High-specific-activity ¹³¹iodine-metaiodobenzylguanidine for therapy of unresectable pheochromocytoma and paraganglioma

Abstract

Pheochromocytomas and paragangliomas (PPG) are rare cancers arising from the adrenal medulla (pheochromocytoma) or autonomic ganglia (paraganglioma). They have highly variable biological behavior. Most PPG express high-affinity norepinephrine transporters, allowing active uptake of the norepinephrine analog, ¹³¹iodine-metaiodobenzylguanidine (¹³¹I-MIBG). Low-specific-activity forms of ¹³¹I-MIBG have been used since 1983 for therapy of PPG. High-specific-activity ¹³¹I-MIBG therapy improves hypertension management, induces partial radiological response or stable disease, decreases biochemical markers of disease activity and is well tolerated by patients. This drug, approved in the USA in July 2018, is the first approved agent for patients with unresectable, locally advanced or metastatic PPG and imaging evidence of metaiodobenzylguanidine uptake, who require systemic anticancer therapy.

Introduction & overview of the market

Pheochromocytomas and paragangliomas (PPG) are rare neoplasms arising from neuroectodermal-derived cells in the adrenal medulla (pheochromocytoma) or from cells associated with autonomic paraganglia (paragangliomas). Sympathetic paragangliomas generally arise in the thoracoabdominal region and secrete catecholamines in about 91% of cases [1]. Parasympathetic paragangliomas arise in the head and neck, and in sacral regions. They secrete catecholamines in a minority of cases (9%) [1]. PPG are classed as nonepithelial neuroendocrine tumors, in distinction to ‘carcinoid’ neuroendocrine tumors, with which they share many features [2].

All PPG have some potential for metastatic spread and even nonmetastatic disease may have high morbidity due to local invasion. Furthermore, up to 37% of paragangliomas (generally those associated with germline genetic mutations) can be multifocal [3]. This makes it difficult to define true metastases, unless they are in tissues where chromaffin cells are not normally expressed, for example, bone or lymph nodes [3,4]. For these reasons the designation ‘benign’ is no longer recommended in relation to these tumors [3]. Approximately 10% of pheochromocytomas, 40% of sympathetic paragangliomas and 5% of head and neck paragangliomas (most often vagal) metastasize [3].

Progression of metastatic PPG is highly variable. Of the 27% of 272 patients with malignant PPG who died of disease during follow-up, the median survival was 6 years (1 week–17 years) from primary diagnosis, whereas median disease-specific survival for the whole group was 34 years [5]. Grading scales for PPG have been developed with high negative predictive value (low scores essentially ruling out the likelihood of subsequent metastatic disease) but low positive predictive value [6].

Accurate determination of the incidence of malignant or unresectable PPG is not a trivial problem. A recent Danish study suggested an incidence of pheochromocytoma and sympathetic paraganglioma of approximately three per million [7]. This estimate would include smaller pheochromocytomas which were cured surgically, and which would not be classified as malignant. Additionally, the estimate would not include metastatic or unresectable paragangliomas which were not catecholamine secreting. Other authors suggest an annual incidence of pheochromocytoma and sympathetic paraganglioma of 9.5 per million and up to ten per million for head and neck paragangliomas [3]. An incidence of 0.79 per million for malignant pheochromocytomas and sympathetic paragangliomas was suggested from Surveillance, Epidemiology, and End Results Program (SEER) data [8], which would not include malignant or unresectable paragangliomas not associated with catecholamine secretion (mainly head and neck).

Presenting symptoms of head and neck paragangliomas are generally related to the site and size of the primary and metastatic or multifocal tumors [1]. Typical symptoms include neck mass, headache, cranial nerve palsy, unilateral tinnitus, pulsation or deafness [1]. Pheochromocytomas and sympathetic paragangliomas may produce symptoms either related to the site and size of the primary and metastatic or multifocal tumors (e.g., abdominal mass, or abdominal or chest pain), or related to tonic or episodic hormonal secretion of catecholamines by these lesions. Catecholamines may produce characteristic features of these tumors (episodic or persistent hypertension, and episodic sweating, palpitations, headaches or pallor). Many other symptoms may be produced by these tumors (e.g., weight loss, tremor, constipation and anxiety), giving rise to long delays in diagnosis [9]. Cardiovascular dysfunction, including arrhythmias, cardiomyopathy, shock and hypertensive crises, may occur because of the circulating catecholamine excess, and is a significant cause of morbidity [10]. Increasingly, PPG are discovered as incidental findings on imaging, or as smaller lesions, not associated with abnormal catecholamine levels, in patients identified with specific germline genetic mutations [11].

