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Childhood Tumour Trust e Linfa spiegano insieme la rivoluzione Selumetinib alla comunità internazionale di pazienti

The Children’s Tumor Foundation Conference 2020 has just ended.  This year the group from the foundation, led by Annette Bakker Ph.D President Children’s Tumor Foundation has revolutionised the presentation of the conference in light of the COVID-19 pandemic and instead of the usual face to face format it was held via video-conference.  Not only was the scientific integrity of the conference maintained using this format, but the conference attendance was broadened to allow for both patient representatives and students to attend for free. Through the video conferencing platform all the scientists, and medical professionals who work for us non-stop, this time been able to update us on the scientific progress whilst maintaining social distancing.

We will summarize the main results presented at the conference, in a few informative bulletins starting with the presentation of Dr. Widemann’s group on the drug called selumetinib.

First Report

Selumetinib treatment: The frontier of hope

Selumetinib (AstraZeneca) is part of the MEK inhibitor family and it has just been approved by the Food and Drug Administration (FDA), for NF1-related inoperable, symptomatic plexiform neurofibromas in paediatric patients. This is an exciting result since FDA is the main American body that decides whether or not a drug is effective in patients and establishes also the the way it is taken of administration.

At the CTF Conference, Dr. Brigitte Widemann and Dr. Andrea Gross summarized the promising results of the phase II trial, recently published in the prestigious “New England journal of Medicine” in the article entitled: “Selumetinib in Children with Inoperable Plexiform Neurofibromas” *.

The clinicians explained that 50 children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas have been enrolled in a Phase II trial to ascertain the effectiveness of the drug on different clinical outcomes including pain; quality of life, disfigurement, and function. Selumetinib was administered orally to children twice daily on a continuous dosing schedule (28-day cycles) for several cycles all along one year. 35 of these children (70%) responded to the drug and had durable tumour shrinkage and clinical benefit. The clinicians reported clinically meaningful improvements, in fact, selumetinib significantly decreased pain, enhanced daily functioning and functional outcomes of strength and range of motion.

The further wonderful news is that the group also presented a very interesting poster illustrating the preliminary results of selumetinib treatment in adults (title: Phase II Trial of the MEK 1/2 Inhibitor Selumetinib, in Adults with Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas; First author: Dr. O’Sullivan Coyne). In fact, a phase II single site study of selumetinib in 27 adults with NF1 and inoperable plexiform neurofibromas is ongoing. It evaluates different outcomes of symptomatic and growing plexiform neurofibromas, and includes pharmacodynamic analysis, standardized patient-reported outcomes (PROs) and functional outcomes a volume tumour reduction. Indeed, the primary goal is to determine the objective response rate (plexiform volume decrease ≥20%) with selumetinib, correlating clinical and imaging responses (3D Magnetic Resonance Imaging, MRI) with biochemical analysis. As in the trial dedicated to children, also in adults clinically encouraging improvements have been reported.

Although selumetinib is generally well tolerated, there have been some minor adverse effects reported including, nausea, vomiting and diarrhoea. The European Medicine Agency (EMA), which represents the European counterpart of the FDA agency, is considering the selumetinib for approval, hopefully, it will be soon!

During the Childen’s Tumor Foundation conference others therapeutic options have been reported, but this will be the argument of the next articles.

* We would like help you in understanding better the content of the present article. Thus, we will give you brief explanations of A) MEK inhibitor; B) Farmaco-dynamic; C) What Trial Phase II is.

  1. Inhibitor means a drug that is able to stop the activity of any molecule. Selumetinib, is able to block the activity of an enzyme with a strange name: MEK. Why did scientists decided to stop MEK activity with a drug? What makes MEK so important?

Imagine driving a car: you need the accelerator and the brake. If you press the accelerator the car runs, conversely, if you press the brake the car decelerates and even stops. Similarly, the cell is guided to multiplicate its self (proliferate into two daughters’ cells) by an enzyme called Ras, working as an accelerator.

When Ras is active the cell proliferates. Of course, as in any car, also in the cells there is a brake, called neurofibromine that controls Ras it-self. In patients affected by neurofibromatosis type 1, the neurofibromine does not work well and consequently, Ras looks like an accelerator with a foot pushing continuously on it. In absence of a brake, the cells are induced to go on with proliferation. Scientists decided to intervene looking directly in the car motor. They realized that the accelerator Ras, in order to prompt cell proliferation, requires to transmit the “signal” to the motor thought a mechanical arm made by many “levers”. The last of these is called MEK.

So, they thought that blocking MEK would block the mechanical arm commanding, the scientists say “signaling”, to the engine to accelerate. That’s why they made several drugs, called MEK inhibitors, including selumetinib, designed to interfere with the MEK lever and to cause the car’s engine to slow down.

  • Pharmaco-dynamic is the study of the drug interaction with the target molecule i.e. the molecule the drug was designed to interact with. Thus, it investigates the drug-molecule interaction dynamic.
  • Phase II trial: it is the second round of experimentation in humans, providing information about the efficacy of the drug.

Federica Chiara, PhD, University of Padova, Italy / Linfa OdV

Dr Carly Jim, Manchester Metropolitan University, UK / Childhood Tumour Trust.