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Heymach JV, Yu HA, Besse B, Cheng Y, Tan DSW, Wei L, Wacheck V, Nishio M. REZILIENT3: randomized phase III study of first-line zipalertinib plus chemotherapy in patients with EGFR exon 20 insertion-mutated NSCLC. Future Oncol 2025; 21:549-556. [PMID: 39957151 PMCID: PMC11845107 DOI: 10.1080/14796694.2025.2457294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/20/2025] [Indexed: 02/18/2025] Open
Abstract
There remains a significant unmet need for effective and tolerable treatments for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations in the first-line setting. First and later generation EGFR tyrosine kinase inhibitors (TKIs) have shown efficacy for common EGFR mutations; however, their effectiveness against ex20ins mutations is limited, and platinum-based chemotherapy remains part of the standard of care. Data suggest that combining chemotherapy with EGFR inhibitors offers promise for EGFR ex20ins-mutated NSCLC. REZILIENT3 is an ongoing phase III study evaluating the efficacy and safety of zipalertinib (an orally available, irreversible EGFR-TKI) plus first-line standard-of-care platinum-based chemotherapy with chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations.Clinical Trial Registration: NCT05973773 (ClinicalTrials.gov).
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Affiliation(s)
- John V. Heymach
- Department of Thoracic, Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Helena A. Yu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Benjamin Besse
- Department of Cancer Medicine, Institut Gustave Roussy, Paris-Saclay University, Villejuif, France
| | - Ying Cheng
- Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China
| | - Daniel SW. Tan
- Division of Medical Oncology, National Cancer Center Singapore, Duke-NUS Medical School, Singapore
| | - Li Wei
- Clinical Development, Taiho Oncology, Inc, Princeton, NJ, USA
| | - Volker Wacheck
- Clinical Development, Taiho Oncology, Inc, Princeton, NJ, USA
| | - Makoto Nishio
- Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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Swain S, Narayan RK, Mishra PR. Unraveling the interplay: exploring signaling pathways in pancreatic cancer in the context of pancreatic embryogenesis. Front Cell Dev Biol 2024; 12:1461278. [PMID: 39239563 PMCID: PMC11374643 DOI: 10.3389/fcell.2024.1461278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 08/13/2024] [Indexed: 09/07/2024] Open
Abstract
Pancreatic cancer continues to be a deadly disease because of its delayed diagnosis and aggressive tumor biology. Oncogenes and risk factors are being reported to influence the signaling pathways involved in pancreatic embryogenesis leading to pancreatic cancer genesis. Although studies using rodent models have yielded insightful information, the scarcity of human pancreatic tissue has made it difficult to comprehend how the human pancreas develops. Transcription factors like IPF1/PDX1, HLXB9, PBX1, MEIS, Islet-1, and signaling pathways, including Hedgehog, TGF-β, and Notch, are directing pancreatic organogenesis. Any derangements in the above pathways may lead to pancreatic cancer. TP53: and CDKN2A are tumor suppressor genes, and the mutations in TP53 and somatic loss of CDKN2A are the drivers of pancreatic cancer. This review clarifies the complex signaling mechanism involved in pancreatic cancer, the same signaling pathways in pancreas development, the current therapeutic approach targeting signaling molecules, and the mechanism of action of risk factors in promoting pancreatic cancer.
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Peters GJ, Kathmann I, Giovannetti E, Smid K, Assaraf YG, Jansen G. The role of l-leucovorin uptake and metabolism in the modulation of 5-fluorouracil efficacy and antifolate toxicity. Front Pharmacol 2024; 15:1450418. [PMID: 39234107 PMCID: PMC11371747 DOI: 10.3389/fphar.2024.1450418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 07/30/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND L-Leucovorin (l-LV; 5-formyltetrahydrofolate, folinic acid) is a precursor for 5,10-methylenetetrahydrofolate (5,10-CH2-THF), which is important for the potentiation of the antitumor activity of 5-fluorouracil (5FU). LV is also used to rescue antifolate toxicity. LV is commonly administered as a racemic mixture of its l-LV and d-LV stereoisomers. We compared dl-LV with l-LV and investigated whether d-LV would interfere with the activity of l-LV. METHODS Using radioactive substrates, we characterized the transport properties of l-LV and d-LV, and compared the efficacy of l-LV with d-LV to potentiate 5FU-mediated thymidylate synthase (TS) inhibition. Using proliferation assays, we investigated their potential to protect cancer cells from cytotoxicity of the antifolates methotrexate, pemetrexed (Alimta), raltitrexed (Tomudex) and pralatrexate (Folotyn). RESULTS l-LV displayed an 8-fold and 3.5-fold higher substrate affinity than d-LV for the reduced folate carrier (RFC/SLC19A1) and proton coupled folate transporter (PCFT/SLC46A1), respectively. In selected colon cancer cell lines, the greatest enhanced efficacy of 5FU was observed for l-LV (2-fold) followed by the racemic mixture, whereas d-LV was ineffective. The cytotoxicity of antifolates in lymphoma and various solid tumor cell lines could be protected very efficiently by l-LV but not by d-LV. This protective effect of l-LV was dependent on cellular RFC expression as corroborated in RFC/PCFT-knockout and RFC/PCFT-transfected cells. Assessment of TS activity in situ showed that TS inhibition by 5FU could be enhanced by l-LV and dl-LV and only partially by d-LV. However, protection from inhibition by various antifolates was solely achieved by l-LV and dl-LV. CONCLUSION In general l-LV acts similar to the dl-LV formulations, however disparate effects were observed when d-LV and l-LV were used in combination, conceivably by d-LV affecting (anti)folate transport and intracellular metabolism.
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Affiliation(s)
- Godefridus J. Peters
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Ietje Kathmann
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Pisa, Italy
| | - Kees Smid
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Yehuda G. Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, The Technion-Israel Institute of Technology, Haifa, Israel
| | - Gerrit Jansen
- Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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Belloni A, Pugnaloni A, Rippo MR, Di Valerio S, Giordani C, Procopio AD, Bronte G. The cell line models to study tyrosine kinase inhibitors in non-small cell lung cancer with mutations in the epidermal growth factor receptor: A scoping review. Crit Rev Oncol Hematol 2024; 194:104246. [PMID: 38135018 DOI: 10.1016/j.critrevonc.2023.104246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/16/2023] [Accepted: 12/18/2023] [Indexed: 12/24/2023] Open
Abstract
Non-Small Cell Lung Cancer (NSCLC) represents ∼85% of all lung cancers and ∼15-20% of them are characterized by mutations affecting the Epidermal Growth Factor Receptor (EGFR). For several years now, a class of tyrosine kinase inhibitors was developed, targeting sensitive mutations affecting the EGFR (EGFR-TKIs). To date, the main burden of the TKIs employment is due to the onset of resistance mutations. This scoping review aims to resume the current situation about the cell line models employed for the in vitro evaluation of resistance mechanisms induced by EGFR-TKIs in oncogene-addicted NSCLC. Adenocarcinoma results the most studied NSCLC histotype with the H1650, H1975, HCC827 and PC9 mutated cell lines, while Gefitinib and Osimertinib the most investigated inhibitors. Overall, data collected frame the current advancement of this topic, showing a plethora of approaches pursued to overcome the TKIs resistance, from RNA-mediated strategies to the innovative combination therapies.
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Affiliation(s)
- Alessia Belloni
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | - Armanda Pugnaloni
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | - Maria Rita Rippo
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | - Silvia Di Valerio
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | - Chiara Giordani
- Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences on Ageing (IRCCS INRCA), Ancona, Italy
| | - Antonio Domenico Procopio
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy; Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences on Ageing (IRCCS INRCA), Ancona, Italy
| | - Giuseppe Bronte
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy; Clinic of Laboratory and Precision Medicine, National Institute of Health and Sciences on Ageing (IRCCS INRCA), Ancona, Italy.
