Background Intensified therapy with platinum-based regimens for pediatric brain tumors has dramatically increased the number of pediatric brain tumor survivors (PBTS) but frequently causes permanent sensorineural hearing loss (SNHL). Although neurocognitive decline in PBTS is known to be associated with radiation therapy (RT), SNHL represents a potential additional contributor whose long-term impact has yet to be fully determined. Methods The neurocognitive impact of significant SNHL (Chang Scale ≥2b) in PBTS was assessed through a retrospective cohort study of audiograms and neurocognitive testing. Scores for neurocognitive domains and subtest task performance were analyzed to identify specific strengths and weakness for PBTS with SNHL. Results In a cohort of PBTS (n=58) treated with platinum therapy, significant SNHL was identified in over half (55%, n=32/58), of which the majority required hearing aids (72%, 23/32). RT exposure was approximately evenly divided between those with and without SNHL. PBTS were 6.7±0.6 and 11.3±0.7 years old at diagnosis and neurocognitive testing, respectively. In multivariate analyses adjusted for RT dose, SNHL was independently associated with deficits in intelligence, executive function, and verbal reasoning skills. Subtests revealed PBTS with SNHL to have poor learning efficiency but intact memory and information acquisition. Conclusion SNHL in PBTS increases the risk for severe therapy-related intellectual and neurocognitive deficits. Additional prospective investigation in malignant brain tumors is necessary to validate these findings through integration of audiology and neurocognitive assessments and to identify appropriate strategies for neurocognitive screening and rehabilitation specific to PBTS with and without SNHL.

Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45–115 mg/m2/dose in children and 100–150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib’s rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988.

10504 Background: Lorlatinib, a potent ALK inhibitor, exerts unprecedented activity against neuroblastoma (NB) derived xenografts harboring common crizotinib-resistant ALK mutations, leading to a first in child phase I study. Methods: R/R NB patients (pts) > 12 months, with ALK mutations/amplification and prior ALK inhibitor (ALKi) treatment were eligible. Lorlatinib was administered in 28-day courses (C). For pts < 18 years, 5 dose levels (DL) (45, 60, 75, 95, 115 mg/m2/day) were assessed. DL5 (115 mg/m2/day) expansion is enrolling (cohort A1). For patients > 18 years, two DL (DL3a the adult RP2D of 100 mg/day and DL4a at 150mg/day) were assessed (cohort A2). Primary endpoint was dose-limiting toxicity (DLT) during C1 and neurocognitive toxicity through C2. Blood samples for circulating tumor DNA (ctDNA) were matched to radiologic restaging. Results: From 9/2017 to 1/2019, 33 eligible patients enrolled (13 with prior ALKi therapy), with median age (range) 5.5 years (2-17) on A1, 21.5 years (15-50) on A2. In A1, 3 pts each enrolled onto DL1-3, with no DLT’s. 5/10 pts enrolled on DL4, with no DLT’s. 1/3 on DL5 had a DLT of grade 3 diarrhea, with expansion ongoing. In cohort A2, 5 patients enrolled at 100 mg/day with no DLT’s; 6 enrolled at 150 mg/day, with one DLT (grade 4 reversible psychosis). Most common treatment-related adverse events were weight gain (90%, grade 1-3), hyperlipidemia (90%, grade 1-3), concentration/memory impairment (23%, grade 1-2), peripheral neuropathy (13%; grade 1-2, A2 only), and peripheral edema (10%; grade 1, A2 only). Lorlatinib steady state exposure at DL3 and DL4 was in the range of exposures seen in adult lung cancer patients at the 100 mg and 200 mg DLs. In A1, 1/18 had partial response (PR), 3/18 had minor responses (MR), and 4/18 had stable disease (SD). Of pts with MR, 2/3 had PR of soft tissue and 1/3 had complete response (CR) by MIBG. In A2 pts, 1/10 had CR, 3/10 PR, and 3/10 MR; Notably, 2/3 with PR had CR by MIBG. Of the pts with MR, one had PR and one CR by MIBG. Responses occurred across dose levels, ALK mutations, and in ALKi pre-treated pts with median courses of 2 (1-24) on A1 and 10.5 (2-28) on A2. Serial ctDNA results showed mutant ALK variant allele frequency trajectories that correlated with clinical response and emergence of novel ALK mutations in cis that corresponded with disease progression. Conclusions: Inhibition of ALK-driven NB with lorlatinib occurs with manageable toxicity and objective anti-tumor activity. Prospective ctDNA allows for monitoring of disease and evolution of resistance. Clinical trial information: NCT03107988.