Brief Report: Potent clinical and radiological response to larotrectinib in TRK fusion-driven high-grade glioma

NTRK gene fusions affecting the tropomyosin receptor kinase (TRK) protein family have been found to be oncogenic drivers in a broad range of cancers. Small molecule inhibitors targeting TRK activity, such as the recently Food and Drug Administration-approved agent larotrectinib (Vitrakvi®), have shown promising efficacy and safety data in the treatment of patients with TRK fusion cancers. NTRK gene fusions can be detected using several different approaches, including fluorescent in situ hybridization, reverse transcription polymerase chain reaction, immunohistochemistry, next-generation sequencing, and ribonucleic acid-based multiplexed assays. Identifying patients with cancers that harbor NTRK gene fusions will optimize treatment outcomes by providing targeted precision therapy.

Pediatric high‐grade gliomas (pHGG) constitute 8% to 12% of primary brain tumors in childhood. The most widely utilized treatment encompasses surgical resection followed by focal radiotherapy and temozolomide. However, experiences over past decades have not demonstrated improved outcomes. pHGG have been classified into different molecular subgroups defined by mutations in histone 3, IDH gene, MAPK pathway, and others, thereby providing a rationale for various targeted therapies. Additionally, immunotherapy and drug repurposing have also become attractive adjunctive treatments. This review focuses on past, present, and emerging treatments for pHGG integrating molecular research with the mainstream pediatric drug development in Europe and the United States to sketch a way forward in the development of novel therapeutic approaches. The implementation of randomized clinical trials with adaptive designs, underpinned by a robust biological rationale, and harnessing collaboration between the pharmaceutical industry, academia, regulators and patients/parents organizations will be essential to improve the outcomes for these children.

The availability of an unprecedented massive amount of data has provided a magnificent window of opportunity for the development of new drugs. There are currently more drugs in development targeting cancer than any other disease. While this has brought us new waves of drugs, the counterpart is that with these new molecules we have different mechanisms of action, drug kinetics and dynamics, response types and toxicity profiles, which impair classical early clinical trial designs from being effective and efficient. What we once treated as a 'one-size-fits-all' homogeneous disease, has now been uncovered to be a rather heterogeneous condition with multiple targetable mutations. As this generates endless scenarios, it will be impossible to design single 'me-too' trials for every different disease, target, biomarker and agent. To overcome this, we must focus on improving early phase studies, undoubtedly the most critical step from bench to bedside. Goals include decreasing clinical development times, lowering research and development costs and optimizing decisions in advancing through the several phases with a higher degree of certainty in exchange for less failed attempts. We need more informative and, really, transformative early phase designs that seek to obtain the typical late phase objectives in a time continuum and to allow for more robust and efficient go/no-go decisions. With this in mind, different classes of drugs seem to fit with different designs, which present solutions to the different challenges that they pose after finding the maximum tolerated dose/optimum biological dose. This article reviews these concepts and designs and how they can adapt to this new reality in early phase investigation.