In a phase II trial (FIRSTMAPPP) reported in The Lancet, Eric Baudin, MD, and colleagues found that the multikinase inhibitor sunitinib was active in patients with metastatic progressive pheochromocytomas and paragangliomas.
As stated by the investigators, “No randomized controlled trial has ever been done in patients with metastatic pheochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib.”
Eric Baudin, MD
Study Details
The double-blind trial enrolled 78 patients with sporadic or inherited disease from sites in France, Italy, Germany, and the Netherlands. Patients were randomly assigned between December 2011 and January 2019 to receive sunitinib at 37.5 mg per day (n = 39) or placebo (n = 39), with treatment continued until disease progression or unacceptable toxicity. A total of 25 patients (32%) had germline SDHx variants and 54 (69%) had received previous therapies. Crossover to the sunitinib group was permitted. The primary endpoint of the trial was the rate of progression-free survival at 12 months.
12-Month Progression-Free Survival
Progression-free survival at 12 months was observed in 14 patients (36%, 90% confidence interval [CI] = 23%–50%) in the sunitinib group vs 7 patients (19%, 90% CI = 11%–31%) in the placebo group, meeting the prespecified criteria for declaring sunitinib an effective therapy.
Median follow-up was 29.7 months (interquartile range [IQR] = 18.4–37.0 months). Median progression-free survival was 8.9 months (IQR = 3.4–19.5 months) in the sunitinib group vs 3.6 months (IQR = 3.0–8.6 months) in the placebo group; rates at 12 and 24 months were 35.9% vs 18.9% and 17.6% vs 8.4%, respectively. A total of 27 patients (69%) in the placebo group crossed over to receive sunitinib. Overall survival rates at 12 and 24 months were 78.3% vs 75.2% and 56.7% vs 58.1%, respectively.
KEY POINTS
- Findings indicated that sunitinib is an effective therapy in this setting.
- 12-month progression-free survival rates were 36% in the sunitinib group vs 19% in the placebo group.
Adverse Events
The most common grade 3 or 4 adverse events in the sunitinib group and the placebo group were asthenia (18% vs 3%), hypertension (13% vs 10%), and back or bone pain (3% vs 8%). Adverse events led to the discontinuation of sunitinib in 14% of those receiving the agent. Adverse events led to death in three patients in the sunitinib group, due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding (the latter considered treatment-related). Adverse events led to death in two patients in the placebo group, due to aspiration pneumonia and septic shock.
The investigators concluded, “This first randomized trial supports the use of sunitinib as the medical option with the highest level of evidence for antitumor efficacy in progressive metastatic pheochromocytomas and paragangliomas.”
Dr. Baudin, of the Department of Imaging, Endocrine Oncology Unit, Gustave Roussy, University Paris Saclay, Villejuif, is the corresponding author for The Lancet article.
Disclosure: The study was funded by the French Ministry of Health, German Ministry of Education and Research, and others. For full disclosures of the study authors, visit thelancet.com.