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Zhou J, Qin H, Miao J, Liu R, Wang W. Efficacy observation and prognosis analysis of EGFR-TKIs alone versus EGFR-TKIs plus chemotherapy in advanced lung adenocarcinoma with EGFR Exon 19 Deletion, Exon 21 L858R mutation: A historical cohort study. Medicine (Baltimore) 2023; 102:e34110. [PMID: 37390279 PMCID: PMC10313250 DOI: 10.1097/md.0000000000034110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 06/05/2023] [Indexed: 07/02/2023] Open
Abstract
The aim of this study was to investigate the clinical efficacy and determine the prognostic value of Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) alone versus EGFR-TKIs plus chemotherapy for the treatment of advanced lung adenocarcinoma with EGFR Exon 19 Deletion(19Del), Exon 21 L858R (L858R) mutation. The demographic and clinical characteristics of 110 newly diagnosed metastatic lung adenocarcinoma patients with the EGFR 19Del, L858R mutation from June 2016 to October 2018 were retrospectively analyzed. Total remission rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and patient 1-year/2-year survival between EGFR-TKIs combined with first-line platinum-containing double-drug chemotherapy (Observation) group and an EGFR-TKIs alone (Control) group were evaluated and analyzed. For lung adenocarcinoma patients with the EGFR 19Del, L858R mutation, the Observation group had a better ORR (81.4% vs 52.2%), mPFS (12.0 vs 9 months), and 2-year survival (72.1% vs 52.2%) than the Control group, and the differences were statistically significant (P < .05), but DCR (95.3% vs 88.1%) and 1-year survival (90.7% vs 83.6%) were not significantly different between the groups (P > .05). For lung adenocarcinoma with the EGFR 19Del mutation, the Observation group showed a better ORR (81.8% vs 54.3%), and mPFS (14.5 vs 11.0 months) than the Control group, and the differences were statistically significant (P < .05), but DCR (95.5% vs 91.4%), 1-year survival (90.9% vs 85.7%), and 2-year survival (72.7% vs 60.0%) were not significantly different (P > .05). For lung adenocarcinoma with the EGFR L858R mutation, the Observation group showed a better ORR (81.0% vs 50.0%), mPFS (12.0 vs 9.0 months), and 2-year survival (71.4% vs 43.8%) than the Control group (P < .05), but DCR (95.2% vs 84.4%) and 1-year survival (90.5% vs 81.3%) were not significantly different (P > .05). Compared to EGFR-TKIs alone, EGFR-TKIs combined with chemotherapy improved ORR and mPFS in cases of advanced lung adenocarcinoma with EGFR 19Del, L858R mutation. In particular, patients with the EGFR L858R mutation showed a long-term survival benefit trend. EGFR-TKIs combined chemotherapy may therefore be a viable treatment method for delaying targeted drug resistance.
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Affiliation(s)
- Jinhua Zhou
- Department of Respiratory Medicine, The Second Hospital of Shandong University, Jinan, P.R. China
- Department of Respiratory Medicine, Jining First People’s Hospital, Jining, P.R. China
| | - Hongya Qin
- Department of Respiratory Medicine, Jining First People’s Hospital, Jining, P.R. China
| | - Jianlong Miao
- Department of Respiratory Medicine, Jining First People’s Hospital, Jining, P.R. China
| | - Ruijuan Liu
- Department of Respiratory Medicine, Jining First People’s Hospital, Jining, P.R. China
| | - Wei Wang
- Department of Respiratory Medicine, The Second Hospital of Shandong University, Jinan, P.R. China
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Sun SJ, Han JD, Liu W, Wu ZY, Zhao X, Yan X, Jiao SC, Fang J. Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer. World J Clin Cases 2022; 10:6069-6081. [PMID: 35949840 PMCID: PMC9254173 DOI: 10.12998/wjcc.v10.i18.6069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 03/13/2022] [Accepted: 04/15/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC).
AIM To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.
METHODS This multicenter, open-label, pilot randomized controlled trial enrolled 68 EGFR-mutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy + icotinib groups.
RESULTS The median progression-free survival in the icotinib alone and chemotherapy + icotinib groups was 8.0 mo (95%CI: 3.84-11.63) and 13.4 mo (95%CI: 10.18-16.33), respectively (P = 0.0249). No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen (all P > 0.05).
CONCLUSION A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.
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Affiliation(s)
- Sheng-Jie Sun
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Jin-Di Han
- Department of Internal Oncology of Chest, Beijing Cancer Hospital, Beijing 100142, China
| | - Wei Liu
- Peking Cancer Hospital Palliative Care Center, Beijing Cancer Hospital, Beijing 100142, China
| | - Zhi-Yong Wu
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Xiao Zhao
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Xiang Yan
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Shun-Chang Jiao
- Department of Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Jian Fang
- Department of Internal Oncology of Chest, Beijing Cancer Hospital, Beijing 100142, China
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Micro-RNA-215 and -375 regulate thymidylate synthase protein expression in pleural mesothelioma and mediate epithelial to mesenchymal transition. Virchows Arch 2022; 481:233-244. [PMID: 35461395 PMCID: PMC9343276 DOI: 10.1007/s00428-022-03321-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 04/03/2022] [Accepted: 04/05/2022] [Indexed: 11/15/2022]
Abstract
The standard front-line treatment for pleural mesothelioma (PM) is pemetrexed-based chemotherapy, whose major target is thymidylate synthase (TS). In several cancer models, miR-215 and miR-375 have been shown to target TS, while information on these miRNAs in PM are still limited although suggest their role in epithelial to mesenchymal transition. Seventy-one consecutive PM tissues (4 biphasic, 7 sarcomatoid, and 60 epithelioid types) and 16 commercial and patient-derived PM cell lines were screened for TS, miR-215, and miR-375 expression. REN and 570B cells were selected for miR-215 and miR-375 transient transfections to test TS modulation. ZEB1 protein expression in tumor samples was also tested. Moreover, genetic profile was investigated by means of BAP1 and p53 immunohistochemistry. Expression of both miR-215 and miR-375 was significantly higher in epithelioid histotype. Furthermore, inverse correlation between TS protein and both miR-215 and miR-375 expression was found. Efficiently transfected REN and 570B cell lines overexpressing miR-215 and miR-375 showed decreased TS protein levels. Epithelioid PM with a mesenchymal component highlighted by reticulin stain showed significantly higher TS and ZEB1 protein and lower miRNA expression. A better survival was recorded for BAP1 lost/TS low cases. Our data indicate that miR-215 and miR-375 are involved in TS regulation as well as in epithelial-to-mesenchymal transition in PM.
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Papini F, Sundaresan J, Leonetti A, Tiseo M, Rolfo C, Peters GJ, Giovannetti E. Hype or hope - Can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC? Crit Rev Oncol Hematol 2021; 166:103454. [PMID: 34455092 DOI: 10.1016/j.critrevonc.2021.103454] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/07/2021] [Accepted: 08/10/2021] [Indexed: 02/08/2023] Open
Abstract
Three generations of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) have been developed for treating advanced/metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations, while a fourth generation is undergoing preclinical assessment. Although initially effective, acquired resistance to EGFR-TKIs usually arises within a year due to the emergence of clones harboring multiple resistance mechanisms. Therefore, the combination of EGFR-TKIs with other therapeutic agents has emerged as a potential strategy to overcome resistance and improve clinical outcomes. However, results obtained so far are ambiguous and ideal therapies for patients who experience disease progression during treatment with EGFR-TKIs remain elusive. This review provides an updated landscape of EGFR-TKIs, along with a description of the mechanisms causing resistance to these drugs. Moreover, it discusses the current knowledge, limitations, and future perspective regarding the use of EGFR-TKIs in combination with other anticancer agents, supporting the need for bench-to-bedside approaches in selected populations.
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Affiliation(s)
- Filippo Papini
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Fondazione Pisana per la Scienza, Pisa, Italy
| | - Janani Sundaresan
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Alessandro Leonetti
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Marcello Tiseo
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Christian Rolfo
- The Center of Thoracic Oncology at the Tisch Cancer Institute, Mount Sinai, NYC, United States
| | - Godefridus J Peters
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Biochemistry, Medical University of Gdansk, Poland
| | - Elisa Giovannetti
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Fondazione Pisana per la Scienza, Pisa, Italy.
