Abstract
The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6–12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. ClinicalTrials.gov number: NCT00874614.
Introduction
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and paraganglia, respectively (Jimenez 2018). Each year, approximately 500–1600 new cases of PPGLs are diagnosed in the United States (Grogan et al. 2011, Hamidi et al. 2017). Although most PPGLs are localized and surgical resection is the standard first-line intervention, locally invasive or metastatic disease is estimated to occur in 10–35% of cases (Amar et al. 2005, Grogan et al. 2011, Kimura et al. 2014, Hamidi et al. 2017, Lam 2017, Wakabayashi et al. 2019, Fishbein et al. 2021). Patients with metastatic or unresectable PPGLs have high morbidity and mortality rates owing to disease progression and/or cardiovascular sequelae (Feng et al. 2011, Ayala-Ramirez et al. 2012, Roman-Gonzalez et al. 2018).
PPGLs usually hypersecrete catecholamines, which are responsible for many of the observed signs and symptoms of disease, including paroxysmal hypertension, palpitations, anxiety, headaches, and constipation (van Berkel et al. 2014, Thosani et al. 2015, Falhammar et al. 2018). Patients with these tumors are prone to developing catecholamine-mediated crises characterized by hypertensive emergencies and cardiovascular events (Zelinka et al. 2012). Elevated urinary fractionated and plasma free metanephrines have been shown to be sensitive diagnostic markers of PPGL (Sawka et al. 2003, Lenders et al. 2014, Corcuff et al. 2017). In addition, patients with metastatic PPGLs have been reported to have higher metanephrine levels than those with localized PPGLs (Feng et al. 2011). Although less sensitive in the diagnostic setting, chromogranin A (CgA) levels may also be valuable in following response to therapy and monitoring for recurrence (Parisien-La Salle et al. 2021). Annual biochemical follow-up is typically life-long for patients at high risk for recurrent or metastatic disease (i.e. those with paraganglioma, diagnosis at a young age, multiple or large primary tumors, or genetic mutations) (Ayala-Ramirez et al. 2011, Plouin et al. 2016).
High-specific-activity (HSA) I-131 meta-iodobenzylguanidine (MIBG) is the first and only US Food and Drug Administration (FDA)-approved treatment for patients aged 12 years and older with iobenguane-scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy (AZEDRA® 2021). The unique synthesis and manufacturing of HSA I-131 MIBG permits an administered dose that consists almost entirely of I-131–labeled MIBG (Vaidyanathan & Zalutsky 1993, Coleman et al. 2009, Barrett et al. 2010, Vallabhajosula & Nikolopoulou 2011, Noto et al. 2018, Pryma et al. 2019). Approval of the drug was supported by the results of a pivotal phase 2 clinical trial demonstrating improvement of blood pressure control in the majority of patients being treated for hypertension and a high clinical benefit rate (>90%) including partial responses noted in individuals treated with two doses (~37 GBq; (~1000 mCi)) (Pryma et al. 2019). Prior treatment paradigms for unresectable PPGL included the research and compassionate use of conventional, low-specific-activity I-131 MIBG and cytotoxic chemotherapy with cyclophosphamide, vincristine, and dacarbazine (Loh et al. 1997, Gonias et al. 2009, Plouin et al. 2012, Niemeijer et al. 2014, van Hulsteijn et al. 2014, Jimenez et al. 2019).
Given that most PPGLs secrete catecholamines and the clinical presentation is frequently related to their secretory products, it is reasonable to postulate a correlation between treatment efficacy and biomarker response. A retrospective analysis evaluating 16 studies reported complete biochemical response (CR) rates of 0–27%, 16–100% partial response (PR), and 0–63% stable disease (SD) with low-specific-activity I-131 MIBG therapy (van Hulsteijn et al. 2014). In a phase 1 study of HSA I-131 MIBG for 21 patients with metastatic or recurrent PPGL, best biochemical response (CR or PR) rates of 80% for serum CgA and 64% for total metanephrines were observed (Noto et al. 2018).
Previously, as the biochemical response was a secondary endpoint and not the focus of our pivotal clinical study, we only described limited topline data for select biomarkers at a single 12-month time point (Pryma et al. 2019). Here, we report for the first time, best biochemical responses at any time point for serum CgA and total plasma free and urinary metanephrines, plasma free and urinary normetanephrine, and plasma free and urinary metanephrine (including waterfall plots for all patients), longitudinal biomarker responses for the study duration (0 to 12 months including 3-, 6-, and 9-month time points), the extent of biochemically SD and progressive disease (PD), and significant correlations with objective responses and the primary endpoint for the pivotal trial with HSA I-131 MIBG in patients with metastatic or recurrent, unresectable PPGL.
Subjects and methods
Trial design, patients, and treatment
A multicenter, open-label, single-arm trial was conducted under a Special Protocol Assessment agreement with the FDA. The primary efficacy endpoint was the proportion of evaluable patients with at least a 50% reduction of all baseline antihypertensive medications lasting for at least 6 months beginning in the first 12 months following the first therapeutic dose. Key secondary endpoints included the evaluation of radiographic tumor and biochemical tumor marker responses. Patients were enrolled at 10 centers in the United States and followed for 12 months for efficacy and up to 5 years for long-term safety. Baseline demographics and concomitant medications were recorded.
