A multi-disciplinary forum of researchers, pharmaceutical industry representatives, patient advocacy organizations, and regulatory agency representatives from the United States and Europe recently published recommendations to address targeted drug development of mitogen-activated protein kinase (MAPK) pathway inhibitors. The result of an ACCELERATE forum held in collaboration with the FDA and EMA (European Medicines Agency), the paper also provides insights into how better clinical endpoints can be developed to actively reflect modern cancer treatment successes for children with MAPK pathway anomalies.   

The Pediatric Brain Tumor Foundation participated in this forum and the publication of the forum’s findings as a patient advocate, bringing the challenges of children with MAPK pathway brain tumors and their families into focus for the committee. 

A MAPK pathway is a chain of proteins in a cell that’s responsible for communication—transmitting a signal from a receptor on the cell’s surface to the DNA in the cell’s nucleus. A growing body of research has found that the MAPK pathway plays a key role in the development of many pediatric cancers, including the most common form of pediatric brain tumors, low-grade gliomas.

ACCELERATE forums, held three times per year, are an opportunity for scientists, government regulatory agencies, patient advocates, and the pharmaceutical industry to determine which therapy, based on current evidence, is considered to have the highest potential to address pediatric cancer patients’ unmet needs. The goal is to help prioritize therapies to better meet the needs of patients and increase the feasibility of pediatric developments.

One area the MAPK forum focused on was the use of combination therapy in clinical trials. In adult clinical trials, it’s standard to use multiple therapies at once. However, until recently, pediatric clinical trials have been limited to using one targeted therapy. The group agreed that MAPK pathway anomalies may require a combination of different targeted therapies to have the maximum impact for children.

The committee also determined that new clinical/functional end-points should be agreed upon with regulatory agencies when a drug targeting the MAPK pathway is being reviewed for approval. Currently, the primary determinant for the success of a clinical trial is its survivorship rate. However, since the survival rates for pediatric low-grade glioma patients are relatively high, this endpoint does not adequately represent the positive impact that some targeted therapies are having on cancer patients’ and survivors’ quality of life.

Because of this, certain drugs may be viewed as “unsuccessful,” even if they offer significant improvements over other treatments. This outdated view on a drug’s success can have a waterfall effect on its continued development: The FDA or EMA may reject it for ‘on-label use,’ which then impacts a pharmaceutical company’s inclination to develop the drug and insurers’ inclinations to cover it. This most often results in a loss of interest in further drug development for the specific indication, which can impact patients’ quality of life.

Due to the success of targeted MAPK pathway inhibitors in clinical trials, the group also recommended that these drugs be included in front-line studies and that data generated be better aligned with regulatory requirements. Improved cooperation between regulatory agencies and clinical trialists will yield a more detailed understanding of this class of targeted drugs, so that children diagnosed with MAPK pathway diseases stand to receive the optimal benefit from treatments while minimizing their toxicity.

Although the survival rate for pediatric low-grade glioma patients is high, the impact of current treatments leaves an indelible imprint on children, both in the short and long term. The Pediatric Brain Tumor Foundation’s hope, and the hope of all pediatric cancer advocates, is that more targeted drugs will be developed which reduce the complications and compromises patients currently experience.

You can join us in our mission to end all childhood brain cancer. Sign up today at www.curethekids.org/stay-connected to stay up to date about opportunities to get involved through advocacy, fundraising, and donating. You can also read a more detailed review of the committee’s findings in the European Journal of Cancer, published here.


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