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Wang Q, Gao W, Gao F, Jin S, Qu T, Lin F, Zhang C, Zhang J, Zhang Z, Chen L, Guo R. Efficacy and acquired resistance of EGFR-TKI combined with chemotherapy as first-line treatment for Chinese patients with advanced non-small cell lung cancer in a real-world setting. BMC Cancer 2021; 21:602. [PMID: 34034713 PMCID: PMC8152122 DOI: 10.1186/s12885-021-08291-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 05/04/2021] [Indexed: 12/24/2022] Open
Abstract
Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting. Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity. Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.67–23.33] vs. 11.70 months [95% CI, 10.81–12.59], p < 0.001). Subgroup analysis showed a similar trend of results. The median OS was not reached in the combination group and was 38.50 (95% CI, 35.30–41.70) months in the EGFR-TKI monotherapy group (p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08291-9.
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Affiliation(s)
- Qianqian Wang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Wen Gao
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Fangyan Gao
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Shidai Jin
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Tianyu Qu
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Fan Lin
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, 101Longmian Avenue, Nanjing, 211166, Jiangning, China
| | - Chen Zhang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Jingya Zhang
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Zhihong Zhang
- Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China.
| | - Liang Chen
- Department of Thoracic and Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China.
| | - Renhua Guo
- Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, 300, Guangzhou Road, Nanjing, 210029, Jiangsu, China.
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Wu Q, Luo W, Li W, Wang T, Huang L, Xu F. First-Generation EGFR-TKI Plus Chemotherapy Versus EGFR-TKI Alone as First-Line Treatment in Advanced NSCLC With EGFR Activating Mutation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Oncol 2021; 11:598265. [PMID: 33928022 PMCID: PMC8076535 DOI: 10.3389/fonc.2021.598265] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 03/04/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE The aim of this meta-analysis was to evaluate efficacy and toxicity of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in combination with chemotherapy (CT) compared to EGFR-TKI monotherapy as first-line treatment in advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutation. METHODS A systematic literature search of randomized controlled trials using Cochrane Library, PubMed, Embase, and Web of Science, was performed up to Jan. 7th, 2020. Hazard ratios (HRs) with 95% confidence intervals (CI) were calculated as effect values for progress-free survival (PFS) and overall survival (OS). Risk ratio (RR) and Odds ratio (OR) were calculated as effect values for objective response rate (ORR) and toxicity, respectively. RESULTS A total of eight randomized trials involving 1,349 advanced NSCLC patients with sensitive EGFR mutation were included in the meta-analysis. All patients in both groups received first-generation TKI as first-line treatment. The pooled HR of PFS and OS was 0.56 (95% CI = 0.50-0.64; P <0.00001) and 0.70 (95% CI = 0.54-0.90; P = 0.005), respectively. Subgroup analysis showed significantly higher OS advantages in patients receiving doublet CT (P = 0.02) and concurrent therapy (P = 0.002). The ORR in the EGFR-TKI plus CT group was significantly higher than in the EGFR-TKI monotherapy group (RR = 1.18, 95% CI = 1.10-1.26). The combination regimen showed a higher incidence of chemotherapy-induced toxicities. Subgroup analysis indicated that doublet chemotherapy rather than single-agent chemotherapy significantly increased incidence of grade 3 or higher leukopenia, neutropenia and anemia. CONCLUSIONS Compared with EGFR-TKI monotherapy, the combination of first-generation EGFR-TKI and CT, especially when applying concurrent delivery of platinum-based doublet chemotherapeutic drugs, significantly improve ORR and prolong PFS and OS in first-line treatment for advanced EGFR-mutated NSCLC. Although increasing incidence of chemotherapy-induced toxicities occurs in the combination group, it is well tolerated and clinically manageable.
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Affiliation(s)
- Qiang Wu
- Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Wuxia Luo
- Department of Oncology, Chengdu First People’s Hospital, Chengdu, China
| | - Wen Li
- Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Wang
- Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Lin Huang
- Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Feng Xu
- Lung Cancer Center & Institute, West China Hospital, Sichuan University, Chengdu, China
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Takegahara K, Usuda J, Inoue T, Sonokawa T, Matsui T, Matsumoto M. Antiaging gene Klotho regulates epithelial-mesenchymal transition and increases sensitivity to pemetrexed by inducing lipocalin-2 expression. Oncol Lett 2021; 21:418. [PMID: 33841579 PMCID: PMC8020392 DOI: 10.3892/ol.2021.12679] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 11/11/2020] [Indexed: 12/17/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is considered to serve an important role in the metastatic/invasive ability of cancer cells, in the acquisition of drug resistance, and in metabolic reprogramming. In the present study, it was hypothesized that the Klotho gene is involved in the metastatic/invasive ability of lung cancer. We previously reported an association between Klotho expression and overall survival in patients with small cell lung cancer and large cell neuroendocrine cancer. We also found that Klotho expression was associated with EMT-related molecules in lung squamous cell carcinoma. The present study aimed to analyze the function of the Klotho gene and to elucidate its relevance to the regulation of the EMT. For this purpose, GFP-Klotho plasmids were transfected into lung adenocarcinoma cells (A549) and cell lines with stable expression (A549/KL-1 and A549/KL-2) were established. A549/KL-1 cells expressed higher levels of Klotho protein by western blot analysis compared with A549/KL-2 cells. In western blotting of A549 and A549/KL-1 cells, the expression of the mesenchymal marker N-cadherin was found to be completely inhibited in A549/KL-1 cells suggesting that Klotho expression may regulate the EMT in cancer cells via the inhibition of N-cadherin. The results of the sensitivity tests demonstrated that A549/KL-1 cells were significantly more sensitive to pemetrexed compared with A549 cells (IC50 A549/KL-1 vs. A549 cells, 0.1 µM vs. 0.7 µM). The results of the microarray analysis demonstrated that a very high level of lipocalin-2 (LCN2) expression was induced in the A549/KL-1 cells. Klotho overexpression completely suppressed the expression of mesenchymal markers, such as N-cadherin and Snail1 (Snail). The results of the present study suggested that there may be a new mechanism of action for the antitumor effects of pemetrexed, namely, LCN2-mediated modulation of N-cadherin expression. Klotho expression during cancer treatment has great potential as a predictor for efficacy of pemetrexed and as a factor in the selection of personalized medicine for postoperative adjuvant chemotherapy.
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Affiliation(s)
- Kyoshiro Takegahara
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Jitsuo Usuda
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Tatsuya Inoue
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Takumi Sonokawa
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Takuma Matsui
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
| | - Mitsuo Matsumoto
- Department of Thoracic Surgery, Nippon Medical School, Tokyo 113-8603, Japan
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Cheng F, Peng X, Meng G, Pu Y, Luo K, He B. Poly(ester-thioether) microspheres co-loaded with erlotinib and α-tocopheryl succinate for combinational therapy of non-small cell lung cancer. J Mater Chem B 2021; 8:1728-1738. [PMID: 32022097 DOI: 10.1039/c9tb02840d] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Polymer microspheres are attracting wide attention in localized cancer therapy owing to the excellent biocompatibility and drug loading capacity, controllable biodegradation speeds, and minimized systemic toxicity. Herein, we presented poly(ester-thioether) microspheres, porous and nonporous, as drug depots for localized therapy of non-small cell lung cancer (NSCLC). Specifically, erlotinib and α-tocopheryl succinate (α-TOS), which are respectively an epidermal growth factor receptor (EGFR) inhibitor and mitochondria destabilizer, were efficiently loaded into porous and nonporous poly(ester-thioether) microspheres for the treatment of EGFR-overexpressing NSCLC (A549 cells). The poly(ester-thioether) microspheres significantly improved the bioavailability of both erlotinib and α-TOS in comparison to the free drug combination, realizing synergistic inhibition of A549 cells both in vitro and in vivo. The porous microspheres displayed faster degradation and drug release than the nonporous counterpart, thereby showing better anticancer efficacy. Overall, our study reported a new anticancer strategy of erlotinib and α-TOS combination for therapy of NSCLC, and established that poly(ester-thioether) microspheres could be a robust and biodegradable reservoir for drug delivery and localized cancer therapy.
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Affiliation(s)
- Furong Cheng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China. and Center for Translational Medicine, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China
| | - Xinyu Peng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China.
| | - Guolong Meng
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China.
| | - Yuji Pu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China.
| | - Kui Luo
- Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bin He
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, China.