Eligible patients were aged 12 years or older with a confirmed diagnosis of metastatic or unresectable PPGL and the ability to provide written informed consent. Patients included in the study were ineligible for curative surgery and had received prior therapy for PPGL that had failed or were not candidates for chemotherapy or other curative therapies at study entry. All patients were on a stable antihypertensive medication regimen for at least 30 days prior to the first therapeutic dose, had at least one tumor site identified by CT or MRI, and had definitive MIBG avidity. Key exclusion criteria were a platelet count of <80,000/µL, an absolute neutrophil count of <1200/µL, and a creatinine clearance of <30 mL/min.
Patients underwent treatment planning by receiving ~185 MBq (5 mCi) of the drug, followed by serial whole-body scans to assess MIBG avidity and biodistribution and to conduct dosimetry calculations to determine radiation absorbed dose to normal organs (Noto et al. 2018, Jimenez et al. 2019, Pryma et al. 2019). Patients who showed MIBG tumor avidity received up to two therapeutic doses of the drug, each planned at ~18.5 GBq (500 mCi) or 296 MBq/kg (8 mCi/kg) for patients weighing ≤62.5 kg, administered intravenously approximately 90 days apart. Individualized dose reduction was undertaken to ensure that radiation-absorbed doses to critical organs would not exceed published toxicity limits after two therapeutic doses (Barrett et al. 2010). To receive the second therapeutic dose of the drug, patients’ hematologic values were required to return to baseline levels or within the normal range within 24 weeks following the first therapeutic dose. Patients who did not receive the second therapeutic dose were requested to be followed for study assessments including biomarkers.
Efficacy assessments
As previously described (Pryma et al. 2019), blood pressure response, the study’s primary endpoint, was measured by determining whether a patient had at least a 50% reduction of all baseline antihypertensive medications for a minimum of 6 months. Radiographic tumor response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 (Therasse et al. 2000). Each patient underwent a baseline CT/MRI study of the chest, abdomen, and pelvis and had follow-up tumor imaging every 3 months during the 12-month efficacy period. Patients whose CT/MRI study showed PR or CR underwent a follow-up CT/MRI study for confirmation. Biochemical tumor markers associated with PPGL (serum CgA, plasma and 24-h urinary catecholamines (norepinephrine, epinephrine)) and plasma free and urinary fractionated metanephrines (metanephrine, normetanephrine) were measured for evaluation of response. Tumor marker samples were collected as per study protocol laboratory manual guidelines (ACM Global Central Laboratory; Rochester, NY, USA) at multiple predefined time points for all treated patients and assessed by a central laboratory. Brief descriptions of these proprietary biochemical assays are provided later. Since this study was initiated in 2009, methoxytyramine was not evaluated. As prespecified in the study analysis plan, patients with hypersecretory tumors with any biomarker ≥1.5 times the upper limit of normal (ULN) at baseline were included in this data analysis. This cut-off was chosen in order to include patients with oligometastatic unresectable disease in whom plasma metanephrines and normetanephrines are not higher than 4× ULN, thus allowing for correlation analysis with the primary and secondary endpoints. Biochemical CR (normalization), PR (>50% decrease from baseline value but remaining above ULN), SD (≤50% decrease from baseline value or increase by ≤50% of baseline value, and remaining above the ULN), and PD (>50% increase from baseline value) were confirmed at the next assessment. Following treatment, tumor markers were measured every 2 weeks during weeks 2–24 and monthly during months 7–12 following the first therapeutic HSA I-131 MIBG infusion. The biochemical response was defined as biochemical CR and PR; best responses were determined at any time point after the first treatment dose. To assess the impact of the concomitant use of proton pump inhibitors (PPIs) on CgA response, these patients were identified for additional analyses.
Biomarker assays
All proprietary biochemical assays for this analysis were performed by a central laboratory. CgA levels were determined using a complement-enzyme-linked immunosorbent assay. Plasma and 24-h urinary catecholamines were determined by HPLC. Plasma free and urinary fractionated metanephrine and normetanephrine levels were determined using a liquid chromatography and tandem mass spectrometry system.
Statistical analyses
Patients included in this analysis received at least one therapeutic dose of the drug. No imputation for missing values, other than partial dates, was performed. Descriptive statistics are presented. For continuous measures, the mean, standard deviation, median, range, and sample size were calculated. For categorical measures, the number of patients and respective percentages in each category were determined. Pearson correlations between numerically transformed biochemical tumor marker responses and either (i) the primary endpoint or (ii) objective tumor response by RECIST 1.0 were computed and presented as appropriate. Fisher’s exact P-values for the categorical response tabulations were also calculated and presented. All statistical analyses and data listings were produced using SAS software version 9.4 or JMP software version 14.2 (SAS Institute, Cary, NC, USA).
Trial oversight
Each study center’s Institutional Review Board (IRB) approved the study protocol and all amendments. Those IRBs include the Duke University Health System Institutional Review Board for Clinical Investigations; The University of Texas M.D. Anderson Cancer Center Office of Protocol Research; the Rhode Island Hospital IRB; the Western Institutional Review Board (WIRB); the University of Pennsylvania Insitutional Review Board; and the John Hopkins Medicine Office of Human Subjects Research Institutional Review Board #1.
A written informed consent form was signed by all patients (or, for patients younger than 18 years, legal guardians). This study was performed in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guidelines, and all applicable regulations. An independent data monitoring committee was established and utilized to safeguard study integrity and assess the safety and efficacy of the interventions.
