Despite discoveries related to neuroblastoma genomics and immune evasion, patients diagnosed with high-risk neuroblastoma are subjected to a largely empiric and vastly intensive regimen of genotoxic chemotherapy, radiation and GD2-targeted immunotherapy that, although effective, has substantial acute and long-term side effects. A group of investigators led by Dr. Yeal P. Mossé of the Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, both in Philadelphia, PA, US has sought to change this paradigm by developing and implementing biomarker-directed precision therapies.

In a New Approaches to Neuroblastoma Therapy (NANT) Consortium phase I NANT2015-02 study of lorlatinib given alone or in combination with chemotherapy, lorlatinib was safe and tolerable in paediatric, adolescent and adult patients with relapsed or refractory ALK-mutated or ALK-amplified neuroblastoma. The findings are published on 3 April 2023 in the Nature Medicine and support lorlatinib’s rapid translation into active phase III studies for patients with newly diagnosed high-risk, ALK-driven neuroblastoma.

Neuroblastoma is an aggressive extracranial solid tumour. Gain-of-function mutations in the ALK oncogene were identified as the genetic aetiology of familial neuroblastoma and as the most common somatic single-nucleotide variants in neuroblastoma, positioning ALK as the most frequently mutated oncogene tractable for targeted therapy. Furthermore, relapsed neuroblastoma harborus increased somatic mutations, with enrichment of ALK-activating subclonal/clonal mutations compared to newly diagnosed tumours.

A phase I study of ceritinib in children with ALK-driven malignancies showed a response rate (RR) of 20% with responses primarily observed in patients with an ALK R1275 mutation. A phase II study of crizotinib in children with refractory or relapsed ALK-mutated neuroblastoma reported an RR of 15%; in stark contrast, far more objective and sustained responses were observed in ALK-fusion-driven refractory or relapsed anaplastic large cell lymphoma (RR 90%) and inflammatory myofibroblastic tumours (RR 86%), highlighting the difference between therapeutic targeting of full-length mutated ALK in neuroblastoma compared to cytoplasmic ALK fusion proteins in other cancers.

The authors wrote in the background that primary resistance to crizotinib and early-generation ALK inhibitors represents a major obstacle for common ALK hotspot mutations in neuroblastoma, supporting the need for next-generation ALK tyrosine kinase inhibitors (TKIs) with improved selectivity and potency against neuroblastoma de novo resistant ALK mutations.

Lorlatinib demonstrates high potency across acquired ALK-activating mutations in adult cancers, including the intractable ALK variants (F1174L and F1245C) found de novo in neuroblastoma. Lorlatinib exerts potent activity in ALK-driven neuroblastoma pre-clinical models in vivo, with antitumour doses 10–30-fold lower than crizotinib. Lorlatinib induced complete tumour regression in both crizotinib-resistant and sensitive neuroblastoma-derived xenografts harbouring F1174L, F1245C or R1275Q ALK mutations, demonstrating lorlatinib’s potential to overcome crizotinib resistance. These data provided the pre-clinical rationale for the clinical development of lorlatinib for patients with ALK-driven neuroblastoma.

The study primary aims were to determine the side effects, pharmacokinetics and recommended phase 2 dose (RP2D) of lorlatinib administered both as monotherapy and in combination with topotecan/cyclophosphamide. Secondary endpoints were response rate (RR) and 123I-metaiodobenzylguanidine (MIBG) response. RR was defined as complete response (CR) plus partial response (PR) and a modified RR defined as CR plus PR plus minor responses (MRs).

The study had four parts: phase I dose escalation for <18 years (A1); phase I dose escalation for ≥18 years (A2); dose escalation for lorlatinib with topotecan/cyclophosphamide for <18 years (B2), all determined by 3 + 3 design; and dose expansion for single-agent lorlatinib (B1). In the article published in the Nature Medicine, the study investigators reported the data for cohorts A1, A2 and B2 that have met the pre-specified protocol endpoints for determination of the RP2D, description of side effects and antitumour activity.

Patients ≥12 months with measurable or evaluable refractory or relapsed high-risk neuroblastoma, including central nervous system (CNS) metastases and/or prior treatment with ALK TKIs aside from lorlatinib, were eligible. Dose limiting toxicities (DLTs) occurring in course 1 and CNS DLTs occurring in courses 1 and 2 informed dose escalation and RP2D determination. Patients were evaluable for dose escalation if they had received ≥75% of expected doses or experienced a DLT in courses 1 or 2. The study is ongoing. Lorlatinib was evaluated at 45–115 mg/m2/dose in children and 100–150 mg in adults.  

Neurobehavioural functioning was routinely assessed to provide real-time measures of cognition, behaviour and mood during lorlatinib administration. Patients who received any amount of lorlatinib were considered evaluable for response unless deemed by central review to have inadequate imaging to assess overall response. An exploratory aim to prospectively determine the frequency of circulating tumour cell-free DNA detection of ALK and acquired mutations at study entry and with each disease evaluation was performed and will be reported separately.

Common adverse events were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioural adverse events 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 RR (CR/PR/MR) for those <18 years was 30%, 67% for ≥18 years, 63% for chemotherapy combination in <18 years and 48% of responders achieved MIBG complete responses.

Younger patients treated with lorlatinib monotherapy, in particular those also harbouring MYCN amplification, had fewer responses than older patients. MYCN amplification is a truncal event in neuroblastoma that is almost never detected in tumours of patients >12 years of age, and it portends an especially aggressive disease course at relapse. The authors supposed that, due to intratumour heterogeneity and clonal evolution, mutations in ALK are branched events in these patients and that lorlatinib monotherapy will be insufficient. They observed objective responses in two patients with MYCN amplification treated with lorlatinib in combination with chemotherapy, suggesting that MYCN-amplified, ALK-mutated disease can potentially be overcome with the addition of chemotherapy.

Based on the results of this phase I study, which supports the hypothesis that lorlatinib will be safe and effective for patients with newly diagnosed ALK-driven, high-risk neuroblastoma, the study team recently implemented a major amendment to replace crizotinib with lorlatinib in the Childrenʼs Oncology Group phase III study. Incorporation of lorlatinib in the European phase III study in collaboration with the International Society of Paediatric Oncology European Neuroblastoma is planned as well. The authors concluded that integration of a potent targeted therapy in the treatment of newly diagnosed patients with ALK-aberrant, high-risk neuroblastoma holds substantial promise for improving patient outcomes.

The study was funded by US National Cancer Institute (NCI) grant and Pfizer, Inc. Additional support came from NCI grants, as well as Solving Kids Cancer US/UK, the Children’s Neuroblastoma Cancer Foundation, The Band of Parents, the EVAN Foundation, Wade’s Army, the Ronan Thompson Foundation, the Catherine Elizabeth Blair Memorial Foundation, the St. Baldrick’s Foundation, the V Foundation for Cancer Research, Alex’s Lemonade Stand Foundation, and Cookies for Kids Cancer.


Goldsmith KC, Park JR, Kayser K, et al. Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results. Nature Medicine; Published online 3 April 2023. DOI: