ceritinib and Adenocarcinoma

Ceritinib is a new anaplastic lymphoma kinase (ALK) inhibitor that has shown greater potency in patients with advanced ALK-rearranged non-small cell lung cancer, including those who had disease progression in crizotinib treatment. Here we reported, after several months of ceritinib treatment, two patients with advanced ALK-rearranged pulmonary adenocarcinoma exhibited a spectrum of respiratory symptoms like cough and dyspnea, with significantly higher inflammatory indicators. Chest computed tomography (CT) showed multiple bilateral and peripheral lesions in lungs. The prior considerations taken into account were disease progression or infection. However, biopsies of the pulmonary nodules revealed features of granulomatous inflammation without definite cancer cells. We documented for the first time that ceritinib might be associated with pulmonary granulomatous inflammation, and clinicians should be alert to the possibility that the rare adverse event emerged during ceritinib treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease Progression; Humans; Inflammation; Lung; Lung Neoplasms; Pneumonia; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

ALK, RET and ROS1 fusions have been identified as treatable targets in 5%-15% of non-small-cell lung cancers, and thanks to the advanced sequencing technologies, their new partner genes have been steadily detected. Here we identified a rare fusion of ALK (GCC2-ALK) in a patient with advanced lung adenocarcinoma and monitored the treatment efficacy of ALK inhibitors on this patient. We further performed in vitro functional studies of this fusion protein for evaluating its oncogenic potential.. The GCC2-ALK fusion gene was identified by targeted next generation sequencing (NGS) from the tumor DNA samples, and its fusion product was confirmed by Sanger sequencing the cDNA product. The functional study of GCC2-ALK was performed in Ba/F3 cells with cell proliferation and viability assays. The activation of downstream signaling pathways of ALK and their responses to crizotinib inhibition were studied in HEK-293 and 293T cells with ectopic expression of GCC2-ALK. In parallel, disease progression in the patient was monitored by computed tomography scanning and targeted NGS of either liquid or tissue biopsy samples throughout and after crizotinib treatment.. Similarly to EML4-ALK, the GCC2-ALK fusion protein promotes IL-3-independent growth of Ba/F3 cells. Ectopic expression of GCC2-ALK leads to hyper-activation of ALK downstream signaling that can be inhibited by crizotinib. Crizotinib treatment of the patient resulted in 18 months of progression free survival without any trace of GCC2-ALK fusion in the liquid biopsies. Re-biopsy of a lung lesion at progression identified the re-occurrence of GCC2-ALK. The patient was then administrated with a second-generation ALK inhibitor, ceritinib, and received partial response until the last follow-up.. We identified and functionally validated GCC2-ALK as a constitutively activated fusion in NSCLC. The patient was benefited from crizotinib treatment initially and then ceritinib after progression, suggesting GCC2-ALK as a novel therapeutic target for ALK inhibitors.

Topics: Adenocarcinoma; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Cell Line, Tumor; Crizotinib; Female; Golgi Matrix Proteins; HEK293 Cells; Humans; Lung Neoplasms; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrimidines; Sulfones

Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) are usually effective in lung adenocarcinoma patients with anaplastic lymphoma kinase (ALK) rearrangement. However, even after a good response to ALK-TKI therapy, most patients acquire resistance to these agents. Histological transformation is one of several suggested mechanisms of acquired resistance to ALK-TKIs. The clinicopathologic features of four patients with ALK-expressing adenocarcinoma and neuroendocrine features were analyzed.. We selected combined neuroendocrine differentiation in pulmonary adenocarcinoma cases with positive ALK immunostaining. Neuroendocrine differentiation was confirmed by CD56 immunohistochemical stain. Additional ALK fluorescence in situ hybridization (FISH) study and epidermal growth factor receptor (EGFR) mutation tests were also performed.. All four cases were positive for ALK immunohistochemistry and no EGFR mutations were detected. Interestingly, the results of ALK FISH assays showed rearrangement in only two cases. Three cases showed combined adenocarcinoma and neuroendocrine component without history of ALK-TKI administration; one of them was treated with crizotinib and experienced partial tumor regression. The remaining case had an adenocarcinoma at initial biopsy and she showed a partial response to crizotinib, and neuroendocrine changes were visible on second biopsy. Then she was treated with ceritinib and achieved a partial response.. We suggest that ALK-rearranged adenocarcinoma with combined neuroendocrine component is responsive to ALK-TKIs. Moreover, even after neuroendocrine transformation as a result of resistance to ALK-TKIs, the tumor may have partial response to second generation ALK-TKIs.

