Sunitinib effective in malignant pheochromocytoma and paraganglioma

FIRSTMAPPP is the first international randomised study in malignant progressive pheochromocytoma and paragangliomas. After eight years of enrolment, FIRSTMAPPP provides the highest level of evidence ever reached in this very rare cancer and demonstrates that sunitinib is effective in patients with malignant, non-resectable, progressive malignant pheochromocytoma and paraganglioma.

Malignant pheochromocytoma and paraganglioma (MPPGL) are highly vascularised tumours arising from the adrenal medulla and paraganglia. MPPGL is a very rare cancer with an annual incidence of less than one per million. A strong expression of VEGF, PDGF and their receptors has been described in PPGL. These results, as well as additional preclinical and clinical data, have justified the choice of sunitinib as the first drug to investigate in MPPGL by a board of experts in 2008.

FIRSTMAPPP study design

FIRSTMAPPP is a double-blind academic randomised phase II trial with 15 participating centres across 4 European countries. Patients with malignant, non-resectable, progressive PPGL were randomised (1:1) to sunitinib therapy (37.5 mg/d, continuous dosing) or placebo and were stratified for SDHB status and line of treatment. Patients with hypertension that could not be controlled, abnormal cardiac function or prior treatment with tyrosine kinase inhibitors or anti-VEGF angiogenic inhibitors were excluded from the study. Patients were evaluated every 12 weeks. At time of progression, crossover was allowed. The primary endpoint of the trial was progression-free survival (PFS) at 12 months, according to real-time central review. On the basis of a two-step Simon model (alpha 10%, power 90%), the study aimed for 74 patients, assuming a PFS improvement at 12 months from 20 to 40%. Eleven or more patients out of 37 with no progression at 12 months were expected to conclude that sunitinib is effective. The placebo group served as an internal control to validate the hypothesis of the Simon design with a 12-month PFS rate of 20%. Secondary endpoints included overall survival (OS), PFS, objective response rate (ORR), time to progression, duration of response (DOR) and safety.

Results

After eight years of enrolment, 78 patients were included in the study. Thirty-two percent of patients had an SDHB mutation, 60% had received prior therapy, 50% had pheochromocytoma and 50% had paraganglioma primaries, 40% had hypertension and 60% had bone metastases. Thirty-nine patients were randomised in each arm. After a median follow-up of 27.2 months, 14 patients in the sunitinib arm did not show disease progression at one year and the primary endpoint was thus met. Progression-free survival at 12 months in the sunitinib arm was 35.9%, as compared to 18.9% in the placebo arm. Patients treated with sunitinib demonstrated a median PFS of 8.9 months, compared to only 3.6 months in the placebo group. Median sunitinib treatment duration was 11 months (range, 0-37), compared to 4 months in the placebo arm (range, 0-35). In total, 87% of placebo patients crossed over to treatment with sunitinib. Overall, 31% and 8% of patients in the sunitinib and placebo arms respectively obtained a partial response. Of the twelve patients with SDHB-positive mutations, six had a partial response (50%), four had stable disease (33%) and two had progressive disease (17%), following treatment with sunitinib.

Among the 78 patients, 48 patients (61%) experienced a grade 3-5 adverse events; 28 (72%) in the sunitinib arm vs. 20 (51%) in the placebo arm, including asthenia-fatigue (18% vs. 3%, respectively), hypertension (10% vs. 6%), and bone pain (0% vs. 10%). Dose reductions were needed in 59% of patients in the sunitinib arm and in 13% of patients in the placebo arm. Drug withdrawal for an adverse events was reported in 14% and 0% of patients in the sunitinib and placebo arm, respectively. Three deaths occurred in the sunitinib arm (due to rectal bleeding-pelvic bone metastases, respiratory insufficiency, and peritoneal carcinomatosis). However, only the death due to rectal bleeding was deemed to be drug-related. In the placebo-arm, one death due to cerebrovascular ischemia was reported.

Conclusion

FIRSTMAPPP is the first randomised trial in the field of malignant pheochromocytoma and paraganglioma. In this study, sunitinib was associated with a 35.9% 12-month progression-free survival. In addition, 37.5 mg sunitinib per day was manageable and partial responses were not restricted to SDHB-mutated patients. This is the highest level of evidence ever reached in this very rare cancer. Therefore, sunitinib becomes the therapeutic option with the most robust evidence of antitumor activity in progressive malignant pheochromocytoma and paraganglioma.

Reference

Baudin E, Goichot B, Berruti A, et al. FIrst International Randomized STudy in MAlignant Progressive Pheochromocytoma and Paraganliomas (FIRSTMAPPP): an academic double-blind trial investigating sunitinib. Presented at ESMO 2021; Abstract 5670_PR.