pf-06463922 and Cell-Transformation--Neoplastic

Topics: Adenocarcinoma of Lung; Aminopyridines; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 15; Humans; Lactams; Lung Neoplasms; Mice; Mice, Nude; Microtubule-Associated Proteins; Neoplasm Proteins; Oncogene Proteins, Fusion; Pyrazoles; Receptor Protein-Tyrosine Kinases; Xenograft Model Antitumor Assays

Small cell transformation is a well-recognized mechanism of resistance to EGFR-TKI therapy in EGFR-mutant NSCLC, yet it remains a poorly-described phenomenon in ALK-rearranged NSCLC.. Chart and literature review.. We report a case of a patient with ALK-rearranged lung cancer progressing on three-lines of ALK-targeted therapies, with development of acquired resistance to lorlatinib, with both transformation to a neuroendocrine carcinoma, and acquisition of ALK 1196 M.. Given the inevitable development of resistance in ALK + NSCLC, if feasible, re-biopsy on progression should be standard over liquid biopsy. Neuroendocrine carcinoma transformation remains an important mechanism of acquired resistance to lorlatinib.

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; ErbB Receptors; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Liver Neoplasms; Lung Neoplasms; Male; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Neoplasm Staging; Pyrazoles; Tomography, X-Ray Computed

Development of the acquired ALK G1202R solvent front mutation and small cell lung cancer (SCLC) transformation have both been independently reported as resistance mechanisms to ALK inhibitors in ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) patients but have not been reported in the same patient. Here we report an ALK+ NSCLC patient who had disease progression after ceritinib and then alectinib where an ALK G1202R mutation was detected on circulating tumor (ct) DNA prior to enrollment onto a trial of another next generation ALK inhibitor, lorlatinib. The patient's central nervous system (CNS) metastases responded to lorlatinib together with clearance of ALK G1202R mutation by repeat ctDNA assay. However, the patient developed a new large pericardial effusion. Resected pericardium from the pericardial window revealed SCLC transformation with positive immunostaining for synaptophysin, chromogranin, and ALK (D5F3 antibody). Comprehensive genomic profiling (CGP) of the tumor infiltrating pericardium revealed the retainment of an ALK rearrangement with emergence of an inactivating Rb1 mutation (C706Y) and loss of exons 1-11 in p53 that was not detected in the original tumor tissue at diagnosis. The patient was subsequently treated with carboplatin/etoposide and alectinib, but had rapid clinical deterioration and died. The patient never received crizotinib. This case illustrates that multiple/compound resistance mechanisms to ALK inhibitors can occur and provide supporting information that loss of p53 and Rb1 are important in SCLC transformation. If clinically feasible, tissue-based re-biopsy allowing histological examination and CGP remains the gold standard to assess resistance mechanism(s) and to direct subsequent rational clinical care.

Topics: Adult; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Transformation, Neoplastic; Crizotinib; Disease Progression; Drug Resistance, Neoplasm; Fatal Outcome; Female; Humans; Lactams; Lactams, Macrocyclic; Liquid Biopsy; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplastic Cells, Circulating; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retinoblastoma Binding Proteins; Small Cell Lung Carcinoma; Ubiquitin-Protein Ligases