Sunitinib in Malignant Pheochromocytoma/Paraganglioma Show Efficacy, May Change Future Practice

Among patients with malignant pheochromocytoma and paraganglioma, treatment with sunitinib (Sutent) demonstrated improved efficacy, according to data from the FIRSTMAPPP trial presented at the 2021 ESMO Congress.

MPPGL, a very rare cancer with an annual incidence < 1 per million, are highly vascularized tumors that arise from the adrenal medulla and paraganglia, with strong expression of VEGF, PDGF, and VEGFR-1/2, according to Eric Baudin, MD, PhD. At the Congress, he reported on the first academic randomized, double-blind phase 2 FIRSTMAPPPstudy results assessing sunitinib efficacy compared to placebo in patients with MPPGL.

“Together with a team of experts and also both of translational researchers, we elected sunitinib as the first drug to investigate in [MPPHLs]. The design and clinical method [were created based on] extreme toxicities to this cancer, compatibility of hormone- and drug-related hypertension, behavior of the group of tumors, and absence of standard,” explained Baudin, Department of Endocrine Oncology, Gustave Roussy.

Patients with malignant, non-resectable progressive PPGL were randomized 1:1, stratified by SDHB status and line of treatment, to receive either 37.5 mg sunitinib per day with continuous dosing or placebo.

Main inclusion criteria were metastatic disease, pre-treatment, inherited disease, evaluable RECIST 1.1 criteria, and progressive disease within 18 months, according to RECIST. Exclusion criteria was comprised of hypertension that could not be controlled, abnormal cardiac function, and treatment with prior tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors.

Patients were evaluated every 12 weeks. At time of progression, crossover was allowed.

The primary end point of the trial was progression-free survival (PFS) at 12 months, according to real-time central review. Secondary end points included overall survival (OS), PFS, time to progression, duration of response, and safety. Exploratory objectives of the study were predictors and surrogates (symptoms, genetic status, FDG-PET, conventional imaging, hormones, quality of life, safety), hormone response, and cardiovascular management.

In 8 years, 78 patients were enrolled in the trial. In total, 32% had a SDHB mutation, 40% were receiving first-line treatment, 40% had hypertension, and 60% had bone metastases.

Median follow-up was 27.2 months.

Of the 39 patients treated with sunitinib, 14 (35.9%) had no progression at 1 year, compared with 18.9% in the placebo arm, meeting the trial’s primary endpoint.

Those treated with sunitinib demonstrated a media PFS of 8.9 months (95% CI, 5.5-12.7), compared with 3.6 months (95% CI, 3.1-6.1) in the placebo group.

Median sunitinib treatment duration was 11 months (range, 0-37), compared with 4 months in the placebo arm (range, 0-35), of which 87% crossed over to treatment with sunitinib.

Of the patients with SDHB-positive mutations, 6 had a partial response (50%), 4 had stable disease (33%) and 2 had progressive disease (17%) following treatment with sunitinib.

In total, 48 patients (61%) experienced a grade 3 or higher adverse event (AE)–28 (72%) in the sunitinib arm and 20 (51%) on the placebo arm–including asthenia-fatigue (18% vs 3%, respectively), hypertension (10% vs 6%), and bone pain (0% vs 10%). Drug decrease occurred in 59% vs 13%, respectively, in the sunitinib and placebo arms, and drug withdrawal from an AE occurred in 14% vs 0%. Three deaths occurred in the sunitinib arm (rectal bleeding-pelvic bone metastases, respiratory insufficiency, and peritoneal carcinomatosis); however, only 1 death was drug related (rectal bleeding). One death occurred in the placebo arm (ischemia cerebrovascular).

“This is the highest level of evidence ever reached in this very rare cancer,” Baudin concluded. “This is practice changing, if sunitinib becomes a therapeutic option, with the most robust evidence of anti-tumor activity in progressing metastatic pheochromocytoma and paraganglioma.”

Invited discussant, Rocio Garcia-Carbonero, MD, Gastrointestinal (GI) Tumor Unit, Hospital Universitario Doce de Octubre in Madrid, agreed that the data could be practice changing for this patient population moving forward.

“I think this is a positive trial; sunitinib is active in these patients. Efficacy is particularly relevant in but not restricted to SDHB-mutated tumors. Safety seems to be reasonable and manageable. So, this is the first and largest trial ever conducted in the field of metastatic PPGL,” she said.

“This is the highest level of evidence ever reached in this very rare cancer. It is in the range of all the systemic treatment options included in clinical guidelines. And I do agree with Dr. Baudin: It is practice changing. And sunitinib has become the therapeutic options with the most solid and robust evidence of anti-tumor activity that we have to date.”

_Reference:

_{1. Baudin E, Goichot B, Berruti A, et al. First International Randomized Study in Malignant Progressive Pheochromocytoma and Paragangliomas (FIRSTMAPPP): An academic double-blind trial investigating sunitinib. Annals of Oncology. 2021;32(suppl_5): S621-S625. doi:10.1016/annonc/annonc700.}