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Lou Y, Xu J, Zhang Y, Lu J, Chu T, Zhang X, Wang H, Zhong H, Zhang W, Han B. Chemotherapy Plus EGFR-TKI as First-Line Treatment Provides Better Survival for Advanced EGFR-Positive Lung Adenocarcinoma Patients: Updated Data and Exploratory In Vitro Study. Target Oncol 2020; 15:175-184. [PMID: 32170554 DOI: 10.1007/s11523-020-00708-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Previously, we demonstrated that treatment with gefitinib combined with pemetrexed plus carboplatin chemotherapy improved progression-free survival (PFS) compared to gefitinib or chemotherapy alone in lung adenocarcinoma patients with sensitizing EGFR mutations. OBJECTIVE In the present study, we updated the long-term overall survival (OS) of the combination therapy and the gefitinib groups. Furthermore, the possible mechanisms underlying the effects of combination therapy were investigated. PATIENTS AND METHODS Lung adenocarcinoma patients harboring sensitizing EGFR mutations received either gefitinib plus chemotherapy (n = 40) or gefitinib alone (n = 41), and long-term survival was assessed. The pharmacological interaction between gefitinib and pemetrexed was evaluated in the PC-9 lung adenocarcinoma cell line using a colorimetric assay for assessing cell metabolic activity (MTT assay). The influence of combined treatment with gefitinib plus pemetrexed on gene expression profiles and signaling pathways was investigated using microarrays and Ingenuity Pathway Analysis (IPA). RESULTS On the last day of follow-up (28 September 2018), 30 (75.0%) patients in the combination group and 35 (85.4%) patients in the gefitinib group had died. The 2-year and 3-year survival rates of the combination versus gefitinib were 85.0% versus 56.1% (P = 0.004) and 52.5% versus 24.4% (P = 0.009), respectively. The median OS was 37.9 months (95% CI: 17.3-58.6) for the combination group and 25.8 months (95% CI: 19.2-32.3) for the gefitinib group (HR = 0.56, 95% CI: 0.34-0.91, P = 0.02). A synergistic inhibitory effect between gefitinib and pemetrexed was observed in the lung adenocarcinoma cell line PC-9. Furthermore, widespread gene expression changes and critical signaling pathways such as AKT signaling were identified, which might be responsible for the synergism seen with the combination treatment. CONCLUSIONS Combined treatment with gefitinib plus pemetrexed resulted in improved OS over gefitinib alone. A synergistic inhibitory effect between gefitinib and pemetrexed was observed on lung adenocarcinoma cell growth. Gene expression profile analysis revealed potential signaling pathways, including AKT signaling, contributing to the synergism. CLINICAL TRIAL REGISTRATION NUMBER NCT02148380.
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Affiliation(s)
- Yuqing Lou
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Jianlin Xu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Yanwei Zhang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Jun Lu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Tianqing Chu
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Xueyan Zhang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Huimin Wang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Hua Zhong
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China
| | - Wei Zhang
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China.
| | - Baohui Han
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China.
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Van Der Steen N, Keller K, Dekker H, Porcelli L, Honeywell RJ, Van Meerloo J, Musters RJP, Kathmann I, Frampton AE, Liu DSK, Ruijtenbeek R, Rolfo C, Pauwels P, Giovannetti E, Peters GJ. Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function. J Cell Physiol 2020; 235:8085-8097. [PMID: 31960422 PMCID: PMC7540474 DOI: 10.1002/jcp.29463] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 12/23/2019] [Indexed: 12/15/2022]
Abstract
In non-small cell lung cancer, sensitizing mutations in epidermal growth factor receptor (EGFR) or cMET amplification serve as good biomarkers for targeted therapies against EGFR or cMET, respectively. Here we aimed to determine how this different genetic background would affect the interaction between the EGFR-inhibitor erlotinib and the cMET-inhibitor crizotinib. To unravel the mechanism of synergy we investigated the effect of the drugs on various parameters, including cell cycle arrest, migration, protein phosphorylation, kinase activity, the expression of drug efflux pumps, intracellular drug concentrations, and live-cell microscopy. We observed additive effects in EBC-1, H1975, and HCC827, and a strong synergism in the HCC827GR5 cell line. This cell line is a clone of the HCC827 cells that harbor an EGFR exon 19 deletion and has been made resistant to the EGFR-inhibitor gefitinib, resulting in cMET amplification. Remarkably, the intracellular concentration of crizotinib was significantly higher in HCC827GR5 compared to the parental HCC827 cell line. Furthermore, live-cell microscopy with a pH-sensitive probe showed a differential reaction of the pH in the cytoplasm and the lysosomes after drug treatment in the HCC827GR5 in comparison with the HCC827 cells. This change in pH could influence the process of lysosomal sequestration of drugs. These results led us to the conclusion that lysosomal sequestration is involved in the strong synergistic reaction of the HCC827GR5 cell line to crizotinib-erlotinib combination. This finding warrants future clinical studies to evaluate whether genetic background and lysosomal sequestration could guide tailored therapeutic interventions.
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Affiliation(s)
- Nele Van Der Steen
- Center for Oncological ResearchUniversity of AntwerpAntwerpBelgium
- Department of PathologyAntwerp University HospitalAntwerpBelgium
- Laboratory of Medical OncologyAmsterdam Universities Medical Centers, VUmcAmsterdamThe Netherlands
| | - Kaylee Keller
- Laboratory of Medical OncologyAmsterdam Universities Medical Centers, VUmcAmsterdamThe Netherlands
| | - Henk Dekker
- Laboratory of Medical OncologyAmsterdam Universities Medical Centers, VUmcAmsterdamThe Netherlands
| | - Letizia Porcelli
- Experimental Pharmacology LaboratoryIRCCS Istituto Tumori "Giovanni Paolo II"BariItaly
| | - Richard J. Honeywell
- Laboratory of Medical OncologyAmsterdam Universities Medical Centers, VUmcAmsterdamThe Netherlands
| | - Johan Van Meerloo
- Department of Pediatric Oncology/HematologyVUmcAmsterdamThe Netherlands
| | | | - Ietje Kathmann
- Laboratory of Medical OncologyAmsterdam Universities Medical Centers, VUmcAmsterdamThe Netherlands
| | - Adam E. Frampton
- Division of Cancer, Department of Surgery & CancerImperial CollegeLondonUnited Kingdom
- Department of Clinical & Experimental Medicine, Faculty of Health & Medical SciencesUniversity of SurreyGuildfordUnited Kingdom
| | - Daniel S. K. Liu
- Division of Cancer, Department of Surgery & CancerImperial CollegeLondonUnited Kingdom
| | - Rob Ruijtenbeek
- Pamgene International BVPamGene‘s‐HertogenboschThe Netherlands
| | - Christian Rolfo
- Center for Oncological ResearchUniversity of AntwerpAntwerpBelgium
- Phase I‐Early Clinical Trials Unit, Oncology DepartmentAntwerp University HospitalAntwerpBelgium
| | - Patrick Pauwels
- Center for Oncological ResearchUniversity of AntwerpAntwerpBelgium
- Department of PathologyAntwerp University HospitalAntwerpBelgium
| | - Elisa Giovannetti
- Laboratory of Medical OncologyAmsterdam Universities Medical Centers, VUmcAmsterdamThe Netherlands
- Cancer Pharmacology Lab, AIRC Start‐Up UnitFondazione Pisana per la ScienzaPisaItaly
| | - Godefridus J. Peters
- Laboratory of Medical OncologyAmsterdam Universities Medical Centers, VUmcAmsterdamThe Netherlands
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Nakahara Y, Shimokawa T, Misumi Y, Nogami N, Shinkai T, Seki N, Hosomi Y, Hida N, Okamoto H. Phase I/II study of erlotinib plus S-1 for patients with previously treated non-small cell lung cancer: Thoracic Oncology Research Group (TORG) 0808/0913. Invest New Drugs 2020; 39:202-209. [PMID: 32803700 PMCID: PMC7851018 DOI: 10.1007/s10637-020-00985-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 08/06/2020] [Indexed: 11/25/2022]
Abstract
Introduction In preclinical data, the combination therapy with S-1 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) had a synergistic antitumor effect on non-small cell lung cancer (NSCLC), regardless of the EGFR mutation status. Patients and Methods Patients with previously treated NSCLC and adequate organ function regardless of EGFR mutation status were eligible for the phase I study, with wild-type EGFR were eligible for the phase II study. Treatment consisted of erlotinib 150 mg/body orally once every day and S-1 60 mg/m2, 70 mg/m2, or 80 mg/m2 (level 0, level 1, or level 2) orally on days 1-14 every three weeks. The primary endpoint for the phase I study was the determination of the recommended dose (RD), the phase II study was the overall response rate (ORR). Results A total of 7 patients with performance-status (PS) 0 or 1 were enrolled as subjects in phase I. Five of these subjects were EGFR-mutation positive. Four subjects were enrolled at S-1 dose level 1 and 3 were enrolled at S-1 dose level 2. No dose-limiting toxicities were observed in these subjects. The RD was decided as erlotinib 150 mg/body and S-1 80 mg/m2. In phase I, 5 subjects achieved partial response, and the ORR was 71.4%. A total of 10 patients with PS 0, 1, or 2 EGFR-wild type NSCLC were enrolled in phase II. In phase II, the ORR was 10.0%, and the disease control rate (DCR) was 40.0%. After the enrollment of 10 subjects, enrollment was stopped based on two treatment-related deaths. Conclusion The combination therapy of erlotinib plus S-1 was not feasible in the EGFR wild-type NSCLC at least and early stopped. Trial registration: UMIN-CTR Identifier: 000003421 (2010/03/31, phase I), 000003422 (2010/03/31, Phase II).
