Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial.

in Lancet (London, England) by Eric Baudin, Bernard Goichot, Alfredo Berruti, Julien Hadoux, Salma Moalla, Sandrine Laboureau, Svenja Nölting, Christelle de la Fouchardière, Tina Kienitz, Timo Deutschbein, Stefania Zovato, Laurence Amar, Magalie Haissaguerre, Henri Timmers, Patricia Niccoli, Antongiulio Faggiano, Moussa Angokai, Livia Lamartina, Florina Luca, Deborah Cosentini, Stefanie Hahner, Felix Beuschlein, Marie Attard, Matthieu Texier, Martin Fassnacht, ,

TLDR

  • The study looked at whether sunitinib, a medicine used to treat certain types of tumors, was safe and effective for people with metastatic phaeochromocytomas and paragangliomas. The study found that the medicine was effective in slowing down the growth of the tumors, and that it was generally safe for people to take. The study also looked at some limitations and suggested some future research directions. The study was funded by several organizations.

Abstract

No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment. From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. 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. This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.

Overview

  • The study aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). The primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1).
  • The study used a randomised controlled trial design, with 78 patients enrolled, 39 in each group. The study aimed to determine the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. The primary endpoint was the rate of progression-free survival at 12 months, which was met with a 12-month progression-free survival rate of 36% in the sunitinib group and 19% in the placebo group. The study also evaluated the safety of sunitinib, with the most frequent grade 3 or 4 adverse events being asthenia, hypertension, and back or bone pain in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group, while two deaths occurred in the placebo group. The study supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. The study was funded by the French Ministry of Health, the German Ministry of Education and Research, the German Research Foundation, the EU Seventh Framework Programme, and a private donator grant.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions, specifically the use of sunitinib versus placebo in patients with metastatic phaeochromocytomas and paragangliomas. The study found that the 12-month progression-free survival rate was significantly higher in the sunitinib group (36%) compared to the placebo group (19%). The study also evaluated the safety of sunitinib, with the most frequent grade 3 or 4 adverse events being asthenia, hypertension, and back or bone pain in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group, while two deaths occurred in the placebo group. The study supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. The study was funded by the French Ministry of Health, the German Ministry of Education and Research, the German Research Foundation, the EU Seventh Framework Programme, and a private donator grant.

Implications and Future Directions

  • The study's findings have significant implications for the field of research or clinical practice, as they provide evidence for the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. The study also identifies potential limitations, such as the small sample size and the need for long-term follow-up to evaluate the long-term safety and efficacy of sunitinib. Future research directions could include larger studies with longer follow-up to evaluate the long-term safety and efficacy of sunitinib, as well as studies to evaluate the combination of sunitinib with other therapies. The study was funded by the French Ministry of Health, the German Ministry of Education and Research, the German Research Foundation, the EU Seventh Framework Programme, and a private donator grant.
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