Prior to 2000, about 10% of PPG were thought to be genetically driven and three associated genes had been identified (RET in multiple endocrine neoplasia 2, VHL in Von Hippel–Lindau syndrome and NF1 in neurofibromatosis). It is now understood that about 40% of these tumors are associated with pathogenic germline mutations in over 20 genes, with many other PPG exhibiting somatic mutations in the same genes [6]. These genetic mutations segregate into four subgroups: mutations conferring a pseudohypoxic phenotype (e.g., VHL and SDHx genes), activated growth factor kinase signaling pathways (e.g., RET and NF1 genes), alterations in Wnt signaling and PPG with expression of adrenocortical genes [12]. These underlying genetic mechanisms may result in differences relevant to diagnosis and therapy between tumor groups. Thus, SDHB gene-mutated PPG have lesser affinity for metaiodobenzylguanidine (MIBG) as an imaging or therapeutic agent [13], but may have better response than others to either temozolomide or other chemotherapy [14,15]. It is anticipated that genetic identification will improve the understanding of patient-specific prognosis [16] and individualized therapeutic targeting [17].

Currently available interventions

Currently available therapeutic approaches for these tumors include surgical resection, intravenous targeted radiation therapy (¹³¹iodine-MIBG [¹³¹I-MIBG or ¹³¹I-iobenguane] and somatostatin receptor directed agents), chemotherapy and other tumor-directed therapies, external beam radiation, ablation and embolization procedures. High-specific-activity (HSA)-¹³¹I-MIBG is currently the only US FDA-approved intervention for PPG.

Assessment of intervention studies is difficult because of the rarity of malignant PPG and the difficulty of accruing patients to clinical trials [18], generally retrospective nature of the studies, variable indications for initiation of therapy (symptoms, tumor progression or extent), variable end points (tumor regression or stabilization, biochemical resolution, or symptom control) and heterogeneity of patients accrued (including variable genetics, progression [19] and prognosis [5]).

Surgery

Surgical resection is the therapy of choice for sympathetic PPG, if it can be safely achieved, as it is the only potentially curative therapy. Approximately 1% of patients with apparently complete resections of pheochromocytomas or paragangliomas of the chest, abdomen or pelvis, develop recurrent disease each year, for up to 15 years after surgery [20]. For disease that is not amenable to complete surgical resection, there may still be improved overall survival (OS), biochemical changes and symptoms from partial tumor resections [21]. Surgical resection is also the treatment of choice for parasympathetic paragangliomas that are amenable to safe surgery. However, careful observation of small, asymptomatic, head and neck parasympathetic paragangliomas can also be considered, in view of the potential morbidity of surgical intervention (including cranial nerve and vascular injury) [22]. In head and neck paragangliomas, surgical resection has been combined with pre-operative embolization procedures to improve outcomes, although the degree of added benefit is unclear [23].

Chemotherapy

Combination chemotherapy for malignant pheochromocytoma using cyclophosphamide, dacarbazine and vincristine was first described in 1985 [24]. In a review of multiple chemotherapy regimens in 54 patients over 31 years, responders (those with improved hypertension or tumor size reduction) were all treated with cyclophosphamide and dacarbazine, and had an OS of 6.4 years (vs 3.7 years in nonresponders) [25]. Other studies have suggested benefit for various regimens of temozolomide in patients with PPG associated with the SDHB mutation [14].

There are multiple, completed or ongoing, clinical research trials involving mTOR and tyrosine kinase inhibitors, including everolimus, sunitinib, cabozantinib, axitinib, lenvatinib and dovitinib. Novel immune therapy strategies are also being explored, for example, an early phase trial with the oncomimetic peptide vaccine, EO2401, in combination with the PD-1 inhibitor, pembrolizumab. Additionally, trials of hypomethylating and TRAIL inducer agents are ongoing, and other potential agents have been discussed though have not progressed [26–29]. So far these studies have not yielded clinical practice changing outcomes.

External beam radiation therapy

Although PPG are relatively radiation resistant, newer developments in image guidance and alternative particle generation, allowing better contouring of radiation energy, have resulted in greater use of external beam radiation therapy techniques for both head and neck paragangliomas and bone and body lesions. This is especially important in areas with potentially high morbidity from surgical intervention (e.g., carotid body or jugulotympanic tumors) because of their proximity to blood vessels and cranial nerves. External beam radiation results in high levels of local control and symptom relief in head and neck and other paragangliomas, although the definitions of benefit (tumor regression vs local control) are highly variable in different series [30,31].