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Affiliation(s)
- Yoshiro Nakahara
- Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan.
- Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
- Department of Thoracic Oncology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-ku, Yokohama, Kanagawa, 241-8515, Japan.
| | - Tsuneo Shimokawa
- Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama, Kanagawa, 240-8555, Japan
| | - Yuki Misumi
- Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama, Kanagawa, 240-8555, Japan
| | - Naoyuki Nogami
- Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou Minami-Umemoto, Matsuyama, Ehime, 791-0280, Japan
| | - Tetsu Shinkai
- Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou Minami-Umemoto, Matsuyama, Ehime, 791-0280, Japan
- Department of Medical Oncology, Shonan Eastern General Hospital, 500, Nishikubo, Chigasaki, Kanagawa, 253-0083, Japan
| | - Nobuhiko Seki
- Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo, 173-0014, Japan
| | - Yukio Hosomi
- Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan
| | - Naoya Hida
- Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama, Kanagawa, 240-8555, Japan
- Department of Respiratory Medicine, Yokohama-City Seibu Hospital of St. Marianna University School of Medicine, 1197-1, Yasashi-cho, Asahi-ku, Yokohama, Kanagawa, 241-0811, Japan
| | - Hiroaki Okamoto
- Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama, Kanagawa, 240-8555, Japan
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First-iGAP: A Randomized Placebo-Controlled Phase II Study of First-line Intercalated Gefitinib and Pemetrexed-Cisplatin Chemotherapy for Never-Smoker Lung Adenocarcinoma Patients. Clin Lung Cancer 2020; 21:e572-e582. [PMID: 32605893 DOI: 10.1016/j.cllc.2020.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/25/2020] [Accepted: 05/06/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND We aimed to evaluate whether intercalated combination of EGFR tyrosine kinase inhibitor gefitinib and chemotherapy improves survival outcomes in never-smokers with advanced lung adenocarcinoma. PATIENTS AND METHODS Never-smokers with chemo-naive stage IIIB/IV lung adenocarcinoma were randomly assigned to receive either gefitinib or placebo on days 5 to 18 of a 3-weekly cycle of pemetrexed and cisplatin. Chemotherapy was given up to 9 cycles, after which gefitinib or placebo was given daily. Patients in the placebo arm who had progression were crossed over to receive gefitinib. RESULTS Between June 2012 and December 2014, 76 patients with median age of 58.0 years were randomized, 39 on gefitinib and 37 on the placebo arm. EGFR mutation was positive in 34 (44.7%) patients. Baseline characteristics were well balanced between the 2 arms. The gefitinib arm had a better response rate (79.5% vs. 51.4%, P = .010) and median progression-free survival (PFS) (12.4 vs. 6.7 months, hazard ratio [HR] 0.49, P = .005) than the placebo arm; however, there was no statistically significant difference in median overall survival between the 2 arms (31.8 vs. 22.9 months, HR 0.78, P = .412). The PFS benefit of intercalated use of gefitinib over placebo was more apparent for patients with EGFR-mutant tumors (13.3 vs. 7.8 months, P = .025) than those with EGFR-wild-type tumors (8.2 vs. 6.6 months, P = .063). Overall, there was no difference in the frequency of severe adverse effect between the 2 arms. CONCLUSIONS Intercalated combination of gefitinib with pemetrexed and cisplatin was well tolerated and improved PFS in never-smoker patients with lung adenocarcinoma.
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Scodes S, Cappuzzo F. Determining the appropriate treatment for different EGFR mutations in non-small cell lung cancer patients. Expert Rev Respir Med 2020; 14:565-576. [PMID: 32233809 DOI: 10.1080/17476348.2020.1746646] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Epidermal growth factor receptor (EGFR) mutations occur in a significant fraction of non-small cell lung cancer (NSCLC) patients. Most common activating mutations are in-frame deletion in exon 19 and point mutation in exon 21. EGFR tyrosine kinase inhibitors (TKIs) represent standard of care of EGFR mutated patients bearing common mutations. Therapy for individuals carrying uncommon mutations, such as G719X, L861Q, S768I, is less defined and few options exist for individuals harboring EGFR exon 20 mutations. In all mutated patients, drug resistance remains the most critical clinical problem and new agents and strategies are under investigation.Areas covered: We have reviewed the current status of NSCLC EGFR mutated treatment by analyzing data from preclinical studies, clinical prospective and retrospective trials in order to analyze current and future options for patients harboring different EGFR mutations.Expert opinion: At the present time, available data demonstrated that osimertinib is the best EGFR-TKI for front-line therapy. Other agents, such as dacomitinib, and new drug combinations, such as regimens including anti-angiogenic agents or chemotherapy, demonstrated to significantly prolong progression-free survival or overall survival, representing potential alternative to osimertinib. Many questions remain opened, including best drug sequencing and needing of new therapeutic approaches extending patient survival and cure rate.
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Affiliation(s)
- Simona Scodes
- Department of Oncology and Hematology, AUSL Romagna, Ravenna, Italy
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Yang JCH, Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, Kim JH, Hozak RR, Nguyen TS, Zhang WL, Enatsu S, Puri T, Orlando M. A Randomized Phase 2 Study of Gefitinib With or Without Pemetrexed as First-line Treatment in Nonsquamous NSCLC With EGFR Mutation: Final Overall Survival and Biomarker Analysis. J Thorac Oncol 2020; 15:91-100. [DOI: 10.1016/j.jtho.2019.09.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/17/2019] [Accepted: 09/18/2019] [Indexed: 01/13/2023]
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Rebuzzi SE, Alfieri R, La Monica S, Minari R, Petronini PG, Tiseo M. Combination of EGFR-TKIs and chemotherapy in advanced EGFR mutated NSCLC: Review of the literature and future perspectives. Crit Rev Oncol Hematol 2019; 146:102820. [PMID: 31785991 DOI: 10.1016/j.critrevonc.2019.102820] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/11/2019] [Accepted: 10/13/2019] [Indexed: 12/18/2022] Open
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improved clinical outcome compared to chemotherapy in EGFR mutated advanced non-small cell lung cancer (NSCLC) patients. Nonetheless, acquired resistance develops within 10-14 months and 20-30% of EGFR-mutated patients do not respond to EGFR-TKI. In order to delay or overcome acquired resistance to EGFR-TKIs, combination therapies of EGFR-TKIs with chemotherapy has been investigated with conflicting results. Early studies failed to show a survival benefit because of a lack of patient selection, but more recently clinical studies in EGFR mutated patients have shown promising results. This review summarizes preclinical and clinical studies of combination of EGFR-TKIs, including the third-generation TKI osimertinib, with chemotherapy in first- and second-line settings, using concurrent or intercalated treatment strategies. In the new era of third-generation EGFR-TKIs, new studies of this combination strategy are warranted.
