Results from the phase II FIRSTMAPPP study support the potential use of the tyrosine kinase inhibitor sunitinib in two rare neuroendocrine malignancies—pheochromocytoma and paraganglioma. Sunitinib significantly improved the primary endpoint of progression-free survival vs placebo, according to this first randomized, double-blind evidence for sunitinib in this setting. The results were presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2021.1
At 12 months, the primary endpoint of progression-free survival was improved from 18.9% for those in the placebo group to 35.9% for those randomly assigned to sunitinib. Median progression-free survival was 8.9 months with sunitinib vs 3.6 months with placebo, a difference of 5.3 months favoring the tyrosine kinase inhibitor.
A difference in objective response rate was also seen in the trial: 31% among all patients receiving sunitinib vs 8% for those assigned to placebo. Patients in the sunitinib arm with succinate dehydrogenase complex, subunit B (SDHB)-mutated tumors had a 50% objective response rate.
Eric Baudin, MD
“These results are practice-changing,” stated lead author Eric Baudin, MD, of Institut Gustave Roussy, Villejuif, France. “Sunitinib has become the therapeutic option with the most robust evidence of antitumor activity in progressive malignant pheochromocytoma and paraganglioma.”
FIRSTMAPPP was a double-blind, randomized, phase II trial conducted at 15 centers in 4 European countries. Over 8 years, the study randomly assigned 78 patients with malignant nonresectable pheochromocytoma and paraganglioma in a 1:1 ratio to receive continuous sunitinib at 37.5 mg/d or placebo.
“The design and clinical method were based on extreme toxicities to this cancer, compatibility of hormone- and drug-related hypertension, behavior of this group of tumors, and the absence of standard therapy,” Dr. Baudin explained.
Stratification factors were SDHB mutation status (associated with an inherited predisposition to these rare tumors) and line of treatment. Patients were evaluated every 12 weeks. All patients had metastatic disease and had had disease progression within the previous 18 months. Exclusion factors were uncontrolled hypertension, abnormal cardiac function, and prior treatment with tyrosine kinase inhibitors or VEGF-targeting angiogenesis inhibitors.
“The first patient was assigned to treatment in 2011, and data lock occurred 10 years later,” Dr. Baudin noted. Baseline characteristics were well balanced between the two study arms. The median age was 53 years; 19% of patients were male. Among all patients, 32% had an SDHB mutation, 50% had pheochromocytoma, and 50% had paraganglioma; 40% were receiving first-line treatment; 40% had hypertension; and 60% had bone metastasis. Median follow-up was 27.2 months.
The median duration of sunitinib therapy was 11 months, compared with 4 months in the placebo arm. The majority (87%) of patients given placebo crossed over to sunitinib at disease progression. Among patients with an SDHB mutation, six had a partial response (50%), four had stable disease (33%), and two developed progressive disease in the sunitinib arm.
Among all patients, 48 (61%) developed a grade 3 or higher adverse event, including 28 patients (72%) given sunitinib and 20 (51%) given placebo. The most common grade 3 or 4 adverse events in the sunitinib arm were asthenia/fatigue and hypertension.
Among sunitinib-treated patients, dose reductions were needed in 59%, and drug discontinuations due to adverse events were reported in 14%. Of the three deaths reported in the sunitinib arm, one was deemed drug-related (rectal bleeding).
DISCLOSURE: Dr. Baudin has served on an advisory board for Novartis, AAA Pharma, Pfizer, and Hutchinson Pharma; and has received research support from Pfizer, Novartis, HRA Pharma, and Ipsen.
1. Baudin E, Goichot B, Berutti A, et al: First International Randomized Study in Malignant Progressive Pheochromocytoma and Paraganglioma (FIRSTMAPPP). ESMO Congress 2021. Abstract 5670. Presented September 20, 2021.
The invited discussant of the FIRSTMAPP study, Rocio Garcia-Carbonero, MD, of Hospital Universitario 12 de Octubre, Madrid, emphasized that pheochromocytoma and paraganglioma are rare tumors, and once they become metastatic, which is even more rare, there are few treatment options.
“This is very...