Peptide radionuclide receptor therapy

Lutathera^® (¹⁷⁷Lu-DOTATATE) was approved in Europe in 2017 and in the USA in 2018 for therapy of adults with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Although not approved for PPG in the USA, the National Comprehensive Cancer Network Guidelines suggest its consideration for locally unresectable or metastatic PPG, if somatostatin receptor imaging is positive [32]. Malignant PPG generally have higher expression of somatostatin receptors (the target of ¹⁷⁷Lu-DOTATATE), than of functional norepinephrine transporters (NET; the target of MIBG), as determined by the relative sensitivity of ^Ga68-DOTATATE PET imaging (>90%) to ¹²³I-MIBG imaging (as low as 38%, although some of this apparent difference is related to the superior resolution of PET vs scintigraphic scans) [33]. A recent meta-analysis of 201 patients with PPG in 12 studies, who received either ⁹⁰Y-DOTATOC or ¹⁷⁷Lu-DOTATATE peptide radionuclide receptor therapy (PRRT), noted an objective response of 25%, disease control rate of 84%, clinical response of 61% and biochemical response of 64% [34]. Prospective studies of PRRT in PPG are ongoing.

Conventional ¹³¹I-MIBG

¹³¹I-MIBG has been used for therapy of PPG since the 1980s. The form of ¹³¹I-MIBG used has been designated as conventional, carrier-added or low-specific-activity ¹³¹I-MIBG, to differentiate it from the HSA or no carrier-added form of ¹³¹I-MIBG, recently approved in the USA. The chemical and nuclear differences between conventional and HSA-¹³¹I-MIBG are detailed below.

There are multiple retrospective studies describing the use of conventional ¹³¹I-MIBG in patients with PPG. A meta-analysis of 243 patients with PPG in 17 studies revealed an objective radiological response of 30%, disease control rate of 82% and biochemical response of 51%. Regimens ranged widely from 50–3200 mCi over 1–12 administrations. Many studies were small (ranging from 5–49, mean 14, subjects) [35]. The largest single study in the meta-analysis, and the only prospective trial of conventional ¹³¹I-MIBG, was that of Gonias et al., presenting data on 49 subjects with ¹²³I-MIBG-avid metastatic pheochromocytomas or paragangliomas [36]. The primary objective of the study was to determine the radiological response at 1 year after initial therapy, with secondary aims to describe OS, event-free survival and grade 3 and 4 toxicity. The ¹³¹I-MIBG was prepared on-site with a specific activity of about 27 mCi/mg. Subjects had one to three separate infusions, with a total dose of 492–3191 mCi (median 818 mCi in the first infusion); 69% receiving one and 22% receiving two infusions (see Table 1). Radiological results included 9% complete response, 18% partial response (PR) and 53% stable disease (SD) after a single dose. Estimated 5-year OS was 64% and event-free survival was 47%. Subjects receiving single doses of greater than 500 mCi had peripheral stem cell harvest prior to infusion and four subjects, receiving single doses of 733–1030 mCi, required stem cell rescue. Acute hypertension was noted in 14%, generally within 30 min of the onset of ¹³¹I-MIBG infusion [36].

Table 1. . Responses and toxicity of high-specific-activity and conventional forms of ¹³¹iodine-metaiodobenzylguanidine in two prospective Phase II trials.

