Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results
Kelly C Goldsmith1,2, Julie R Park3,4, Kimberly Kayser5
1Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
Abstract:
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 .
Insights
Lorlatinib shows promise for ALK-driven neuroblastoma, demonstrating safety and efficacy in pediatric and adult patients. This third-generation ALK inhibitor is effective both as a single agent and in combination with chemotherapy.
Area of Science:
- Oncology
- Pharmacology
- Pediatric Medicine
Background:
- Neuroblastomas frequently exhibit anaplastic lymphoma kinase (ALK) aberrations, leading to resistance against crizotinib but sensitivity to lorlatinib.
- Existing treatments for relapsed or refractory ALK-driven neuroblastoma have limitations, necessitating novel therapeutic strategies.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of lorlatinib in children and adults with relapsed or refractory ALK-driven neuroblastoma.
- To assess the efficacy of lorlatinib, both as a single agent and in combination with chemotherapy, through response rates and MIBG scans.
Main Methods:
- A first-in-child study enrolled pediatric and adult patients with relapsed/refractory ALK-driven neuroblastoma.
- Lorlatinib was administered as a single agent to children (12 months to <18 years) and adults (≥18 years), and in combination with topotecan/cyclophosphamide to children.
- Safety, pharmacokinetics, RP2D, response rates, and 123I-metaiodobenzylguanidine (MIBG) response were evaluated.
Main Results:
- Common adverse events included hypertriglyceridemia (90%), hypercholesterolemia (79%), and weight gain (87%). Neurobehavioral adverse events were primarily observed in adults.
- The RP2D for lorlatinib in children was 115 mg/m², and 150 mg for adults as a single agent.
- Single-agent response rates were 30% in children and 67% in adults. In the chemotherapy combination arm for children, the response rate was 63%, with 48% achieving MIBG complete responses.
Conclusions:
- Lorlatinib is a safe and effective treatment option for pediatric and adult patients with relapsed or refractory ALK-driven neuroblastoma.
- The established RP2D supports the progression of lorlatinib into phase 3 trials for high-risk, newly diagnosed neuroblastoma.
- Lorlatinib demonstrates significant clinical activity, including MIBG responses, highlighting its potential to improve outcomes for neuroblastoma patients.
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