The first FDA approved treatment for ultra-rare endocrine tumors

Patients diagnosed with pheochromocytoma or paraganglioma, tumors that form within certain endocrine tissues, such as the adrenal glands, may have abnormal endocrine activity due to the synthesis and release of catecholamines that predispose to cardiovascular disease. They are typically diagnosed while the disease is localized and can be effectively removed in surgery. However, between 15 and 20% of patients are diagnosed after they have already progressed to late-stage metastatic disease, which carries a graver prognosis, with a survival rate of just 50-60% after five years.

Fortunately, there is now an effective treatment available for patients with unresectable, locally advanced or metastatic pheochromocytoma and paraganglioma (PPGL). A recent review in Cancers from Dr. Camilo Jimenez and colleagues at the MD Anderson Cancer Center in Houston, Texas, describes the development and clinical impact of this drug, high-specific-activity iodine-131 metaiodobenzylguanidine (HSA-MIBG)¹, which is now marketed as AZEDRA® by Progenics Pharmaceuticals.

The first iteration of MIBG was developed in 1979, by the late Donald Wieland, and colleagues at the University of Michigan², to help image the adrenal medulla — a gland adjacent to the kidney in which these tumors form. MIBG binds to a protein commonly expressed on the surface of PPGL cells, which facilitates the transport of the neurotransmitter norepinephrine. Jimenez notes that this effective tumor-labeling technique also revealed a promising therapeutic avenue. “People noticed that if we use it at high doses, the concentration of radioactivity may kill the tumor cells,” he says.

One of the earliest reports of this therapeutic approach, known today as low-specific activity (LSA)-MIBG, was published in 1984³, and a number of clinicians subsequently administered it to PPGL patients. The resulting data highlighted the clear promise of this treatment. For example, one review of 116 patients found that LSA-MIBG induced tumor shrinkage or eradication in 30% of cases and kept progression in check for another 57%⁴. The vast majority of these studies were retrospective, and used a range of different doses, which made it difficult to draw robust conclusions about how to best employ LSA-MIBG. “They had many variables that were quite heterogeneous,” says Jimenez. It was not until 2009 that the drug was subjected to a formal phase 2 clinical trial⁵, which not only demonstrated clear medical benefit but also produced serious, and in some cases, lethal, toxic effects in many patients due to the high dose employed.

One of the key problems with this formulation was the inefficiency of the radiolabeling strategy, which leaves behind many unmodified ‘cold’ MIBG molecules. This results in poor tumor-killing efficiency when administered at lower doses, and also creates the potential for side-effects from the excessive levels of cold MIBG, which can exceed the number of radiolabeled molecules by a ratio of 2,000:1. These ‘cold’ MIBG molecules prevent the reuptake of norepinephrine, increasing norepinephrine’s extracellular concentration and exacerbating manifestations of catecholamine excess, such as acute hypertensive crisis. In 2010, a team of researchers at Molecular Insight Pharmaceuticals devised an alternative chemical strategy for radiolabeling, which enabled them to generate high-specific activity (HSA)-MIBG⁶. This formulation can deliver 100–200-fold higher levels of radiation to tumor cells at lower overall doses, resulting in a safer and more effective treatment. Molecular Insight was subsequently acquired by Progenics in 2013, who oversaw the completion of clinical testing and development of the drug.

Unlike LSA-MIBG, HSA-MIBG was subjected to the standard clinical trials regimen for drugs entering the market. Following initial phase 1 trials, which established an optimal dose for metastatic PPGL patients and demonstrated that the drug is reasonably safe, HSA-MIBG was subjected to a pivotal multi-center phase 2 trial in 68 patients with this advanced form of the cancer, one of the largest prospective studies conducted⁷. The primary endpoint of the trial was control of hypertension, an important consequence of the abnormal endocrine activity associated with these tumors, and 25% of patients had this response. More importantly, the vast majority of patients experienced either meaningful reduction in tumor size or a lack of progression. “We were able to obtain clinical benefit in more than 90% of our patients,” says Jimenez, who was an investigator for the phase 2 study.

Another important outcome was the fact that the drug exhibited a tolerable safety profile in patients. Among the most serious potential risks of treatment with LSA-MIBG at doses required to treat cancer are severe cardiovascular and pulmonary adverse events. In contrast, with HSA-MIBG, no severe hypertension or catecholamine crises were noted. Another serious risk of treatment is depletion of bone marrow cells—two patients in the phase 2 trial of LSA-MIBG died as a consequence of this⁵. “In our phase 2 trial, 23% of patients had bone marrow suppression that was considered severe,” says Jimenez. “But all of those patients recovered over time, and there was no need for the bone marrow transplantation.” On the strength of these safety and efficacy data, AZEDRA received approval from the US Food & Drug Administration in late 2018.

Jimenez and his co-authors see abundant opportunities to further bolster HSA-MIBG’s efficacy. Many cancer patients today receive combination therapies that incorporate a variety of agents, and similar approaches could also prove advantageous for HSA-MIBG. For example, some data suggest that treatment with chemotherapy drugs could enhance the sensitivity of tumor cells to this radiotherapy strategy. Tyrosine kinase inhibitor drugs, which selectively act on various signaling proteins that contribute to the resilience and uncontrolled growth of tumor cells, could also prove to be potent partners. One case report has described how a combination of MIBG and the tyrosine kinase inhibitor sunitinib put a patient into full remission for nine months⁸.

It is also clear that certain patients are inherently more likely to respond well to treatment. “In the clinical trials, there have been patients treated with the drug four years ago who continue to have an excellent clinical response,” says Jimenez. The factors contributing to this enhanced response are unclear, but genetics could play a role. Jimenez notes that genetic factors contribute to tumor formation and progression in up to 70% of patients. Moreover, certain mutations may render advanced PPGL particularly vulnerable or resistant to HSA-MIBG.

Even if these questions are unresolved for now, advanced PPGL patients finally have access to a new therapeutic option that could greatly improve their likelihood of achieving meaningful and durable disease control. “Finally, we have the opportunity to think bigger in the field of therapeutics for metastatic pheochromocytoma,” says Jimenez. “And maybe someday will be able to achieve a cure for patients who have these cancers.”