FDA Approval Summary: Eflornithine for High-Risk Neuroblastoma Following Prior Multiagent, Multimodality Therapy.

On December 13, 2023, the U.S. Food and Drug Administration (FDA) approved eflornithine (IWILFIN, US WorldMeds) to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. The approval was based on an externally controlled trial (ECT) consisting of a single-arm trial, Study 3(b), compared to an external control derived from a National Cancer Institute (NCI)/Children's Oncology Group (COG)-sponsored clinical trial (Study ANBL0032) and supported by confirmatory evidence. In the protocol-specified primary analysis, the event-free survival (EFS) hazard ratio (HR) was 0.48 (95% confidence interval [CI]: 0.27, 0.85) and overall survival (OS) HR was 0.32 (95% CI: 0.15, 0.70). The most common adverse reactions (≥5%) were hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. Notably, this is the first oncology drug approval which relies on an ECT as the primary clinical data to support substantial evidence of effectiveness. This was made possible by a distinctly high-quality, comparable external control dataset with consistent treatment effect estimations demonstrated in multiple sensitivity and supportive analyses. Eflornithine's manageable safety profile and strong nonclinical and mechanistic data provided further support for the approval, and the evidentiary package was evaluated in the context of high unmet need in a rare, life-threatening cancer.

Molecular-targeted therapy for childhood low-grade glial and glioneuronal tumors.

Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials.

Considering Functional Outcomes as Efficacy Endpoints in Pediatric Low-Grade Glioma Clinical Trials: An FDA Educational Symposium.

In October 2022, the FDA Oncology Center of Excellence hosted an educational symposium entitled, "Considering Functional Outcomes as Efficacy Endpoints in Pediatric Low-Grade Glioma (pLGG) Clinical Trials." The symposium brought together patient advocates, regulators from the FDA and the European Medicines Agency (EMA), and an international group of academic thought leaders in the field of pediatric neuro-oncology to discuss the potential role of functional outcomes, including visual acuity, motor function, and neurocognitive performance, as endpoints in clinical trials enrolling patients with pLGG. The panel discussed challenges and opportunities regarding the selection, implementation, and evaluation of clinical outcome assessments in these functional domains and outlined key considerations for their inclusion in future clinical trial design and role in new drug development.

FDA Approval Summary: Selpercatinib for the Treatment of Advanced RET Fusion-Positive Solid Tumors.

On September 21, 2022, the FDA granted accelerated approval to selpercatinib (Retevmo, Eli Lilly and Company) for the treatment of adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. The approval was based on data from Study LOXO-RET-17001 (LIBRETTO-001; NCT03157128), an international, non-randomized, multi-cohort clinical trial that included patients with advanced solid tumors harboring RET alterations. The overall response rate in 41 patients with locally advanced or metastatic RET fusion-positive solid tumors other than non-small cell lung cancer (NSCLC) or thyroid cancer was 44% [95% confidence interval (CI), 28%-60%], with median duration of response 24.5 months (95% CI, 9.2-not evaluable). Patients with 10 of 14 tumor types with a variety of fusion partners had objective responses, including patients with the following tumors: pancreatic adenocarcinoma, colorectal, salivary, unknown primary, breast, soft-tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma. The recommendation for approval was supported by results from LIBRETTO-001 in patients with RET fusion-positive NSCLC and thyroid cancer, which formed the basis of prior approvals in these tumor types. The most common adverse reactions (>25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. This is the first tissue-agnostic approval of a RET-directed targeted therapy.

FDA Approval Summary: Mobocertinib for Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

On September 15, 2021, the FDA granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals USA, Inc.) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The approval was based on data from Study AP32788-15-101 (NCT02716116), an international, non-randomized, multi-cohort clinical trial that included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The overall response rate in 114 patients whose disease had progressed on or after platinum-based chemotherapy was 28% [95% confidence interval (CI), 20%-37%] with a median duration of response of 17.5 months (95% CI, 7.4-20.3). The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a Boxed Warning for QTc prolongation and torsades de pointes. This is the first approval of an oral targeted therapy for patients with advanced EGFR exon 20 insertion mutation-positive NSCLC.

