Abstract ED01-02: Successes and failures of targeted drug development in pediatric tumors
Authors: Fox Elizabeth 
Published: March 2020

Eighty percent of children diagnosed with cancer are cured with multimodality therapy including cytotoxic chemotherapy. However, up to 40% of survivors of childhood cancer have at least one serious chronic medical condition as a consequence of curative therapy. Thus, patients, families, clinicians, researchers, and regulatory agencies enthusiastically endorse the development of targeted therapy to improve survival, decrease life threatening acute toxicity, and late effects of therapy for childhood cancer. Genomic characterization demonstrates that the tumor mutational burden in childhood cancers is low. For children with cancer a small number of drugs, such as NTRK inhibitors have had major unequivocal successes including initial regulatory approvals that include specific dosing in children. Other molecularly targeted drugs have achieved moderate success, however, many have failed despite strong pre-clinical rationale. As of June 2019, 25 drugs have been FDA approved for use in children with cancer including five tyrosine kinase inhibitors (3 BCR-ABL inhibitors and 2 NTRK inhibitors), and one mTOR inhibitor. A single drug, dinutuximab, was approved for a pediatric specific indication in high-risk neuroblastoma. This parallels recent European Medicines Agency authorizations that include indications for treating childhood cancer in 10 of 177 anti-cancer drug approvals. Similar to adults, the era of targeted therapies in children with cancer began with imatinib. Drugs targeting BCR-ABL in chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) in children include imatinib, dasatinib, and nilotinib. Point mutations in the kinase domain of the BCR-ABL fusion protein result in resistance to imatinib. Dasatinib, nilotinib, and ponatinib were developed to overcome resistance. Each has a specific role in caring for children with CML or Ph+ ALL. Ph-like ALL, a high-risk acute leukemia in children and young adults, is characterized by genomic alterations and activation of signaling pathways including JAK/STAT, amenable to inhibition tyrosine kinase inhibitors. The landmark age and histology agnostic global approval of larotrectinib and entrectinib was based on durable objective responses in patients with tumors harboring NTRK fusions enrolled on early phase clinical trials. Larotrectinib has produced dramatic objective responses in children and adults with cancer harboring NTRK fusions including a very rare cancer, infantile fibrosarcoma which is NTRK fusion positive in at least 95% cases. In addition to potent inhibition NTRK fusions, initial clinical trials of larotrectinib included adults and children as well as a pediatric appropriate formulation. Children with brain tumors harboring NTRK1,2,3 or ROS1 fusions have had rapid, durable objective responses to entrectinib. MAP kinase pathway aberrations occur in childhood cancer including rhabdomyosarcoma and brain tumors. Everolimus is approved for patients with subependymal giant cell astrocytoma. Dabrafenib and vemurafenib have produced durable objective responses in patients with pediatric low-grade glioma harboring BRAF V600E mutations. Selumetinib has been FDA approved for the treatment of plexiform neurofibromas in children with neurofibromatosis type 1 and may have activity in children and adolescents with solid tumors harboring MAP kinase aberrations. Overall, the success of MAP kinase inhibition in children with cancer has been modest, leading to consideration for combinatorial approaches. Crizotinib is approved for the treatment of ALK-positive metastatic NSCLC and has activity in children with refractory Anaplastic Large Cell Lymphoma (ALCL) and inflammatory myofibroblastic tumors, both associated with ALK fusions. Trials are ongoing to determine the activity of crizotinib and other ALK inhibitors in children with neuroblastoma with known translocations, mutations or amplifications in the ALK gene. Clinical trials of multi-targeted kinase inhibitors including cabozantinib, regorafenib, sorafenib and vandetanib have demonstrated activity in a variety of solid tumors. Clinical trials of these agents have been based on mechanistic rationale and pre-clinical evaluation rather than biomarker selection. Through large scale genomic sequencing efforts in the US and Europe actionable molecular alterations including mutations, amplifications and fusions have been identified in a variety of childhood cancers. Compared to cancers in adults, these molecular aberrations occur less frequently in most cancers in children. However, due to dramatic objective responses and the potential for improved response with decreased toxicity, efforts to evaluate and incorporate targeted agents into multimodality therapy for children with cancer remains a major focus. To date, multi-targeted kinase inhibitors and drugs that target fusion oncoproteins that are histology-agnostic oncogenic drivers in cancers that occur in both child and adults have been most successful. Understanding the characteristics of successful target- drug pairs is critically important to the prioritization of new drugs and clinical trials in children as well as the development of new therapies for pediatric specific targets.

Citation Format: Elizabeth Fox. Successes and failures of targeted drug development in pediatric tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr ED01-02. doi:10.1158/1535-7163.TARG-19-ED01-02