BOSTON — The tyrosine kinase inhibitor cabozantinib (Cabometyx/Cometriq, Exelixis) may be a useful treatment for patients with malignant unresectable pheochromocytomas and paragangliomas, preliminary phase 2 data suggest.
The findings were presented May 18 here at the American Association of Clinical Endocrinologists (AACE) 2018 Annual Scientific & Clinical Congress by Camilo Jimenez, MD, of MD Anderson Cancer Center, Houston, Texas.
All but about 15% of the rare neuroendocrine tumors, pheochromocytomas, and paragangliomas are benign. But because there are no histologic, genetic, or molecular markers of malignancy, the presence of metastases is usually the first signal that the tumor is malignant. “And by that time, the disease is already advanced,” Jimenez told Medscape Medical News.
Malignant pheochromocytomas and paragangliomas are frequently characterized by an excessive secretion of catecholamines, large tumor burden, and decreased overall survival. There are currently no approved treatments. “It’s a very big challenge in clinical practice,” Jimenez said.
Cabozantinib, already approved for the treatment of advanced renal cell carcinoma (as Cabometyx) and metastatic medullary thyroid cancer (as Cometriq), is an anti-angiogenic tyrosine kinase inhibitor that also targets the c-Met receptor. Mutations of that receptor also occur in patients with pheochromocytomas and paragangliomas, he explained.
In the trial of 14 patients, which is still ongoing, “the drug seems to be effective and a substantial number of people respond to it. Therefore, it could be an option,” Jimenez said.
But, he cautioned that “it is not an easy drug” to use and that clinicians prescribing it need to be familiar with both the oncologic and endocrinologic manifestations of the tumor and the drug’s potential toxicities. Blood pressure, glucose, and catecholamine levels need to be controlled prior to its use, he emphasized.
Asked to comment, session moderator David Lieb, MD, program director of the endocrinology fellowship program at Eastern Virginia Medical School, Norfolk, told Medscape Medical News that cabozantinib is a “potential option for patients who have a tumor that causes significant morbidity and mortality. It’s important that clinical trials like this be done so that drugs come to market that can treat a very difficult type of cancer.”
Targeting the Tumors in a Different Way
Thus far, the study has enrolled 14 patients, including 10 with measurable metastases, meaning that they were located in organs such as the lymph nodes, liver, and lungs where radiographic assessment is possible, as opposed to those with metastases confined to the bone. Seven patients had pheochromocytomas and seven paragangliomas.
The patients were an average age of 53 years (range, 37–79). Twelve had previously undergone surgery and six had had prior chemotherapy. Cabozantinib was started at an initial daily dose of 60 mg, titrated down to 20 or 40 mg depending on tolerability.
All but one of the 10 patients with measurable disease achieved a partial or moderate response by the Response Evaluation Criteria in Solid Tumors (RECIST), and disease progressed in just one patient. Blood pressure improved in four patients.
Median progression-free survival was 12.1 months, with a range of 0.9 to 37 months, compared with 5 months prior to receiving cabozantinib (range 0.9–8 months).
Among the four patients with only bone metastases, blood pressure improved in two over a treatment duration of 6 to 18 months.
Adverse events including hand and foot syndrome, dysgeusia, mucositis, fatigue, weight loss, hypertension, and diarrhea occurred in most patients, but were nearly all grade 1 or 2 in severity. There were single grade 3 cases of elevated pancreatic enzymes and rectal fistula. No grade 4 or 5 adverse events occurred.
At this time, six patients are continuing on active treatment. Three patients have been able to tolerate the 60 mg/day dose, and the rest required reductions to 20 or 40 mg.
Indeed, Lieb noted that all tyrosine kinase inhibitors have significant side effects. Moreover, one of the most common is hypertension, which is already a major risk in patients with pheochromocytomas and paragangliomas.
“So it’s important to have data to show that the hypertension is controlled,” he stressed.
The benefit in patients with bone metastases is also important, Lieb commented, as bone is sometimes resistant to other treatments.
Overall, Lieb said that cabozantinib and related agents are “probably the future for treating this type of disease,” because they “target the tumor in a way that’s very different from what the other treatments do.”
The study was investigator-initiated and not sponsored by the manufacturer.
Rather, Jimenez told the audience, a patient who eventually died of malignant paraganglioma in her early 30s and her housemates raised the money for the trial.
Jimenez and Lieb have reported no relevant financial relationships.
American Association of Clinical Endocrinologists (AACE) 2018 Annual Scientific & Clinical Congress. May 18, 2018; Boston, Massachusetts. Abstract 142.
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