cabozantinib and Adenocarcinoma-of-Lung

A new chimeric fusion transcript of KIF5B (the kinesin family 5B gene) and the RET (Rearranged during Transcription) oncogene, KIF5B-RET, was found in 1-2% of lung adenocarcinomas (LADCs) in 2012. Several related clinical trials for non-small cell lung cancer (NSCLC) with KIF5B-RET rearrangements using existing RET inhibitors, such as cabozantinib, lenvatinib, vandetanib, sunitinib, ponatinib, and AUY922, have been swiftly initiated by the discovery of the KIF5B-RET fusion gene. Anti-RET activity and the status of clinical development of cabozantinib for KIF5B-RET fusion-positive NSCLC are discussed.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anilides; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Kinesins; Lung Neoplasms; Proto-Oncogene Proteins c-ret; Pyridines; Treatment Outcome

The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes. In an unselected population of non-small cell lung carcinomas (NSCLCs), RET fusions are present in 1% to 2% of cases. This incidence increases substantially, however, in never-smokers with lung adenocarcinomas that lack other known driver oncogenes. Although preclinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors, clinical data on response are lacking. We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase II trial for patients with RET fusion-positive NSCLCs (NCT01639508). Confirmed partial responses were observed in 2 patients, including one harboring a novel TRIM33-RET fusion. A third patient with a KIF5B-RET fusion has had prolonged stable disease approaching 8 months (31 weeks). All three patients remain progression-free on treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anilides; Disease-Free Survival; Gene Fusion; Humans; Lung Neoplasms; Prospective Studies; Proto-Oncogene Proteins c-ret; Pyridines

Lung cancer is a leading cause of cancer-related mortality worldwide. Currently, targeted therapy has proved highly efficient in the treatment of advanced non-small cell lung cancer (NSCLC). Mesenchymal-epithelial transition factor (MET) is considered a validated molecular target in NSCLC. Given the low incidence of MET exon 14 skipping mutation, the planning of precision treatment for patients is a clinical problem that needs to be solved. In this report, we present a MET-positive case that benefited from crizotinib and cabozantinib treatment.. A 77-year-old patient was diagnosed with lung adenocarcinoma in our hospital. Positron emission tomography-computed tomography (PET-CT) showed a right upper lobe mass (58 × 56 mm, SUVmax 15.6), right hilar enlarged lymph nodes, and multiple bone and left adrenal metastases (c-T3N1M1c).. MET exon 14 mutation (exon14, c.2888-1G>C) was examined using the lung puncture sample by next generation sequencing. Therefore, the patient was diagnosed with late-stage lung adenocarcinoma with MET exon14 skipping gene mutation.. Crizotinib was given as the first-line treatment from August 2019. Considering the resistance of crizotinib, cabozantinib was given for second-line treatment.. Crizotinib was administered (250 mg bid) for 8 months, and her disease achieved partial regression (PR) and progression-free survival (PFS), which lasted for 8 months. The patient also reached PR after the second-line treatment with cabozantinib, and is currently under follow-up, with an overall survival (OS) of >12 months.. As MET exon 14 skipping mutation is rare in clinical practices, MET-TKIs (tyrosine kinase inhibitors) treatment can boost curative effects and improve prognosis of patients with advanced lung adenocarcinoma. This case report supports a rationale for the treatment of lung adenocarcinoma patients with a MET exon 14 skipping mutation and provides alternative treatment options for these types of NSCLC patients.

Topics: Adenocarcinoma of Lung; Aged; Anilides; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Therapy, Combination; Epithelial-Mesenchymal Transition; Exons; Female; Humans; Lung Neoplasms; Mutation; Proto-Oncogene Proteins c-met; Pyridines; Treatment Outcome

Topics: Adenocarcinoma of Lung; Anilides; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Proto-Oncogene Proteins c-ret; Pyridines

Lung cancer is a series of gene-driven disease. EGFR, ALK, and ROS1 are 3 major driver genes that play an important role in lung cancer development and precision management. Additionally, rare genetic alterations continue to be discovered and may become novel targets for therapy. The RET gene is one of such rare genetic alteration of non-small cell lung cancer (NSCLC). In this report, we present a RET-positive case that benefited from cabozantinib treatment.. A 50-year-old male patient was diagnosed with lung adenocarcinoma 2 years ago, at that time he received palliative surgery of pulmonary carcinoma and completed 4 cycles of chemotherapy with gemcitabine and cisplatin. Six months later, he was hospitalized in our cancer center due to the disease recurrence, presenting with pleural metastasis.. Gene alteration was examined using the intraoperative specimen by PCR method, and KIF5B/RET gene fusion was detected. Therefore, the patient was diagnosed with late-stage lung adenocarcinoma with RET gene mutation.. The patient received treatment with cabozantinib from June 2017.. Cabozantinib was administered (140 mg orally, once daily) for approximate 9 months, and his disease achieved stable disease (SD). During that period, there were no severe adverse events (AE), except for a grade II rash (CTCAE 4.0).. We found that the RET fusion gene is a novel driver molecular of lung adenocarcinoma in patients without common mutations in such genes as EGFR, ALK, and ROS1. This case report supports a rationale for the treatment of lung adenocarcinoma patients with a RET fusion and provides alternative treatment options for these types of NSCLC patients.

