436 results on '"Mok, A."'
Search Results
2. Update on International Cooperative Groups Studies in Thoracic Malignancies: The Emergence of Immunotherapy.
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Shukla, Navika D, Salahudeen, Ameen A, Taylor, Gregory A, Ramalingam, Suresh S, Vokes, Everett E, Goss, Glenwood D, Decker, Roy H, Kelly, Karen, Scagliotti, Giorgio V, Mok, Tony S, and Wakelee, Heather A
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Humans ,Thoracic Neoplasms ,Prognosis ,Immunotherapy ,International Cooperation ,Clinical Trials as Topic ,Clinical trials ,Mesothelioma ,Non–small-cell lung cancer ,Small cell lung cancer ,Thymic carcinoma ,Non-small-cell lung cancer ,Lung ,Lung Cancer ,Cancer ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Cancer cooperative groups have historically played a critical role in the advancement of non-small-cell lung cancer therapy. Representatives from cooperative groups worldwide convene at the International Lung Cancer Congress annually. The International Lung Cancer Congress had its 17th anniversary in the summer of 2016. The present review highlights the thoracic malignancy studies discussed by presenters. The included studies are merely a sample of the trials of thoracic malignancies ongoing globally.
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- 2018
3. Construction and Validation of Two Novel Nomograms for Predicting the Overall Survival and Cancer-Specific Survival of NSCLC Patients with Bone Metastasis
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Dong Q, Deng J, Mok TN, Chen J, and Zha Z
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lung cancer ,metastasis ,seer ,prognosis ,Medicine (General) ,R5-920 - Abstract
Qiu Dong,1 Jialin Deng,2 Tsz Ngai Mok,1 Junyuan Chen,1 Zhengang Zha1 1Center for Bone, Joint and Sports Medicine, The First Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2School of Medicine, Jinan University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Junyuan Chen; Zhengang ZhaCenter for Bone, Joint and Sports Medicine, The First Hospital of Jinan University, Jinan University, No. 613, Huangpu Avenue West, Guangzhou, 510515, Guangdong, People’s Republic of ChinaTel +86 134 8029 9854; +86 173 6182 0624Email chenjunyuan@jnu.edu.cn; zhazhengang1965@163.comBackground: Bone metastasis (BM) is the most common site of metastasis in non-small cell lung carcinoma (NSCLC). We aimed to construct and validate 2 novel nomograms predicting the 3-, 6-, and 12-months overall survival (OS) and cancer-specific survival (CSS).Methods: The clinical data of 7480 patients between 2010 and 2016 were enrolled from the Surveillance, Epidemiology, and End Results database (SEER). The patients were allocated randomly to training and validation cohorts in a 7:3 ratio. Cox proportional hazards regression models were used to identify prognostic risk factors and establish 2 nomograms. The prediction accuracy of nomograms was assessed by C-index, the area under the ROC curve (AUC), and calibration curves.Results: A total of 244998 NSCLC patients were identified between 2010 and 2016, with 7480 found with BM, accounting for 3.1%. Overall, 7480 patients were enrolled in the OS nomogram construction and were randomized to the training set (n = 5236) and the validation set (n = 2244). Age, sex, race, marital status, histology, grade, primary site, T stage, N stage, liver metastasis, surgery, radiotherapy, and chemotherapy were found to correlate with OS. A total of 7422 samples were included in the CSS nomogram construction, randomly grouped into training set (n = 5195) and the validation set (n = 2227). Age, sex, race, histology, grade, primary site, T stage, N stage, brain metastasis, liver metastasis, surgery, radiotherapy, and chemotherapy were associated with CSS. Two nomograms were conducted to predict the 3-, 6-, and 12-months OS and CSS. The ROC curves and exhibited good performance for predicting OS and CSS.Conclusion: We established and validated 2 high-performance nomograms to assist clinical doctors in making personalized treatment decisions.Keywords: lung cancer, metastasis, SEER, prognosis
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- 2021
4. Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor Prognosis.
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Karachaliou, Niki, Chaib, Imane, Cardona, Andres Felipe, Berenguer, Jordi, Bracht, Jillian Wilhelmina Paulina, Yang, Jie, Cai, Xueting, Wang, Zhigang, Hu, Chunping, Drozdowskyj, Ana, Servat, Carles Codony, Servat, Jordi Codony, Ito, Masaoki, Attili, Ilaria, Aldeguer, Erika, Capitan, Ana Gimenez, Rodriguez, July, Rojas, Leonardo, Viteri, Santiago, Molina-Vila, Miguel Angel, Ou, Sai-Hong Ignatius, Okada, Morihito, Mok, Tony S, Bivona, Trever G, Ono, Mayumi, Cui, Jean, Ramón Y Cajal, Santiago, Frias, Alex, Cao, Peng, and Rosell, Rafael
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Animals ,Humans ,Mice ,Carcinoma ,Non-Small-Cell Lung ,Lung Neoplasms ,Disease Models ,Animal ,Receptor Protein-Tyrosine Kinases ,Cell Adhesion Molecules ,Neoplasm Proteins ,Proto-Oncogene Proteins ,RNA ,Small Interfering ,Antigens ,CD ,Survival Analysis ,Xenograft Model Antitumor Assays ,Gene Expression Profiling ,Proteomics ,Cell Survival ,Gene Expression Regulation ,Neoplastic ,Enzyme Activation ,Drug Resistance ,Neoplasm ,Mutation ,Models ,Biological ,Adult ,Aged ,Aged ,80 and over ,Middle Aged ,Female ,Male ,ErbB Receptors ,AXL ,CDCP1 ,Combination therapies ,EGFR ,Lung cancer ,Resistance ,and over ,Antigens ,CD ,Carcinoma ,Non-Small-Cell Lung ,Disease Models ,Animal ,Drug Resistance ,Neoplasm ,Gene Expression Regulation ,Neoplastic ,Models ,Biological ,RNA ,Small Interfering ,Clinical Sciences ,Public Health and Health Services - Abstract
Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p=0.0407) and overall survival (hazard ratio of 2.23, p=0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing.
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- 2018
5. Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-Small Cell Lung Cancer Associated With Poor Prognosis
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Karachaliou, Niki, Chaib, Imane, Cardona, Andres Felipe, Berenguer, Jordi, Bracht, Jillian Wilhelmina Paulina, Yang, Jie, Cai, Xueting, Wang, Zhigang, Hu, Chunping, Drozdowskyj, Ana, Servat, Carles Codony, Servat, Jordi Codony, Ito, Masaoki, Attili, Ilaria, Aldeguer, Erika, Capitan, Ana Gimenez, Rodriguez, July, Rojas, Leonardo, Viteri, Santiago, Molina-Vila, Miguel Angel, Ou, Sai-Hong Ignatius, Okada, Morihito, Mok, Tony S, Bivona, Trever G, Ono, Mayumi, Cui, Jean, Ramón y Cajal, Santiago, Frias, Alex, Cao, Peng, and Rosell, Rafael
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Women's Health ,Genetics ,Clinical Research ,Lung Cancer ,Cancer ,Lung ,5.1 Pharmaceuticals ,4.2 Evaluation of markers and technologies ,Adult ,Aged ,Aged ,80 and over ,Animals ,Antigens ,CD ,Antigens ,Neoplasm ,Carcinoma ,Non-Small-Cell Lung ,Cell Adhesion Molecules ,Cell Survival ,Disease Models ,Animal ,Drug Resistance ,Neoplasm ,Enzyme Activation ,ErbB Receptors ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Neoplastic ,Humans ,Lung Neoplasms ,Male ,Mice ,Middle Aged ,Models ,Biological ,Mutation ,Neoplasm Proteins ,Proteomics ,Proto-Oncogene Proteins ,RNA ,Small Interfering ,Receptor Protein-Tyrosine Kinases ,Survival Analysis ,Xenograft Model Antitumor Assays ,Axl Receptor Tyrosine Kinase ,Lung cancer ,EGFR ,Resistance ,AXL ,CDCP1 ,Combination therapies ,Public Health and Health Services ,Clinical sciences ,Epidemiology - Abstract
Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo. In Cohort 1, CUB domain-containing protein-1 (CDCP1) was an independent negative prognostic factor for progression-free survival (hazard ratio of 1.79, p=0.0407) and overall survival (hazard ratio of 2.23, p=0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs, in both cohorts of patients. Our preclinical experiments revealed that several RTKs and non-RTKs, were up-regulated at baseline or after treatment with gefitinib or osimertinib. TPX-0005 plus EGFR TKI suppressed expression and activation of RTKs and downstream signaling intermediates. Co-expression of CDCP1 and AXL is often observed in EGFR-mutation-positive tumors, limiting the efficacy of EGFR TKIs. Co-treatment with EGFR TKI and TPX-0005 warrants testing.
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- 2018
6. Transbronchial Techniques for Lung Cancer Treatment: Where Are We Now?
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Joyce W. Y. Chan, Ivan C. H. Siu, Aliss T. C. Chang, Molly S. C. Li, Rainbow W. H. Lau, Tony S. K. Mok, and Calvin S. H. Ng
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lung cancer ,transbronchial ablation techniques ,robotic bronchoscopy ,local treatment ,lung cancer screening ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The demand for parenchyma-sparing local therapies for lung cancer is rising owing to an increasing incidence of multifocal lung cancers and patients who are unfit for surgery. With the latest evidence of the efficacy of lung cancer screening, more premalignant or early-stage lung cancers are being discovered and the paradigm has shifted from treatment to prevention. Transbronchial therapy is an important armamentarium in the local treatment of lung cancers, with microwave ablation being the most promising based on early to midterm results. Adjuncts to improve transbronchial ablation efficiency and accuracy include mobile C-arm platforms, software to correct for the CT-to-body divergence, metal-containing nanoparticles, and robotic bronchoscopy. Other forms of energy including steam vapor therapy and pulse electric field are under intensive investigation.
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- 2023
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7. Next‐generation sequencing using tissue specimen collected with a 1.1 mm‐diameter cryoprobe in patients with lung cancer.
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Kim, Mi‐Hyun, Kim, Soo Han, Lee, Geewon, Mok, Jeongha, Lee, Min Ki, Song, Ju Sun, and Eom, Jung Seop
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NUCLEOTIDE sequencing ,LUNG cancer ,BRONCHOSCOPES ,CANCER patients ,RNA sequencing ,LUNG diseases - Abstract
Background and Objective: Next‐generation sequencing (NGS) analysis is considered standard for lung cancer diagnosis in clinical practice. Little is known about the feasibility of NGS using tumour tissue sampled with a 1.1 mm‐diameter cryoprobe. We aimed to investigate the suitability of specimens obtained by transbronchial cryobiopsy (TBC) using a 1.1 mm‐diameter cryoprobe for NGS analysis. Methods: Patients with lung cancer who underwent TBC using a 1.1 mm‐diameter cryoprobe for NGS testing between October 2020 and April 2023 were enrolled. A 4.0‐ or 3.0 mm‐diameter bronchoscope with radial probe endobronchial ultrasound and virtual bronchoscopic navigation was used to detect peripheral lung lesions. All procedures were performed under fluoroscopic guidance. Data were analysed retrospectively. Results: A total of 56 patients underwent TBC using a 1.1 mm cryoprobe for NGS testing, during the study period. Most patients (98%) were in the advanced stage of lung cancer (recurrent or inoperable disease of stages III or IV). The diagnostic yield of NGS for DNA and RNA sequencing was 95% each (53 of 56). Moderate bleeding was noted in three patients (5%) and none of the study patients developed life‐threatening complications, such as pneumothorax or lung infection. Conclusion: TBC using a 1.1 mm‐diameter cryoprobe is a useful and safe tool for NGS analysis, for both DNA and RNA sequencing. [ABSTRACT FROM AUTHOR]
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- 2024
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8. The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in 2016.
