pentaacetate) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), that accommodate radioisotopes either for diagnosis (e.g., Gallium 68 [Ga 68] or Indium 111 [In 111]) or therapy (e.g., Lutetium 177 [Lu 177] or Yttrium 90 [Y 90]).¹⁷

In June 2016, the US Food and Drug Administration (FDA) approved Netspot™ (Advanced Accelerator Applications USA Inc, Millburn, NJ), the first kit for the preparation of Ga 68-DOTATATE (DOTA-0-Tyr3-Octreotate) injection for PET/CT of somatostatin receptor-positive NETs and, in January 2018, approved LUTATHERA® (Lu 177 DOTATATE) injection for the treatment of somatostatin receptor-positive GEP-NETs in the foregut, midgut, and hindgut in adults. More recently, in August 2019, the FDA approved Ga 68 DOTATOC (DOTA -Phe -Tyr octreotide) injection, developed by University of Iowa Health Care (UIHC) PET Imaging Center in Iowa, for PE) imaging of SSTR-positive gastroenteropancreatic neuroendocrine tumors.¹⁸

LUTATHERA comprises DOTA-0-Tyr3-Octreotate, which is in turn linked to a radionuclide (Lu 177). LUTATHERA binds with greatest affinity to SST-2 receptors on the cell membrane of GEP-NET cells and is subsequently internalized within tumor cells. Thereafter, somatostatin receptor-positive cells and their immediate neighboring cells are damaged through the formation of free radicals induced by the beta emission from Lu 177.

We should note that these agents have been clinically available in Europe for some time but it is only recently that the US has begun to embrace this technology. The development and subsequent approval of LUTATHERA as the standard of care for metastatic, low-grade NETs exemplifies a successful collaboration between academia and industry, both in basic science and clinical research, of which we collectively have played a pivotal role over the years.

In order to appreciate the history underpinning the development and most recent FDA approvals of Ga 68 DOTATOC/DOTATATE and Lu 177 DOTATATE, we must go back in time to the early 1980s (Fig. 1).^18–29 The nidus for development of these companion RT products was the synthesis of octreotide (Sandostatin®) by Bauer and colleagues at Sandoz (now Novartis, East Hanover, NJ).²⁰ This was followed shortly afterwards by the visualization of octreotide-specific binding sites using an autoradiography technique^{21, 30} and subsequent development of scintigraphic imaging using I 123-labelled Tyr3-octreotide.²⁴ The investigators who pioneered this new imaging technique are shown posing for a photograph taken at Erasmus University Rotterdam, The Netherlands, in 1987 (Figure 2).

FIGURE 1.

A timeline of the development of PRRT and theranostics beginning with the use of ¹³¹I combined with ¹³⁰I to diagnose and treat patients with thyroid cancer.

FIGURE 2.

Historic photograph of the first ever visualization of somatostatin receptor bearing tumors in a rat using In 111-DTPA-D-Phe-octreotide pioneered by Eric Krenning and Steven Lamberts, taken at Erasmus University Rotterdam, The Netherlands, in 1987 with members of the SANDOZ (Novartis) research team. From left to right: Peter Marbach, Jean Pierre Lalain, Eric Krenning, Steven Lamberts, Willem Bakker (glasses), Alan Harris, Christian Bruns, Viktor Boerlin, Pieter Van Roon. Kneeling left to right Wout Breeman, Ana Bijlstra (back), Peter Kooy. (Photograph courtesy of V Boerlin MD, ©Alan G Harris.

Krenning et al were the first to report the use of In 111-labelled DTPA attached to octreotide as both an imaging and therapeutic agent in a single patient.²⁵ These investigators showed that In 111-DTPA-D-Phe-1-octreotide resulted in a high degree of diagnostic accuracy in a variety of tumor types: 86% of carcinoids, 89% of neuroblastomas, 86% of pheochromocytomas, 94% of paragangliomas and 80% of PNETs.³¹ Since then, somatostatin receptor imaging utilizing Lu-177-DOTATATE (Lu 177-DOTA-Tyr3-octreotate) in combination with SPECT and CT substantially improved sensitivity and specificity and led to the first FDA and EMA (European Medicines Agency) radiopharmaceutical for PRRT.³²

We should highlight that the most recent enhancement in somatostatin receptor-based imaging employs the positron emitter Ga 68 to label various somatostatin analogues in order to locate NETs using a PET/CT scan.³³ Octreotide or octreotate (which possesses greater SSR-2 affinity) is linked to Ga 68 by means of the chelator DOTA and gives rise to several versions of approved imaging modalities, including Ga 68-DOTATOC and Ga 68-DOTATATE.³³ Utilization of the Ga 68 isotope allows for faster image acquisition and superior spatial resolution, compared with previous radioisotopes.³³ We now recognize that somatostatin receptor-based imaging has evolved into a critical component in the diagnosis and work up of patients with NETs and allows the entire body to be examined for metastases in a single session. There is general agreement among practitioners that the clinical indications for this type of imaging are multifaceted and include: anatomically locating primary NETs as well as distant metastases, optimizing disease staging, appropriately identifying patients for subsequent PRRT, and performing post-treatment follow ups to screen for disease relapse.³³