Results
The patient flow for this trial is summarized in Fig. 1. Sixty-eight patients received at least one dose of HSA I-131 MIBG. Select baseline clinical characteristics are presented in Table 1.
Patient flow diagram for the phase 2 trial.
Citation: Endocrine-Related Cancer 30, 2; 10.1530/ERC-22-0236
Select demographics and baseline characteristics of 68 patients with advanced pheochromocytoma or paraganglioma who received at least 1 therapeutic dose of high-specific-activity I-131 meta-iodobenzylguanidine (HSA I-131 MIBG). All data are no. of patients (%) unless otherwise indicated.
| Characteristics | No. of patients (%) |
|---|---|
| Sex | |
| Male | 39 (57.4) |
| Female | 29 (42.6) |
| Age, years | |
| Mean (s.d.) | 50.9 (13.9) |
| Median (range) | 54.5 (16–72) |
| <18 | 1 (1.5) |
| 18–30 | 7 (10.3) |
| 31–64 | 49 (72.1) |
| >64 | 11 (16.2) |
| Primary diagnosis | |
| Pheochromocytoma | 53 (77.9) |
| Paraganglioma | 14 (20.6) |
| Pheochromocytoma + paraganglioma | 1 (1.5) |
| Baseline elevated tumor marker status | |
| Norepinephrine | 32 (47.1) |
| Mixed catecholamines | 24 (35.3) |
| Epinephrine | 4 (5.9) |
| None | 6 (8.8) |
| No data available | 2 (2.9) |
| Prior MIBG treatments | |
| Yes | 21 (30.9) |
| No | 47 (69.1) |
| Location of metastasesa | |
| Lung and/or liver metastases | 32 (50) |
| No lung or liver metastases | 32 (50) |
| Bone metastases | |
| Yes | 39 (57.4) |
| No | 29 (42.6) |
aData provided for 64 patients with evaluable target lesions at baseline.
Best overall (complete response + partial response) biochemical tumor marker response
Fifty-four (79%) patients had high plasma total metanephrines, 53 (78%) had high urinary fractionated metanephrines, and 49 (72%) patients had elevated serum CgA levels. The proportions of patients achieving a biochemical response (CR or PR) in plasma analyses at any time after treatment with at least one dose of HSA I-131 MIBG were as follows: total free metanephrines 69%, free metanephrine 71%, and free normetanephrine 63%. Corresponding proportions for urinary analyses were as follows: total metanephrines 70%, metanephrine 56%, and normetanephrine 65%. Eighty percent of patients achieved a biochemical response (CR or PR) for serum CgA. (Table 2 and Fig. 2A, B, C, D, E, F and G). The best biochemical response rates in only patients who received two therapeutic doses of HSA I-131 MIBG were higher when compared to all treated patients (Fig. 3).
Best biochemical tumor marker response at any time point for (A) total plasma free metanephrines (normetanephrine + metanephrine); (B) total fractionated urinary metanephrines (normetanephrine + metanephrine); (C) plasma free normetanephrine; (D) urinary normetanephrine; (E) plasma free metanephrine; (F) urinary metanephrine; (G) chromogranin A.
Citation: Endocrine-Related Cancer 30, 2; 10.1530/ERC-22-0236
Proportion of patients with a biochemical response (CR + PR) at any time point for all patients receiving a therapeutic dose of HSA I-131 MIBG (blue bars) compared to patients who received two doses (red bars). PNM: plasma normetanephrine; UM: urinary metanephrine; PM: plasma metanephrine; UM: urinary normetanephrine.
Citation: Endocrine-Related Cancer 30, 2; 10.1530/ERC-22-0236
Best overall biomarker response in patients with elevated baseline biomarkers.
| Chromogranin A | Plasma total metanephrines | Urine total metanephrines | Plasma normetanephrine | Urine normetanephrine | Plasma metanephrine | Urine metanephrine | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | No. | % | |
| Patients receiving any therapeutic dose of HSA I-131 MIBG | ||||||||||||||
| Baseline 1.5× upper limit of normal | 49 | - | 54 | - | 53 | - | 56 | - | 52 | - | 17 | - | 16 | - |
| Complete response + partial responses | 39 | 80 | 37 | 69 | 37 | 70 | 35 | 63 | 34 | 65 | 12 | 71 | 9 | 56 |
| Complete response | 22 | 45 | 6 | 11 | 12 | 23 | 4 | 7 | 10 | 19 | 2 | 12 | 2 | 13 |
| Partial response | 17 | 35 | 31 | 57 | 25 | 47 | 31 | 55 | 24 | 46 | 10 | 59 | 7 | 44 |
| Stable disease | 8 | 16 | 16 | 30 | 15 | 28 | 20 | 36 | 17 | 33 | 3 | 18 | 7 | 44 |
| Progressive disease | 2 | 4 | 1 | 2 | 1 | 2 | 1 | 2 | 1 | 2 | 2 | 12 | 0 | 0 |
| Patients receiving two therapeutic doses of HSA I-131 MIBG | ||||||||||||||
| Baseline 1.5× upper limit of normal | 35 | - | 40 | - | 40 | - | 40 | - | 38 | 12 | - | 13 | - | |
| Complete response + partial responses | 30 | 86 | 31 | 78 | 31 | 78 | 30 | 75 | 28 | 74 | 10 | 83 | 9 | 69 |
| Complete response | 20 | 57 | 4 | 10 | 10 | 25 | 3 | 8 | 7 | 18 | 1 | 8 | 2 | 15 |
| Partial response | 10 | 29 | 27 | 68 | 21 | 53 | 27 | 68 | 21 | 55 | 9 | 75 | 7 | 54 |
| Stable disease | 5 | 14 | 9 | 23 | 8 | 20 | 10 | 25 | 9 | 24 | 2 | 17 | 4 | 31 |
| Progressive disease | 0 | 0 | 0 | 0 | 1 | 3 | 0 | 0 | 1 | 3 | 0 | 0 | 0 | 0 |
HSA I-131 MIBG, high-specific-activity I-131 meta-iodobenzylguanidine.
