• Ou Sai-Hong Ignatius SI Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, USA; Chao Family Comprehe, Thomas K Lee, Lauren Young, Maria Y Fernandez-Rocha, Dean Pavlick, Alexa B Schrock, Viola W Zhu, Jeffrey Milliken, Siraj M Ali, and Barbara J Gitlitz.
• 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.
• Lung Cancer. 2017 Apr 1; 106: 110-114.

AbstractDevelopment 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.Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

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