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Tan, Daniel SW, Yom, Sue S, Tsao, Ming S, Pass, Harvey I, Kelly, Karen, Peled, Nir, Yung, Rex C, Wistuba, Ignacio I, Yatabe, Yasushi, Unger, Michael, Mack, Philip C, Wynes, Murry W, Mitsudomi, Tetsuya, Weder, Walter, Yankelevitz, David, Herbst, Roy S, Gandara, David R, Carbone, David P, Bunn, Paul A, Mok, Tony SK, and Hirsch, Fred R
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Humans ,Carcinoma ,Non-Small-Cell Lung ,Brain Neoplasms ,Lung Neoplasms ,Protein Kinase Inhibitors ,Consensus ,Drug Resistance ,Neoplasm ,Mutation ,ErbB Receptors ,Brain metastases ,EGFR mutation ,Non–small cell lung cancer ,Resistance ,Therapy ,Tyrosine kinase inhibitor ,Non-small cell lung cancer ,Carcinoma ,Non-Small-Cell Lung ,Drug Resistance ,Neoplasm ,Receptor ,Epidermal Growth Factor ,Lung Cancer ,Lung ,Cancer ,Clinical Research ,Oncology & Carcinogenesis ,Clinical Sciences ,Cardiorespiratory Medicine and Haematology ,Oncology and Carcinogenesis - Abstract
Mutations in the epidermal growth factor receptor gene (EGFR) represent one of the most frequent "actionable" alterations in non-small cell lung cancer (NSCLC). Typified by high response rates to targeted therapies, EGFR tyrosine kinase inhibitors (TKIs) are now established first-line treatment options and have transformed the treatment paradigm for NSCLC. With the recent breakthrough designation and approval of the third-generation EGFR TKI osimertinib, available systemic and local treatment options have expanded, requiring new clinical algorithms that take into account individual patient molecular and clinical profiles. In this International Association for the Study of Lung Cancer commissioned consensus statement, key pathologic, diagnostic, and therapeutic considerations, such as optimal choice of EGFR TKI and management of brain metastasis, are discussed. In addition, recommendations are made for clinical guidelines and research priorities, such as the role of repeat biopsies and use of circulating free DNA for molecular studies. With the rapid pace of progress in treating EGFR-mutant NSCLC, this statement provides a state-of-the-art review of the contemporary issues in managing this unique subgroup of patients.
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- 2016
9. Genome-wide association analysis identifies six new loci associated with forced vital capacity
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Loth, Daan W, Artigas, María Soler, Gharib, Sina A, Wain, Louise V, Franceschini, Nora, Koch, Beate, Pottinger, Tess D, Smith, Albert Vernon, Duan, Qing, Oldmeadow, Chris, Lee, Mi Kyeong, Strachan, David P, James, Alan L, Huffman, Jennifer E, Vitart, Veronique, Ramasamy, Adaikalavan, Wareham, Nicholas J, Kaprio, Jaakko, Wang, Xin-Qun, Trochet, Holly, Kähönen, Mika, Flexeder, Claudia, Albrecht, Eva, Lopez, Lorna M, de Jong, Kim, Thyagarajan, Bharat, Alves, Alexessander Couto, Enroth, Stefan, Omenaas, Ernst, Joshi, Peter K, Fall, Tove, Viñuela, Ana, Launer, Lenore J, Loehr, Laura R, Fornage, Myriam, Li, Guo, Wilk, Jemma B, Tang, Wenbo, Manichaikul, Ani, Lahousse, Lies, Harris, Tamara B, North, Kari E, Rudnicka, Alicja R, Hui, Jennie, Gu, Xiangjun, Lumley, Thomas, Wright, Alan F, Hastie, Nicholas D, Campbell, Susan, Kumar, Rajesh, Pin, Isabelle, Scott, Robert A, Pietiläinen, Kirsi H, Surakka, Ida, Liu, Yongmei, Holliday, Elizabeth G, Schulz, Holger, Heinrich, Joachim, Davies, Gail, Vonk, Judith M, Wojczynski, Mary, Pouta, Anneli, Johansson, Åsa, Wild, Sarah H, Ingelsson, Erik, Rivadeneira, Fernando, Völzke, Henry, Hysi, Pirro G, Eiriksdottir, Gudny, Morrison, Alanna C, Rotter, Jerome I, Gao, Wei, Postma, Dirkje S, White, Wendy B, Rich, Stephen S, Hofman, Albert, Aspelund, Thor, Couper, David, Smith, Lewis J, Psaty, Bruce M, Lohman, Kurt, Burchard, Esteban G, Uitterlinden, André G, Garcia, Melissa, Joubert, Bonnie R, McArdle, Wendy L, Musk, A Bill, Hansel, Nadia, Heckbert, Susan R, Zgaga, Lina, van Meurs, Joyce BJ, Navarro, Pau, Rudan, Igor, Oh, Yeon-Mok, Redline, Susan, Jarvis, Deborah L, Zhao, Jing Hua, Rantanen, Taina, O'Connor, George T, and Ripatti, Samuli
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Biological Sciences ,Genetics ,Human Genome ,Rare Diseases ,Lung ,Cancer ,Lung Cancer ,Respiratory ,Cohort Studies ,Databases ,Genetic ,Follow-Up Studies ,Forced Expiratory Volume ,Genetic Loci ,Genetic Predisposition to Disease ,Genome ,Human ,Genome-Wide Association Study ,Humans ,Lung Diseases ,Meta-Analysis as Topic ,Polymorphism ,Single Nucleotide ,Prognosis ,Quantitative Trait Loci ,Respiratory Function Tests ,Spirometry ,Vital Capacity ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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- 2014
10. Ambient fine particulate matter inhibits 15-lipoxygenases to promote lung carcinogenesis
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Ming-Yue Li, Li-Zhong Liu, Wende Li, Calvin S. H. Ng, Yi Liu, Angel W. Y. Kong, Zhili Zhao, Shanshan Wang, Haolong Qi, Hao Jia, Shucai Yang, Jing Du, Xiang Long, Rocky L. K. Ho, Ernest C. W. Chak, Innes Y. P. Wan, Tony S. K. Mok, Malcolm J. Underwood, Nirmal Kumar Gali, Zhi Ning, and George G. Chen
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Lung cancer ,PM2.5 ,NNK ,15-lipoxygenases (15-LOXs) ,Epigenetic and post-translational regulation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Epidemiological observations have demonstrated that ambient fine particulate matter with d p
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- 2019
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11. Lipofection of Single Guide RNA Targeting MMP8 Decreases Proliferation and Migration in Lung Adenocarcinoma Cells
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Oscar David Hernandez Maradiaga, Pooi Ling Mok, Gothai Sivapragasam, Antony V. Samrot, Mohammed Safwan Ali Khan, Aisha Farhana, Badr Alzahrani, Jiabei Tong, Thilakavathy Karuppiah, Narcisse M. S. Joseph, and Suresh Kumar Subbiah
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CRISPR-Cas9 ,single guide RNA ,lipofection ,lung cancer ,epithelial to mesenchymal transition (EMT) ,matrix metalloproteinase 8 (MMP8) ,Medicine (General) ,R5-920 - Abstract
Background and Objectives: Matrix metalloproteinases (MMP) have been implicated as major determinants of tumour growth and metastasis, which are considered two of the main hallmarks of cancer. The interaction of MMP8 and other signalling molecules within and adjacent tumoral tissues, including immune cells, are rather elusive, particularly of adenocarcinoma cell type. In this study, we aimed to investigate the role of MMP8 in non-small cell lung cancer proliferation and invasiveness potential. Materials and Methods: We individually lipofected with two different single guide RNA (sgRNAs) that specifically targeted on MMP8, with CRISPR-Cas 9 protein into the cells. Results: Our results clearly indicated that the lipofection of these complexes could lead to reduced ability of A549 cells to survive and proliferate to form colonies. In addition, when compared to non-transfected cells, the experimental cell groups receiving sgRNAs demonstrated relatively decreased migration rate, hence, wider wound gaps in scratch assay. The quantitative real time-polymerase chain reaction (qRT-PCR) demonstrated significant reduction in the MAP-K, survivin and PI3-K gene expression. MMP8 might have protective roles over tumour growth and spread in our body. Conclusions: The delivery of sgRNAs targeting on the MMP8 gene could induce tumour cell death and arrest cell migratory activity.
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- 2021
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12. A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study)
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Ang, Yvonne L. E., Zhao, Xiaotian, Reungwetwattana, Thanyanan, Cho, Byoung-Chul, Liao, Bin-Chi, Yeung, Rebecca, Loong, Herbert H., Kim, Dong-Wan, Yang, James Chih-Hsin, Lim, Sun Min, Ahn, Myung-Ju, Lee, Se-Hoon, Suwatanapongched, Thitiporn, Kongchauy, Kanchaporn, Ou, Qiuxiang, Yu, Ruoying, Tai, Bee Choo, Goh, Boon Cher, Mok, Tony S. K., and Soo, Ross A.
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LUNG cancer ,DRUG efficacy ,RESEARCH ,PATIENT aftercare ,DNA ,GENETIC mutation ,SEQUENCE analysis ,CONFIDENCE intervals ,EPIDERMAL growth factor receptors ,PARONYCHIA ,PROTEIN-tyrosine kinase inhibitors ,TREATMENT effectiveness ,RESEARCH funding ,PROGRESSION-free survival ,DRUG side effects ,DRUG resistance in cancer cells ,LONGITUDINAL method ,OVERALL survival ,DISEASE risk factors ,EVALUATION - Abstract
Simple Summary: Lung cancers with EGFR gene mutations treated with targeted therapy often develop another genetic change (T790M) that allows them to be treated with a further targeted therapy, Osimertinib, with good outcomes. The gold standard for the detection of these changes is to perform a tissue biopsy, but this is not always feasible. This study aimed to evaluate the outcomes of treatment with Osimertinib in patients who have a T790M mutation detected by non-invasive blood testing rather than tissue testing, and to explore the further genetic changes and DNA levels that can be detected in the blood during Osimertinib treatment. We demonstrated good tumour shrinkage and survival outcomes in this population, comparable to studies of patients identified through tissue testing. Levels of DNA markers in the blood before and during treatment with Osimertinib predicted outcomes. Based on this, blood testing for T790M can be used as a surrogate marker to guide Osimertinib use. Epidermal growth factor receptor (EGFR) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard modality of T790M testing, but it is invasive. We evaluated the efficacy of Osimertinib in patients with EGFR mutant NSCLC and T790M in circulating tumour DNA (ctDNA). PLASMA is a prospective, open-label, multicentre single-arm Phase II study. Patients with advanced NSCLC harbouring sensitizing EGFR and T790M mutations in plasma at progression from ≥one 1G/2G TKI were treated with 80 mg of Osimertinib daily until progression. The primary endpoint was the objective response rate (ORR); the secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicities. Plasma next-generation sequencing was performed to determine Osimertinib resistance mechanisms and assess serial ctDNA. A total of 110 patients from eight centres in five countries were enrolled from 2017 to 2019. The median follow-up duration was 2.64 (IQR 2.44–3.12) years. The ORR was 50.9% (95% CI 41.2–60.6) and the DCR was 84.5% (95% CI 76.4–90.7). Median PFS was 7.4 (95% CI 6.0–9.3) months; median OS was 1.63 (95% CI 1.35–2.16) years. Of all of the patients, 76% had treatment-related adverse events (TRAEs), most commonly paronychia (22.7%); 11% experienced ≥ Grade 3 TRAEs. The ctDNA baseline load and dynamics were prognostic. Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Identification of lung cancer specific differentially methylated regions using genome-wide DNA methylation study
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Hong, Yoonki, Hong, Seok-Ho, Oh, Yeon-Mok, Shin, Seung-Ho, Choi, Sun Shim, and Kim, Woo Jin
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- 2018
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14. Construction and Validation of Two Novel Nomograms for Predicting the Overall Survival and Cancer-Specific Survival of NSCLC Patients with Bone Metastasis
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Qiu Dong, Tsz Ngai Mok, Jialin Deng, Zhengang Zha, and Junyuan Chen
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Oncology ,medicine.medical_specialty ,business.industry ,Bone metastasis ,International Journal of General Medicine ,General Medicine ,Nomogram ,medicine.disease ,Cancer specific survival ,SEER ,lung cancer ,Internal medicine ,medicine ,Overall survival ,metastasis ,prognosis ,business ,Original Research - Abstract
