The primary endpoint of the FIRSTMAPPP study was met. The study provides the highest level of evidence ever reached to support the antitumour role of a systemic treatment option in patients with aggressive metastatic phaeochromocytomas and paragangliomas, and supports sunitinib as a potential candidate for first-line therapy. Higher response rate observed in patients with pathogenic germline SDHB variant constitute the first steps towards a personalised approach in this patient cohort.
The FIRSTMAPPP study is the first in the field of patients with metastatic phaeochromocytomas and paragangliomas and one of the very few randomised controlled trials in the field of ultra-rare cancers as recently defined by an annual incidence of less than one per million. The best feasible methodology was applied including a placebo-controlled, double-blind randomised trial design. Findings are reported by Dr. Eric Baudin of the Department of Imaging, Endocrine Oncology Unit, Gustave Roussy, University Paris Saclay in Villejuif, France and colleagues on behalf of the ENDOCAN-COMETE and ENSAT Networks on 22 February 2022 in The Lancet.
Main characteristics of metastatic phaeochromocytomas and paragangliomas include inherited diseases in up to 50% of cases, including germline SDHB variants that have prognostic impact, hormone-related hypertension in up to 80%, and bone metastases in up to 70% of cases. As metastatic phaeochromocytomas and paragangliomas are indolent in some cases, the decision to initiate systemic treatment is mainly based on the presence of uncontrolled hormone secretion or documented tumour progression.
So far, no randomised controlled trial in patients with metastatic phaeochromocytomas and paragangliomas has been published. Meta-iodobenzylguanidine therapy and dacarbazine-based cytotoxic chemotherapy constitute the two main historical options. Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor directed against VEGFR, PDGFR, and RET. In 2008, a group of experts selected sunitinib as the choice of drug to be investigated in patients with metastatic phaeochromocytomas and paragangliomas. In the absence of robust prospective data, a placebo was chosen as the best control group by the same group of experts.
The FIRSTMAPPP study is an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase II study. A total of 14 academic centres across four European countries were involved. The study investigators aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. Eligible participants were adults with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas.
Patients were randomly assigned 1:1 to receive either oral sunitinib or placebo. Randomisation was stratified according to SDHB status (mutation present versus wild type) and number of previous systemic therapies (0 versus ≥1). Primary endpoint was the rate of progression-free survival (PFS) at 12 months according to real-time central review by RECIST v1.1. Based on a two-step Simon model, the study team aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month PFS rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. The study is closed for enrolment.
From 1 December 2011 to 31 January 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enroled (39 patients per group). A total, 25 of 78 patients (32%) had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month PFS in 14 of 39 patients (36%, 90% confidence interval [CI] 23–50) in the sunitinib group. In the placebo group, the 12-month PFS in 7 of 39 patients was 19% (90% CI 11–31), validating the hypotheses of study design.
The most frequent grade 3 or 4 adverse events were asthenia (18% and 3%), hypertension (13% and 10%), and back or bone pain (3% and 8%) in the sunitinib and placebo groups. Three deaths occurred in the sunitinib group; these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock.
The authors commented that more than 10 years after the inclusion of the first patient in the FIRSTMAPPP study, the therapeutic options have changed for metastatic phaeochromocytomas and paragangliomas. As the first randomised controlled study in the field of patients with metastatic phaeochromocytomas and paragangliomas, FIRSTMAPPP is a major step forward to supporting sunitinib as the best validated treatment option and a potential candidate for first-line treatment in progressive metastatic phaeochromocytomas and paragangliomas. The placebo-control group study design used in FIRSTMAPPP does not allow the claim that sunitinib is superior to any other treatment option.
In an accompanied comment, Dr. Mitsuhide Naruse of the Endocrine Center and Clinical Research Center, Ijinkai Takeda General Hospital in Kyoto, Japan and Dr. William F Young Jr of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine and Science in Rochester, MN, US wrote that leveraging of the experience in endocrine oncology, including the randomised controlled trial for adrenocortical carcinoma and the infrastructure of multicentre collaboration has made the FIRSTMAPPP study possible.
Although this research marks a new stage in treating patients with metastatic phaeochromocytoma and paraganglioma, achieving complete control and cure remains distant. Because of the substantial adverse-effect profile, sunitinib should be reserved for patients with documented progressive disease. The FIRSTMAPPP trial is a major step forward, but further progress is needed on comprehensive treatment strategies that prioritise and combine treatment based on clinical findings. The establishment of multidisciplinary teams in specialised centres for determining individualised treatment strategies and the development of more effective novel molecular targeted drugs according to the methods meticulously established by the FIRSTMAPPP trial are eagerly awaited according to the commentators.
This study was funded by the French Ministry of Health, through the National Institute for Cancer, the German Ministry of Education and Research, the German Research Foundation within the CRC/Transregio 205/2, and a grant from the EU Seventh Framework Programme grants. Sunitinib and placebo were provided by Pfizer. A private donator grant supported two expert meetings of the FIRSTMAPPP Tumour Board.
References
- Baudin E, Goichot B, Berruti A, et al. on behalf of the ENDOCAN-COMETE and ENSAT Networks. Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial. The Lancet; Published online 22 February 2024. DOI: https://doi.org/10.1016/S0140-6736(23)02554-0
- Naruse M, Young Jr WF. Targeted molecular medicine: advances in the treatment of metastatic phaeochromocytoma and paraganglioma. The Lancet; Published online 22 February 2024. DOI: https://doi.org/10.1016/S0140-6736(23)02828-3