Highlights of FDA Oncology Approvals in 2022: Tissue-Agnostic Indications, Dosage Optimization, and Diversity in Drug Development.

In 2022, cancer drug development continued to progress rapidly despite the lingering COVID-19 pandemic. Highlights of U.S. drug approvals for oncology indications this year include ongoing development in rare diseases and molecular subgroups, improved dosage optimization, and updated data for drugs granted accelerated approval, with confirmatory studies demonstrating verification of clinical benefit in some instances, as well as indication withdrawal when clinical benefit was not verified.

FDA Approval Summary: Cabozantinib for Differentiated Thyroid Cancer.

On September 17, 2021, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine (RAI)-refractory or ineligible. This is the first approval for patients with RAI-refractory locally advanced or metastatic DTC who have progressed following prior therapy and the first approval in pediatric patients with DTC. The approval was based on data from COSMIC-311 (Study XL184-311, NCT03690388), an international, randomized, double-blind trial in which patients with locally advanced or metastatic RAI-refractory DTC that progressed during or following treatment with at least one VEGFR-targeting tyrosine kinase inhibitor were treated with either cabozantinib 60 mg orally once daily (N = 170) or placebo with best supportive care (N = 88). The primary efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review per RECIST 1.1. The median PFS was 11.0 months [95% confidence interval (CI), 7.4-13.8] in the cabozantinib arm compared with 1.9 months (95% CI, 1.9-3.7) in the control arm, with an HR of 0.22 (95% CI, 0.15-0.31). The endpoint of ORR was not met. No new safety signals were identified with the exception of hypocalcemia, which was added as a warning in the product labeling.

Developing a New Set of ACGME Milestones for Child Neurology Residency.

BACKGROUND: The Educational Milestones developed by the Accreditation Council for Graduate Medical Education (ACGME) are a construct used to evaluate the development of core competencies during residency and fellowship training. The milestones were developed to create a framework for professional development during graduate medical education. The first iteration of milestones for the child neurology residency was implemented in 2015. In the years that followed, the ACGME received and reviewed feedback about the milestones and set out to revise them. METHODS: A committee was assembled to review the original milestones and develop a new set of milestones. The group was also encouraged to not only consider the child neurology residency graduate of today but also the graduate of tomorrow, taking into account growing fields such as genetics and technology. RESULTS: A diverse group of 12 individuals, including 10 child neurologists (all of whom were current or previous program directors or associate program directors), one child neurology resident, and one non-physician program coordinator, were recruited from programs of varying size across the country. CONCLUSIONS: The committee developed a revision to the child neurology milestones. All changes made were with a focus on how the milestones can be useful to trainees, program directors, and clinical competency committee members. Implementation and further feedback should help guide future revisions. These changes should help trainees, clinical competency committee members, and program directors find more meaning from their use.

Update on Pediatric Brain Tumors: the Molecular Era and Neuro-immunologic Beginnings.

PURPOSE OF REVIEW: To provide an update on the current landscape of pediatric brain tumors and the impact of novel molecular insights on classification, diagnostics, and therapeutics. RECENT FINDINGS: Scientific understanding of the genetic basis of central nervous system tumors has expanded rapidly over the last several years. The shift in classification of tumors to a molecularly based schema, accompanied by a growing number of early phase clinical trials of therapies aimed at inhibiting tumoral genetic and epigenetic programs, as well as those attempting to harness and magnify the immune response, has allowed a deeper pathophysiologic understanding of brain tumors and simultaneously provided opportunities for novel treatment. Over the last 5 years, there has been tremendous growth in the field of pediatric neuro-oncology with increasing understanding of the genetic and epigenetic heterogeneity of CNS tumors. Attempts are underway to translate these insights into tumor-specific treatments.

Reduced language connectivity in pediatric epilepsy.

