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Activating point mutations in Anaplastic Lymphoma Kinase (ALK ) have positioned ALK as the only mutated oncogene tractable for targeted therapy in neuroblastoma. Cells with these mutations respond to lorlatinib in pre-clinical studies, providing the rationale for a first-in-child Phase 1 trial (NCT03107988) in patients with ALK-driven neuroblastoma. To track evolutionary dynamics and heterogeneity of tumors, and to detect early emergence of lorlatinib resistance, we collected serial circulating tumor DNA samples from patients enrolled on this trial. Here we report the discovery of off-target resistance mutations in 11 patients (27%), predominantly in the RAS-MAPK pathway. We also identify newly acquired secondary compound ALK mutations in 6 (15%) patients, all acquired at disease progression. Functional cellular and biochemical assays and computational studies elucidate lorlatinib resistance mechanisms. Our results establish the clinical utility of serial circulating tumor DNA sampling to track response and progression and to discover acquired resistance mechanisms that can be leveraged to develop therapeutic strategies to overcome lorlatinib resistance. Inhibition of ALK is initially effective in patients with ALK-driven lung cancer but resistance often arises. Here, the authors use circulating tumour DNA, collected as part of a phase I trial investigating lorlatinib (ALK inhibitor) in pediatric patients with ALK-driven neuroblastoma, to detect early resistance mechanisms.

The Anaplastic Lymphoma Kinase ( ALK ) gene is a receptor tyrosine kinase (RTK) with expression restricted to the developing nervous system. Most neuroblastomas express native ALK protein on the cell surface and ALK is uniformly overexpressed in fusion-positive rhabdomyosarcoma and in subsets of metastatic colorectal carcinoma, melanoma, ovarian carcinoma, and breast carcinoma. Here, we first confirm that ALK RNA, protein, and tumor cell surface expression is elevated in multiple pediatric and adult malignancies with minimal expression in childhood normal tissues. We then demonstrate that a humanized ALK-directed antibody conjugated to pyrrolobenzodiazepine (CDX0239-PBD) is internalized in ALK-expressing neuroblastoma cell lines with cell surface expression-dependent cytotoxicity. Finally, we show that CDX0239-PBD exhibits potent antitumor efficacy including maintained complete responses in ALK-expressing patient and cell line-derived neuroblastoma, fusion-positive rhabdomyosarcoma, and colorectal carcinoma xenograft models. These data support the clinical development of a first-in-class ALK-directed antibody-drug conjugate (ADC) for multiple pediatric and adult ALK-expressing malignancies. The native anaplastic lymphoma kinase (ALK) oncofetal protein is expressed in neuroblastoma and in multiple pediatric and adult solid tumors. Here, the authors show an ALK-directed antibody-drug conjugate with therapeutic efficacy in ALK-expressing preclinical models.