Topics: Adenocarcinoma; Adult; Aged; Anaplastic Lymphoma Kinase; CD56 Antigen; ErbB Receptors; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Pancreatic metastasis from non-small cell lung cancer (NSCLC) is usually asymptomatic or presents with abdominal pain, acute pancreatitis, or jaundice. A lung primary is associated with worse survival compared to pancreatic metastases from other organs. Surgical treatment of solitary metastasis to the pancreas from NSCLC has been reviewed in several studies, one of which had a notable disease-free interval. To our knowledge, there are no prior reports of targeted therapy of pancreatic metastasis of NSCLC followed by a significant response. Herein we report the case of a 31-year-old female with a solitary pancreatic metastasis from ALK-rearranged lung adenocarcinoma despite treatment with chemotherapy and crizotinib; she presented with symptoms of hyperglycemia. Targeted therapy with ceritinib (LDK378) led to symptomatic improvement and a significant radiologic response in the lung and pancreas, but not in the brain.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Humans; Hyperglycemia; Lung Neoplasms; Magnetic Resonance Imaging; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Neoplasm Staging; Protein Kinase Inhibitors; Pyrimidines; Radiotherapy, Adjuvant; Receptor Protein-Tyrosine Kinases; Sulfones; Tomography, X-Ray Computed; Translocation, Genetic; Treatment Outcome

Clinical outcomes of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer according to ALK fusion variants are not clear. We aimed to investigate the prevalence of ALK fusion variants and to compare clinical outcomes according to ALK fusion variants.. A retrospective analysis was conducted on patients with advanced ALK-rearranged adenocarcinoma treated with chemotherapy and ALK inhibitors. ALK rearrangement was identified by fluorescence in situ hybridization and confirmed by immunohistochemistry. Peptide nucleic acid-mediated quantitative polymerase chain reaction assays, designed to detect 28 types of echinoderm microtubule-associated protein-like 4 (EML)-ALK rearrangements, were performed. Clinicopathological analysis and treatment outcomes with platinum-based chemotherapy, pemetrexed therapy, and ALK inhibitors-including crizotinib and ceritinib-were evaluated.. A total of 52 patients with ALK-rearranged lung adenocarcinoma were enrolled. EML4-ALK variant 1 (v1) was the most common variant (38.5 %) followed by the non-EML4 variant (36.5 %), EML4-ALK variant 3a/b (19.2 %), and EML4-ALK variant 2 (5.8 %). No clinicopathological distinction was found between the different ALK fusion variants. Treatment response rates for each therapeutic agent did not differ according to ALK fusion variant. However, EML4 variants, especially v1, showed significantly longer progression-free survival (PFS) on pemetrexed treatment than did non-EML4 variants (median 31.1 months versus 5.7 months, P = 0.003). PFS with platinum-based chemotherapy and ALK inhibitors did not differ according to ALK fusion variant. Multivariate survival analysis using Cox's regression model revealed v1 as the only predictive factor for prolonged PFS on pemetrexed.. Among ALK fusion variants, v1 is the most common subtype. It showed superior progression-free survival on pemetrexed than did non-EML4 variants. No survival difference was demonstrated between variants treated with crizotinib or ceritinib.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; Anaplastic Lymphoma Kinase; Crizotinib; Disease-Free Survival; Female; Gene Rearrangement; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Mutation; Oncogene Proteins, Fusion; Pemetrexed; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Treatment Outcome

The treatment of advanced non-small cell lung cancer (NSCLC) has dramatically changed over the last decade. It has developed from an unspecific approach based on platinum doublet chemotherapy to a personalized, molecularly targeted therapy. Crizotinib is a new tyrosine kinase inhibitor approved for the treatment of NSCLC with gene rearrangement of EML4 and ALK. Despite good initial responses, patients treated with crizotinib relapse after an average of 10 months. In this case report, we present a patient with acquired crizotinib resistance whose adenocarcinoma responded to a second course of crizotinib following a drug holiday and chemotherapy with pemetrexed. This is the second case report to suggest that retreatment with crizotinib is an option for patients with initial benefit from ALK inhibition.

Topics: Adenocarcinoma; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Crizotinib; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

The echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified in patients with non-small cell lung cancer. To the best of our knowledge, there are only three cell lines harboring the EML4-ALK fusion gene, which have contributed to the development of therapeutic strategies. Therefore, we tried to establish a new lung cancer cell line harboring EML4-ALK.. A 61-year-old Japanese female presented with chest discomfort. She was diagnosed with left lung adenocarcinoma with T4N3M1 Stage IV. Although she was treated with chemotherapy, her disease progressed with massive pleural effusion. Because the EML4-ALK rearrangement was found in a biopsied specimen using fluorescence in situ hybridization, she was treated with crizotinib. She did well for 3 months.. Tumor cells were obtained from the malignant pleural effusion before treatment with crizotinib. Cells continued to proliferate substantially for several weeks. The cell line was designated ABC-11. The EML4-ALK fusion protein and genes were identified in ABC-11 cells using fluorescence in situ hybridization and immunohistochemistry, respectively. ABC-11 cells were sensitive to crizotinib and next-generation ALK inhibitors (ceritinib and AP26113), as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Phosphorylated ALK protein and its downstream signaling were suppressed by treatment with crizotinib in western blotting. Furthermore, we could transplant ABC-11 cells subcutaneously into BALB/c nu/nu mice.. We successfully established a new lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. This cell line could contribute to future research of EML4-ALK-positive lung cancer both in vivo and in vitro.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Cell Cycle Proteins; Cell Line, Tumor; Crizotinib; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Microtubule-Associated Proteins; Middle Aged; Oncogene Proteins, Fusion; Pleural Effusion, Malignant; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Serine Endopeptidases; Signal Transduction; Sulfones