OBJECTIVE: Functional connectivity (FC) among language regions is decreased in adults with epilepsy compared to controls, but less is known about FC in children with epilepsy. We sought to determine if language FC is reduced in pediatric epilepsy, and examined clinical factors that associate with language FC in this population. METHODS: We assessed FC during an age-adjusted language task in children with left-hemisphere focal epilepsy (n = 19) compared to controls (n = 19). Time series data were extracted for three left regions of interest (ROIS) and their right homologues: inferior frontal gyrus (IFG), middle frontal gyrus (MFG), and Wernicke's area (WA) using SPM8. Associations between FC and factors such as cognitive performance, language dominance, and epilepsy duration were assessed. RESULTS: Children with epilepsy showed decreased interhemispheric connectivity compared to controls, particularly between core left language regions (IFG, WA) and their right hemisphere homologues, as well as decreased intrahemispheric right frontal FC. Increased intrahemispheric FC between left IFG and left WA was a positive predictor of language skills overall, and naming ability in particular. FC of language areas was not affected by language dominance, as the effects remained only when examining participants with left language dominance. Overall FC did not differ according to duration of epilepsy or age of onset. SIGNIFICANCE: FC during a language task is reduced in children, similar to findings in adults. In specific, children with left focal epilepsy demonstrated decreased interhemispheric FC in temporal and frontal language connections and decreased intrahemispheric right frontal FC. These differences were present near the onset of epilepsy. Greater FC between left language centers is related to better language ability. Our results highlight that connectivity of language areas has a developmental pattern and is related to cognitive ability.

Characterization of atypical language activation patterns in focal epilepsy.

OBJECTIVE: Functional magnetic resonance imaging is sensitive to the variation in language network patterns. Large populations are needed to rigorously assess atypical patterns, which, even in neurological populations, are a minority. METHODS: We studied 220 patients with focal epilepsy and 118 healthy volunteers who performed an auditory description decision task. We compared a data-driven hierarchical clustering approach to the commonly used a priori laterality index (LI) threshold (LI < 0.20 as atypical) to classify language patterns within frontal and temporal regions of interest. We explored (n = 128) whether IQ varied with different language activation patterns. RESULTS: The rate of atypical language among healthy volunteers (2.5%) and patients (24.5%) agreed with previous studies; however, we found 6 patterns of atypical language: a symmetrically bilateral, 2 unilaterally crossed, and 3 right dominant patterns. There was high agreement between classification methods, yet the cluster analysis revealed novel correlations with clinical features. Beyond the established association of left-handedness, early seizure onset, and vascular pathology with atypical language, cluster analysis identified an association of handedness with frontal lateralization, early seizure onset with temporal lateralization, and left hemisphere focus with a unilateral right pattern. Intelligence quotient was not significantly different among patterns. INTERPRETATION: Language dominance is a continuum; however, our results demonstrate meaningful thresholds in classifying laterality. Atypical language patterns are less frequent but more variable than typical language patterns, posing challenges for accurate presurgical planning. Language dominance should be assessed on a regional rather than hemispheric basis, and clinical characteristics should inform evaluation of atypical language dominance. Reorganization of language is not uniformly detrimental to language functioning.

The effect of seizure focus on regional language processing areas.

PURPOSE: To determine the effect of seizure focus location within the left hemisphere on the expression of regional language dominance. METHODS: In this cross-sectional study we investigated 90 patients (mean age 23.3 ± 12.9 years) with left hemisphere focal epilepsy (mean age onset 11.7 ± 8.3 years). Eighteen patients had a frontal lobe focus and 72 had a temporal lobe focus (43 mesial; 29 neocortical). Subjects performed an auditory word definition language paradigm using 3 Tesla blood oxygen level dependent (BOLD) EPI functional magnetic resonance imaging (fMRI). Data were analyzed in SPM2. Regional laterality indices (LIs) for inferior frontal gyrus (IFG), and Wernicke's area (WA), were calculated using a bootstrap method. Categorical language dominance and mean LI were analyzed. KEY FINDINGS: Mean WA LI was lower for subjects with a mesial temporal focus compared with a frontal focus (p = 0.04). There was a greater proportion of atypical language in WA for subjects with a mesial temporal focus compared with a frontal focus (χ(2) = 4.37, p = 0.04). WA LI did not differ for subjects with a neocortical focus compared with a mesial focus or a frontal focus. Mean IFG LI and proportion of atypical language in IFG were similar across seizure focus groups. Age and age of onset were not correlated with mean laterality in WA or IFG. Epilepsy duration tended to be negatively correlated with WA LI (r = -0.18, p = 0.10), but not IFG LI. SIGNIFICANCE: Temporal lobe foci have wide-ranging effects on the distributed language system. In contrast, the effects of a frontal lobe focus appear restricted to anterior rather than posterior language processing areas.