Qiu Dong,1 Jialin Deng,2 Tsz Ngai Mok,1 Junyuan Chen,1 Zhengang Zha1 1Center for Bone, Joint and Sports Medicine, The First Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, Peopleâs Republic of China; 2School of Medicine, Jinan University, Guangzhou, Guangdong, Peopleâs Republic of ChinaCorrespondence: Junyuan Chen; Zhengang ZhaCenter for Bone, Joint and Sports Medicine, The First Hospital of Jinan University, Jinan University, No. 613, Huangpu Avenue West, Guangzhou, 510515, Guangdong, Peopleâs Republic of ChinaTel +86 134 8029 9854; +86 173 6182 0624Email chenjunyuan@jnu.edu.cn; zhazhengang1965@163.comBackground: Bone metastasis (BM) is the most common site of metastasis in non-small cell lung carcinoma (NSCLC). We aimed to construct and validate 2 novel nomograms predicting the 3-, 6-, and 12-months overall survival (OS) and cancer-specific survival (CSS).Methods: The clinical data of 7480 patients between 2010 and 2016 were enrolled from the Surveillance, Epidemiology, and End Results database (SEER). The patients were allocated randomly to training and validation cohorts in a 7:3 ratio. Cox proportional hazards regression models were used to identify prognostic risk factors and establish 2 nomograms. The prediction accuracy of nomograms was assessed by C-index, the area under the ROC curve (AUC), and calibration curves.Results: A total of 244998 NSCLC patients were identified between 2010 and 2016, with 7480 found with BM, accounting for 3.1%. Overall, 7480 patients were enrolled in the OS nomogram construction and were randomized to the training set (n = 5236) and the validation set (n = 2244). Age, sex, race, marital status, histology, grade, primary site, T stage, N stage, liver metastasis, surgery, radiotherapy, and chemotherapy were found to correlate with OS. A total of 7422 samples were included in the CSS nomogram construction, randomly grouped into training set (n = 5195) and the validation set (n = 2227). Age, sex, race, histology, grade, primary site, T stage, N stage, brain metastasis, liver metastasis, surgery, radiotherapy, and chemotherapy were associated with CSS. Two nomograms were conducted to predict the 3-, 6-, and 12-months OS and CSS. The ROC curves and exhibited good performance for predicting OS and CSS.Conclusion: We established and validated 2 high-performance nomograms to assist clinical doctors in making personalized treatment decisions.Keywords: lung cancer, metastasis, SEER, prognosis
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- 2021
15. Plain language summary of the CROWN study comparing lorlatinib with crizotinib for people with untreated non-small cell lung cancer
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Todd M. Bauer, Julien Mazieres, Anna Polli, Benjamin Solomon, Enriqueta Felip, Gerson Peltz, Alice T. Shaw, Filippo de Marinis, Tony Mok, Geoffrey Liu, Yasushi Goto, A.M. Calella, Holger Thurm, and Dong Wan Kim
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Cancer Research ,medicine.medical_specialty ,Crizotinib ,business.industry ,Cancer ,General Medicine ,medicine.disease ,Lorlatinib ,Clinical trial ,Oncology ,Internal medicine ,medicine ,Vomiting ,Liver function ,medicine.symptom ,Lung cancer ,business ,Weight gain ,medicine.drug - Abstract
This is a summary of a research study (known as a clinical trial) called CROWN. The study tested two medicines called lorlatinib and crizotinib in participants with untreated non-small cell lung cancer that had spread to other parts of their body. All those who took part had changes in a gene called ALK, which is involved in cell growth. In total, 296 participants from 23 countries took part. Half the participants took lorlatinib and half took crizotinib. After participants started taking lorlatinib or crizotinib, they were checked regularly to see if their tumors had grown or spread to other parts of their body (known as tumor progression) and to monitor any side effects. After 1 year of treatment, the participants who took lorlatinib were twice as likely to be alive with no tumor growth as the participants who took crizotinib. More participants who took lorlatinib had cancer that shrank (76%) compared with the participants who took crizotinib (58%). This was also true of the participants whose cancer had spread to their brain. The most common side effects in participants who took lorlatinib were increases in the amount of cholesterol and triglycerides (a type of fat) in their blood, swelling, weight gain, nerve damage, unclear thoughts, and diarrhea. Among the participants who took crizotinib, the most common side effects were diarrhea, feeling like you want to throw up, sight problems, swelling, vomiting, changes in liver function, and feeling tired. Overall, the CROWN study showed that fewer participants with advanced ALK+ non-small cell lung cancer died or had tumor growth with lorlatinib compared with crizotinib treatment. ClinicalTrials.gov NCT number: NCT03052608 .
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- 2021
16. Ambient fine particulate matter inhibits 15-lipoxygenases to promote lung carcinogenesis
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Li, Ming-Yue, Liu, Li-Zhong, Li, Wende, Ng, Calvin S. H., Liu, Yi, Kong, Angel W. Y., Zhao, Zhili, Wang, Shanshan, Qi, Haolong, Jia, Hao, Yang, Shucai, Du, Jing, Long, Xiang, Ho, Rocky L. K., Chak, Ernest C. W., Wan, Innes Y. P., Mok, Tony S. K., Underwood, Malcolm J., Gali, Nirmal Kumar, Ning, Zhi, and Chen, George G.
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- 2019
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17. A case of paraneoplastic neurological syndrome expressing dual antineuronal antibodies: Anti-hu and recoverin
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Ryu, Ho-Sung, Lee, Shin, Park, Dong, and Lee, Jong-Mok
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Lung cancer ,Neurophysiology ,Antibodies ,Small cell lung cancer ,Parks ,Cancer diagnosis ,Cancer ,Cancer metastasis ,Encephalomyelitis ,Health - Abstract
Byline: Ho-Sung. Ryu, Shin. Lee, Dong. Park, Jong-Mok. Lee Paraneoplastic neurological syndromes (PNS) are a group of heterogeneous disorders that are not caused by direct invasion or metastasis but are [...]
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- 2020
18. ALTA-2: Phase II study of brigatinib in patients with ALK-positive, advanced non-small-cell lung cancer who progressed on alectinib or ceritinib
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Pingkuan Zhang, Junwu Shen, Myung-Ju Ahn, Tony Mok, Fabrice Barlesi, Sai-Hong Ignatius Ou, and Edward S. Kim
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Adult ,Male ,Alectinib ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Brigatinib ,Carbazoles ,Drug Administration Schedule ,03 medical and health sciences ,Clinical Trials, Phase II as Topic ,Organophosphorus Compounds ,0302 clinical medicine ,Piperidines ,Carcinoma, Non-Small-Cell Lung ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Sulfones ,030212 general & internal medicine ,Lung cancer ,Protein Kinase Inhibitors ,Response Evaluation Criteria in Solid Tumors ,Ceritinib ,Crizotinib ,business.industry ,General Medicine ,Middle Aged ,medicine.disease ,Progression-Free Survival ,respiratory tract diseases ,Pyrimidines ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Disease Progression ,Quality of Life ,Female ,business ,Progressive disease ,medicine.drug - Abstract
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved outcomes in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC). However, almost all patients eventually develop progressive disease on first-line ALK TKIs (e.g., crizotinib, alectinib and ceritinib). Brigatinib, a second-generation ALK TKI, may show efficacy in alectinib- and ceritinib-refractory ALK+ NSCLC. We describe the rationale and design of ALTA-2, a Phase II study of brigatinib in patients with locally advanced/metastatic ALK+ NSCLC and documented progressive disease on alectinib or ceritinib. The primary end point is confirmed objective response rate per independent review committee using response evaluation criteria in solid tumors version 1.1. Secondary end points include duration of response, progression-free survival, overall survival, safety and health-related quality of life.
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- 2021
19. Overcoming therapy resistance in EGFR-mutant lung cancer
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Pasi A. Jänne, Antonio Passaro, Solange Peters, and Tony Mok
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Cancer Research ,Lung Neoplasms ,biology ,business.industry ,Mutant ,Disease ,Therapeutic resistance ,medicine.disease ,respiratory tract diseases ,ErbB Receptors ,Clinical trial ,Oncology ,Drug Resistance, Neoplasm ,Carcinoma, Non-Small-Cell Lung ,Mutation ,Cancer research ,biology.protein ,Humans ,Medicine ,Epidermal growth factor receptor ,Treatment resistance ,business ,Lung cancer ,Protein Kinase Inhibitors ,Tyrosine kinase - Abstract
Tyrosine kinase inhibitors (TKIs) have dramatically changed the clinical prospects of patients with non-small cell lung cancer harboring epidermal growth factor receptor (EGFR)-activating mutations. Despite prolonged disease control and high tumor response rates, all patients eventually progress on EGFR TKI treatment. Here, we review the mechanisms of acquired EGFR TKI resistance, the methods for monitoring its appearance, as well as current and future efforts to define treatment strategies to overcome resistance. Passaro and colleagues discuss recent advances in treating EGFR-mutant lung cancer, including methods for detecting disease and tracking therapy response, developments in understanding of resistance mechanisms and ongoing clinical trials to circumvent therapeutic resistance to EGFR targeting.
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- 2021
20. Dacomitinib as first-line treatment for EGFR mutation-positive non-small cell lung cancer
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Kumar Prabhash, Tony Mok, Thanyanan Reungwetwattana, and Nitesh Rohatgi
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Pharmacology ,biology ,medicine.disease ,Dacomitinib ,First line treatment ,chemistry.chemical_compound ,Egfr tki ,chemistry ,Egfr mutation ,Drug Discovery ,Genetics ,medicine ,Cancer research ,biology.protein ,Molecular Medicine ,Non small cell ,Epidermal growth factor receptor ,Lung cancer ,Epidermal growth factor receptor tyrosine kinase - Abstract
Introduction: Dacomitinib is a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). Recent results from ARCHER 1050, the first randomized, open-label, Phase 3 tr...
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- 2021
21. Canakinumab with and without pembrolizumab in patients with resectable non-small-cell lung cancer: CANOPY-N study design
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Tuochuan Dong, Tony Sk Mok, Jay M. Lee, Masahiro Tsuboi, Cecile Blin, Ana Gómez-Rueda, Edward S. Kim, Vanessa Q. Passos, Vanessa Rodrik-Outmezguine, Pilar Garrido, Luis Gorospe, Jean-Louis Pujol, Amparo Benito, and Nicolas Moreno
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Adult ,Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Adolescent ,medicine.medical_treatment ,Interleukin-1beta ,Programmed Cell Death 1 Receptor ,Disease ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Young Adult ,03 medical and health sciences ,Clinical Trials, Phase II as Topic ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Humans ,Medicine ,Pneumonectomy ,Lung cancer ,Lung ,Neoplasm Staging ,Randomized Controlled Trials as Topic ,business.industry ,General Medicine ,Immunotherapy ,medicine.disease ,Neoadjuvant Therapy ,Immune checkpoint ,Clinical trial ,Canakinumab ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
Canakinumab is a human IgGκ monoclonal antibody, with high affinity and specificity for IL-1β. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial, evaluating canakinumab for cardiovascular disease, provided the first signal of the potential of IL-1β inhibition on lung cancer incidence reduction. Here, we describe the rationale and design for CANOPY-N, a randomized Phase II trial evaluating IL-1β inhibition with or without immune checkpoint inhibition as neoadjuvant treatment in patients with non-small-cell lung cancer. Patients with stage IB to IIIA non-small-cell lung cancer eligible for complete resection will receive canakinumab or pembrolizumab as monotherapy, or in combination. The primary end point is major pathological response by central review; secondary end points include overall response rate, major pathological response (local review), surgical feasibility rate and pharmacokinetics.Lay abstract A previous study showed that canakinumab reduced the risk of lung cancer in patients with heart disease. Canakinumab blocks an inflammatory protein called IL-1β that is involved in cancer. Anti-cancer drugs used before surgery (‘neo-adjuvant’) can improve the success rate of surgery and may help prevent the cancer from returning. Neo-adjuvant trials help us understand how the drugs work and how they affect cancer. CANOPY-N (NCT03968419) is an ongoing randomized, exploratory, Phase II clinical trial testing canakinumab and pembrolizumab (a different cancer immunotherapy), alone or combined, for patients with early non-small-cell lung cancer. The study will test whether treatment can kill most cancer cells in the surgery sample (‘major pathological response’). It will also investigate other effects on cancer biology, levels of molecules that measure possible clinical benefit (‘biomarkers’) and side effects.