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Affiliation(s)
- Sara Elena Rebuzzi
- Medical Oncology, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy; Medical Oncology Unit 1, Ospedale Policlinico San Martino IST, University of Genova, Largo Rosanna Benzi 10, 16143, Genova, Italy.
| | - Roberta Alfieri
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126, Parma, Italy.
| | - Silvia La Monica
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126, Parma, Italy.
| | - Roberta Minari
- Medical Oncology, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy.
| | - Pier Giorgio Petronini
- Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126, Parma, Italy.
| | - Marcello Tiseo
- Medical Oncology, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy; Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126, Parma, Italy.
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Yue-Yun C, Ye H, Yang F, Qing L, Pan-Pan L, Zhen-Yu D. Sequential Administration of EGFR-TKI and Pemetrexed Achieved a Long Duration of Response in Advanced NSCLC Patients with EGFR-mutant Tumours. Asian Pac J Cancer Prev 2019; 20:2415-2420. [PMID: 31450915 PMCID: PMC6852816 DOI: 10.31557/apjcp.2019.20.8.2415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Indexed: 02/05/2023] Open
Abstract
Objectives: The optimal combination of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
(TKIs) and chemotherapy has helped to improve therapeutic effects in non-small-cell lung cancer (NSCLC). This study
aimed to explore the progression free survival (PFS) of patients after sequential administration of TKI and pemetrexed
chemotherapy. Methods: This study retrospectively screened treatment-naive advanced NSCLC patients harbouring
EGFR mutations who were prescribed a TKI and salvaged with pemetrexed chemotherapy or vice versa. The total,
initial and salvage PFS were collected. Results: The total PFS including both the initial and salvage PFS was 18.0 mon
(95% CI: 14.1–21.9 mon), which was not influenced by the sequence of administration (TKI first: 18.0 mon, 95% CI:
15.8–20.2 mon, pemetrexed first: 16.1 mon, 95% CI: 9.1–23.1 mon, HR 0.92, P=0.748). A longer PFS was achieved
for TKI over chemotherapy in both the initial (10.6 and 5.9 mon, HR 2.62, P=0.001) and salvage therapy (12.0 and 6.0
mon, HR 1.29, P=0.001). TKI remained effective either before (10.6 mon) or after (12.0 mon) chemotherapy (HR 0.96,
P=0.853). The same trend was observed for chemotherapy (5.9 and 6.0 mon for initial and salvage therapy, respectively,
HR 0.82, P=0.417). Conclusions: The sequential administration of TKI and pemetrexed chemotherapy achieved a long
PFS and was a suitable treatment for advanced NSCLC.
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Affiliation(s)
- Chen Yue-Yun
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Hong Ye
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Fu Yang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Li Qing
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Lin Pan-Pan
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Ding Zhen-Yu
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
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La Monica S, Minari R, Cretella D, Flammini L, Fumarola C, Bonelli M, Cavazzoni A, Digiacomo G, Galetti M, Madeddu D, Falco A, Lagrasta CA, Squadrilli A, Barocelli E, Romanel A, Quaini F, Petronini PG, Tiseo M, Alfieri R. Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC. J Exp Clin Cancer Res 2019; 38:222. [PMID: 31138260 PMCID: PMC6537372 DOI: 10.1186/s13046-019-1240-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 05/21/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The third generation Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) osimertinib has been initially approved for T790M positive Non-Small Cell Lung Cancer (NSCLC) and more recently for first-line treatment of EGFR-mutant T790M negative NSCLC patients. Similarly to previous generation TKIs, despite the high response rate, disease progression eventually occurs and current clinical research is focused on novel strategies to delay the emergence of osimertinib resistance. In this study we investigated the combination of osimertinib with pemetrexed or cisplatin in EGFR-mutated NSCLC cell lines and xenografts. METHODS Tumor growth was evaluated in a PC9T790M xenograft model and tissue composition was morphometrically determined. PC9, PC9T790M and HCC827 cell lines were employed to test the efficacy of osimertinib and chemotherapy combination in vitro. Cell viability and cell death were evaluated by MTT assay and fluorescence microscopy. Protein expression and gene status were analysed by Western blotting, fluorescence in situ hybridization analysis, next-generation sequencing and digital droplet PCR. RESULTS In xenograft models, osimertinib significantly inhibited tumor growth, however, as expected, in 50% of mice drug-resistance developed. A combination of osimertinib with pemetrexed or cisplatin prevented or at least delayed the onset of resistance. Interestingly, such combinations increased the fraction of fibrotic tissue and exerted a long-lasting activity after stopping therapy. In vitro studies demonstrated the stronger efficacy of the combination over the single treatments in inhibiting cell proliferation and inducing cell death in PC9T790M cells as well as in T790M negative PC9 and HCC827 cell lines, suggesting the potential role of this strategy also as first-line treatment. Finally, we demonstrated that osimertinib resistant clones, either derived from resistant tumors or generated in vitro, were less sensitive to pemetrexed prompting to use a chemotherapy regimen non-containing pemetrexed in patients after progression to osimertinib treatment. CONCLUSIONS Our results identify a combination between osimertinib and pemetrexed or cisplatin potentially useful in the treatment of EGFR-mutated NSCLC patients, which might delay the appearance of osimertinib resistance with long-lasting effects.
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Affiliation(s)
- Silvia La Monica
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Roberta Minari
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Daniele Cretella
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Lisa Flammini
- Food and Drug Department, University of Parma, Parma, Italy
| | - Claudia Fumarola
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Mara Bonelli
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Andrea Cavazzoni
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | - Maricla Galetti
- Italian Workers’ Compensation Authority (INAIL) Research Center, Parma, Italy
- Center of Excellence for Toxicological Research (CERT), University of Parma, Parma, Italy
| | - Denise Madeddu
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Angela Falco
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | - Anna Squadrilli
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | - Alessandro Romanel
- Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy
| | - Federico Quaini
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | - Marcello Tiseo
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Roberta Alfieri
- Department of Medicine and Surgery, University of Parma, Parma, Italy
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Massoud MA, El-Sayed MA, Bayoumi WA, Mansour B. Cytotoxicity and Molecular Targeting Study of Novel 2-Chloro-3- substituted Quinoline Derivatives as Antitumor Agents. LETT DRUG DES DISCOV 2019. [DOI: 10.2174/1570180815666180604090924] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background: Quinoline scaffold acts as “privileged structure” for anticancer drug design. Certain derivatives showed good results through different mechanisms as topoisomerase 1 and kinase inhibition. </P><P> Methods: A new series of 2-chloro-3-(2-amino-3-cyano-4H-chromene, 4H-pyranyl and fused 1- cyclohexen-4-yl)quinoline structures (3-5, 6 and 7) were designed, synthesized, and evaluated for their in vitro antitumor activity. All compounds were tested by MTT assay against a panel of four different human tumor cell lines. The inhibitory activity of selected compounds was assessed on topoisomerase 1 and epidermal growth factor receptor tyrosine kinase via ELISA. In addition, compounds 7b and 3a were docked into the X-ray crystal structure of Topo 1 and EGFR enzymes, respectively to explain the molecular basis of the potent activity. </P><P> Results: Compounds 3a, 3b and 7b showed characteristic efficacy profile. 7b showed the best cytotoxic activity on all types of tested cell lines with IC50 range (15.8±1.30 to 28.2±3.37 µM), relative to 5-fluoruracil of IC50 range (40.7±2.46 to 63.8±2.69 µM). Via ELISA, 7b and 3a showed characteristic inhibition profile on Topo 1 and EGFR-TK respectively. In addition, 7b has scored binding energy (101.61 kcal/mol) and six hydrogen bonds with amino acids conserved residues in the enzyme pocket. </P><P> Conclusion: Analysis of results revealed that compounds 7a and 7b mainly were Topo 1 inhibitors while 3a was mainly EGFR inhibitor. This property may be exploited to design future quinoline derivatives as antitumor agents with enhanced selectivity towards either of the two molecular targets.