Topics: Adenocarcinoma of Lung; Anilides; Carcinoma, Non-Small-Cell Lung; Gene Fusion; Humans; Kinesins; Lung Neoplasms; Male; Middle Aged; Proto-Oncogene Proteins c-ret; Pyridines

The mesenchymal-to-epithelial transition (MET) gene is altered and becomes a driver mutation in up to 5% of non-small-cell lung cancer (NSCLC). We report our institutional experience treating patients with MET exon 14 skipping (METex14) mutations, including responses to the MET inhibitors crizotinib and cabozantinib. We identified cases of NSCLC with METex14 mutations using an institutionally developed or commercial next-generation sequencing assay. We assessed patient and disease characteristics by retrospective chart review. Some patients were treated off-label by the physician with crizotinib or cabozantinib, and tumor responses to these agents were assessed. A total of 15 patients with METex14-mutated NSCLC were identified, predominantly male (n=10) with a smoking history (60%) and a median age of 74.0 years. No other actionable somatic mutations were detected. Stage distribution included 26.7% stage I, 6.7% stage II, 6.7% stage III, and 60.0% stage IV. Among patients treated with crizotinib or cabozantinib (n=6), three patients showed partial response and one patient showed stable disease on the basis of RECIST criteria. Four patients experienced side effects requiring drug holiday, reduction, or cessation. Our findings highlight the diversity in presentation and histology of NSCLC with METex14 mutations, which were found in the absence of other actionable driver mutations. We observed evidence of tumor response to crizotinib and cabozantinib, supporting the previous reports that METex14 mutations in NSCLC are actionable driver events.

Topics: Adenocarcinoma of Lung; Aged; Aged, 80 and over; Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Crizotinib; Epithelial-Mesenchymal Transition; Exons; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Proto-Oncogene Proteins c-met; Pyridines; Retrospective Studies

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Anilides; Aniline Compounds; Crizotinib; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Piperazines; Pyridines

Rearranged ROS1 is a crizotinib-sensitive oncogenic driver in lung cancer. The development of acquired resistance, however, poses a serious clinical challenge. Consequently, experimental and clinical validation of resistance mechanisms and potential second-line therapies is essential.. We report the discovery of a novel, solvent-front ROS1(D2033N) mutation in a patient with CD74-ROS1-rearranged lung adenocarcinoma and acquired resistance to crizotinib. Crizotinib resistance of CD74-ROS1(D2033N) was functionally evaluated using cell-based assays and structural modeling.. In biochemical and cell-based assays, the CD74-ROS1(D2033N) mutant demonstrated significantly decreased sensitivity to crizotinib. Molecular dynamics simulation revealed compromised crizotinib binding due to drastic changes in the electrostatic interaction between the D2033 residue and crizotinib and reorientation of neighboring residues. In contrast, cabozantinib binding was unaffected by the D2033N substitution, and inhibitory potency against the mutant was retained. Notably, cabozantinib treatment resulted in a rapid clinical and near-complete radiographic response in this patient.. These results provide the first example of successful therapeutic intervention with targeted therapy to overcome crizotinib resistance in a ROS1-rearranged cancer. Clin Cancer Res; 22(10); 2351-8. ©2015 AACR.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anilides; Antigens, Differentiation, B-Lymphocyte; Cell Line, Tumor; Clinical Trials, Phase II as Topic; Crizotinib; Drug Resistance, Neoplasm; Female; Histocompatibility Antigens Class II; Humans; Lung Neoplasms; Middle Aged; Mutation; Oncogenes; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines

Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped, and understanding of mechanisms of resistance to MET TKIs is limited. Here, we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that MET. With several structurally distinct MET inhibitors undergoing development for treatment of NSCLC, it is critical to identify mechanism-based therapies for drug resistance. We demonstrate that an acquired MET

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anilides; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Treatment Outcome

Oncogenic rearrangements of the RET gene have recently been described in 1% to 2% of lung adenocarcinomas. We report five cases of RET-rearranged lung adenocarcinoma with an unusual constellation of clinical and histologic features that has not previously been described in tumors with this genomic alteration. The age at diagnosis of the five patients (4F, 1M) ranged from 44 to 77 years. All were never-smokers. Radiologically, four tumors showed lymphangitic spread within the lungs at presentation; three of these had multiple bilateral lung nodules. Histology showed psammoma bodies within the tumor in four of five cases. Molecular testing for activating EGFR mutations by standard genotyping and ALK expression by immunohistochemistry was negative in all cases. Additional molecular analysis was prompted by the clinical profile in that all five patients were never-smokers with metastatic, relapsed, and/or refractory disease; and also by unusual histologic findings in two cases. Comprehensive genomic profiling performed by means of a clinical grade cancer gene panel next-generation sequencing assay demonstrated a KIF5B-RET fusion in three; and fluorescence in-situ hybridization documented a RET rearrangement in two. Three of the patients were treated with the RET inhibitor cabozantinib. By Response Evaluation Criteria In Solid Tumors (RECIST) criteria, two had a confirmed partial response (at 6 weeks and 4 weeks) and one had stable disease. Our findings suggest that the combination of lymphangitic spread and psammoma bodies may be characteristic of a subset of advanced stage RET-rearranged lung adenocarcinomas. These findings should prompt additional molecular testing for RET translocations, particularly in never-smokers with EGFR- and ALK-negative lung adenocarcinoma.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Anilides; Female; Gene Rearrangement; Humans; Immunohistochemistry; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Molecular Targeted Therapy; Proto-Oncogene Proteins c-ret; Pyridines; Treatment Outcome

RET has recently been identified as a potential new oncogenic driver in a subset of patients with non-small cell lung cancer (NSCLC). In this issue of Cancer Discovery, Drilon and colleagues report preliminary trial data with a RET inhibitor in RET fusion-positive NSCLC, validating RET as a therapeutic target in lung cancer.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anilides; Humans; Lung Neoplasms; Proto-Oncogene Proteins c-ret; Pyridines