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- 2021
22. The patient’s perspective on treatment with dacomitinib: patient-reported outcomes from the Phase III trial ARCHER 1050
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Rickard Sandin, Arlene Reisman, Jean Paty, Yi-Long Wu, Jesus Corral, R. Linke, Seiji Niho, Tony Mok, Maria Rita Migliorino, Adam Pluzanski, Ki Hyeong Lee, Kazuhiko Nakagawa, Xiangdong Zhou, Ying Cheng, and Oren Meyers
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Adult ,Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Treatment duration ,Administration, Oral ,Drug Administration Schedule ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Gefitinib ,Quality of life ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Activities of Daily Living ,medicine ,Humans ,Patient Reported Outcome Measures ,Lung cancer ,Protein Kinase Inhibitors ,Response Evaluation Criteria in Solid Tumors ,Aged ,Quinazolinones ,Health related quality of life ,Dose-Response Relationship, Drug ,business.industry ,Repeated measures design ,General Medicine ,Middle Aged ,medicine.disease ,Progression-Free Survival ,humanities ,Dacomitinib ,ErbB Receptors ,030104 developmental biology ,Oncology ,chemistry ,Gain of Function Mutation ,030220 oncology & carcinogenesis ,Quality of Life ,Female ,Dose reduction ,business ,medicine.drug - Abstract
Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.
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- 2021
23. Deep learning–based dynamic PET parametric Ki image generation from lung static PET.
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Wang, Haiyan, Wu, Yaping, Huang, Zhenxing, Li, Zhicheng, Zhang, Na, Fu, Fangfang, Meng, Nan, Wang, Haining, Zhou, Yun, Yang, Yongfeng, Liu, Xin, Liang, Dong, Zheng, Hairong, Mok, Greta S. P., Wang, Meiyun, and Hu, Zhanli
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POSITRON emission tomography computed tomography ,LUNG cancer ,CANCER diagnosis ,PEARSON correlation (Statistics) ,DEEP learning - Abstract
Objectives: PET/CT is a first-line tool for the diagnosis of lung cancer. The accuracy of quantification may suffer from various factors throughout the acquisition process. The dynamic PET parametric K
i provides better quantification and improve specificity for cancer detection. However, parametric imaging is difficult to implement clinically due to the long acquisition time (~ 1 h). We propose a dynamic parametric imaging method based on conventional static PET using deep learning. Methods: Based on the imaging data of 203 participants, an improved cycle generative adversarial network incorporated with squeeze-and-excitation attention block was introduced to learn the potential mapping relationship between static PET and Ki parametric images. The image quality of the synthesized images was qualitatively and quantitatively evaluated by using several physical and clinical metrics. Statistical analysis of correlation and consistency was also performed on the synthetic images. Results: Compared with those of other networks, the images synthesized by our proposed network exhibited superior performance in both qualitative and quantitative evaluation, statistical analysis, and clinical scoring. Our synthesized Ki images had significant correlation (Pearson correlation coefficient, 0.93), consistency, and excellent quantitative evaluation results with the Ki images obtained in standard dynamic PET practice. Conclusions: Our proposed deep learning method can be used to synthesize highly correlated and consistent dynamic parametric images obtained from static lung PET. Key Points: • Compared with conventional static PET, dynamic PET parametric Ki imaging has been shown to provide better quantification and improved specificity for cancer detection. • The purpose of this work was to develop a dynamic parametric imaging method based on static PET images using deep learning. • Our proposed network can synthesize highly correlated and consistent dynamic parametric images, providing an additional quantitative diagnostic reference for clinicians. [ABSTRACT FROM AUTHOR]- Published
- 2023
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24. Selenite as a dual apoptotic and ferroptotic agent synergizes with EGFR and KRAS inhibitors with epigenetic interference.
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Chan, Lok Seng, Liu, Johnson, Li, Molly S. C., Li, Lili, Tao, Qian, and Mok, Tony S. K.
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DNA demethylation ,EPIDERMAL growth factor receptors ,SELENOPROTEINS ,DNA methylation ,EPIGENETICS ,LUNG cancer - Abstract
Background: Selenium, an essential trace element, has previously been investigated as a pro-apoptotic and DNA demethylation agent. It sensitizes the response to chemotherapy in patients who were refractory to cytotoxic agents. Meanwhile, ferroptosis is a novel approach to cancer treatment by triggering cell death and reversing drug resistance. The role of selenium in treating cancer cells harboring druggable oncogenic alterations and its underlying mechanism are largely unknown. Results: We treated lung adenocarcinoma cell lines—EGFR-mutant H1975 (H1975
EGFR p.L858R and p.T790M ) and KRAS-mutant H358 (H358KRAS p.G12C ), with sodium selenite to examine its effect on cell apoptosis, ferroptosis, and DNA methylation, as well as its interaction with existing targeted therapy, osimertinib, and adagrasib. We observed selenite to be a dual apoptotic and ferroptotic agent on lung cancer cells, associated with the activation of p38-ATF4-DDIT3 axis in the unfolded protein response. Ferroptosis induction was more remarkable in H1975 than H358. Selenite also altered cellular DNA methylation machinery through downregulating DNMT1 and upregulating TET1, though not as a major mechanism of its activity. Low-dose selenite synergized with osimertinib in EGFR-mutant H1975, and with adagrasib in KRAS-mutant H358, with stronger synergism observed in H1975. Conclusion: These results suggest that selenite is a potential apoptotic and ferroptotic drug candidate for the treatment of especially EGFR- and potentially KRAS-mutant lung cancer. [ABSTRACT FROM AUTHOR]- Published
- 2023
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25. ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer
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A. Passaro, N. Leighl, F. Blackhall, S. Popat, K. Kerr, M.J. Ahn, M.E. Arcila, O. Arrieta, D. Planchard, F. de Marinis, A.M. Dingemans, R. Dziadziuszko, C. Faivre-Finn, J. Feldman, E. Felip, G. Curigliano, R. Herbst, P.A. Jänne, T. John, T. Mitsudomi, T. Mok, N. Normanno, L. Paz-Ares, S. Ramalingam, L. Sequist, J. Vansteenkiste, I.I. Wistuba, J. Wolf, Y.L. Wu, S.R. Yang, J.C.H. Yang, Y. Yatabe, G. Pentheroudakis, S. Peters, and Pulmonary Medicine
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Consensus ,Lung Neoplasms ,treatment ,EGFR ,Hematology ,targeted therapy ,Medical Oncology ,testing ,ErbB Receptors ,lung cancer ,Oncology ,SDG 3 - Good Health and Well-being ,consensus ,Carcinoma, Non-Small-Cell Lung ,Humans - Abstract
The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.
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- 2022
26. Estrogen receptor alpha promotes smoking-carcinogen-induced lung carcinogenesis via cytochrome P450 1B1
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Li, Ming-Yue, Liu, Yi, Liu, Li-Zhong, Kong, Angel W. Y., Zhao, Zhili, Wu, Bin, Long, Xiang, Wu, Jun, Ng, Calvin S. H., Wan, Innes Y. P., Du, Jing, Mok, Tony S. K., Underwood, Malcolm J., and Chen, George G.
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- 2015
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27. Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer: 2-year follow-up from a randomized, open-label, phase 3 study (CheckMate 078)
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Ang Li, Alexander Luft, Shun Lu, Jifeng Feng, Tony Mok, Ying Cheng, R.A. Soo, Yuankai Shi, Hua Zhong, Zhiyong Ma, Hai-Yan Tu, Yee Hong Chia, Elena Poddubskaya, You Lu, Li Zhang, Yi-Long Wu, Jianying Zhou, Jie Wang, Lin Wu, Yiping Zhang, Amy Li, Jianhua Chang, Chengping Hu, and Kejing Ying
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,China ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Phases of clinical research ,Docetaxel ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Lung cancer ,Chemotherapy ,business.industry ,medicine.disease ,Discontinuation ,Nivolumab ,030104 developmental biology ,Tolerability ,030220 oncology & carcinogenesis ,business ,Follow-Up Studies ,medicine.drug - Abstract
Background In the phase 3 CheckMate 078 study, nivolumab showed significant overall survival (OS) benefit and superior tolerability versus docetaxel in a predominantly Chinese patient population with non-small cell lung cancer (NSCLC). However, data on long-term outcomes with immunotherapy in Asian patients are limited. We report 2-year efficacy and safety data. Methods Patients with advanced/metastatic NSCLC and disease progression after platinum-doublet chemotherapy were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks; n = 338) or docetaxel (75 mg/m2 every 3 weeks; n = 166) until progression, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was OS; secondary endpoints included progression-free survival, objective response rate, and safety. Results After 25.9 months minimum follow-up, 21 patients (6 %) remained on nivolumab versus 0 on docetaxel. Median OS was 11.9 months with nivolumab versus 9.5 months with docetaxel (HR: 0.75; 95 % CI: 0.61–0.93); 2-year OS rates were 28 % versus 18 %, respectively. Survival benefits were observed across a variety of predefined subgroups. At 2 years, 39 % and 0 % of responders had ongoing responses with nivolumab and docetaxel, respectively. Grade 3–4 treatment-related adverse events occurred in 12 % of patients with nivolumab versus 47 % with docetaxel, leading to discontinuation in 4 % and 5 % of patients, respectively. No new treatment-related deaths occurred. Conclusion At 2 years, nivolumab maintained a favorable safety profile and continued to demonstrate superior OS versus docetaxel in this predominantly Chinese patient population with previously treated NSCLC. These data are consistent with long-term outcomes from the global CheckMate 017/057 studies.
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- 2021
28. Randomized clinical trial of pembrolizumab vs chemotherapy for previously untreated Chinese patients with PD‐L1‐positive locally advanced or metastatic non–small‐cell lung cancer: KEYNOTE‐042 China Study
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Yi‐Long Wu, Li Zhang, Yun Fan, JianYing Zhou, Qing Zhou, Wei Li, ChengPing Hu, GongYan Chen, Xin Zhang, CaiCun Zhou, Thao Dang, Sara Sadowski, Debra A. Kush, Yu Zhou, Ben Li, and Tony Mok
- Subjects
Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,China ,Lung Neoplasms ,non–small‐cell lung cancer ,medicine.medical_treatment ,Short Report ,Pembrolizumab ,chemotherapy ,Antibodies, Monoclonal, Humanized ,PD-L1 Positive ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lung cancer ,Cancer Therapy and Prevention ,Aged ,Chemotherapy ,business.industry ,Hazard ratio ,Middle Aged ,medicine.disease ,Carboplatin ,Pemetrexed ,chemistry ,programmed death ligand 1 ,030220 oncology & carcinogenesis ,Female ,pembrolizumab ,business ,medicine.drug - Abstract
In the global KEYNOTE‐042 study (Clinicaltrials.gov, NCT02220894), pembrolizumab significantly improved overall survival (OS) vs chemotherapy in patients with previously untreated programmed death ligand 1 (PD‐L1)‐positive locally advanced/metastatic non–small‐cell lung cancer (NSCLC) without EGFR/ALK alterations. We present results from patients in KEYNOTE‐042 enrolled from China in the global or extension study (NCT03850444; protocol identical to global study). Patients were randomized 1:1 (stratified by ECOG performance status 0 vs 1, squamous vs nonsquamous histology and PD‐L1 tumor proportion score [TPS] ≥50% vs 1%‐49%) to 35 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) or investigator's choice of 4 to 6 cycles of carboplatin plus paclitaxel or pemetrexed Q3W with optional pemetrexed maintenance for nonsquamous tumors. Primary endpoints were OS in patients with PD‐L1 TPS ≥50%, ≥20% or ≥1%. Two hundred sixty‐two patients (pembrolizumab, n = 128; chemotherapy, n = 134) were enrolled from China. At data cutoff (February 21, 2020; median follow‐up, 33.0 [range, 25.6‐41.9] months), pembrolizumab was shown to improve OS vs chemotherapy in patients with PD‐L1 TPS ≥50% (hazard ratio [95% CI], 0.63 [0.43‐0.94]), TPS ≥20% (0.66 [0.47‐0.92]) and TPS ≥1% (0.67 [0.50‐0.89]). Grade 3 to 5 treatment‐related adverse events occurred less frequently with pembrolizumab vs chemotherapy (19.5% vs 68.8%). In 22 patients who completed 35 cycles of pembrolizumab, objective response rate was 77.3% and median duration of response was 27.6 months. Consistent with the global KEYNOTE‐042 study, pembrolizumab improved OS vs chemotherapy in this study of Chinese patients with locally advanced/metastatic NSCLC and PD‐L1 TPS ≥1%, supporting first‐line pembrolizumab monotherapy for PD‐L1‐positive advanced/metastatic NSCLC in China., What's new? The global KEYNOTE‐042 clinical study helped establish single‐agent pembrolizumab, an anti‐PD‐1 monoclonal antibody, as a standard first‐line treatment option in patients with previously untreated PD‐L1‐positive locally advanced/metastatic non–small‐cell lung cancer (NSCLC) without EGFR/ALK aberrations. Because disease characteristics and responses to anticancer therapy may differ between Asian and other populations, there is a need to evaluate these treatments specifically in Asian patients. Here, the authors show that pembrolizumab also improved overall survival and was better tolerated than chemotherapy among Chinese patients with PD‐L1 TPS ≥1% in the KEYNOTE‐042 study. These data support first‐line pembrolizumab monotherapy for PD‐L1‐positive advanced/metastatic NSCLC in China.