Biomarker responses over time
As indicated in Table 1, the majority of patients with metastatic or unresectable tumors exclusively or predominantly secrete norepinephrine. Therefore, to further assess catecholaminergic biomarker responses, norepinephrine and normetanephrines were evaluated over time. The number and proportion of patients who had confirmed biochemical PR or CR following treatment increased over time. For serum CgA (n = 49), plasma (n = 52) and urinary (n = 41) norepinephrine, and plasma free (n = 57) and urinary (n = 53) normetanephrine, responses were observed in at least 10% of evaluable patients as early as 3 months from the first dose (Fig. 4). Responses of specific biomarkers to HSA I-131 MIBG are described as follows:
Individual biochemical tumor marker responses: percentage of patient responders (complete response plus partial response) over time. CgA: chromogranin A; NM: normetanephrines; NE: norepinephrine.
Citation: Endocrine-Related Cancer 30, 2; 10.1530/ERC-22-0236
Serum chromogranin A
The percentage of serum CgA-related tumor marker responders (CR + PR) steadily increased in the 12 months following the first therapeutic dose reaching 68% (19/28) (Fig. 4). Only 4 of 28 patients (14%) were confirmed to have PD at the 12-month time point (Table 3).
Biomarker response rates over time.
| Biomarker | No. (%) | |||
|---|---|---|---|---|
| Month 3 | Month 6 | Month 9 | Month 12 | |
| Serum chromogranin A | ||||
| No. of patients | 43 | 38 | 28 | 28 |
| Complete + partial responses | 13 (30) | 21 (55) | 17 (61) | 19 (68) |
| Complete response | 3 (7) | 8 (21) | 9 (32) | 8 (29) |
| Partial response | 10 (23) | 13 (34) | 8 (29) | 11 (39) |
| Stable disease | 28 (65) | 16 (42) | 10 (36) | 5 (18) |
| Progressive disease | 2 (5) | 1 (3) | 1 (4) | 4 (14) |
| Plasma free normetanephrine | ||||
| No. of patients | 43 | 39 | 29 | 25 |
| Complete + partial responses | 7 (16) | 12 (31) | 11 (38) | 11 (44) |
| Complete response | 1 (2) | 2 (5) | 2 (7) | 0 (0) |
| Partial response | 6 (14) | 10 (26) | 9 (31) | 11 (44) |
| Stable disease | 35 (81) | 25 (64) | 17 (59) | 13 (52) |
| Progressive disease | 1 (2.3) | 2 (5) | 1 (3) | 1 (4) |
| Urinary normetanephrine | ||||
| No. of patients | 41 | 38 | 29 | 25 |
| Complete + partial responses | 7 (17) | 8 (21) | 6 (21) | 9 (36) |
| Complete response | 1 (2) | 1 (3) | 1 (3) | 1 (4) |
| Partial response | 6 (15) | 7 (18) | 5 (17) | 8 (32) |
| Stable disease | 32 (78) | 26 (68) | 20 (69) | 13 (52) |
| Progressive disease | 2 (5) | 4 (11) | 3 (10) | 3 (12) |
| Plasma norepinephrine | ||||
| No. of patients | 42 | 38 | 30 | 29 |
| Complete + partial responses | 5 (12) | 10 (26) | 10 (33) | 9 (31) |
| Complete response | 0 (0) | 0 (0) | 0 (0) | 1 (3) |
| Partial response | 5 (12) | 10 (26) | 10 (33) | 8 (28) |
| Stable disease | 37 (88) | 27 (71) | 20 (67) | 19 (66) |
| Progressive disease | 0 (0) | 1 (3) | 0 (0) | 1 (3) |
| Urinary norepinephrine | ||||
| No. of patients | 33 | 32 | 24 | 19 |
| Complete + partial responses | 7 (21) | 10 (32) | 6 (25) | 8 (42) |
| Complete response | 2 (6) | 4 (13) | 4 (17) | 3 (16) |
| Partial response | 5 (15) | 6 (19) | 2 (8) | 5 (26) |
| Stable disease | 22 (67) | 19 (59) | 15 (63) | 9 (47) |
| Progressive disease | 4 (12) | 3 (9) | 3 (13) | 2 (11) |
Thirty-five of 68 (51.5%) patients received concomitant PPI treatment. Of the 49 patients with elevated baseline CgA, 27 (55.1%) were receiving PPIs. The best CgA response for the 27 patients receiving PPIs was 21 (78%) CR/PR, 4 (15%) SD, and 2 (7%) PD. The best CgA response for the 22 patients that did not receive PPIs was 18 (82%) CR/PR, 4 (18%) SD, and 0 (0%) PD.
