Research findings set the stage for GLOBOTRK, a clinical trial with targeted therapy for NTRK and ROS1 fusions

Cancer cells cheat death, evading the systems the body puts in place to keep them in check. But how cancer cheats creates vulnerabilities that can be exploited therapeutically. One of the ways that cancer cheats is by using genetic mutations to grow and proliferate continually. 

These mutations can include fusions that occur when two genes that were never meant to be together are joined, such as when the oncogenes NTRK or ROS1 become fused to another gene, which causes them to remain continuously active. The resulting fusion proteins send cells strong proliferation signals and suppress the systems that prevent unrestrained growth. However, by cheating their fate in this way, the resulting cancers harbor a targetable vulnerability.

Entrectinib is a targeted therapy for NTRK and ROS1 fusion–positive solid tumors, specifically designed to block the proliferation signals from fusion proteins. In a recent European Journal of Oncology study, children with cancers that contained either NTRK (72.7%) or ROS1 fusions (65%), who had not responded well to other therapies, responded well to entrectinib.

“It’s been a very gratifying experience to see patients benefit,” said corresponding author Elizabeth Fox, MD, St. Jude Clinical Trials Research senior vice president, Comprehensive Cancer Center associate director for clinical research and Department of Oncology member, who helped lead the pediatric trial. “We followed all of these patients for over two years and saw a rapid and durable response with few side effects.” 

Betting on entrectinib for childhood brain tumors

Entrectinib’s performance was particularly impressive in brain tumors, where its inhibition of these fusion proteins had a significant impact. Entrectinib reached a 50% overall response rate in children with central nervous system tumors. Another 40% of children with these tumors achieved stable disease, where their tumor stopped growing, though it did not disappear. These responses are a significant improvement over standard therapies, which often fail to control these diseases.

“This is an oral drug that really gets to and helps with these aggressive brain tumors,” Fox said. “The next step is to find if we can help these children avoid serious surgeries and radiation treatments that can leave them with disabilities.” 

The European Journal of Oncology trial only gave entrectinib to pediatric patients who had already received some other form of therapy that failed to control the disease. At St. Jude, a new study called GLOBOTRK, which is actively recruiting, is giving entrectinib to young children with NTRK or ROS1 fusion–positive tumors as a first treatment. This may eliminate the need for other therapies with known long-term side effects.

“GLOBOTRK is a clinical trial testing two things,” said the study’s principal investigator, Daniel Moreira, MD, MEd, St. Jude Global Neuro-Oncology program co-director, and Department of Global Pediatric Medicine assistant member. “The first is: If we bring this forward as a frontline therapy for new patients worldwide, will they benefit and avoid problems associated with standard therapies? The second is learning how to run a truly global clinical trial in both highly resourced and resource-limited settings. Pediatric cancer isn’t isolated to highly resourced countries like the U.S., so if we want to make headway against these diseases, we need to learn how to conduct clinical trials across the world.” 

Running GLOBOTRK, a global clinical trial for childhood brain tumors

Thankfully, childhood brain tumors are rare. However, that makes testing targeted therapies challenging, as reaching enough patients to prove statistical significance is difficult. Therefore, GLOBOTRK is recruiting patients not just at St. Jude in Memphis, TN, but also in Egypt, India, Jordan, Brazil and Peru, as proving even small improvements in care requires recruiting many children to participate. However, “it’s not just a numbers game,” Moreira explained. “Even if the medication has the potential to improve outcomes, we also need to show it is a feasible treatment across care contexts.” 

To that end, entrectinib is formulated to be easy to administer orally, indicating it may be ideally suited to help treat children worldwide, where access to dedicated infusion centers is not always guaranteed. As a frontline targeted therapy, it could help avoid chemotherapy use so that children will not become immunocompromised, lowering infection risk. With so many positives about the therapy, challenges have come from logistical hurdles rather than the treatment.

“This is the first St. Jude–led clinical trial that will open in resource-limited countries,” Moreira said. “We are discovering and learning how to run a global trial, overcoming steep learning curves to get children access to these new cancer therapies.” 

One example of a challenge is moving tissue sections across international boundaries. As part of the trial, patients will have a biopsy of their cancer taken to be reviewed at St. Jude. Navigating how to ship patient samples internationally while meeting the regulatory requirements of all six countries was a difficult multi-year task. Moreira has encountered and learned to overcome such challenges as the trial’s lead investigator, with the hospital’s collaborators remaining positive and supportive.

“Everybody in pediatric cancer, even abroad, knows St. Jude,” Moreira explained. “When we came asking to collaborate on GLOBOTRK, many agreed with very little convincing, as we already have working relationships with them. They know St. Jude is the only institution that would engage in doing something like this in the whole world, putting the resources, time, financial and operational resources toward running this global trial, providing global access to this inhibitor to show its efficacy and help other hospitals advocate for its purchase and use in patients from their countries in the future.”

Beating cancer at its own game

Both Fox’s work with entrectinib in the earlier trial and Moreira’s work with GLOBOTRK highlight the power of targeted therapies. Scientists identified how NTRK and ROS1 fusion proteins help cancer cheat death. They then created a drug to target that vulnerability, advancing from adult clinical trials to pediatrics in less than a decade, now moving to an international approach. 

“This is a phenomenal step forward in pediatric oncology,” Fox said. “With our ability to design, test and deploy these types of targeted therapies, we can steal back the years that these children would otherwise lose to these cancers while also protecting their health from the serious side effects of conventional therapies.”

“The question about these exciting, targeted therapies has been how to get access to the patients who need them,” Moreira said. “Now, St. Jude is leading, showing the world how to get these drugs to the patient who would benefit.”