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- 2020
29. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer
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Shaw, A. T., Bauer, T. M., De Marinis, F., Felip, E., Goto, Y., Liu, G., Mazieres, J., Kim, D. -W., Mok, T., Polli, A., Thurm, H., Calella, A. M., Peltz, G., Solomon, B. J., and Soto Parra, H.
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Male ,Alectinib ,Lung Neoplasms ,Carcinoma, Non-Small-Cell Lung/drug therapy ,medicine.medical_treatment ,030204 cardiovascular system & hematology ,Macrocyclic ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,hemic and lymphatic diseases ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,030212 general & internal medicine ,Non-Small-Cell Lung ,Manchester Cancer Research Centre ,General Medicine ,Middle Aged ,Crizotinib/adverse effects ,Intention to Treat Analysis ,Female ,Hyperlipidemias/chemically induced ,medicine.drug ,Adult ,Lactams, Macrocyclic/adverse effects ,Lactams ,Lactams, Macrocyclic ,Anaplastic Lymphoma Kinase/antagonists & inhibitors ,Antineoplastic Agents ,Hyperlipidemias ,03 medical and health sciences ,Crizotinib ,ROS1 ,medicine ,Humans ,Lung Neoplasms/drug therapy ,Lung cancer ,Aged ,Chemotherapy ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,Carcinoma ,Cancer ,Antineoplastic Agents/adverse effects ,medicine.disease ,Survival Analysis ,Lorlatinib ,Mutation ,Cancer research ,business - Abstract
BACKGROUND: Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with ALK-positive non-small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK-positive NSCLC is unclear. METHODS: We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK-positive NSCLC who had received no previous systemic treatment for metastatic disease. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included independently assessed objective response and intracranial response. An interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred. RESULTS: The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; PCONCLUSIONS: In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. (Funded by Pfizer; CROWN ClinicalTrials.gov number, NCT03052608.).
- Published
- 2020
30. KRAS G12C mutations in Asia: a landscape analysis of 11,951 Chinese tumor samples
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Herbert Ho-Fung Loong, Ming Yao, Lunxu Liu, Jian Guo, Jicheng Yao, Xianfeng Jin, Tao Jiang, Yutong Xing, Gen Lin, Tony Mok, Mingjiang Li, Chunyan Cheng, Nan Du, Zhihua Shi, Hanqing Lin, Yanzhi Cui, and Kai Wang
- Subjects
0301 basic medicine ,endocrine system diseases ,Oncogene ,Colorectal cancer ,business.industry ,Incidence (epidemiology) ,Cancer ,medicine.disease ,medicine.disease_cause ,digestive system diseases ,respiratory tract diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Concomitant ,Cancer research ,medicine ,Original Article ,KRAS ,Lung cancer ,business ,neoplasms ,Gene - Abstract
Background Kirsten rat sarcoma vial oncogene (KRAS) is one of the most prevalent oncogenes in multiple cancer types, but the incidence is different between the Asian and non-Asian populations. The recent development of KRAS G12C targeting drug has shown great promise. It is thus important to understand the genomic landscape of KRAS G12C in a specific population. Methods Sequencing data of 11,951 tumor samples collected from 11/2016 to 7/2019 from multiple centres in China were analyzed for KRAS mutation status. Concomitant genomic aberrations were further analyzed in tumors with KRAS G12C mutations, which were sequenced with comprehensive cancer panel including over 450 cancer-related genes. Smoking status and its correlation with KRAS were analyzed in 2,235 lung cancer cases within this cohort. Results KRAS mutations were identified in 1978 (16.6%) patient samples. Specifically, KRAS G12C accounted for 14.5% (n=286) of all KRAS mutations. G12C was most commonly seen in lung cancer (4.3%), followed by colorectal cancer (2.5%) and biliary cancer (2.3%). Almost all patients (99.6%) with G12C mutations had concomitant genomic aberrations. These were most commonly associated with the RAS/RTK pathway including BRAF and PI3KCA mutations. Moreover, KRAS mutation was positively correlated with smoking status in lung adenocarcinomas. Conclusions The overall incidence of KRAS G12C mutations remains low in the Chinese population. The most common tumor types harboring KRAS G12C mutations are in patients suffering from lung, colorectal and biliary cancers.
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- 2020
31. Transbronchial Techniques for Lung Cancer Treatment: Where Are We Now?
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Chan, Joyce W. Y., Siu, Ivan C. H., Chang, Aliss T. C., Li, Molly S. C., Lau, Rainbow W. H., Mok, Tony S. K., and Ng, Calvin S. H.
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TREATMENT of lung tumors ,SURGICAL robots ,CATHETER ablation ,STEAM ,ELECTRICITY ,RADIOTHERAPY ,ABLATION techniques ,NANOPARTICLES ,BRONCHOSCOPY - Abstract
Simple Summary: Traditionally, local treatment of lung cancers mainly consists of three branches: surgical resection, radiotherapy, and percutaneous ablation. With the advent of new technologies such as electromagnetic navigation bronchoscopy and robotic bronchoscopy, transbronchial therapies are being developed. This gives substantial hope to high-risk patients, especially those who have had prior chest radiation exposure or frail patients who could not tolerate surgery, as they would otherwise be excluded from the currently established forms of local treatment. In addition, demand for local ablation is also rising due to an increasing incidence of multiple synchronous lung cancers arising in the same patient. In this review, we discuss state-of-the-art transbronchial techniques for lung cancer treatment. The demand for parenchyma-sparing local therapies for lung cancer is rising owing to an increasing incidence of multifocal lung cancers and patients who are unfit for surgery. With the latest evidence of the efficacy of lung cancer screening, more premalignant or early-stage lung cancers are being discovered and the paradigm has shifted from treatment to prevention. Transbronchial therapy is an important armamentarium in the local treatment of lung cancers, with microwave ablation being the most promising based on early to midterm results. Adjuncts to improve transbronchial ablation efficiency and accuracy include mobile C-arm platforms, software to correct for the CT-to-body divergence, metal-containing nanoparticles, and robotic bronchoscopy. Other forms of energy including steam vapor therapy and pulse electric field are under intensive investigation. [ABSTRACT FROM AUTHOR]
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- 2023
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32. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial
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Tony S K Mok, Yi-Long Wu, Iveta Kudaba, Dariusz M Kowalski, Byoung Chul Cho, Hande Z Turna, Gilberto Castro, Vichien Srimuninnimit, Konstantin K Laktionov, Igor Bondarenko, Kaoru Kubota, Gregory M Lubiniecki, Jin Zhang, Debra Kush, Gilberto Lopes, Grigory Adamchuk, Myung-Ju Ahn, Aurelia Alexandru, Ozden Altundag, Anna Alyasova, Orest Andrusenko, Keisuke Aoe, Antonio Araujo, Osvaldo Aren, Oscar Arrieta Rodriguez, Touch Ativitavas, Oscar Avendano, Fernando Barata, Carlos Henrique Barrios, Carlos Beato, Per Bergstrom, Daniel Betticher, Larisa Bolotina, Michiel Botha, Sayeuri Buddu, Christian Caglevic, Andres Cardona, Hugo Castro, Filiz Cay Senler, Carlos Alexandre Sydow Cerny, Alvydas Cesas, Gee-Chen Chan, Jianhua Chang, Gongyan Chen, Xi Chen, Susanna Cheng, Ying Cheng, Nelly Cherciu, Chao-Hua Chiu, Saulius Cicenas, Daniel Ciurescu, Graham Cohen, Marcos Andre Costa, Pongwut Danchaivijitr, Flavia De Angelis, Sergio Jobim de Azevedo, Mircea Dediu, Tsvetan Deliverski, Pedro Rafael Martins De Marchi, Flor de The Bustamante Valles, Zhenyu Ding, Boyan Doganov, Lydia Dreosti, Ricardo Duarte, Regina Edusma-Dy, Sergey Emelyanov, Mustafa Erman, Yun Fan, Luis Fein, Jifeng Feng, David Fenton, Gustavo Fernandes, Carlos Ferreira, Fabio Andre Franke, Helano Freitas, Yasuhito Fujisaka, Hector Galindo, Christina Galvez, Doina Ganea, Nuno Gil, Gustavo Girotto, Erdem Goker, Tuncay Goksel, Gonzalo Gomez Aubin, Luis Gomez Wolff, Hakan Griph, Mahmut Gumus, Jacqueline Hall, Gregory Hart, Libor Havel, Jianxing He, Yong He, Carlos Hernandez Hernandez, Venceslau Hespanhol, Tomonori Hirashima, Chung Man James Ho, Atsushi Horiike, Yukio Hosomi, Katsuyuki Hotta, Mei Hou, Soon Hin How, Te-Chun Hsia, Yi Hu, Masao Ichiki, Fumio Imamura, Oleksandr Ivashchuk, Yasuo Iwamoto, Jana Jaal, Jacek Jassem, Christa Jordaan, Rosalyn Anne Juergens, Diego Kaen, Ewa Kalinka-Warzocha, Nina Karaseva, Boguslawa Karaszewska, Andrzej Kazarnowicz, Kazuo Kasahara, Nobuyuki Katakami, Terufumi Kato, Tomoya Kawaguchi, Joo Hang Kim, Kazuma Kishi, Vitezslav Kolek, Marchela Koleva, Petr Kolman, Leona Koubkova, Ruben Kowalyszyn, Dariusz Kowalski, Krassimir Koynov, Doran Ksienski, Takayasu Kurata, Gerli Kuusk, Lyudmila Kuzina, Ibolya Laczo, Guia Elena Imelda Ladrera, Konstantin Laktionov, Gregory Landers, Sergey Lazarev, Guillermo Lerzo, Krzysztof Lesniewski Kmak, Wei Li, Chong Kin Liam, Igor Lifirenko, Oleg Lipatov, Xiaoqing Liu, Zhe Liu, Sing Hung Lo, Valeria Lopes, Karla Lopez, Shun Lu, Gaston Martinengo, Luis Mas, Marina Matrosova, Rumyana Micheva, Zhasmina Milanova, Lucian Miron, Tony Mok, Matias Molina, Shuji Murakami, Yasuharu Nakahara, Tien Quang Nguyen, Takashi Nishimura, Adrian Ochsenbein, Tatsuo Ohira, Ronny Ohman, Choo Khoon Ong, Gyula Ostoros, Xuenong Ouyang, Elena Ovchinnikova, Ozgur Ozyilkan, Lubos Petruzelka, Xuan Dung Pham, Pablo Picon, Bela Piko, Artem Poltoratsky, Olga Ponomarova, Patrice Popelkova, Gunta Purkalne, Shukui Qin, Rodryg Ramlau, Bernardo Rappaport, Felipe Rey, Eduardo Richardet, Jaromir Roubec, Paul Ruff, Andrii Rusyn, Hideo Saka, Jorge Salas, Mario Sandoval, Lucas Santos, Toshiyuki Sawa, Kasan Seetalarom, Mesut Seker, Nobuhiko Seki, Freddy Seolwane, Lucinda Shepherd, Sergii Shevnya, Andrea Kazumi Shimada, Yaroslav Shparyk, Ivan Sinielnikov, Daniela Sirbu, Oren Smaletz, Joao Paulo Holanda Soares, Aumkhae Sookprasert, Giovanna Speranza, Virote Sriuranpong, Zinaida Stara, Wu-Chou Su, Shunichi Sugawara, Waldemar Szpak, Kazuhisa Takahashi, Nagio Takigawa, Hiroshi Tanaka, Jerry Tan Chun Bing, Qiyou Tang, Pavel Taranov, Hermes Tejada, Lye Mun Tho, Yoshitaro Torii, Dmytro Trukhyn, Maria Turdean, Hande Turna, Grygoriy Ursol, Jaroslav Vanasek, Mirta Varela, Marcela Vallejo, Luis Vera, Ana-Paula Victorino, Tomas Vlasek, Ihor Vynnychenko, Buhai Wang, Jie Wang, Kai Wang, Yilong Wu, Kazuhiko Yamada, Chih-Hsin Yang, Takuma Yokoyama, Toshihide Yokoyama, Hiroshige Yoshioka, Fulden Yumuk, Angela Zambrano, Juan Jose Zarba, Oleg Zarubenkov, Marius Zemaitis, Li Zhang, Xin Zhang, Jun Zhao, Caicun Zhou, Jianying Zhou, Qing Zhou, and Alfred Zippelius
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medicine.medical_specialty ,Chemotherapy ,education.field_of_study ,Performance status ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Population ,Phases of clinical research ,General Medicine ,Pembrolizumab ,030204 cardiovascular system & hematology ,medicine.disease ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Carcinoma ,030212 general & internal medicine ,business ,Lung cancer ,education - Abstract
Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.
