pf-06463922 and Neoplasms

Topics: Aminopyridines; Humans; Lactams; Neoplasms; Phenotype; Pyrazoles

Advances in genomic technologies and the development of targeted therapeutics are making the use of precision medicine increasingly possible. In this study, we explored whether precision medicine can be applied for the management of refractory/relapsed pediatric solid tumors by discovering actionable alterations using targeted panel sequencing. Samples of refractory/relapsed pediatric solid tumors were tested using a targeted sequencing panel covering the exonic DNA sequences of 381 cancer genes and introns across 22 genes to detect clinically significant genomic aberrations in tumors. The molecular targets were tiered from 1 to 5 based on the presence of actionable genetic alterations, strength of supporting evidence, and drug availability in the Republic of Korea. From January 2016 to October 2018, 55 patients were enrolled. The median time from tissue acquisition to drug selection was 29 d (range 14-39), and tumor profiling was successful in 53 (96.4%) patients. A total of 27 actionable alterations in tiers 1-4 were detected in 20 patients (36.4%), and the majority of actionable alterations were copy number variations. The tiers of molecular alterations were tier 1 (clinical evidence) in 4 variants, tier 2 (preclinical evidence) in 8 variants, tier 3 (consensus opinion) in 2 variants, and tier 4 (actionable variants with a drug that is available in other countries but not in the Republic of Korea) in 9 variants. In one patient with relapsed neuroblastoma with ALK F1174L mutation and ALK amplification, lorlatinib was used in a compassionate use program, and it showed some efficacy. In conclusion, using a targeted sequencing panel to discover actionable alterations in relapsed/refractory pediatric solid tumors was practical and feasible.

Topics: Adolescent; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Child; Child, Preschool; DNA Copy Number Variations; DNA Mutational Analysis; Drug Resistance, Neoplasm; Exons; Feasibility Studies; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Lactams; Lactams, Macrocyclic; Male; Molecular Targeted Therapy; Mutation; Neoplasm Recurrence, Local; Neoplasms; Precision Medicine; Pyrazoles; Republic of Korea; Young Adult

Personalized cancer therapy is based on a patient's tumor lineage, histopathology, expression analyses, and/or tumor DNA or RNA analysis. Here, we aim to develop an in vitro functional assay of a patient's living cancer cells that could complement these approaches. We present methods for developing cell cultures from tumor biopsies and identify the types of samples and culture conditions associated with higher efficiency of model establishment. Toward the application of patient-derived cell cultures for personalized care, we established an immunofluorescence-based functional assay that quantifies cancer cell responses to targeted therapy in mixed cell cultures. Assaying patient-derived lung cancer cultures with this method showed promise in modeling patient response for diagnostic use. This platform should allow for the development of co-clinical trial studies to prospectively test the value of drug profiling on tumor-biopsy-derived cultures to direct patient care.

Topics: Acrylamides; Aminopyridines; Anaplastic Lymphoma Kinase; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Biopsy; Crizotinib; ErbB Receptors; Erlotinib Hydrochloride; Feeder Cells; Fluorescent Antibody Technique; Gene Expression; High-Throughput Screening Assays; Humans; Keratin-18; Keratin-8; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Neoplasms; Piperazines; Precision Medicine; Primary Cell Culture; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Tumor Cells, Cultured

We report the preclinical evaluation of PF-06463922, a potent and brain-penetrant ALK/ROS1 inhibitor. Compared with other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK-driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors because of secondary ALK kinase domain mutations and/or brain metastases.

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Lactams; Lactams, Macrocyclic; Mice; Mutation; Neoplasms; NIH 3T3 Cells; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases; Xenograft Model Antitumor Assays