The first randomized Phase 3 trial utilizing Lu 177 DOTATATE to treat patients with progressive midgut NETs was the Neuroendocrine Tumors Therapy (NETTER-1) study, published in the New England Journal of Medicine in 2017.²⁹ This trial enrolled patients with midgut NETs that had metastasized or were locally advanced or inoperable and had progressed despite treatment with long-acting octreotide. Eligible patients (n = 229) were randomized to receive either Lu 177 DOTATATE (four treatments every 8 weeks, with a maximum cumulative dose of 29.6 GBq) combined with standard dose of octreotide (30 mg IM [intramuscular] every 4 weeks) or high-dose octreotide (60 mg every 4 weeks). Patients in each arm were followed for up to 5 years. Although we recognize that definitive evidence of an overall survival benefit will have to wait until the final data analysis, an interim analysis showed that subjects receiving LUTATHERA (vs high-dose octreotide) had a 79% significantly lower risk of disease progression or death (hazard ratio, 0.21; 95% CI, 0.13—0.33, P < 0.001). The study showed no evidence of renal toxicity and low rates of Grade 3 or 4 hematologic effects when Lu 177 DOTATATE was administered with a renal protective agent (amino acid solution). Adverse events occurred at a significantly (P < 0.001) higher incidence in the Lu 177 DOTATATE group (vs active control group) included nausea (59% vs 13%), vomiting (47% vs 10%), thrombocytopenia (25% vs 1%), and lymphopenia (18% vs 2%).

Interestingly, as reported in 2017 by Fani and colleagues, Lu 177 somatostatin antagonists may offer the opportunity to deliver a greater dose of absorbed radiation to NETs even though these agents are not internalized within tumor cells (in contrast to Lu 177-DOTA-octreotate agonists).³⁴ A recent study by Krebs and colleagues evaluated the use of a novel somatostatin antagonist Ga 68-DOTA-JR11 for PET imaging of advanced NETs.³⁵ The authors found that Ga 68-DOTA-JR11 was rapidly taken up by tumors with a high tumor/background ratio and a low liver background, a finding that may be beneficial in identifying liver metastases. Further, a number of antagonist molecules, in addition to those binding to G-protein coupled receptors, are in the early stages of clinical development.

These authors believe that a likely progression of the RT model of NET management will involve the utilization of new radioisotopes and new targeting agents beyond DOTATOC and DOTATATE. Radionuclides are unstable atoms that become stable by emitting radiation such as alpha particles, beta particles, or electromagnetic radiation (X-rays and gamma rays) or combinations thereof, each with differing deposition of energy in tissues along the track travelled (linear energy transfer [LET]). Targeted radionuclide therapy has historically focused on the use of beta-emitters but recent studies suggest that alpha emitters may potentially be more effective theranostic radioisotopes due to preferred dose deposition within the cell nucleus.³⁶ Beta emitters, such as Lu 177 and Y 90, and positron emitters (beta plus decay) such as Ga 68, have an average path length in the range of μm to mm resulting in damage to adjacent cells and normal tissues (referred to as a cross-fire effect) and whose energy deposition may be insufficient to cause tumor cell death.³⁷ In contrast, alpha emitters (e.g., Astatine 211 [At 211] and lead 212 [Pb 212]) give rise to densely ionizing radiation that travels shorter distances in tissue (nm to μm) and delivers high-energy radiation to a single cell, particularly within the cell nucleus, with minimal cross-fire effects and less impact on normal tissues.

We cannot stress enough that RT of NETS has far-reaching therapeutic implications and paved the way for the development of treatments for other cancer types.^17,38 This includes, for example, pancreatic and liver carcinoma, multiple myeloma, leukemia, non-Hodgkin lymphoma, and metastatic castrate-resistant prostate cancer (mCRPC) as well as advanced (Grade 3) NETs, which often do not express SST-2 receptors and fail to respond well to Lu 177 or Y 90-DOTATOC or DOTATATE.³⁹ In a recent prospective single-arm study of mCRPC patients with progressive disease on second-line hormonal therapy and/or docetaxel chemotherapy, Lu 177-PSMA (prostate specific membrane antigen)-617 resulted in a disease control rate (assessed by radiographic and molecular responses) of 71% at the end of assessment (median duration 28 months), with a median overall survival of 14 months and median progression-free survival of 11.8 months.⁴⁰ Further, a recent expansion of the theranostic concept involves the cytokine receptor CXCR4 present in patients with neuroendocrine carcinoma, multiple myeloma, and leukemia. An antagonist to the CXCR4 receptor (pentixifor) can be coupled to the DOTA chelator to generate a theranostic pair: Ga 68-pentixifor for imaging and Lu 177-pentixifor for therapy.³⁹ However, we recognize that the clinical usefulness of this approach may be impacted by the potential for bone marrow toxicity. Each of these targeted agents is likely to be radiolabeled with an alpha emitter such as Pb 212 or At 211 in the coming months with keen observation needed regarding the normal organs of limiting toxicity for each target-radionuclide combination.

Finally, we would like to speculate on the future of RT in nuclear oncology and cancer therapy. We believe that individualized therapy of tumors will undoubtedly continue to evolve and focus more on molecular features (e.g., SSTR or PSMA expression) rather than the organ of tumor origin. This personalized, precision therapeutic approach will focus on the use of cancer-type specific biomarkers and molecular imaging (using PET, SPECT, MRI, gamma camera) for selecting patients and directing appropriate radionuclide therapy. We also expect that individualized therapy will likely include radionuclide agents targeting various enzymatic pathways, cell surface receptors, and clonal variations as well as include combinations of alpha- and beta-emitters to take advantage of different energy levels, path lengths, and bystander effects. New combination regimens providing more comprehensive treatment and less morbidity and improved outcomes may involve the use of RT in combination with immunotherapies (e.g., PD-1/PD-L1 [programmed death-ligand 1/programmed death-ligand 1] and CTCL-4 [cytotoxic T-lymphocyte–associated antigen 4] immune checkpoint inhibitors), mammalian target of rapamycin (mTOR) agents (e.g., everolimus), and cytotoxic chemotherapy (e.g., streptozotocin, capecitabine, and temozolomide). In light of the multiple facets of RT, we can visualize a multidisciplinary team approach to optimize access to and delivery of care to patients with NETs, and, most importantly, improve clinical outcomes and quality of life.