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- 2019
33. Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study
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D.R. Camidge, Joonghyun Ahn, Walter Bordogna, Johannes Noe, Maurice Pérol, Shirish M. Gadgeel, Dai Woo Kim, Tony Mok, Rafal Dziadziuszko, Solange Peters, S-H.I. Ou, Vlatka Smoljanovic, Alice T. Shaw, Rafael Rosell, Magalie Hilton, and Thorsten Ruf
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0301 basic medicine ,Alectinib ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Crizotinib ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Clinical endpoint ,medicine ,Humans ,Anaplastic Lymphoma Kinase ,Progression-free survival ,Lung cancer ,Protein Kinase Inhibitors ,business.industry ,Hazard ratio ,Hematology ,medicine.disease ,Progression-Free Survival ,Confidence interval ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Background The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). Patients and methods Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. Results Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32–0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46–0.98). The 5-year OS rate was 62.5% (95% CI 54.3–70.8) with alectinib and 45.5% (95% CI 33.6–57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34–1.00)] and those without [HR 0.76 (95% CI 0.45–1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. Conclusions Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. Clinical trials number NCT02075840.
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- 2020
34. Tannic Acid Inhibits Non-small Cell Lung Cancer (NSCLC) Stemness by Inducing G0/G1 Cell Cycle Arrest and Intrinsic Apoptosis
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Kyoung-Jin Jang, Dong Young Kang, Eun Seong Jo, Doh Hoon Kim, Nipin Sp, Alexis Rugamba, Young Mok Yang, and Ji-Seung Yoo
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A549 cell ,Cancer Research ,Cell cycle checkpoint ,Intrinsic apoptosis ,non-small cell lung cancer (NSCLC) ,macromolecular substances ,General Medicine ,respiratory system ,medicine.disease ,respiratory tract diseases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,chemistry ,Gentamicin protection assay ,Apoptosis ,030220 oncology & carcinogenesis ,Tannic acid ,medicine ,Cancer research ,Lung cancer - Abstract
Background/aim Non-small cell lung cancer (NSCLC) is one among the most common cancers worldwide. Recently, dietary phytochemicals have been reported as an attractive approach to improve the symptoms of NSCLC patients. Tannic acid is a natural polyphenol, which is known to have anticancer effects on in vitro models of breast, gingival and colon cancer. However, the molecular mechanisms associated with the actions of tannic acid on A549 human lung cancer cells have not been elucidated. Materials and methods In this study, we analyzed the effect of tannic acid on A549 cells and their underlying mechanisms using western blotting, flow cytometry, invasion assay and tumorsphere formation assay. Results Tannic acid treatment suppressed the viability of A549 cells through cell cycle arrest and induction of the intrinsic pathways of apoptosis. In addition, the various malignant phenotypes of A549 cells including invasion, migration, and stemness were inhibited by tannic acid treatment. Conclusion Tannic acid could be used as an effective inhibitor of lung cancer progression.
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- 2020
35. Albuminuria, Kidney Function, and Cancer Risk in the Community
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Yejin Mok, Yingying Sang, Kunihiro Matsushita, Elizabeth A. Platz, Shoshana H. Ballew, Corinne E. Joshu, and Josef Coresh
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Oncology ,medicine.medical_specialty ,biology ,Epidemiology ,Proportional hazards model ,business.industry ,030232 urology & nephrology ,Renal function ,Cancer ,Original Contribution ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Prostate cancer screening ,Cystatin C ,Internal medicine ,medicine ,Albuminuria ,biology.protein ,030212 general & internal medicine ,medicine.symptom ,skin and connective tissue diseases ,Lung cancer ,business ,Kidney disease - Abstract
Few studies have comprehensively investigated the association of 2 key kidney disease measures, estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR), with cancer incidence. In 8,935 participants at the baseline (1996–1998) from the Atherosclerosis Risk in Communities study, we quantified the associations of eGFR (based on creatinine and cystatin C) and ACR with cancer risk using Cox regression models adjusted for potential confounders. Due to changing guidelines for prostate cancer screening during the follow-up period, we investigated overall cancer, overall nonprostate cancer, and site-specific cancer. During a median follow-up of 14.7 years, 2,030 incident cancer cases occurred. In demographically adjusted models, low eGFR and high ACR were associated with cancer incidence (both overall and overall nonprostate cancer). These associations were attenuated after adjusting for other shared risk factors, with a significant association remaining only for ACR (≥103 compared with 5 mg/g) and overall nonprostate cancer. For site-specific cancer, only high ACR showed a significant association with lung and urinary tract cancers. Of these, the association between ACR and lung cancer appeared most robust in several sensitivity analyses. Kidney disease measures, particularly high ACR, were independently associated with cancer risk. The association between ACR and lung cancer was uniquely robust, warranting future studies to explore potential mechanisms.
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- 2020
36. Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study of Lung Cancer
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Maria E. Arcila, Umberto Malapelle, Giorgio V. Scagliotti, Christopher Abbosh, Lynette M. Sholl, Daniel Tan, Ignacio I. Wistuba, Christian Rolfo, Charles Swanton, Rafal Dziadziuszko, Charu Aggarwal, Rebecca Bunn, Heather A. Wakelee, Nir Peled, Maximilian Diehn, Fabrice Barlesi, M. Wynes, Trever G. Bivona, Philip C. Mack, Janet Freeman-Daily, Lecia V. Sequist, Caroline Dive, David R. Gandara, Natasha B. Leighl, Luis E. Raez, Tony Mok, Tetsuya Mitsudomi, Chandra P. Belani, Rolfo, C., Mack, P., Scagliotti, G. V., Aggarwal, C., Arcila, M. E., Barlesi, F., Bivona, T., Diehn, M., Dive, C., Dziadziuszko, R., Leighl, N., Malapelle, U., Mok, T., Peled, N., Raez, L. E., Sequist, L., Sholl, L., Swanton, C., Abbosh, C., Tan, D., Wakelee, H., Wistuba, I., Bunn, R., Freeman-Daily, J., Wynes, M., Belani, C., Mitsudomi, T., and Gandara, D.
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Consensus ,Lung Neoplasms ,Druggability ,Consensu ,NSCLC ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Humans ,IASLC ,Liquid biopsy ,Lung cancer ,Genotyping ,Oncogene ,ctDNA ,Immunotherapy ,Oncogene addicted ,business.industry ,Cancer ,Oncogenes ,medicine.disease ,Precision medicine ,Egfr mutation ,Adenocarcinoma ,business ,Human - Abstract
Although precision medicine has had a mixed impact on the clinical management of patients with advanced-stage cancer overall, for NSCLC, and more specifically for lung adenocarcinoma, the advances have been dramatic, largely owing to the genomic complexity and growing number of druggable oncogene drivers. Furthermore, although tumor tissue is historically the "accepted standard" biospecimen for these molecular analyses, there are considerable innate limitations. Thus, liquid biopsy represents a practical alternative source for investigating tumor-derived somatic alterations. Although data are most robust in NSCLC, patients with other cancer types may also benefit from this minimally invasive approach to facilitate selection of targeted therapies. The liquid biopsy approach includes a variety of methodologies for circulating analytes. From a clinical point of view, plasma circulating tumor DNA is the most extensively studied and widely adopted alternative to tissue tumor genotyping in solid tumors, including NSCLC, first entering clinical practice for detection of EGFR mutations in NSCLC. Since the publication of the first International Association for the Study of Lung Cancer (IASLC) liquid biopsy statement in 2018, several additional advances have been made in this field, leading to changes in the therapeutic decision-making algorithm for advanced NSCLC and prompting this 2021 update. In view of the novel and impressive technological advances made in the past few years, the growing clinical application of plasma-based, next-generation sequencing, and the recent Food and Drug and Administration approval in the United States of two different assays for circulating tumor DNA analysis, IASLC revisited the role of liquid biopsy in therapeutic decision-making in a recent workshop in October 2020 and the question of "plasma first" versus "tissue first" approach toward molecular testing for advanced NSCLC. Moreover, evidence-based recommendations from IASLC provide an international perspective on when to order which test and how to interpret the results. Here, we present updates and additional considerations to the previous statement article as a consensus from a multidisciplinary and international team of experts selected by IASLC.