Responses and toxicity	HSA-131I-MIBG	Conventional 131I-MIBG
Radiation administered, mCi	– Median total dose: 965 – Range: 102–1096 – Infusions: 1–2	– Median first dose: 818 – Range first dose: 492–1160 – Range total doses: 492–3191 – Infusions: 1–3
≥50% decrease in antihypertensives for ≥6 months, subjects achieving response (%)	25%	Not stated
5-year OS, subjects treated (%) Median OS, months	36% 37 months	64% 78 months
PFS, months	Not stated	34 months
Radiological response, subjects achieving response (%)	After single dose – CR: 0 – PR: 0 – SD: 71% After all doses – CR: 0 – PR: 30% – SD: 68%	After single dose – CR: 9% – PR: 18% – SD: 53% After second doses – CR: 17% – PR: 33% – SD: 25%
Hormonal response, subjects achieving response in serum or urine metanephrines or catecholamines (%)	CR + PR: 44%	After single dose – CR: 19% – PR: 16% After second doses – CR: 57% – PR: 14%
Acute hypertension during 131I-MIBG infusion, subjects showing effect (%)	–	14%
≥Grade 3 hematologic adverse effects, subjects showing effect (%)	– Decreased Plt: 41% – Decreased WCC: 41%, decreased Neut: 38% – MDS/leukemia: 7% (1–7 year) – Stem cell rescue: 0 – Other hematological support†: 25%	– Decreased Plt: 83% – Decreased WCC: 85%, decreased Neut: 87% – MDS/leukemia 4% (2–6 year) – Stem cell rescue: 6% – Other hematological support: not stated
Grade 3–4 nonhematological adverse effects, subjects showing effect (%)	– Pneumonitis: 1% – Acute or chronic kidney injury: 7% at 6 or 12 months	BOOP/ARDS: 8% (3/4 receiving one dose of >1000 mCi)

^†Includes platelet or red blood cell transfusions, granulocyte stimulating factor or erythropoietin.

¹³¹I-MIBG: ¹³¹Iodine-metaiodobenzylguanidine; ARDS: Acute respiratory distress syndrome; BOOP: Bronchiolitis obliterans organizing pneumonia; CR: Complete response; HSA: High-specific-activity; MDS: Myelodysplastic syndrome; Neut: Neutrophil count; OS: Overall survival; PFS: Progression-free survival; PR: Partial response; Plt: Platelet; SD: Stable disease; WCC: White blood cell count.

Data taken from [36,37,38].

Introduction to the compound

Norepinephrine transporters

Sympathetic presynaptic neurons synthesize and secrete dopamine, norepinephrine and epinephrine, which activate postsynaptic adrenergic and dopaminergic receptors. Catecholamines then undergo reuptake into the presynaptic neurons, via the saturable NET, and uptake to presynaptic vesicles, via vesicular monoamine transporters. Based on the structures of antihypertensives (bretylium and guanethidine) known to have an affinity for adrenergic nerves and cellular uptake via NET, MIBG was developed as an optimized imaging agent for the adrenal medulla [39]. The labeling of MIBG with isotopes of iodine was a breakthrough in nuclear imaging of NET-expressing tissues and therapy [40,41]. Expression of functional NET, as evidenced by positive imaging on ¹²³I-MIBG planar and single-photon emission computed tomography scans, is present in 92% of pheochromocytomas and 64% of paragangliomas [42], although as few as 20% of head and neck (mainly parasympathetic) paragangliomas are positive [43]. The uptake of MIBG does vary with genetic background, being significantly reduced in tumors of patients with SDHB mutations [44]. This may account for the wide variation in MIBG scan results in different series.

Chemistry

Wieland et al. synthesized ¹³¹I-MIBG using a radioiodine exchange reaction with an MIBG precursor, followed by anion exchange column purification, yielding material with a low specific activity (0.6–0.8 mCi/mg) [39]. Various modifications of exchange reaction chemistry followed but all resulted in predominantly nonradioactive MIBG product (<0.1% ¹³¹I-MIBG). Hunter [45] radiolabeled a polymer-bound benzylguanidine precursor with high efficiency and purified a product of specific activity of ≥3 Ci/mg. Molecular Insight Pharmaceuticals (MA, USA) developed further modifications of this solid-phase methodology using polystyrene resin and a stanylbenzylguanidine precursor (Ultratrace^®). The precursor is displaced from the resin upon oxidation with ¹³¹I-sodium iodide and separates into the liquid phase [46]. The HSA (2500 mCi/mg) AZEDRA^® compound is based on Ultratrace technology.

The potential benefits of HSA-¹³¹I-MIBG relate to the large excess of unlabeled MIBG produced by prior conventional methodologies. Unlabeled MIBG may compete for tumor uptake with ¹³¹I-MIBG, leading to decreased cytotoxic effects. There has not been a head-to-head comparative trial of conventional ¹³¹I-MIBG and HSA-¹³¹I-MIBG, but HSA-¹³¹I-MIBG images demonstrated significantly higher tumor to background activity and improved tumor shrinkage in mouse xenograft tumor models [47,48]. Additionally, because cellular reuptake of catecholamines via NET is saturable, the therapeutic use of high doses of low-specific-activity ¹³¹I-MIBG may lead to high synaptic concentrations of catecholamines, causing symptoms of catecholamine excess. This was evident in preclinical studies where MIBG infusions caused dose-dependent hypertension in dogs [48] and in clinical trials, where grade 3 hypertension was seen in 14% of subjects shortly after initiation of therapeutic conventional ¹³¹I-MIBG infusions [36].