Plasma and urinary norepinephrine
Plasma norepinephrine-related tumor marker response (CR + PR) stabilized in the 9–12 months following the first therapeutic dose with 33% (10/30) of patients responding at the 9-month time point and only 1 of 29 patients (3%) confirmed to have PD at the 12-month point (Fig. 4 and Table 3). The percentage of urinary norepinephrine-related tumor marker responders (CR + PR) increased in the 12 months following the first therapeutic dose reaching 42% (8/19) (Fig. 4). Only 2 of 19 patients (10.5%) were confirmed to have PD at the 12-month point (Table 3).
Plasma free and urinary normetanephrine
The percentage of plasma free normetanephrine-related tumor marker responders (CR + PR) steadily increased in the 12 months following the first therapeutic dose (Fig. 4) with 44% (11/25) responding and only one of 25 patients (4%) was confirmed to have PD at the 12-month point (Table 3). The percentage of urinary normetanephrine-related tumor marker responders (CR + PR) also steadily increased in the 12 months following the first therapeutic dose reaching a 36% (9/25) response rate (Fig. 4). Three of 25 patients (12%) were confirmed to have a >50% increase in urinary normetanephrine levels (PD) at the 12-month point (Table 3).
Correlation of biomarker response rates to primary endpoint and objective response rates
Overall biomarker responses correlated weakly but significantly with responder status for the primary outcome assessment (i.e. >50% reduction in antihypertensive medications for at least 6 months; Table 4). For all patients with hypersecretory tumors (with a baseline biochemical marker level of ≥1.5× ULN for all tested biomarkers), a comparison of biomarker response with a reduction in antihypertensive therapy yielded a correlation coefficient of 0.35 (P = 0.006). For patients with norepinephrine-only-hypersecreting tumors, a comparison of biomarker response with antihypertensive therapy yielded a correlation coefficient of 0.47 (P = 0.008). For patients with norepinephrine and epinephrine-hypersecreting tumors, a comparison of biomarker response with antihypertensive therapy yielded a correlation coefficient of 0.37 (P = 0.006).
Correlation of overall tumor biomarker response with the primary endpoint.a
| Overall tumor biomarker response | Primary efficacy outcomea, n (%) | Correlation coefficient (P-value) | ||
|---|---|---|---|---|
| Responder | Non-responder | Fisher’s exact P-value | ||
| All baseline ≥ 1.5x ULN (n = 60) |
Responder | 7 (12) | 6 (10) | 0.35 (0.006) 0.012 |
| Non-responder | 8 (13) | 39 (65) | ||
| NE-hypersecreting (n = 56) | Responder | 7 (12.5) | 6 (11) | 0.37 (0.006) 0.011 |
| Non-responder | 7 (12.5) | 36 (64) | ||
| NE-only-hypersecreting (n = 31) | Responder | 6 (19) | 4 (13) | 0.47 (0.008) 0.015 |
| Non-responder | 3 (10) | 18 (58) | ||
| EPI-only-hypersecreting (n = 4) | Responder | 0 (0) | 0 (0) | N/A |
| Non-responder | 1 (25) | 3 (75) | ||
aPrimary efficacy outcome = reduced antihypertensive medications by ≥50% for at least 6 months.
EPI, epinephrine; NE, norepinephrine; ULN, upper limit of normal.
The overall biomarker response also weakly but significantly correlated with objective tumor response (best confirmed response of CR or PR based on RECIST 1.0 criteria; Table 5). For all patients with hypersecretory tumors, a comparison of biomarker response with objective tumor response yielded a correlation coefficient of 0.36 (P = 0.007).
Correlation of overall tumor biomarker response with objective tumor response.a
| Overall tumor biomarker response | RECIST responsea, n (%) | Correlation coefficient (P-value) | |||
|---|---|---|---|---|---|
| PR | SD | PD | Fisher’s exact P-value | ||
| All baseline ≥ 1.5x ULN (n - =55) |
Responder | 7 (13) | 6 (11) | 0 (0) | 0.36 (0.007) 0.012 |
| Non-responder | 7 (13) | 32 (58) | 3 (5) | ||
| NE-hypersecreting (n = 52) | Responder | 7 (13) | 6 (12) | 0 (0) | 0.38 (0.005) 0.010 |
| Non-responder | 6 (12) | 30 (58) | 3 (6) | ||
| NE-only-hypersecreting (n = 28) | Responder | 5 (18) | 5 (18) | 0 (0) | 0.35 (0.065) 0.091 |
| Non-responder | 3 (11) | 13 (46) | 2 (7) | ||
| EPI-only-hypersecreting (n = 3) | Responder | 0 (0) | 0 (0) | 0 (0) | N/A |
| Non-responder | 1 (33) | 2 (67) | 0 (0) | ||
aBest confirmed response of complete response or partial response according to Response Evaluation Criteria in Solid Tumors.
EPI, epinephrine; NE, norepinephrine; PD, progressive disease; PR, partial response; SD, stable disease; ULN, upper limit of normal.
Discussion
These results indicate that treatment with HSA I-131 MIBG substantially decreases the excessive secretion of catecholamines in patients with metastatic PPGLs. These hormonal reductions are long-lasting, improve over time, and correlate with blood pressure control and oncological responses.
