title: Dual occurrence of ALK G1202R solvent front mutation and small cell lung cancer transformation as resistance mechanisms to second generation ALK inhibitors without prior exposure to crizotinib. Pitfall of solely relying on liquid re-biopsy?
abstract: 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.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, USA; Chao Family Comprehensive Cancer Center, Orange, CA, USA. Electronic address: Ignatius.ou@uci.edu.
authors.forename: Sai-Hong Ignatius
authors.initials: SI
authors.lastname: Ou
authors.affiliation: Department of Pathology, University of California Irvine School of Medicine, Orange, CA, USA.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Lee
authors.affiliation: Foundation Medicine Inc, Cambridge, MA, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Young
authors.affiliation: Chao Family Comprehensive Cancer Center, Orange, CA, USA.
authors.forename: Maria Y
authors.initials: MY
authors.lastname: Fernandez-Rocha
authors.affiliation: Foundation Medicine Inc, Cambridge, MA, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Pavlick
authors.affiliation: Foundation Medicine Inc, Cambridge, MA, USA.
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Schrock
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, USA; Chao Family Comprehensive Cancer Center, Orange, CA, USA; Veterans Affairs Long Beach Healthcare System, Long Beach, CA, USA.
authors.forename: Viola W
authors.initials: VW
authors.lastname: Zhu
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, University of California Irvine School of Medicine, Orange, CA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milliken
authors.affiliation: Foundation Medicine Inc, Cambridge, MA, USA.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Gitlitz
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000077547:Crizotinib; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000627:therapeutic use; D000073890:Liquid Biopsy / Q000379:methods; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles; D011725:Pyridines; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D056286:Retinoblastoma Binding Proteins / Q000235:genetics; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D000631:Aminopyridines; D007769:Lactams; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C000606393:RB1 protein, human; D056286:Retinoblastoma Binding Proteins; D000077547:Crizotinib; D044767:Ubiquitin-Protein Ligases; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C000590786:lorlatinib
keywords: ALK G1202R solvent front mutation; ALK+ NSCLC; Circulating tumor DNA; Lorlatinib; Rb1 C706Y; Small cell lung cancer transformation