Cerebral blood flow and fMRI BOLD auditory language activation in temporal lobe epilepsy.

PURPOSE: Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), an important research and clinical tool, depends on relatively greater transient increases in (regional cerebral blood flow) rCBF than cerebral metabolic rate for oxygen during neural activity. We investigated whether reduced resting rCBF in patients with temporal lobe epilepsy affects BOLD signal during fMRI language mapping. METHODS: We used [(15)O] water positron emission tomography (PET) to measure rCBF, and 3 Tesla echo planar imaging (EPI) BOLD fMRI with an auditory description decision task in 33 patients with temporal lobe epilepsy (16 men; mean age 33.6 ± standard deviation [SD] 10.6 years; epilepsy onset 14.8 ± 10.6 years; mean duration 18.8 ± 13.2 years; 23 left focus, 10 right focus). Anatomic regions drawn on structural MRI, based on the Wake Forest Pick Atlas, included Wernicke's area (WA), inferior frontal gyrus (IFG), middle frontal gyrus (MFG), and hippocampus (HC). Laterality indices (LIs), and asymmetry indices (AIs), were calculated on coregistered fMRI and PET. KEY FINDINGS: Twelve patients had mesial temporal sclerosis (seven on the left), two patients had a tumor or malformation of cortical development (both left), one patient a right temporal cyst, and 18 patients had normal MRI (14 left). Decreasing relative left WA CBF correlated with decreased left IFG voxel activation and decreasing left IFG LI. However, CBF WA AI was not related to left WA voxel activation itself or WA LI. There was a weak positive correlation between absolute CBF and fMRI activation in left IFG, right IFG, and left WA. Patients with normal and abnormal MRI did not differ in fMRI activation or rCBF AIs. SIGNIFICANCE: Reduced WA rCBF is associated with reduced fMRI activation in IFG but not WA itself, suggesting distributed network effects, but not impairment of underlying BOLD response. Hypoperfusion in TLE does not affect fMRI clinical value.

Functional anatomy of listening and reading comprehension during development.

Listening and reading comprehension of paragraph-length material are considered higher-order language skills fundamental to social and academic functioning. Using ecologically relevant language stimuli that were matched for difficulty according to developmental level, we analyze the effects of task, age, neuropsychological skills, and post-task performance on fMRI activation and hemispheric laterality. Areas of supramodal language processing are identified, with the most robust region being left-lateralized activation along the superior temporal sulcus. Functionally, this conjunction has a role in semantic and syntactic processing, leading us to refer to this conjunction as "comprehension cortex." Different from adults, supramodal areas for children include less extensive inferior frontal gyrus but more extensive right cerebellum and right temporal pole. Broader neuroanatomical pathways are recruited for reading, reflecting the more active processing and larger set of cognitive demands needed for reading compared to listening to stories. ROI analyses reveal that reading is a less lateralized language task than listening in inferior frontal and superior temporal areas, which likely reflects the difficulty of the task as children in this study are still developing their reading skills. For listening to stories, temporal activation is stable by age four with no correlations with age, neuropsychological skills or post-task performance. In contrast, frontal activation during listening to stories occurs more often in older children, and frontal activation is positively correlated with better performance on comprehension questions, suggesting that the activation of frontal networks may reflect greater integration and depth of story processing.