Pharmacology

Pharmacokinetics & metabolism

HSA-¹³¹I-MIBG is infused intravenously in two doses of up to 500 mCi (18.5 GBq) each, at least 3 months apart. The dose administered is dependent on bodyweight and critical organ absorbed dose estimates based on 5 mCi dosimetry testing. The radionuclide decays with a principal beta emission of mean energy 191.6 keV, gamma emission of 364.5 keV and a radiation half-life of 8.02 days. The gamma ray dose constant is 2.2 R/mCi h at 1 cm. The gamma emission is attenuated about 1000-fold by 2.5 cm of lead shielding. While specific jurisdictions will determine the requirement for length of inpatient isolation, it is typical for patients receiving HSA-¹³¹I-MIBG to be hospitalized in a radiation safety room for at least four nights with each treatment.

Based on dosimetry studies using 5 mCi doses of HSA-¹³¹I-MIBG, supplemented with 185 μg of unlabeled MIBG to approximate the MIBG level in a therapeutic dose, the elimination half-life was estimated at 38.3 h (see Table 2) [49]. A total of 50% of the injected dose was cleared into the urine in the first 24 h and 80% was cleared into urine by 5 days. Approximately 95% of the excreted radioactivity in the first 24 h is ¹³¹I-MIBG, with a maximum of 3% free ¹³¹I detectable and <1% of other metabolites. There is no hepatic metabolism.

Table 2. . Summary of available clinical trial literature on high-specific-activity ¹³¹iodine-metaiodobenzylguanidine.

Study type and description	Main outcomes	Ref.
Phase I dosimetry: pharmacokinetics and biodistribution study with 5-mCi HSA-131I-MIBG (with added nonradioactive MIBG to equate to MIBG concentration in 500-mCi doses) in adults with metastatic or recurrent PPG (n = 4) or carcinoid (n = 7)	Estimated exposure of 1.4 Gy to marrow and 10.4 Gy to kidney for a single therapy dose of 500 mCi; these are within accepted limits of radiation toxicity	[49–51]
Phase I theranostics: MTD finding study; doses escalating from 6 mCi/kg; 21 adults (3–6/group) with PPG	MTD = 8 mCi/kg (296 MBq/kg); other results: 19% PR (RECIST 1.0); 64% PR or CR (metanephrine response)	[52]
Phase IIA: dose escalation: MTD finding study; dose escalations from 12–18 mCi/kg; 15 subjects, age 3–30 year (mean 8), with neuroblastoma; all given cryopreserved hematopoietic stem cells after dosimetry-guided HSA-131I-MIBG based on critical organ tolerances	MTD (based on nonhematologic DLT) = 55.5 mCi/kg (666 MBq/kg); other results: 13 soft-tissue lesions with tumor-absorbed doses of 26–378 Gy; one CR, three PR, one mixed response, four SD and six PD by imaging criteria	[53]
Phase IIB: open-label, single-arm, efficacy and safety study; 74 subjects, age 16–76 year (median 55), with PPG and hypertension on stable therapy	68 received one dose of HSA-131I-MIBG, 50 received two doses; 25% of 64 subjects had decreased antihypertensive use; PR and SD (RECIST 1.0) in 92% with ≥1 dose; OS: 36.7 months; TEAE: nausea, myelosuppression and fatigue	[37]

¹³¹I-MIBG: ¹³¹Iodine-MIBG; CR: Complete response; DLT: Dose-limiting toxicity; HSA-¹³¹I-MIBG: High-specific-activity ¹³¹I-MIBG; MIBG: Metaiodobenzylguanidine; MTD: Maximum tolerated dose; OS: Overall survival; PD: Progressive disease; PPG: Pheochromocytoma and paraganglioma; PR: Partial response; RECIST: Response Evaluation Criteria in Solid Tumors v1.0; SD: Stable disease; TEAE: Treatment emergent adverse effects.

The estimated radiation absorbed from a 500 mCi (18.5 GBq) administration is 10.4 Gy (range: 7.4–20.4) to kidneys and 1.4 Gy (range: 1.0–2.4) to bone marrow. Generally accepted safety limits are 23 Gy to the kidneys and 2 Gy to the marrow. In patients with mild to moderate renal impairment (creatinine clearance: 30–89 ml/min), 19% required a dose reduction based on dosimetric data predicting a renal dose exceeding 23 Gy (reference).

