Case history:
7-year old boy was diagnosed with high-risk neuroblastoma involving right adrenal mass, bone marrow and multiple bony sites. He was treated with as per high-risk-neuroblastoma-1/ESIOP protocol and remained disease free for three years. Cyclophosphamide-topotecan based chemotherapy was administered when he relapsed in the bone marrow as salvage therapy. No change in disease status was observed after six cycles. Genomic profiling was performed on a biopsy from the primary tumor site to aid clinical decision.
Genomic Profiling Results:
- ALK F1174L
- ATRX W2077*
- MYCN amplification
What would be the treatment strategy given genomic profiling results?
Would this patient respond to treatment with ALK inhibitors in the absence of ALK fusions?
Any novel therapeutic combinations?
Interpretation:
Activating mutation within ALK have been identified in a range of cancers including anaplastic thyroid cancer, NSCLC, IMT and neuroblastoma (NB)(1). In neuroblastoma, single-base missense mutations cluster in key regulatory regions of the kinase domain of ALK and promote ligand-independent constitutive signaling. Notably, mutations in three positions—R1275, F1174, and F1245—represent around 85% of ALK mutations in NB(1).
The mutant ALK proteins contribute substantially to the transformation process in NB, but the extent to which they do so varies among the mutation types. In line with their transforming ability, these mutations also differentially affect the sensitivity of NB to ALK inhibitors. In the context of non-fusion ALK alterations, the COG trial ADVL0912 showed encouraging results with crizotinib monotherapy in children with refractory neuroblastoma(2). Importantly, however, we began to learn about differential sensitivity of ALK mutations. Germane to this case, preclinical studies reported a relative resistance profile of ALK F1174L variant to crizotinib(3). Strikingly, crizotinib induced complete and sustained tumour regression in a panel of R1275Q-mutant xenografts while providing only partial growth inhibition to those driven by F1174L(3). These findings may suggest that F1174L clone may preclude benefit from crizotinib in this patient, which may be overcome with higher-affinity ALK inhibitors. On that note, lorlatinib demonstrated significantly greater potency than crizotinib against three of the most common ALK mutants in NB including F1174L(4,5). Currently, an active phase III trial from Children’s Oncology Group is evaluating the addition of 131I-MIBG or Lorlatinib to standard therapy in high-risk NB patients with ALK mutations (NCT03126916).
Learnings From This Case:
- ALK alterations are an important molecular target, given the role of ALK as a driver oncogene in NB and its actionability
- Distinct prognostic impact and predictive value of different ALK mutations needs to be considered
- There is a rationale for future clinical studies investigating ALK targeted treatment in the frontline setting together with chemotherapy and immunotherapy
References
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