Accelerating the development of lorlatinib to improve cure rates for patients newly diagNOsed ALK-driven high-risk neuroblastoma
Solving Kids' Cancer
Children's Hospital of Philadelphia
Neuroblastoma, the most common solid tumor malignancy of childhood, encapsulates the full spectrum of cancerheterogeneity. This cancer of the developing peripheral sympathetic nervous system shows widely divergent clinical manifestations, with approximately half of patients exhibiting explosively malignant disease with high risk for fatality. Genetic interrogation of neuroblastoma has demonstrated that this observed clinical heterogeneity is molecularly driven. However, current therapy consists of a largely empiric selection of cytotoxic therapies followed by targeted immuNOtherapy used to prevent relapse once remission is achieved. Despite this intensive therapy, cure rates for patients with high-risk neuroblastoma have been stalled in the 50% range and those surviving often suffer lifelong toxicities including deafness, growth and skeletal deficiencies, hormonal dysregulation, learning disabilities and second malignant cancers. The disproportionately high mortality rate for patients with high-risk disease mandates a need for the development of molecular targeted therapies that will ultimately improve survival while minimizing the risk of late effects. Activating mutations in the ALK oncogene are the cause of the hereditary form of neuroblastoma, and importantly these mutations are present in 14% of patients newly diagNOsed with high-risk neuroblastoma, representing a tractable therapeutic target. In addition, emerging data have demonstrated that many newly diagNOsed patients have a hidden small percentage of ALKmutated neuroblastoma cells that ultimately lead to disease relapse, explaining the observation that ALKmutations are more common at relapse compared to diagNOsis. These finding led to our initial study of crizotinib, a first-generation inhibitor of ALK, as a potential treatment for neuroblastoma, and led to the current investigation of crizotinib in patients with newly diagNOsed high-risk neuroblastoma within the Children’s Oncology Group(COG). More recently, through a partnership with Pfizer Pharmaceuticals, we have discovered a highly specific and potent ALK inhibitor, lorlatinib, that has improved anti-neuroblastoma activity and provides a unique opportunity to achieve significant impact in neuroblastoma patients. The successful completion of this project will result in the dramatic transatlantic acceleration of lorlatinib use in parallel Phase 3 trials within COG and International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) that seek tosubstantially improve the event-free survival for patients with newly diagNOsed high-risk neuroblastoma whose tumors harbor an activated ALK gene mutation.
5.1 Pharmaceuticals