This is one of the largest prospective clinical trials to date in patients with advanced PPGL and has demonstrated multiple clinical benefits of HSA I-131 MIBG. Although several patients did not achieve the blood pressure reduction benefit as defined in the primary endpoint, most had a reduction in the number and doses of antihypertensives (Pryma et al. 2019) and later presented with partial radiographic responses that, in this analysis, clearly correlate with tumor biomarker responses in patients with advanced PPGL. Further, it should be noted that this unique primary study endpoint (at least a 50% reduction in baseline antihypertensive medication use lasting for ≥6 months) was decided upon in agreement with the FDA in order to establish clinical benefit and it is now further corroborated by the observed substantial biochemical responses.
Biomarker response rates steadily improved during the 12-month efficacy period following the administration of the first dose of HSA I-131 MIBG. The initial improvement, from the 3-month to the 12-month time point, was consistent with receiving both treatment doses (Fig. 2). The continued improvement in the biomarker response following the initial 6-month period likely represents the continued beneficial effects of cytotoxic radiation to the tumor cells, which were slowly progressing through the cell cycle until their eventual apoptosis or necrosis. This is consistent with the finding that 30% of the patients who received two therapeutic doses had confirmed PR that became evident in the long-term follow-up (Pryma et al. 2019).
This prospective phase 2 study establishes the benchmarks for PPGL biomarker response to therapy over time. The best overall serum CgA-related tumor marker response rates (CR + PR) were observed to be slightly higher (80%) than total metanephrines (70%). CgA expression correlates with the amount of secretory vesicles in neuroendocrine cells, and serum CgA levels correlate with the release of the contents of these vesicles, including from PPGL tumor cells (Gut et al. 2016). The fact that many of the non-primary endpoint responders in our study were nevertheless observed to have an objective tumor response and the majority of patients had a reduction in requirements for antihypertensive medications that lasted less than 6 months, the CgA biomarker may well have captured this non-primary endpoint biochemical response. Importantly, 6 of the 27 patients with elevated CgA that were receiving PPI treatment during the trial either had an SD or PD biomarker response. Given that PPIs are known to increase CgA (Mosli et al. 2012), it is possible that the effects of HSA I-131 MIBG therapy on lowering CgA levels were suboptimal in these patients.
While these biomarker responses to HSA I-131 MIBG are robust, this clinical trial was not designed to evaluate the ability of biomarkers to prospectively serve as potential surrogates for tumor response and/or blood pressure response or provide diagnostic performance criteria such as sensitivity or positive predictive value. However, future studies are warranted to assess these questions and/or determine whether a single biochemical response such as CgA, plasma free or 24-h urine fractionated metanephrines could serve to simplify patient biomarker follow-up.
It should also be noted that with a clinical benefit rate that is quite high (>90% when including patients with SD (objective response) who had some degree of regression and substantially improved blood pressure), these findings are quite consistent with the previously published waterfall plot data (Pryma et al. 2019). Given the observed correlation between biomarker response and long-lasting reduction in antihypertensive medication demand for these hypersecretory tumors (Table 3), assessment of biomarker response is a reasonable objective therapeutic endpoint. However, the observed correlations were weak to moderate likely due to the variability of the many individual biomarker responses.
The current study is not without its limitations. First, since genetic mutations were not recorded for this study, we were unable to determine whether there were any trends regarding a patient’s genetic background and their biomarker responses. Also, although most patients in the study had hypersecretory tumors at the onset of treatment, all patients had hypertension, suggesting that a small subpopulation may have had increased blood pressure independent of their PPGL. Further, given the challenges of identifying and recruiting patients with this rare disease over a period of many years, no effort could be made to control for the proportion of pheochromocytoma patients relative to paraganglioma patients, or for normal vs elevated baseline biomarker levels for a given assay.
In addition, we were unable to test for plasma methoxytyramine levels since the study was initiated in June 2009, well before its recommended usage for PPGL (Kunz et al. 2013). Lastly, longer follow-up data are needed to ascertain the durability of the biomarker response and to determine whether a biomarker response failure may serve as an early indicator of recurrence and/or disease progression, as well as its effect on overall survival.
Conclusions
The diagnostic value of biomarkers for PPGL has been long recognized. The current study affirms the correlation of biomarker response with objective tumor response by RECIST 1.0 as well as reduction of antihypertensive therapy in patients with advanced PPGL in the setting of a multicenter, prospective phase 2 trial following treatment with HSA I-131 MIBG. Furthermore, these clinical and biochemical responses are durable. Collectively, the findings provide substantial efficacy data for HSA I-131 MIBG for adult and pediatric patients aged 12 years and older with iobenguane scan-positive, unresectable, locally advanced or metastatic PPGL who require systemic therapy.
Declaration of interest
NS and VAD are employees of Progenics Pharmaceuticals, Inc., a Lantheus company. CJ, BBC, RBN, JSD, LS and DAP served as investigators for this clinical study.
Funding
Progenics Pharmaceuticals, Inc., a Lantheus company, which has a proprietary commercial interest in AZEDRA® (iobenguane I 131), provided research support for this study.
Disclaimers
The manuscript and its contents are confidential, intended for journal review purposes only, and not to be further disclosed until published.
