Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)

Abstract

Gain-of-function mutations in the ALK oncogene occur in 15% or more of newly diagnosed patients with high-risk neuroblastoma. This discovery positioned ALK as the first tractable molecular target for patients with this disease. However, crizotinib showed limited anti-tumor activity in this phase 2 trial for patients with relapsed ALK+ neuroblastoma. The preclinical mechanism underlying this observation revealed that two of the three hot spot mutations in ALK confer intrinsic resistance to crizotinib due to preferential affinity for ATP binding that could potentially be overcome by higher drug exposures. The observed responses occurred in patients with the most common both germline and somatic hot spot mutation at residue R1275.Despite limited activity and lack of objective responses in patients harboring de novo resistant ALK mutations, we conclude that, while this was possibly a limitation of the number of patients enrolled, this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity. Emerging data with the third generation ALK inhibitor lorlatinib shows promise for patients with ALK-driven neuroblastoma.

Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration

“…In conclusion, the discovery of activating mutations in the ALK receptor more than a decade ago has led to numerous studies to understand the effect of aberrant ALK signaling on NB pathobiology and to devise clinically effective countermeasures. These efforts have yielded a series of ALK inhibitors with the ability to silence oncogenic ALK expression and to block the growth of NB cells in experimental models (Hallberg and Palmer, 2016), but to date, this progress has not translated to clear therapeutic gains (Foster et al, 2021). Although newer generations of inhibitors may be more effective, success with direct targeting of ALK kinase activity would benefit only the approximately 10% of Cell Reports 36, 109363, July 13, 2021 11 Article ll OPEN ACCESS high-risk patients with NB who have tumors harboring activating mutations, leading to efforts to harness ALK as a tumor-associated antigen.…”

Neuroblastoma Molecular Risk-Stratification of DNA Copy Number and ALK Genotyping via Cell-Free Circulating Tumor DNA Profiling

“…A number of studies were able to accurately detect MNA and SCA in serum and plasma from patients with neuroblastoma as a tumor surrogate with varied diagnostic accuracies, which depended on disease stage [7]. In more recent years it became clear that mutations of the ALK tyrosine kinase domain constitute an important potential therapeutic target in neuroblastoma [12] and can be detected in ctDNA [14,15]. In the current clinical setting, surgical or core biopsies are carried out to provide histological diagnosis.…”

“…Lately, the efficacy of ALK inhibitors had shown potential in ALK-driven refractory or relapsed neuroblastoma [12] and is currently being investigated as upfront treatment for newly diagnosed patients with high-risk disease and confirmed ALK mutated tumors (COG ANBL1531, ClinicalTrails.gov identifier NCT03126916). However, access to adequate core needle tissue to determine ALK somatic variants is challenging, with only 10% of samples reported to be successfully genotyped (either mutated or wild type) (COG personal communications).…”

Notable therapeutic response in a patient with systemic juvenile xanthogranuloma with KIF5B‐ALK fusion

“…Crizotinib has been administered for paediatric patients with anaplastic large cell lymphoma (ALCL) and solid tumours, including neuroblastoma, and its tolerability and safety have been established. 13,14 Alectinib was reported to show favourable clinical activity and was well tolerated by paediatric patients with ALK-positive ALCL that progressed under conventional chemotherapy. 15,16 In addition, alectinib had superior CNS activity and significantly delayed the progression of CNS metastases as compared with crizotinib in patients with advanced ALK-positive NSCLC.…”