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Affiliation(s)
- Mohammed A.M. Massoud
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt
| | - Magda A. El-Sayed
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt
| | - Waleed A. Bayoumi
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt
| | - Basem Mansour
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa City, Mansoura, Egypt
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Lim SW, Lee S, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK, Kim ST. Pemetrexed Monotherapy as Salvage Treatment in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapy: A Phase II Single-arm Prospective Trial. J Cancer 2018; 9:2910-2915. [PMID: 30123359 PMCID: PMC6096381 DOI: 10.7150/jca.24948] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 06/09/2018] [Indexed: 12/12/2022] Open
Abstract
Background: We designed a single-arm, open-label phase II study to determine the efficacy and toxicity of pemetrexed monotherapy with vitamin supplementation in patients with refractory colorectal cancer (CRC) that failed to respond to standard treatments including 5-fluorouracil, oxaliplatin, and irinotecan with or without biologic agents. Methods: Patients were treated with pemetrexed 500 mg/m2 on day 1 every 3 weeks, with folic acid and vitamin B12 supplementation. Treatment was continued until disease progression or intolerable toxicity. Between June 2016 and October 2016, 24 patients were enrolled in this study. Results: One patient withdrew consent, leaving a total of 23 patients for evaluation. The median age of the patients was 54.0 years (range, 23.0 to 67.0), and the median ECOG performance status was 1 (1-2). The median number of previous systemic chemotherapies was 3 (range, 2 to 5). There was no patient with complete response (CR) or partial response (PR). However, stable disease was observed in 10 patients (43.4%) and maintained more than 6 months in 7 of 10 patients. The median progression-free survival was 1.6 months (95% CI, 1.1-2.0) and the median overall survival was 9.8 months (95% CI, 5.9-13.6). Grade 3 treatment-related adverse events occurred in one patient with elevated liver enzymes and hematologic adverse event of grade 2 anemia was observed in one patient. There were no cases of dose reduction or treatment-related deaths and all toxicities were manageable. Conclusions: Pemetrexed monotherapy showed moderate disease control and acceptable toxicity profile as salvage therapy for refractory CRC.
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Affiliation(s)
- Sung Won Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Sujin Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
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Cui J, Zhang Y, Su D, Li T, Li Y. Efficacy of combined icotinib and pemetrexed in EGFR mutant lung adenocarcinoma cell line xenografts. Thorac Cancer 2018; 9:1156-1165. [PMID: 30047610 PMCID: PMC6119608 DOI: 10.1111/1759-7714.12818] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 06/21/2018] [Accepted: 06/21/2018] [Indexed: 12/31/2022] Open
Abstract
Background The combination of EGFR tyrosine kinase inhibitors (TKIs) and chemotherapy is thought to increase treatment efficacy in non‐small‐cell lung cancer (NSCLC). This study investigated the efficacy and potential mechanisms of different combined modes of icotinib plus pemetrexed in EGFR‐mutant lung adenocarcinoma cell line xenograft models. Methods Nude mice were subcutaneously injected with EGFR‐mutant human lung adenocarcinoma cells (HCC827) and randomized into six treatment groups. Tumor xenograft volumes were monitored and recorded. Microvessel density (MVD) and proliferation and apoptosis rates were evaluated with CD34 positive cell counting, and Ki‐67 and caspase‐3 scores, respectively, and determined via immunohistochemistry. Thymidylate synthase (TS), EGFR, and downstream signaling molecule expression was detected by Western blotting. Results The volume and weight of tumor xenografts in the sequential pemetrexed followed by icotinib (Pem‐Ico) group and the concurrent icotinib and pemetrexed (Ico + Pem) group were significantly smaller than those in the control, pemetrexed (Pem), icotinib (Ico), and sequential icotinib followed by pemetrexed (Ico‐Pem) groups. Compared to other groups, a decrease in the MVD and proliferation rate and an increase in the apoptosis rate were observed in the Pem‐Ico and Ico + Pem groups. TS expression and EGFR, AKT, and MAPK phosphorylation were significantly reduced in the Pem‐Ico or Ico + Pem groups. Conclusions Pem‐Ico had additive antitumor activity in vivo, similar to Ico + Pem, both of which are suggested as potentially optimized strategies for treating EGFR‐mutant lung adenocarcinoma.
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Affiliation(s)
- Jiadong Cui
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, China.,Department of Respiratory Medicine, Dong'e County People's Hospital, Liaocheng, China
| | - Yan Zhang
- Department of Respiratory Medicine, Jinan No. 4 People's Hospital, Jinan, China
| | - Di Su
- Department of Respiratory Medicine, Dong'e County People's Hospital, Liaocheng, China
| | - Tao Li
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Yu Li
- Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, China
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Tanino R, Tsubata Y, Harashima N, Harada M, Isobe T. Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer. Oncotarget 2018; 9:16807-16821. [PMID: 29682186 PMCID: PMC5908287 DOI: 10.18632/oncotarget.24704] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 03/01/2018] [Indexed: 12/11/2022] Open
Abstract
Pemetrexed (PEM) improves the overall survival of patients with advanced non-small cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 (SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosine-kinase-inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.
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Affiliation(s)
- Ryosuke Tanino
- Division of Medical Oncology & Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Yukari Tsubata
- Division of Medical Oncology & Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Nanae Harashima
- Laboratory of Biometabolic Chemistry, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Mamoru Harada
- Department of Immunology, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Takeshi Isobe
- Division of Medical Oncology & Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan
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Iwama E, Nakanishi Y, Okamoto I. Combined therapy with epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer. Expert Rev Anticancer Ther 2018; 18:267-276. [PMID: 29363369 DOI: 10.1080/14737140.2018.1432356] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have a pronounced clinical benefit for patients with advanced non-small cell lung cancer (NSCLC) positive for EGFR activating mutations. Such individuals inevitably develop resistance to these drugs, however, new treatment strategies to overcome such resistance are being actively pursued. The clinical benefit of EGFR-TKIs for patients with locally advanced NSCLC remains to be clarified. Areas covered: This review summarizes the recent progress in combination treatment with EGFR-TKIs and either chemotherapy or radiotherapy for patients with NSCLC positive for EGFR activating mutations. Expert commentary: Combination therapy with EGFR-TKIs and various other treatment options are under investigation in clinical studies. Although early studies failed to show a clinical benefit for such combination therapy because of a lack of patient selection, clinical studies with patient selection based on EGFR mutation status have shown promising results. Such combination therapy might eventually replace the current standard treatment for patients with NSCLC positive for EGFR activating mutations.
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Affiliation(s)
- Eiji Iwama
- a Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences , Kyushu University , Fukuoka , Japan.,b Research Institute for Diseases of the Chest, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Yoichi Nakanishi
- b Research Institute for Diseases of the Chest, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Isamu Okamoto
- b Research Institute for Diseases of the Chest, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
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27
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Zhang M, Guo H, Zhao S, Wang Y, Yang M, Yu J, Yan Y, Wang Y. Efficacy of epidermal growth factor receptor inhibitors in combination with chemotherapy in advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. Oncotarget 2018; 7:39823-39833. [PMID: 27223081 PMCID: PMC5129973 DOI: 10.18632/oncotarget.9503] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 04/16/2016] [Indexed: 12/18/2022] Open
Abstract
The role of a combination of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy for non-small-cell lung cancer (NSCLC) has not been well established. To clarify this problem, we performed a meta-analysis with 15 studies identified from PubMed, EMBASE and the Cochrane Library. We found that the combined regimen had a significant benefit on progression-free survival (PFS) (hazard ratio (HR) = 0.80; 95% CI = 0.71–0.90; P < 0.001) and the objective response rate (ORR) (RR = 1.35; 95% CI = 1.14–1.59; P < 0.001). However, the combined regimen had no significant impact on overall survival (OS) (HR = 0.96; 95% CI = 0.90–1.03; P = 0.25). Subgroup analysis showed significantly higher OS advantages in EGFR mutation positive patients (P = 0.01), never smokers (P = 0.01), Asian patients (P = 0.02), patients receiving second-line treatment (P < 0.001), and those receiving a sequential combination of EGFR-TKIs and chemotherapy (P = 0.005). The combination regimen showed a higher incidence of grade 3–4 toxicities (leucopenia, neutropenia, febrile neutropenia, anemia, rash, fatigue and diarrhea). In summary, the combination of EGFR-TKIs plus chemotherapy in advanced NSCLC achieved a significantly longer PFS and a higher ORR but not longer OS. Well-designed prospective studies are needed to confirm these findings.