References
Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G & Plouin PF 2005 Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. Journal of Clinical Endocrinology and Metabolism 90 2110–2116. (https://doi.org/10.1210/jc.2004-1398)
Ayala-Ramirez M, Feng L, Habra MA, Rich T, Dickson PV, Perrier N, Phan A, Waguespack S, Patel S & Jimenez C 2012 Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer 118 2804–2812. (https://doi.org/10.1002/cncr.26577)
Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, Busaidy N, Cote GJ, Perrier N & Phan A et al.2011 Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. Journal of Clinical Endocrinology and Metabolism 96 717–725. (https://doi.org/10.1210/jc.2010-1946)
AZEDRA® 2021 Full prescribing information | AZEDRA® (iobenguane | 131). Billercia, MA, USA: Progenics Pharmaceuticals Inc., a Lantheus Company. (available at: https://www.azedra.com/content/pdf/full-prescribing-information.pdf)
Barrett JA, Joyal JL, Hillier SM, Maresca KP, Femia FJ, Kronauge JF, Boyd M, Mairs RJ & Babich JW 2010 Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution. Cancer Biotherapy and Radiopharmaceuticals 25 299–308. (https://doi.org/10.1089/cbr.2009.0695)
Coleman RE, Stubbs JB, Barrett JA, de la Guardia M, Lafrance N & Babich JW 2009 Radiation dosimetry, pharmacokinetics, and safety of ultratrace iobenguane I-131 in patients with malignant pheochromocytoma/paraganglioma or metastatic carcinoid. Cancer Biotherapy and Radiopharmaceuticals 24 469–475. (https://doi.org/10.1089/cbr.2008.0584)
Corcuff JB, Chardon L, El Hajji Ridah I & Brossaud J 2017 Urinary sampling for 5HIAA and metanephrines determination: revisiting the recommendations. Endocrine Connections 6 R87–R98. (https://doi.org/10.1530/EC-17-0071)
Falhammar H, Kjellman M & Calissendorff J 2018 Initial clinical presentation and spectrum of pheochromocytoma: a study of 94 cases from a single center. Endocrine Connections 7 186–192. (https://doi.org/10.1530/EC-17-0321)
Feng F, Zhu Y, Wang X, Wu Y, Zhou W, Jin X, Zhang R, Sun F, Kasoma Z & Shen Z 2011 Predictive factors for malignant pheochromocytoma: analysis of 136 patients. Journal of Urology 185 1583–1590. (https://doi.org/10.1016/j.juro.2010.12.050)
Fishbein L, Del Rivero J, Else T, Howe JR, Asa SL, Cohen DL, Dahia PLM, Fraker DL, Goodman KA & Hope TA et al.2021 The North American Neuroendocrine Tumor Society consensus guidelines for surveillance and management of metastatic and/or unresectable pheochromocytoma and paraganglioma. Pancreas 50 469–493. (https://doi.org/10.1097/MPA.0000000000001792)
Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J, Damon L, Linker C, Sznewajs A & Shiboski S et al.2009 Phase II study of high-dose (131I)metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. Journal of Clinical Oncology 27 4162–4168. (https://doi.org/10.1200/JCO.2008.21.3496)
Grogan RH, Mitmaker EJ & Duh QY 2011 Changing paradigms in the treatment of malignant pheochromocytoma. Cancer Control 18 104–112. (https://doi.org/10.1177/107327481101800205)
Gut P, Czarnywojtek A, Fischbach J, Bączyk M, Ziemnicka K, Wrotkowska E, Gryczyńska M & Ruchała M 2016 Chromogranin A - unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls. Archives of Medical Science 12 1–9. (https://doi.org/10.5114/aoms.2016.57577)
Hamidi O, Young WF Jr, Iniguez-Ariza NM, Kittah NE, Gruber L, Bancos C, Tamhane S & Bancos I 2017 Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years. Journal of Clinical Endocrinology and Metabolism 102 3296–3305. (https://doi.org/10.1210/jc.2017-00992)
Jimenez C 2018 Treatment for patients with malignant pheochromocytomas and paragangliomas: a perspective from the hallmarks of cancer. Frontiers in Endocrinology (Lausanne) 9 277. (https://doi.org/10.3389/fendo.2018.00277)
Jimenez C, Erwin W & Chasen B 2019 Targeted radionuclide therapy for patients with metastatic pheochromocytoma and paraganglioma: from low-specific-activity to high-specific-activity iodine-131 metaiodobenzylguanidine. Cancers 11 1018. (https://doi.org/10.3390/cancers11071018)
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT & Christian MC et al.2000 New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute 92 205–216. (https://doi.org/10.1093/jnci/92.3.205)
Kimura N, Takayanagi R, Takizawa N, Itagaki E, Katabami T, Kakoi N, Rakugi H, Ikeda Y, Tanabe A & Nigawara T et al.2014 Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocrine-Related Cancer 21 405–414. (https://doi.org/10.1530/ERC-13-0494)
Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA, Chen H, Jensen RT, Kim MK & Klimstra DS et al.2013 Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 42 557–577. (https://doi.org/10.1097/MPA.0b013e31828e34a4)