Pharmacodynamics

Because cellular uptake and storage of ¹³¹I-MIBG is dependent on the saturable NET and vesicular monoamine transporters, medications which affect catecholamine uptake or storage will impact specific tissue radiation exposure. These medications (including many common antidepressants, analgesics, decongestants, herbals and drugs of abuse) should not be used for at least five half-lives before and 7 days after each dosimetric or therapeutic dose of ¹³¹I-MIBG [54]. Patients are pretreated with potassium iodide to decrease thyroidal uptake of free ¹³¹I.

Clinical efficacy

Table 2 summarizes the results of human clinical trials with HSA-¹³¹I-MIBG. The pivotal Phase II efficacy and safety trial of HSA-¹³¹I-MIBG was an open-label, multicenter, single-arm study, including patients 12 years or older with ¹³¹I-MIBG-avid, unresectable PPG, who were on a stable antihypertensive regimen [37]. The presence of hypertension favored the inclusion of catecholamine-secreting PPG over nonsecretory lesions (85% had norepinephrine-secreting tumors). Patients with nonsecretory lesions may have been included either because they had essential or other secondary hypertension unrelated to catecholamine secretion, or because they had subthreshold or episodic catecholamine secretory status that was still sufficient to cause hypertension. Evidence of progressive disease was not necessary for study entrance. Subjects had extensive metastatic disease and were heavily pretreated, with 70% having received two or more prior therapies, including 30% with prior conventional ¹³¹I-MIBG and 38 % with prior chemotherapy. Excluded from study were those with significant cardiac, renal, liver or hematologic dysfunction.

The primary end point in the Phase II trial was a 50% reduction from baseline antihypertensive use, lasting at least 6 months. This end point was agreed to by the FDA as part of a special protocol assessment prior to the trial. The choice of this unconventional, clinically measurable cardiovascular primary end point for a pivotal oncology trial has remained highly controversial. The end point did recognize the significance of cardiovascular morbidity in this disorder [10], the high variability of tumor progression and OS [5], making trials using traditional end points, such as progression-free survival and OS difficult and time-consuming, and the difficulty of recruiting patients with this ultrarare disease [18] in competition with other options, such as expanded access conventional ¹³¹I-MIGB in the USA or Europe, or off-label chemotherapy. Secondary end points were more conventional and included tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria, biochemical tumor marker response in those with basal chromogranin A or catecholamines >50% above the upper limit of normal, OS and side effects. Eventually, ten US centers enrolled 68 patients between 2009 and 2016 (with a 4-year suspension of enrollment in 2010 due to funding collapse), for the largest prospective clinical trial in PPG thus far. The only other prospective trial of conventional ¹³¹I-MIBG recruited 50 subjects over 15 years in a single center US study [36].

Of the 74 subjects who received an initial 5 mCi HSA-¹³¹I-MIBG dose to assess MIBG uptake and dosimetry, 68 received a first therapeutic dose of 500 mCi and 50 received a second dose, at a median of 3.45 (range: 2.7–7.6) months later. Administration of the second therapeutic dose required a return to baseline or normalization of hematological values within 24 weeks following the first dose. Failure to resolve myelosuppression within 24 weeks was the most common reason for not receiving a second therapeutic dose. Doses were reduced for low bodyweight (8 mCi/kg for weight <62.5 kg) and based on dosimetry results, with a median cumulative therapeutic dose of 965 (range: 102–1096) mCi.

A reduction of baseline antihypertensive use, lasting at least 6 months, was seen in 17 of the 68 subjects (25%), achieving the prespecified primary end point. Sixty-four subjects had disease evaluable by RECIST 1.0 criteria. Of these, 92% had PR (23%) or SD within 12 months. Biochemical responses in chromogranin A (normalization or >50% decline) were present in 19 of 28 subjects (68%) at 12 months after initial therapy. Between 31 and 44% of evaluable subjects had complete responses or PRs in plasma or urine norepinephrine or normetanephrine, with highest response rate at 1 year. The median OS was 17.5 months after a single therapeutic dose and 48.7 months after two doses. There are no published data on quality of life metrics.