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- 2021
37. Twenty‐five years of Respirology : Advances in lung cancer
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Mei‐Kim Ang and Tony Mok
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Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Internal medicine ,medicine ,Immunotherapy ,Lung cancer ,medicine.disease ,business ,Targeted therapy - Published
- 2019
38. Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: Osimertinib versus platinum‐pemetrexed for T790M mutation‐positive advanced non–small cell lung cancer
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Sabina Patel, Chun-Ming Tsai, X. Huang, Suzanne Jenkins, Makoto Maemondo, Kenneth S. Thress, Aleksandra Markovets, G. Laus, Yi-Long Wu, Yong He, Sang We Kim, Janessa Laskin, Toyoaki Hida, Terufumi Kato, Angelo Delmonte, Suresh S. Ramalingam, Tony Mok, Te Chun Hsia, Ji Youn Han, Vassiliki A. Papadimitrakopoulou, and Myung-Ju Ahn
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,DNA Mutational Analysis ,non-small cell lung cancer (NSCLC) ,Pemetrexed ,Carboplatin ,Circulating Tumor DNA ,03 medical and health sciences ,T790M ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biopsy ,Humans ,Medicine ,Osimertinib ,Digital polymerase chain reaction ,030212 general & internal medicine ,Epidermal growth factor receptor ,Lung cancer ,Lung ,Retrospective Studies ,Acrylamides ,Aniline Compounds ,medicine.diagnostic_test ,biology ,business.industry ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Tumor Burden ,respiratory tract diseases ,ErbB Receptors ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Female ,Cisplatin ,business ,medicine.drug - Abstract
BACKGROUND This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum-pemetrexed according to the plasma T790M status. METHODS Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS; Guardant360, Guardant Health). RESULTS With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for T790M-negative; P
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- 2019
39. 364 KRAS mutations in patients with nonsquamous non–small-cell lung cancer: prevalence and relationship with PD-L1 expression, tumor mutation burden and smoking status
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Delvys Rodriguez-Abreu, Byoung Chul Cho, M.C. Garassino, J. Kobie, Gilberto de Castro, Kazuo Kasahara, Bin Zhao, Gilberto Lopes, Shirish M. Gadgeel, Enriqueta Felip, Yi-Long Wu, Tony Sk Mok, Hande Turna, Martin Reck, Michael Boyer, Roy S. Herbst, Razvan Cristescu, M. Catherine Pietanza, Yongjin Li, Mark Ayers, Edward B. Garon, Dariusz M. Kowalski, Rina Hui, and Hidehito Horinouchi
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Pharmacology ,Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Mutation ,business.industry ,medicine.medical_treatment ,Immunology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Pembrolizumab ,medicine.disease_cause ,Placebo ,medicine.disease ,Internal medicine ,medicine ,Molecular Medicine ,Immunology and Allergy ,Immunohistochemistry ,KRAS ,business ,Lung cancer ,Exome ,RC254-282 - Abstract
BackgroundPembrolizumab is a standard-of-care first-line treatment for advanced/metastatic NSCLC, either as monotherapy (for patients with PD-L1 tumor proportion score [TPS] ≥1%) or combined with platinum chemotherapy. An improved OS benefit has been demonstrated for both pembrolizumab monotherapy and pembrolizumab plus chemotherapy in patients with higher tumor PD-L1 expression, and for pembrolizumab monotherapy in patients with higher tissue tumor mutation burden (tTMB). Mutations in KRAS occur relatively frequently in patients with nonsquamous NSCLC but infrequently in those with squamous NSCLC; most mutations are in codon 12. Notably, the pembrolizumab OS treatment effect was not diminished in patients with KRAS G12C mutations in phase 3 studies evaluating pembrolizumab monotherapy and pembrolizumab in combination with chemotherapy.1 2 Herein we describe prevalence of KRAS mutations among patients with advanced nonsquamous NSCLC from two phase 3 clinical studies evaluating first-line pembrolizumab (KEYNOTE-042 and KEYNOTE-189) and the relationship of such mutations with select patient characteristics.MethodsKEYNOTE-042 (NCT02220894) evaluated pembrolizumab versus platinum-based chemotherapy for advanced PD-L1–positive NSCLC (any histology) without EGFR/ALK alterations. KEYNOTE-189 (NCT02578680) evaluated pembrolizumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone for metastatic nonsquamous NSCLC without EGFR/ALK alterations irrespective of tumor PD-L1 expression. Whole-exome sequencing of tumor tissue and matched normal DNA (blood) was performed for patients with nonsquamous histology. PD-L1 TPS was evaluated using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, USA). Prevalence of KRAS mutations and their relationships with TMB, PD-L1 TPS, and smoking status were analyzed descriptively.Results590 patients with nonsquamous NSCLC were included in these analyses (KEYNOTE-042, n=301; KEYNOTE-189, n=289). Overall, 42.9% of patients had tTMB ≥175 mut/exome, 81.4% were current/former smokers and, 40.3%, 42.7%, and 16.9% had PD-L1 TPS ≥50%, 1–49% and KRAS G12C, G12D, and G12V mutations occurred in 11.0%, 4.1%, and 5.4% of patients, respectively. Prevalence of KRAS mutations by patient characteristics is summarized in the table (table 1). KRAS G12C mutations occurred almost exclusively in current/former smokers. KRAS G12C was enriched in tumors with tTMB ≥175 mut/exome and tumors with PD-L1 TPS ≥50%. Prevalence was highest in tumors with both tTMB ≥175 mut/exome and PD-L1 TPS ≥50%.Abstract 364 Table 1KRAS Mutation PrevalenceConclusionsKRAS G12C mutations occurred with moderate frequency in patients with nonsquamous NSCLC, with most occurring in current/former smokers. KRAS G12C mutations occurred at higher frequency in patient subgroups defined by higher tTMB and PD-L1 TPS.AcknowledgementsMedical writing assistance was provided by Christabel Wilson, MSc, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationKEYNOTE-042, ClinicalTrials.gov, NCT02220894; KEYNOTE-189, ClinicalTrials.gov, NCT02578680ReferencesGadgeel S, Rodriguez-Abreu D, Felip E, et al. KRAS mutational status and efficacy in KEYNOTE-189: pembrolizumab (pembro) plus chemotherapy (chemo) vs placebo plus chemo as first-line therapy for metastatic non-squamous NSCLC. Ann Oncol 2019;30(suppl 11):xi64-xi5.Herbst RS, Lopes G, Kowalski DM, et al. Association of KRAS mutational status with response to pembrolizumab monotherapy given as first-line therapy for PD-L1-positive advanced non-squamous NSCLC in KEYNOTE-042. Ann Oncol 2019;30(suppl 11):xi63-xi4.Ethics ApprovalFor both trials, the protocol and all amendments were approved by the appropriate ethics committee at each center, the study was conducted in accordance with the standards of Good Clinical Practice. Patients provided written informed consent before enrollment.
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- 2021
40. Incorporating circulating tumor DNA detection to radiographic assessment for treatment response in advanced EGFR-mutant lung cancer
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Ian C. Marschner, Tony Mok, Peey-Sei Kok, Thomas John, Chee Khoon Lee, Sarah J. Lord, Kirsty Lee, and Yi-Long Wu
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Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Radiography ,Placebo ,Circulating Tumor DNA ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Biomarkers, Tumor ,Medicine ,Humans ,Lung cancer ,business.industry ,Proportional hazards model ,medicine.disease ,Gemcitabine ,ErbB Receptors ,Response Evaluation Criteria in Solid Tumors ,Circulating tumor DNA ,Mutation ,Erlotinib ,business ,medicine.drug - Abstract
Purpose Response Evaluation Criteria in Solid Tumors (RECIST) has limitations but remains the conventional approach for tumor assessments. We explored whether circulating tumor DNA (ctDNA) can be incorporated into RECIST to provide a more robust measure of tumor response in advanced EGFR-mutant NSCLC. Patients and Methods In FASTACT-2, patients with advanced NSCLC received platinum/gemcitabine intercalated with erlotinib or placebo. EGFR mutation (tumor and plasma ctDNA) was detected using cobas v2. Patients selected for this hypothesis-generating analysis had EGFR mutations (on either tumor or plasma) at baseline and evaluable week 8 plasma EGFR. Week 8 ctDNA and radiologic response status were correlated with survival using landmark cox regression analyses. Results Of the original 451 patients, 86 (19.1%) were eligible for this analysis. 73% (n=63) had detectable ctDNA at baseline. At week 8, 40% (n=34) had radiologic partial response (PR), 60% (n=52) had stable disease (SD); 80% (n=69) had a ctDNA response (undetectable ctDNA). In patients who had initial PR and undetectable ctDNA, 93% (28/30) had ongoing PR subsequently at week 16. The median duration of response was 14.9 months. In patients with SD and undetectable ctDNA at week 8, 28% had radiological PR at week 16. Amongst those with PR at week 8, survival outcomes for those with undetectable vs detectable ctDNA were not statistically significant (PFS HR 0.49, 95%CI 0.16-1.48, p=0.21; OS HR 0.39, 95%CI 0.13-1.19, p=0.10). Amongst those with SD at week 8, there was significantly longer survival for those with undetectable vs detectable ctDNA (PFS HR 0.27, 95% CI 0.13-0.57, p Conclusion In patients with SD, undetectable ctDNA at week 8 correlated with survival improvement. Both radiologic and ctDNA responses are prognostic of PFS. Incorporation of ctDNA with RECIST may improve tumor response assessment in EGFR-mutant NSCLC.
- Published
- 2021
41. Clinical definition of acquired resistance to immunotherapy in patients with metastatic non-small-cell lung cancer
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Scott J. Antonia, F.S. Hodi, Maurice Pérol, Matthew D. Hellmann, Adam J. Schoenfeld, D.S.W. Tan, Scott N. Gettinger, Martin Reck, Melissa Lynne Johnson, Justin F. Gainor, Natasha B. Leighl, Mark M. Awad, Benjamin Solomon, Enriqueta Felip, Tony Mok, Solange Peters, Christine M. Lovly, and J-C. Soria
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Oncology ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,B7-H1 Antigen ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Prospective Studies ,Lung cancer ,Lung ,business.industry ,Cancer ,Hematology ,Immunotherapy ,medicine.disease ,Blockade ,Clinical trial ,Clinical research ,medicine.anatomical_structure ,business ,Progressive disease - Abstract
Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months.
- Published
- 2021
42. Comparison of n-butyl-2-cyanoacrylate and polyvinyl alcohol particles for bronchial artery embolisation in primary lung cancer: a retrospective cohort study.
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Lee, Jae Hwan, Yoon, Chang Jin, Jung, Yun Su, Choi, Won Seok, Lee, Chong-ho, and Lee, Guy Mok
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BRONCHIAL arteries ,POLYVINYL alcohol ,LUNG cancer ,PROPORTIONAL hazards models ,CANCER patients - Abstract
Background: Bronchial artery embolisation (BAE) is an effective treatment option to control haemoptysis in primary lung cancer. However, no studies have investigated optimal embolisation material for BAE in lung cancer patients. Thus, this study aimed to compare the safety and efficacy of BAE performed using n-butyl-2-cyanoacrylate (NBCA) and polyvinyl alcohol (PVA) particles in primary lung cancer patients to determine which embolic material is better for patients with haemoptysis.Methods: This retrospective study was approved by the institutional review board, and consent was waived. The rates of hemostasis, complications, procedure time, dose-area product, and haemoptysis-free survival were retrospectively compared between primary lung cancer (non-small cell [n = 111] and small cell [n = 11]) patients who underwent BAE using NBCA (n = 58) or PVA particles (n = 64) between January 2004 and December 2019. Predictors of recurrent haemoptysis were analysed using the Cox proportional hazard regression model.Results: Among 122 patients (mean age, 66 ± 10 years; range 32-86 years; 103 men), more patients in the NBCA group (81.0%; 47 of 58) achieved complete hemostasis than did patients in the PVA group (53.1%; 34 of 64) (P = 0.002). No major complications were observed in either group. The procedure time (36.4 ± 21.6 vs. 56.3 ± 27.4 min, P < 0.001) was shorter, and the dose-area product (58.6 ± 64.0 vs. 233.5 ± 225.0 Gy*cm2, P < 0.001) was smaller in the NBCA group than in the PVA group. The median haemoptysis-free survival was 173.0 in the NBCA group compared with 20.0 days in the PVA group (P < 0.001). The PVA use (P < 0.001) and coagulopathy (P = 0.014) were independent predictors of shortened haemoptysis-free survival.Conclusion: BAE using NBCA showed significantly superior initial hemostasis with longer haemoptysis-free survival, shorter procedure time, and reduced radiation dose than BAE using PVA particles. The PVA use and coagulopathy were independent predictors of recurrent haemoptysis.Trial Registration: Retrospectively registered. [ABSTRACT FROM AUTHOR]- Published
- 2022
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43. Non-Cystic Fibrosis Bronchiectasis Increases the Risk of Lung Cancer Independent of Smoking Status.
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Hayoung Choi, Hye Yun Park, Kyungdo Han, Juhwan Yoo, Sun Hye Shin, Bumhee Yang, Youlim Kim, Tai Sun Park, Dong Won Park, Ji-Yong Moon, Seung Won Ra, Sang-Heon Kim, Tae-Hyung Kim, Yeon-Mok Oh, Ho Joo Yoon, Jang Won Sohn, Hyun Lee, Choi, Hayoung, Park, Hye Yun, and Han, Kyungdo
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LUNG tumors ,FIBROSIS ,OBSTRUCTIVE lung diseases ,RESEARCH funding ,BRONCHIECTASIS ,SMOKING ,LONGITUDINAL method - Abstract
Rationale: It remains unclear whether non-cystic fibrosis bronchiectasis increases the risk of lung cancer, because smoking history was not considered in previous studies. Objectives: To evaluate whether participants with bronchiectasis have a higher risk of incident lung cancer than those without bronchiectasis with information on smoking status. Methods: This was a population-based cohort study of 3,858,422 individuals who participated in the 2009 National Health Screening Program. We evaluated the incidence of lung cancer in participants with bronchiectasis (n = 65,305) and those without bronchiectasis (n = 3,793,117). We followed the cohort up until the date of lung cancer diagnosis, date of death, or December 2018. Cox proportional hazard regression models were used to evaluate the relative risk of lung cancer between participants with bronchiectasis and those without bronchiectasis. Results: The incidence of lung cancer in participants with bronchiectasis was significantly higher than in those without bronchiectasis (2.1 vs. 0.7 per 1,000 person-years; P < 0.001), with an adjusted hazard ratio (aHR) of 1.22 (95% confidence interval [CI], 1.14-1.30) in the model adjusting for potential confounders and accounting for the competing risk of mortality. Regardless of smoking status, the risk of lung cancer was significantly higher in participants with bronchiectasis than in those without bronchiectasis (aHR, 1.28 [95% CI, 1.17-1.41] for never-smokers; aHR, 1.26 [95% CI, 1.10-1.44] for ever-smokers). Although bronchiectasis did not increase the risk of lung cancer among participants with chronic obstructive pulmonary disease (COPD), it significantly increased the risk of lung cancer in participants without COPD (aHR, 1.19 [95% CI, 1.09-1.31]). Conclusions: The presence of bronchiectasis was associated with a higher risk of lung cancer after considering the smoking status. [ABSTRACT FROM AUTHOR]
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- 2022
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44. NTRK gene fusion testing and management in lung cancer.
