Sunitinib Effective for Malignant Pheochromocytoma/Paraganglioma

Pheochromocytomas and paragangliomas (PPs) are rare neuroendocrine tumors that arise from chromaffin cells in the adrenal medulla or extra-adrenal autonomic paraganglia, respectively. The majority of PPs are benign and treated successfully with surgery. However, a small number of patients (<1 per million people) are diagnosed with malignant PPs (MPPs), defined by the World Health Organization as PPs with the presence of metastases in non-chromaffin organs, most frequently in the bone, liver, lungs, and lymph nodes. The prognosis for patients with MPPs is variable with 5-year survival rates ranging from 40% to 85%. The presence of SDHB mutations and primary tumor size are negative prognostic factors. The management of MPPs is challenging, and there is a high unmet need for better treatment options. These tumors are highly vascularized, and preclinical and early clinical data indicated potential activity of angiogenesis-targeting tyrosine kinase inhibitors such as sunitinib.

At this year’s ESMO congress, results from the international, academic, double-blind, randomized, phase II FIRSTMAPPP trial of sunitinib efficacy in MPPs were presented by Eric Baudin, MD (Gustave Roussy – Cancer Campus, Villejuif, France). A total of 78 patients with non-resectable, progressive MPPs were enrolled over 8 years and treated with either sunitinib (n=39) at a continuous dose of 37.5 mg per day until disease progression, or placebo (n=39). Crossover to sunitinib was permitted for patients progressing on placebo. Patients’ characteristics were well balanced: among all patients, 32% had SDHB mutations; 40% had baseline hypertension; 60% had bone metastases; and for 40% of patients this was first-line treatment. Median follow-up was 27.2 months. The primary endpoint of the trial was met with 35.9% of patients in the sunitinib arm achieving progression-free survival (PFS) at 12 months vs. 18.9% with placebo. Based on the trial’s statistical design, the data supported the efficacy of sunitinib. Median PFS was 8.9 vs. 3.6 months. Partial response (PR) was reported in 31% of patients in the sunitinib arm with a treatment duration of 11 months, compared with 8% and 4 months in the placebo arm, respectively. Of note, PR was not restricted to patients with SDHB-mutated tumors only, although more PRs were reported in patients with SDHB-mutated tumors (50% vs. 26%). The majority of patients in the placebo arm (87%) crossed over to sunitinib at the time of disease progression. Adverse events (AEs) of grade ≥3 were reported in 72% of patients treated with sunitinib vs. 51% with placebo; the most frequent grade 3 – 4 AEs were asthenia/fatigue (18% vs. 3%) and hypertension (10% vs. 6%); there were three deaths in the sunitinib arm (one was not treatment related) vs. one death in the placebo arm.

Dr. Baudin concluded that the results are practice changing, with sunitinib showing ‘the most robust evidence of antitumor activity in progressive MPPs’. The discussant of the trial, Rocio Garcia-Carbonero, MD (University Hospital Madrid, Spain) congratulated the investigators on conducting the first and largest randomized trial in MPPs, which provides the highest level of evidence in this very rare cancer. She highlighted that the trial demonstrates the importance of collaborative academic research and agreed with Dr. Baudin that the results are practice changing.

Baudin E, et al. ESMO 2021; Abstract 5670_PR.