The specific primary end point used in this unblinded, single-arm pivotal trial is problematic because decisions on antihypertensive therapy management were open to research clinician bias. Furthermore, the degree of hypertension (and, therefore, use of antihypertensives) may be affected by multiple factors other than the tumors and their secretions, rendering it a poor surrogate for antitumor activity. It should also be noted that the ability to achieve the primary end point would be diminished, to the extent that there were subjects in the trial whose hypertension was unrelated to pheochromocytoma or sympathetic paraganglioma (e.g., essential hypertension).

Results from the secondary end points (22% objective tumor response by RECIST and 31–44% reduction in catecholamines or metanephrines) do support the findings with the primary end point. Additionally, the secondary end point data were consistent with data from a meta-analysis of 17 studies [35] and with the results noted in the only prior prospective study of conventional ¹³¹I-MIBG [36] (see Table 1), after consideration of the doses administered in each study. While the tumor response rate is modest, it is consistent with the response of 18% in the ¹⁷⁷Lu-DOTATE PRRT trial in patients with well-differentiated gastroenteropancreatic cancer [55]. The median progression-free survival was >30 months in that trial.

Safety & tolerability

Treatment-emergent adverse events associated with therapeutic dosing are noted in Table 1. Notably absent as an early side effect of HSA-¹³¹I-MIBG was hypertension seen within 30 min of initiation of the therapeutic infusion with conventional ¹³¹I-MIBG [36] and postulated to be related to an excess of unlabeled MIBG in the conventional product. Worsening of hypertension, later in the first 24 h after therapeutic infusion, occurred in 22% [38], possibly related to radiation-induced cellular damage and liberation of intracellular catecholamines. Nausea and fatigue were prominent (76 and 60%, respectively), though rarely classed as serious adverse effects. Nausea (generally in the first week after HSA-¹³¹I-MIBG infusion) could relate to gastric mucosal free ¹³¹I uptake [56] or a whole body irradiation effect. Fatigue was also prominent in the first week after infusion, similar to the effect of ¹⁷⁷Lu-DOTATATE PRRT in neuroendocrine tumors [55]. A later phase of fatigue may be related to the development of anemia due to myelosuppression at 6–8 weeks after infusion.

Myelosuppression was the most common grade 3 or 4 adverse effect and occurred in 90% of subjects [37]. The nadir of the neutrophil count occurred at 36 days (range: 27–55) and lasted for 12 days (range: 8–22) after the first dose. Following the second dose, patients with grade 4 neutropenia reached nadir at a median of 43 days (range: 38–47) and remained at nadir for a median of 18.5 days (range: 8–31) [38]. Myelosuppression generally resolved spontaneously within 8 weeks but required hematological support (e.g., red blood cell or platelet transfusions, granulocyte colony-stimulating factor, or erythropoietin) in 17 subjects (25%). Unlike studies using >500 mCi of conventional ¹³¹I-MIBG [36] per infusion, there was no need for stem cell isolation or transplantation.

Later adverse effects of HSA-¹³¹I-MIBG included a decline in renal function over the first year, the development of secondary myelodysplastic syndrome or leukemia and pulmonary complications. The decline in renal function is not noted in the clinical trial description [37], but a 22% clinically significant decrease in glomerular filtration rate and a 7% development of renal failure or acute kidney injury within the first year are noted in the prescribing information brochure [38]. Myelodysplastic syndrome or acute leukemias (lymphocytic or myeloid) were reported in 6.8% of subjects receiving a therapeutic dose of HSA-¹³¹I-MIBG [38], most often after the second therapeutic dose [57]. These serious hematologic effects occurred 1–7 years after the therapy. The potential for cumulated marrow exposure of >2 Gy may explain the apparent increased risk of grade 3 or higher adverse hematological effects, in comparison with ¹⁷⁷Lu-DOTATATE therapy of neuroendocrine tumors, where no patient received a cumulated marrow exposure of >2 Gy [58]. Although pulmonary toxicities (bronchiolitis obliterans organizing pneumonia, acute respiratory distress syndrome and pulmonary embolus) occurred in five of 68 treatments with conventional ¹³¹I-MIBG, there was only one case of (fatal) pneumonitis recorded in studies of the HSA-¹³¹I-MIBG. This occurred at 9 weeks after a single therapeutic dose. A Phase IV study, for long-term safety assessment in subjects who received prior HSA-¹³¹I-MIBG, is ongoing.

Regulatory status

HSA-¹³¹I-MIBG was approved by the FDA in July 2018 for use in patients, 12 years and older, with unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma and imaging evidence of MIBG uptake, who require systemic anticancer therapy. The drug is not currently licensed for use outside of the USA.