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Repetto, Matteo, Chiara Garassino, Marina, Loong, Herbert H., Lopez-Rios, Fernando, Mok, Tony, Peters, Solange, Planchard, David, Popat, Sanjay, Rudzinski, Erin R., Drilon, Alexander, and Zhou, Caicun
- Abstract
• NTRK gene fusions are oncogenic drivers in NSCLC targetable by TRK inhibitors. • It is recommended to identify patients who may benefit from targeted treatment. • RNA-based NGS is considered to be the gold standard testing method. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are recurrent oncogenic drivers found in a variety of solid tumours, including lung cancer. Several tropomyosin receptor kinase (TRK) inhibitors have been developed to treat tumours with NTRK gene fusions. Larotrectinib and entrectinib are first-generation TRK inhibitors that have demonstrated efficacy in patients with TRK fusion lung cancers. Genomic testing is recommended for all patients with metastatic non-small cell lung cancer for optimal drug therapy selection. Multiple testing methods can be employed to identify NTRK gene fusions in the clinic and each has its own advantages and limitations. Among these assays, RNA-based next-generation sequencing (NGS) can be considered a gold standard for detecting NTRK gene fusions; however, several alternatives with minimally acceptable sensitivity and specificity are also available in areas where widespread access to NGS is unfeasible. This review highlights the importance of testing for NTRK gene fusions in lung cancer, ideally using the gold-standard method of RNA-based NGS, the various assays that are available, and treatment algorithms for patients. [ABSTRACT FROM AUTHOR]
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- 2024
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45. The Effect of Adding Biological Factors to the Decision-Making Process for Spinal Metastasis of Non-Small Cell Lung Cancer
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Sung Cheol Park, Jongyeon Son, Bong Soon Chang, Sujung Mok, Hyoungmin Kim, and Sam Yeol Chang
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Oncology ,medicine.medical_specialty ,decompression ,lcsh:Medicine ,Malignancy ,survival ,Article ,03 medical and health sciences ,0302 clinical medicine ,New England Spinal Metastasis Score ,Internal medicine ,medicine ,Clinical significance ,Epidermal growth factor receptor ,Lung cancer ,non-small cell lung cancer ,biology ,Proportional hazards model ,business.industry ,Hazard ratio ,lcsh:R ,General Medicine ,medicine.disease ,spinal metastasis ,030220 oncology & carcinogenesis ,biology.protein ,Uno’s C-index ,Spinal metastasis ,Non small cell ,prognosis ,business ,epidermal growth factor receptor ,030217 neurology & neurosurgery - Abstract
Molecular target therapies have markedly improved the survival of non-small cell lung cancer (NSCLC) patients, especially those with epidermal growth factor receptor (EGFR) mutations. A positive EGFR mutation is even more critical when the chronicity of spinal metastasis is considered. However, most prognostic models that estimate the life expectancy of spinal metastasis patients do not include these biological factors. We retrospectively reviewed 85 consecutive NSCLC patients who underwent palliative surgical treatment for spinal metastases to evaluate the following: (1) the prognostic value of positive EGFR mutation and the chronicity of spinal metastasis, and (2) the clinical significance of adding these two factors to an existing prognostic model, namely the New England Spinal Metastasis Score (NESMS). Among 85 patients, 38 (44.7%) were EGFR mutation-positive. Spinal metastasis presented as the initial manifestation of malignancy in 58 (68.2%) patients. The multivariate Cox proportional hazard model showed that the chronicity of spinal metastasis (hazard ratio (HR) = 1.88, p = 0.015) and EGFR mutation positivity (HR = 2.10, p = 0.002) were significantly associated with postoperative survival. The Uno’s C-index and time-dependent AUC 6 months following surgery significantly increased when these factors were added to NESMS (p = 0.004 and p = 0.022, respectively). In conclusion, biological factors provide an additional prognostic value for NSCLC patients with spinal metastasis.
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- 2021
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46. Testing for COVID-19 in lung cancer patients
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F. De Marinis, Solange Peters, Tony Mok, Tetsuya Mitsudomi, Antonio Passaro, and Ilaria Attili
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2019-20 coronavirus outbreak ,Lung Neoplasms ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,Betacoronavirus ,COVID-19 Testing ,Pandemic ,medicine ,Humans ,Lung cancer ,Pandemics ,biology ,Clinical Laboratory Techniques ,SARS-CoV-2 ,Viral Epidemiology ,business.industry ,COVID-19 ,Hematology ,Coronavirus Infections/diagnosis ,Coronavirus Infections/epidemiology ,Lung Neoplasms/diagnosis ,Lung Neoplasms/epidemiology ,Pneumonia, Viral/diagnosis ,Pneumonia, Viral/epidemiology ,medicine.disease ,biology.organism_classification ,Virology ,Pneumonia ,Oncology ,Coronavirus Infections ,business - Published
- 2020
47. Effects of dose modifications on the safety and efficacy of dacomitinib for EGFR mutation-positive non-small-cell lung cancer
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Geeta Devgan, Adam Pluzanski, Maria Rita Migliorino, Rafael Rosell, Susan Quinn, Weiwei Tan, Jesus Corral, Kazuhiko Nakagawa, Yi-Long Wu, Tony Mok, R. Linke, Ki Hyeong Lee, and Tao Wang
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,EGFR ,NSCLC ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,medicine ,Lung cancer ,Adverse effect ,business.industry ,Incidence (epidemiology) ,First-line ,General Medicine ,medicine.disease ,Dacomitinib ,030104 developmental biology ,chemistry ,Dose ,Egfr mutation ,030220 oncology & carcinogenesis ,Dose reduction ,Non small cell ,business ,Ciencias de la Salud::Oncología [Materias Investigacion] - Abstract
Aim: We evaluated reasons for dacomitinib dose reduction (DR) and examined adverse event (AE) incidence, key efficacy end points (progression-free survival [PFS]/overall survival [OS]), and pharmacokinetics in dose-reducing patients in the ARCHER 1050 trial. Patients & methods: Newly diagnosed patients with EGFR mutation-positive, advanced non-small-cell lung cancer received oral dacomitinib (45 mg once-daily [QD]), with stepwise toxicity-managing DR (30 and 15 mg QD) permitted. Results: Skin toxicities (62.7%) were the most common DR-leading AEs. The AE incidence and severity decreased following DRs. Initial plasma dacomitinib exposure (45 mg QD) was generally lower in patients remaining at 45 mg QD compared with dose-reducing patients. Median PFS and OS were similar in all dacomitinib-treated patients and dose-reducing patients. Conclusion: Tolerability-guided dose modifications enabled patients to continue with dacomitinib and benefit from PFS/OS improvement. Trial registration number: NCT01774721
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- 2019
48. Predictive value of PD-L1 and other clinical factors for chemoimmunotherapy in advanced non-small-cell lung cancer
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Yanni Loh, Craig R. Lewis, Michael Millward, Joanna Lee, Wendy A Cooper, Ian C. Marschner, Tony Mok, Rachel Woodford, Chee Khoon Lee, Richard J. Gralla, Sarah J. Lord, and James Chih-Hsin Yang
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,B7-H1 Antigen ,law.invention ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,Sex Factors ,0302 clinical medicine ,Randomized controlled trial ,law ,Chemoimmunotherapy ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,PD-L1 ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Progression-free survival ,Lung cancer ,Neoplasm Staging ,Randomized Controlled Trials as Topic ,Chemotherapy ,biology ,business.industry ,Patient Selection ,Hazard ratio ,General Medicine ,medicine.disease ,Progression-Free Survival ,030104 developmental biology ,030220 oncology & carcinogenesis ,Meta-analysis ,biology.protein ,business - Abstract
We investigate if PD-L1 expression and other clinical characteristics predict chemoimmunotherapy (CIT) benefits versus chemotherapy in advanced non-small-cell lung cancer. We performed a meta-analysis of randomized controlled trials of CIT versus chemotherapy identified through electronic searches. In seven randomized controlled trials (n = 4170), CIT prolonged progression-free survival over chemotherapy (hazard ratio [HR]: 0.62; 95% CI: 0.58–0.67; p < 0.00001). The treatment benefits differed between PD-L1-high (HR: 0.41; 95% CI: 0.34–0.49) and PD-L1 low (HR: 0.63; 95% CI: 0.55–0.72; interaction-p = 0.00002) and PD-L1-high and PD-L1-negative (HR: 0.72; 95% CI: 0.65–0.80; interaction-p < 0.00001). Similar benefits were observed regardless of gender, EGFR/ALK status and histological subtype. PD-L1 status is predictive of CIT benefit and may assist patient selection and design of future trials.
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- 2019
49. Dacomitinib in the Management of Advanced Non-Small-Cell Lung Cancer
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Tony Mok, Ullas Batra, S. Lau, and Herbert H. Loong
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Oncology ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Antineoplastic Agents ,Disease-Free Survival ,Targeted therapy ,Erlotinib Hydrochloride ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Gefitinib ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Epidermal growth factor receptor ,Lung cancer ,Protein Kinase Inhibitors ,Quinazolinones ,EGFR inhibitors ,Chemotherapy ,biology ,business.industry ,medicine.disease ,Dacomitinib ,ErbB Receptors ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,Quality of Life ,biology.protein ,Erlotinib ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The use of targeted therapy in the management of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer is an important milestone in the management of advanced lung cancer. There are several generations of EGFR tyrosine kinase inhibitors available for clinical use. Dacomitinib is a second-generation irreversible EGFR tyrosine kinase inhibitor with early-phase clinical studies showing efficacy in non-small-cell lung cancer. In the recently published ARCHER 1050 phase III study, dacomitinib given at 45 mg/day orally was superior to gefitinib, a first-generation reversible EGFR tyrosine kinase inhibitor, in improving both progression-free survival and overall survival when given as first-line therapy. There is no prospective evidence to support the use of dacomitinib as subsequent therapy in patients previously treated with chemotherapy or a first-generation EGFR tyrosine kinase inhibitor such as gefitinib and erlotinib. Dacomitinib has not demonstrated any benefit in unselected patients with non-small-cell lung cancer, and its use should be limited to those with known EGFR-sensitizing mutations. Dacomitinib is associated with increased toxicities of diarrhea, rash, stomatitis, and paronychia compared with first-generation EGFR inhibitors. Global quality of life was maintained when assessed in phase III studies. Overall, dacomitinib is an important first- line agent in EGFR-mutated non-small-cell lung cancer in otherwise fit patients whose toxicities can be well managed.
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- 2019
50. Management of common adverse events related to first-line dacomitinib use in EGFR mutation-positive non-small-cell lung cancer: a pooled safety analysis
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Kazuhiko Nakagawa, Qing Zhou, Yi-Long Wu, Kay Noonan, Jesus Corral, Tao Wang, Rickard Sandin, Eric Sbar, Diana Gernhardt, Edward B. Garon, and Tony Mok
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Dry skin ,Medicine ,Lung cancer ,Adverse effect ,Stomatitis ,business.industry ,Incidence (epidemiology) ,General Medicine ,medicine.disease ,Rash ,Dacomitinib ,Diarrhea ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,medicine.symptom ,business - Abstract
Aim: This pooled safety analysis was conducted to analyze incidence and management of key dacomitinib-associated adverse drug reactions (ADRs). Patients & methods: Patients with EGFR mutation-positive advanced non-small-cell lung cancer who received first-line dacomitinib at the 45 mg/day recommended starting dose were included. ADRs were identified based on reasonable association with EGFR tyrosine kinase inhibitors. Results: Overall, 251/255 patients (98%) experienced ADRs. The most common were diarrhea, rash, stomatitis, nail disorder and dry skin. Dose interruptions and dose reductions were reported in 47 and 52% of patients, respectively. Fewer grade 3 key ADRs were observed following dose reductions. Conclusion: Dacomitinib was generally tolerable. Most reported ADRs were known to be associated with EGFR tyrosine kinase inhibitors and were managed with standard medical management and dose modifications.
- Published
- 2019
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