ALK Inhibition for Pediatric Patients With Advanced ALK-Positive Malignancies

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In a phase I dose-escalation and dose-expansion study reported in The Lancet Oncology, Fischer et al found that the ALK inhibitor ceritinib produced durable responses in pediatric patients with relapsed or refractory, locally advanced or metastatic ALK-positive malignancies.

Study Details

In the trial, 83 patients aged ≥ 12 months and < 18 years were enrolled at sites in 10 countries between August 2013 and October 2017, including 40 in the dose-escalation phase and 43 in the dose-expansion phase. In the dose-escalation phase, ceritinib was given once daily at a starting dose of 300 mg/m2 in the fasted state or 320 mg/m2 in the fed state. All patients in the dose-expansion cohort received ceritinib at the recommended dose for expansion in fasting and fed states established in the dose-escalation phase.


The recommended dose for expansion of ceritinib was established as 510 mg/m2 in the fasted state and 500 mg/m2 in the fed state. A total of 55 patients—including 30 with neuroblastoma, 10 with inflammatory myofibroblastic tumor (IMT), 8 with anaplastic large cell lymphoma (ALCL), and 7 with other tumor types—received ceritinib at the recommended dose for expansion; 13 received 510 mg/m2 fasted and 42 received 500 mg/m2 fed.

Objective response was observed in 6 (20%, 95% confidence interval [CI] = 8%–39%) of 30 patients with neuroblastoma, 7 (70%, 95% CI = 33%–93%) of 10 with IMT, 6 (75%, 95% CI = 35%–97%) of 8 with ALCL, and 1 (14%, 95% CI = < 1%–58%) of 7 with other tumor types. Disease control rates were 53% in neuroblastoma, 80% in IMT, 88% in ALCL, and 43% in other tumor types. Median response durations were 15 months (95% CI = 5.8–22.2 months) in responders with neuroblastoma, not reached (95% CI = 3.5 months–not estimable) in responders with IMT, and not reached (95% CI = 2.8 months–not estimable) in responders with ALCL; estimated proportions of responders with ongoing response at 12 months were 50%, 80%, and 67%, respectively.


  • Objective response rates were 20% in neuroblastoma, 70% in IMT, and 75% in ALCL.
  • Estimated proportions of responders with ongoing response at 12 months were 50%, 80%, and 67%, respectively.

Adverse Events

The safety profile of ceritinib was consistent with that observed in adult patients. Among all 83 patients, treatment-related grade 3 or 4 adverse events were reported in 52 (63%), with the most common being increased alanine aminotransferase (ALT, 39%), increased aspartate aminotransferase (AST, 25%), and increased γ-glutamyl transferase (13%). Treatment-related serious adverse events occurred in 18% of patients, the most common being increased ALT, increased AST, and abdominal pain (4% each). Adverse events led to treatment discontinuation in 11% of patients, most commonly due to increased ALT (5%), increased AST (2%), and acute kidney injury (2%). Any-grade treatment-related vomiting (92% vs 81%, all grade 1–2) and nausea (77% vs 48%, all grade 1–2) were more common in patients receiving ceritinib in the fasting state. On-treatment deaths occurred in 12 patients, with 10 due to disease progression (neuroblastoma), 1 due to sepsis, and 1 due to intractable hypotension.

The investigators concluded, “Ceritinib [at] 500 mg/m2 once daily with food is the recommended dose for pediatric patients with ALK-positive malignancies. Ceritinib showed promising preliminary antitumor activity in patients with ALK-positive refractory or recurrent IMT or ALCL, and in a subset of patients with relapsed or refractory neuroblastoma, with a manageable safety profile. Our data support the notion that ALK inhibitors should be considered in therapeutic strategies for pediatric patients with malignancies with genetic ALK alterations.”

Johannes H. Schulte, MD, of the Department of Paediatrics, Division of Oncology and Haematology, Charité – Universitätsmedizin Berlin, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Novartis Pharmaceutical Corporation. For full disclosures of the study authors, visit

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