Lam AK 2017 Update on adrenal tumours in 2017 World Health Organization (WHO) of endocrine tumours. Endocrine Pathology 28 213–227. (https://doi.org/10.1007/s12022-017-9484-5)
Lenders JWM, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SKG, Murad MH, Naruse M, Pacak K, Young WF Jr & Endocrine Society 2014 Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 99 1915–1942. (https://doi.org/10.1210/jc.2014-1498)
Loh KC, Fitzgerald PA, Matthay KK, Yeo PPB & Price DC 1997 The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. Journal of Endocrinological Investigation 20 648–658. (https://doi.org/10.1007/BF03348026)
Mosli HH, Dennis A, Kocha W, Asher LJ & Van Uum SHM 2012 Effect of short-term proton pump inhibitor treatment and its discontinuation on chromogranin A in healthy subjects. Journal of Clinical Endocrinology and Metabolism 97 E1731–E1735. (https://doi.org/10.1210/jc.2012-1548)
Niemeijer ND, Alblas G, van Hulsteijn LT, Dekkers OM & Corssmit EPM 2014 Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta-analysis. Clinical Endocrinology 81 642–651. (https://doi.org/10.1111/cen.12542)
Noto RB, Pryma DA, Jensen J, Lin T, Stambler N, Strack T, Wong V & Goldsmith SJ 2018 Phase 1 study of high-specific-activity I-131 MIBG for metastatic and/or recurrent pheochromocytoma or paraganglioma. Journal of Clinical Endocrinology and Metabolism 103 213–220. (https://doi.org/10.1210/jc.2017-02030)
Parisien-La Salle S, Provençal M & Bourdeau I 2021 Chromogranin A in a cohort of pheochromocytomas and paragangliomas: usefulness at diagnosis and as an early biomarker of recurrence. Endocrine Practice 27 318–325. (https://doi.org/10.1016/j.eprac.2020.09.011)
Plouin PF, Amar L, Dekkers OM, Fassnacht M, Gimenez-Roqueplo AP, Lenders JWM, Lussey-Lepoutre C, Steichen O & Guideline Working Group 2016 European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma. European Journal of Endocrinology 174 G1–G10. (https://doi.org/10.1530/EJE-16-0033)
Plouin PF, Fitzgerald P, Rich T, Ayala-Ramirez M, Perrier ND, Baudin E & Jimenez C 2012 Metastatic pheochromocytoma and paraganglioma: focus on therapeutics. Hormone and Metabolic Research 44 390–399. (https://doi.org/10.1055/s-0031-1299707)
Pryma DA, Chin BB, Noto RB, Dillon JS, Perkins S, Solnes L, Kostakoglu L, Serafini AN, Pampaloni MH & Jensen J et al.2019 Efficacy and safety of high-specific-activity I-131 MIBG therapy in patients with advanced pheochromocytoma or paraganglioma. Journal of Nuclear Medicine 60 623–630. (https://doi.org/10.2967/jnumed.118.217463)
Roman-Gonzalez A, Zhou S, Ayala-Ramirez M, Shen C, Waguespack SG, Habra MA, Karam JA, Perrier N, Wood CG & Jimenez C 2018 Impact of surgical resection of the primary tumor on overall survival in patients with metastatic pheochromocytoma or sympathetic paraganglioma. Annals of Surgery 268 172–178. (https://doi.org/10.1097/SLA.0000000000002195)
Sawka AM, Jaeschke R, Singh RJ & Young WF Jr 2003 A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. Journal of Clinical Endocrinology and Metabolism 88 553–558. (https://doi.org/10.1210/jc.2002-021251)
Thosani S, Ayala-Ramirez M, Roman-Gonzalez A, Zhou S, Thosani N, Bisanz A & Jimenez C 2015 Constipation: an overlooked, unmanaged symptom of patients with pheochromocytoma and sympathetic paraganglioma. European Journal of Endocrinology 173 377–387. (https://doi.org/10.1530/EJE-15-0456)
Vaidyanathan G & Zalutsky MR 1993 No-carrier-added synthesis of meta-(131I)iodobenzylguanidine. Applied Radiation and Isotopes 44 621–628. (https://doi.org/10.1016/0969-8043(9390179-E)
Vallabhajosula S & Nikolopoulou A 2011 Radioiodinated metaiodobenzylguanidine (MIBG): radiochemistry, biology, and pharmacology. Seminars in Nuclear Medicine 41 324–333. (https://doi.org/10.1053/j.semnuclmed.2011.05.003)
van Berkel A, Lenders JW & Timmers HJ 2014 Diagnosis of endocrine disease: biochemical diagnosis of phaeochromocytoma and paraganglioma. European Journal of Endocrinology 170 R109–R119. (https://doi.org/10.1530/EJE-13-0882)
van Hulsteijn LT, Niemeijer ND, Dekkers OM & Corssmit EPM 2014 2014 131I-MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta-analysis. Clinical Endocrinology 80 487–501. (https://doi.org/10.1111/cen.12341)
Wakabayashi H, Inaki A, Yoshimura K, Murayama T, Imai Y, Higuchi T, Jinguji M, Shiga T & Kinuya S 2019 A phase I clinical trial for ((131)I)meta-iodobenzylguanidine therapy in patients with refractory pheochromocytoma and paraganglioma. Scientific Reports 9 7625. (https://doi.org/10.1038/s41598-019-43880-6)
Zelinka T, Petrák O, Turková H, Holaj R, Štrauch B, Kršek M, Vránková AB, Musil Z, Dušková J & Kubinyi J et al.2012 High incidence of cardiovascular complications in pheochromocytoma. Hormone and Metabolic Research 44 379–384. (https://doi.org/10.1055/s-0032-1306294)
