ROS1 Targeted Therapies: Current Status

Azelby, Christine M; Sakamoto, M; Bowles, Daniel W.

doi:10.1007/s11912-021-01078-y

Cited by 35 publications

(31 citation statements)

References 50 publications

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“…After initial PR at one month since treatment initiation, the disease progressed another two months later, leading to a PFS of 3 months. In addition to reduced inhibitory potency compared with next-generation ROS1 inhibitors, progression on crizotinib results from acquisition of resistance mechanism and/or development of CNS disease ( 1 ), which are not uncommon in ROS1 -positive NSCLC. Patil et al.…”

Section: Discussionmentioning

confidence: 99%

“…Chromosomal rearrangements leading to fusion genes that encode a chimeric protein with aberrantly elevated ROS1 kinase activity represent an established oncogenic driver in non-small cell lung cancer (NSCLC). ROS1 -positive patients account for 1-2% of NSCLC cases ( 1 ). Multiple fusion partners have been reported for ROS1 rearrangement, the most common of which being CD74 , followed by SDC4 , EZR , and SLC34A2 ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

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Case Report: Short-Term Response to First-Line Crizotinib Monotherapy in a Metastatic Lung Adenocarcinoma Patient Harboring a Novel TPR-ROS1 Fusion

Wei

Yang

et al. 2022

Front. Oncol.

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ROS1-rearranged patients account for 1-2% of non-small cell lung cancer (NSCLC) cases. Approximately 10 fusion partners have been discovered, while clinical practice is actively generating knowledge of new ones and their therapeutic responses. Herein, we report a patient with stage IV NSCLC that harbored a novel TPR-ROS1 fusion, which demonstrated a rapid but short partial response to first line crizotinib and primary resistance to subsequent ceritinib. Computed tomography detected a pulmonary nodule in a 53-year-old woman who presented with persistent cough. Histopathologic and molecular examination of the tissue biopsy indicated a poorly differentiated adenocarcinoma staining negative for PD-L1 but harbored a novel translocated promoter region (TPR)-ROS1 (T4:R35) gene fusion. Frontline crizotinib monotherapy elicited a rapid partial response after 1 month, although the disease progressed another 2 months later. After another 3 months of continued crizotinib treatment, the patient manifested newly emerged and enlarged lung and brain lesions. Genomic profiling still identified TPR-ROS1 as the only aberration, while a lymph node biopsy indicated PD-L1 immunopositivity. The patient was then treated with ceritinib and progressed within 1 month. She was started on chemotherapy with pemetrexed plus carboplatin and has achieved rapid partial response as of the latest follow-up. In summary, we provided clinical evidence of a novel TPR-ROS1 fusion and its roles as an oncogenic driver in metastatic NSCLC. To the best of our knowledge, ours is the first case to report this fusion in NSCLC. This case was characterized by a rapid yet short-term response to first line crizotinib and primary resistance to subsequent ceritinib, while no known genetic resistance mechanism was identified and other mechanisms including histologic transformation were unlikely. Future research is needed to unveil the resistance mechanism and formulate effective treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Case Report: Short-Term Response to First-Line Crizotinib Monotherapy in a Metastatic Lung Adenocarcinoma Patient Harboring a Novel TPR-ROS1 Fusion

Wei

Yang

et al. 2022

Front. Oncol.

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“…Other NSCLC-related driver mutations act as potential therapeutic targets for NSCLC and help in controlling BM. These include ROS-1, HER-2, RET proto-oncogene, mesenchymalepithelial transition factor receptor tyrosine kinase gene (MET), v-Raf murine sarcoma viral oncogene homologue B1 (BRAF), and tyrosine kinase receptor B (TrkB) [102][103][104]. Experts consider the prevention, delay, and treatment of NSCLC CNS metastasis as a focus for future research, in addition to ongoing related studies.…”

Section: Other Targeted Therapiesmentioning

confidence: 99%

Research Progress and Challenges in the Treatment of Central Nervous System Metastasis of Non-Small Cell Lung Cancer

Wang

Guo

et al. 2021

Cells

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Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors and has high morbidity and mortality rates. Central nervous system (CNS) metastasis is one of the most frequent complications in patients with NSCLC and seriously affects the quality of life (QOL) and overall survival (OS) of patients, with a median OS of untreated patients of only 1–3 months. There are various treatment methods for NSCLC CNS metastasis, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, which do not meet the requirements of patients in terms of improving OS and QOL. There are still many problems in the treatment of NSCLC CNS metastasis that need to be solved urgently. This review summarizes the research progress in the treatment of NSCLC CNS metastasis to provide a reference for clinical practice.

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“…ALK rearrangements are detected in approximately 5% of non-squamous NSCLCs, while the occurrence of ROS1 and RET translocations is around 2%. These gene fusions have increased prevalence in young NSCLC patients and, similarly to EGFR and ALK, are typical for female and smoking-unrelated tumors [20][21][22][23]. NSCLCs carrying druggable rearranged kinases demonstrate spectacular benefit from targeted therapies: several studies involving metastatic NSCLC cases produced median overall survival estimates well above five years, with some categories of patients approaching close to ten years survival threshold [24][25][26].…”

Section: Non-small Cell Lung Cancer (Nsclc)mentioning

confidence: 99%

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

Aleksakhina

Imyanitov

2021

IJMS

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The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.

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ROS1 Targeted Therapies: Current Status

Cited by 35 publications

References 50 publications

Case Report: Short-Term Response to First-Line Crizotinib Monotherapy in a Metastatic Lung Adenocarcinoma Patient Harboring a Novel TPR-ROS1 Fusion

Case Report: Short-Term Response to First-Line Crizotinib Monotherapy in a Metastatic Lung Adenocarcinoma Patient Harboring a Novel TPR-ROS1 Fusion

Research Progress and Challenges in the Treatment of Central Nervous System Metastasis of Non-Small Cell Lung Cancer

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

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