Cabozantinib in Metastatic Pheochromocytomas or Paragangliomas

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In the single-center phase II Natalie trial reported in The Lancet Oncology, Jimenez et al found that cabozantinib was active in patients with unresectable and progressive metastatic pheochromocytomas or paragangliomas (MPPGs).

As stated by the investigators: “Up to 50% of MPPGs are associated with germline pathogenic variants of the SDHB gene. These tumors and many nonfamilial MPPGs exhibit a phenotype that is characterized by abnormal angiogenesis. We aimed to assess the activity and safety of cabozantinib, an antiangiogenic multityrosine kinase inhibitor, in patients with MPPGs.”

Study Details

In the trial, 17 patients enrolled at The University of Texas MD Anderson Cancer Center between March 2015 and May 2021 received cabozantinib at 60 mg/d until disease progression or unacceptable toxicity. The primary outcome measure was investigator-assessed objective response rate.


Median follow-up was 25 months (interquartile range = 18–49 months). A total of 16 patients had measurable disease at baseline. Objective responses (all partial) were observed in 4 of 16 evaluable patients (25.0%, 95% confidence interval [CI] = 7.3%–52.4%). Clinical benefit was observed in 15 patients (93.8%, 95% CI = 69.8%–99.8%) Stable disease for more than 3 years was observed in 4 of 17 patients (24%), and 1 patient (6%) had a response maintained for more than 4 years.


  • Cabozantinib produced objective response in 25% of patients.
  • Median progression-free survival was 6 months (95% CI = 8.1–34.9 months).

Median progression-free survival was 16.6 months (95% CI = 8.1–34.9 months), with a 1-year rate of 58.8% (95% CI = 39.5%–87.6%). Median overall survival was 24.9 months (95% CI = 23.6 months to not reached).

Adverse Events

A total of seven grade 3 adverse events were reported in 6 of 17 patients (35%), including hand-foot syndrome, hypertension, rectal fistula, QT prolongation, asymptomatic hypomagnesemia, and elevated amylase and lipase. Adverse events led to dose reduction in 15 of 17 patients (88%). No grade 4 adverse events were observed, and no treatment-related deaths were reported.

The investigators concluded: “Cabozantinib shows promising activity in patients with MPPGs.”

Camilo Jimenez, MD, of the Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, is the corresponding author of The Lancet Oncology article.

Disclosure: The study was funded by Team NAT Foundation, Margaret Cazalot, and Clarence P. Cazalot. For full disclosures of the study authors, visit

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