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The use of the tyrosine kinase inhibitor (TKI) sunitinib (Sutent) significantly improved progression-free survival (PFS) in patients with malignant pheochromocytoma and paraganglioma (PPGL), an extremely rare neuroendocrine tumor, according to results from the randomized FIRSTMAPPP trial.

The primary endpoint of PFS rate at 12 months was 35.9% for patients randomized to sunitinib compared with 18.9% for those assigned to placebo, with a median PFS that was 5.3 months longer in the sunitinib arm (8.9 vs 3.6 months), reported Eric Baudin, MD, of Institut Gustave Roussy in Villejuif, France, during the virtual European Society for Medical Oncology (ESMO) meeting.

The objective response rate (ORR) among all patients receiving sunitinib was 31%, and was 50% in patients with SDHB-mutated tumors, compared with 8% in the placebo group, results that discussant Rocio Garcia-Carbonero, MD, of Hospital Universitario 12 de Octubre in Madrid, called "remarkable."

"This is practice changing," Baudin said during his presentation. "Sunitinib becomes the therapeutic option with the most robust evidence of antitumor activity in progressive malignant pheochromocytoma and paraganglioma."

Garcia-Carbonero noted that PPGL has an incidence rate of just six new cases per million persons per year, with metastasis occurring in less than one case per million.

"Once we are facing a metastatic disease, our treatment options are very, very limited," she pointed out. These include metaiodobenzylguanidine (a compound combined with radioactive iodine to deliver targeted radiation therapy), peptide receptor radionuclide therapy, or chemotherapy.

"Malignant pheochromocytoma and paraganglioma are highly vascularized tumors arising from the adrenal medulla and paraganglia, and the strong expression of VEGF, PDGF, and their receptors, has been described in PPGL," Baudin explained.

FIRSTMAPPP was a double-blind randomized phase II trial that was conducted at 15 centers in four European countries. Seventy-eight patients (median age 53, 59% men) with malignant non-resectable progressive PPGL were randomized 1:1 to receive sunitinib 37.5 mg per day or placebo. Baseline characteristics were balanced between the study arms. Median follow-up was 27.2 months.

In an intent-to-treat population analysis with a two-step Simon model of 74 patients, the researchers hypothesized that there would be a 20% increase in PFS; sunitinib would be considered effective if at least 11 of 37 patients were without progression at 1 year.

Regarding safety and tolerability, the most common grade 3/4 adverse events among patients in the sunitinib arm were asthenia-fatigue (18%) and hypertension (10%). Dose reductions were required in 59% of patients on sunitinib, and drug discontinuation due to adverse events occurred in 14%. Three deaths were reported in the sunitinib arm, one of which (rectal bleeding in a patient with pelvic bone metastases) was considered to be drug related.

"Does this FIRSTMAPPP clinical trial change our clinical practice?" asked Garcia-Carbonero. She pointed out that TKIs are not included as treatment options in National Comprehensive Cancer Network and ESMO-European Reference Network for Rare Adult Solid Cancers clinical practice guidelines. She also suggested that the evidence provided for other treatment options in clinical guidelines "is very, very poor."

"This is a positive trial -- sunitinib is active in these patients," she added. "This is the first randomized trial -- and largest trial -- ever conducted in the field of metastatic PPGLs. This is the highest level of evidence ever reached in this very rare cancer. Efficacy is reported in the range of other systemic treatment options included in clinical guidelines. And I agree with Dr. Baudin -- it is practice changing, and sunitinib has become the therapeutic option with the most solid and robust evidence of antitumor activity that we have to date."

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