Most professional societies have not updated their guidelines for management of malignant PPG since the regulatory approval. However, the National Comprehensive Cancer Network Guidelines for malignant PPG suggest its use in locally unresectable and distant metastatic disease if the MIBG imaging is positive, while noting that it is the only FDA-approved intervention in this clinical situation.

Discussion

Other malignancies express NET [59] and thus are potential targets for HSA-¹³¹I-MIBG therapy. For example, 68% of ileal carcinoid tumors and lesser proportions of other carcinoid tumors have positive ¹³¹I-MIBG planar scans, suggesting functional NET expression [60]. Patients with gastroenteropancreatic and pulmonary neuroendocrine tumors [61], neuroblastomas [62], and medullary thyroid cancer [63] have been treated with conventional ¹³¹I-MIBG. Patients with neuroblastomas were included in a Phase IIA dose finding study with HSA-¹³¹I-MIBG, all receiving cryopreserved hematopoietic stem cell support. Future trials are expected to assess the role of HSA-¹³¹I-MIBG in these conditions.

Conclusion

Multiple previous studies with conventionally produced ¹³¹I-MIBG have suggested beneficial effects of this agent in patients with PPG. These studies were mainly retrospective, with highly varied populations, therapeutic protocols and follow-up, and gave limited guidance to clinicians treating these patients. HSA-¹³¹I-MIBG has now been shown, in the largest prospective trial to date in this rare disease, to improve hypertension management, decrease elevated catecholamines and achieve PR or SD in significant numbers of patients, with a tolerable side-effect profile. These data have led to it becoming the first drug to achieve FDA approval for use in patients with iobenguane scan positive, unresectable, locally advanced or metastatic PPG, who require systemic anticancer therapy.

Future perspective

Given the expression of NET in other cancers, for example, neuroblastoma and carcinoid tumors, there may be additional indications for HSA-¹³¹I-MIBG therapy in future. We also expect that exciting new understanding of the genetics, molecular pathophysiology and role of dysfunctional mitochondria in PPG, will yield additional therapeutic options for these patients, which may compete with HSA-¹³¹I-MIBG as therapeutic options. Additionally, small retrospective trials support a beneficial effect of ¹⁷⁷Lu-DOTATATE PRRT in patients with PPG, and a prospective trial of this agent in PPG is ongoing. If this trial leads to drug approval, new guidance will be needed to aid clinicians in their decision between these agents in patients with PPG. One could envision a personalized medicine screening to guide therapy for these patients, based on genotype and evidence of somatostatin receptor and NET.

Executive summary.

Mechanism of action

• High-specific-activity-¹³¹iodine-metaiodobenzylguanidine (HSA-¹³¹I-MIBG) is a molecule which incorporates ¹³¹iodine into metaiodobenzylguanidine, a structural homolog of norepinephrine, at high specific activity. It is actively transported into cells via the norepinephrine transporter (NET), which is highly expressed in pheochromocytomas and paragangliomas. Following cellular uptake, it delivers high dose beta and gamma radiation to NET-expressing tumors (pheochromocytomas and paragangliomas and others).

Pharmacokinetic properties

• HSA-¹³¹I-MIBG is primarily renally excreted. The radioactive isotopic half-life is 8 days, but serum radiation drops to <10% within 3 h.

Clinical efficacy

• The pivotal, single-arm, Phase II trial achieved its prespecified primary end point of 6-month reduction in baseline antihypertensive use in 25% of subjects.

• Additionally, 92% had partial response or stable disease by imaging within 12 months; biochemical responses, in chromogranin A or plasma or urine norepinephrine or normetanephrine, occurred in 31–68% of subjects with elevated pretherapy concentrations; and median overall survival was 17.5 months after a single therapeutic dose and 48.7 months after two doses.

Safety & tolerability

• Major side effects included nausea, fatigue and marrow toxicity.

• While myelosuppression generally resolved within 8 weeks, 25% of subjects required hematological support and myelodysplastic syndrome, or leukemia occurred in 6.8%.

Drug interactions

• There are multiple drug interactions with agents affecting metaiodobenzylguanidine uptake via NET.

• These agents must be held for at least five half-lives prior to therapy.

Dosage & administration

• HSA-¹³¹I-MIBG is administered intravenously in two doses at least 3 months apart.

• Each dose is 500 mCi, if not dose reduced based on pretherapy dosimetry or patient weight.