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Affiliation(s)
- Minghui Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Hongsheng Guo
- Department of Medical Oncology, Tianjin Third Central Hospital, Tianjin, 300170, China
| | - Shu Zhao
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yan Wang
- Department of Medical Oncology, Heilongjiang Provincial Hospital, Harbin, 150000, China
| | - Maopeng Yang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Jiawei Yu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yubo Yan
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yan Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
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Wang S, Gao A, Liu J, Sun Y. First-line therapy for advanced non-small cell lung cancer with activating EGFR mutation: is combined EGFR-TKIs and chemotherapy a better choice? Cancer Chemother Pharmacol 2018; 81:443-453. [PMID: 29327274 DOI: 10.1007/s00280-017-3516-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 12/29/2017] [Indexed: 10/18/2022]
Abstract
As the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the median progression-free survival (PFS) up to 18.9 months. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, which limits the first-line PFS. To overcome the resistance and improve overall survival, researchers have tried to identify the resistance mechanisms and develop new treatment strategies, among which a combination of EGFR-TKIs and cytotoxic chemotherapy is one of the hotspots. The data from preclinical and clinical studies on combined EGFR-TKIs and chemotherapy have shown very interesting results. Here, we reviewed the available preclinical and clinical studies on first-line EGFR-TKIs-chemotherapy combination in patients with advanced NSCLC harboring activating EGFR mutation, aiming to provide evidences for more potential choices and shed light on clinical treatment.
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Affiliation(s)
- Shuyun Wang
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, 105 Jiefang Road, Jinan, Shandong, People's Republic of China
| | - Aiqin Gao
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, 105 Jiefang Road, Jinan, Shandong, People's Republic of China
| | - Jie Liu
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, 105 Jiefang Road, Jinan, Shandong, People's Republic of China
| | - Yuping Sun
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, 105 Jiefang Road, Jinan, Shandong, People's Republic of China.
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Differential efficacy of cisplatin plus pemetrexed between L858R and Del-19 in advanced EGFR-mutant non-squamous non-small cell lung cancer. BMC Cancer 2018; 18:6. [PMID: 29291705 PMCID: PMC5749021 DOI: 10.1186/s12885-017-3952-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 12/21/2017] [Indexed: 12/12/2022] Open
Abstract
Background LUX-Lung 3 showed afatinib improved progression-free survival (PFS) compared with cisplatin plus pemetrexed in patients with epidermal growth factor receptor (EGFR) mutations. In this study, chemotherapy efficacy tended to differ between patients with Leu858Arg (L858R) point mutation and Exon 19 deletion (Del-19); PFS in L858R patients (8.1 months) was greater than in Del-19 patients (5.6 months). We investigated whether there is any difference in efficacy of cisplatin plus pemetrexed between Del-19 and L858R. Methods This study is a multicenter retrospective study. We reviewed medical records of patients who had received cisplatin plus pemetrexed as first line chemotherapy. Efficacies were evaluated between EGFR mutation status: Del-19 and L858R. Wild type cases were reference arm only, and not included in any statistical analysis. Results Among 304 patients, 78 (25.7%) harbored EGFR mutations: Del-19 (36/78 patients, 46.2%); and L858R (42/78, 53.8%). Median PFS of L858R group (9.4 months, 95% confidence interval [CI]: 7.0–12.6) was significantly longer than Del-19 group (5.5 months, 95% CI, 3.6–8.6) (p = 0.049). Response rate (RR) and OS presented no significant difference between L858R and Del-19. In multivariate analysis, EGFR mutation status (L858R versus Del-19) was the only significant factor for longer PFS (Hazard ratio [HR]: 0.78, 95% CI: 0.62–0.98) (p = 0.033). Conclusion Our study indicated better efficacy of cisplatin plus pemetrexed in L858R than in Del-19 patients. In EGFR-mutant NSCLC, EGFR-TKIs are undoubtedly the premier therapy. However, in second line or later settings, cisplatin plus pemetrexed regimen may confer higher efficacy for L858R patients.
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Siddiqui A, Vazakidou ME, Schwab A, Napoli F, Fernandez-Molina C, Rapa I, Stemmler MP, Volante M, Brabletz T, Ceppi P. Thymidylate synthase is functionally associated with ZEB1 and contributes to the epithelial-to-mesenchymal transition of cancer cells. J Pathol 2017; 242:221-233. [PMID: 28337746 DOI: 10.1002/path.4897] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 02/28/2017] [Accepted: 03/09/2017] [Indexed: 01/26/2023]
Abstract
Thymidylate synthase (TS) is a fundamental enzyme of nucleotide metabolism and one of the oldest anti-cancer targets. Beginning from the analysis of gene array data from the NCI-60 panel of cancer cell lines, we identified a significant correlation at both gene and protein level between TS and the markers of epithelial-to-mesenchymal transition (EMT), a developmental process that allows cancer cells to acquire features of aggressiveness, like motility and chemoresistance. TS levels were found to be significantly augmented in mesenchymal-like compared to epithelial-like cancer cells, to be regulated by EMT induction, and to negatively correlate with micro-RNAs (miRNAs) usually expressed in epithelial-like cells and known to actively suppress EMT. Transfection of EMT-suppressing miRNAs reduced TS levels, and a specific role for miR-375 in targeting the TS 3'-untranslated region was identified. A particularly relevant association was found between TS and the powerful EMT driver ZEB1, the shRNA-mediated knockdown of which up-regulated miR-375 and reduced TS cellular levels. The TS-ZEB1 association was confirmed in clinical specimens from lung tumours and in a genetic mouse model of pancreatic cancer with ZEB1 deletion. Interestingly, TS itself appeared to have a regulatory role in EMT in cancer cells, as TS knockdown could directly reduce the EMT phenotype, the migratory ability of cells, the expression of stem-like markers, and chemoresistance. Taken together, these data indicate that the TS enzyme is functionally linked with EMT and cancer differentiation, with several potential translational implications. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Aarif Siddiqui
- Junior Research Group 1, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Maria Eleni Vazakidou
- Junior Research Group 1, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Annemarie Schwab
- Junior Research Group 1, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Francesca Napoli
- Junior Research Group 1, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Cristina Fernandez-Molina
- Junior Research Group 1, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Ida Rapa
- Pathology Unit, San Luigi Hospital, University of Turin, Turin, Italy
| | - Marc P Stemmler
- Experimental Medicine I, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Marco Volante
- Pathology Unit, San Luigi Hospital, University of Turin, Turin, Italy
| | - Thomas Brabletz
- Experimental Medicine I, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Paolo Ceppi
- Junior Research Group 1, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
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Salinomycin acts through reducing AKT-dependent thymidylate synthase expression to enhance erlotinib-induced cytotoxicity in human lung cancer cells. Exp Cell Res 2017; 357:59-66. [DOI: 10.1016/j.yexcr.2017.04.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 04/12/2017] [Accepted: 04/18/2017] [Indexed: 01/08/2023]
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Yang JCH, Mok T, Han B, Orlando M, Puri T, Park K. A Review of Regimens Combining Pemetrexed With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in the Treatment of Advanced Nonsquamous Non-Small-Cell Lung Cancer. Clin Lung Cancer 2017; 19:27-34. [PMID: 28743421 DOI: 10.1016/j.cllc.2017.06.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 06/26/2017] [Accepted: 06/27/2017] [Indexed: 11/27/2022]
Abstract
Pemetrexed is a standard first-line treatment for advanced nonsquamous non-small-cell lung cancer (NSCLC), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard first-line treatment for advanced nonsquamous NSCLC with activating EGFR mutations. Pemetrexed and EGFR TKIs have different mechanisms of action and minimally overlapping toxicity profiles; therefore, it is hypothesized that their combination might result in acceptable toxicity, provided that the synergistic antitumor activity observed in preclinical studies is achieved. This review summarizes clinical trials of pemetrexed in combination with an EGFR TKI for the treatment of advanced nonsquamous NSCLC in the first- and second-line settings, using intercalated, sequential, and concurrent treatment strategies. As would be expected, such strategies were most efficacious in patients with the activating EGFR mutations associated with response to an EGFR TKI. In the studies that compared a pemetrexed-EGFR TKI combination with pemetrexed alone or the EGFR TKI alone, the pemetrexed-EGFR TKI combination was more efficacious than the single-agent regimens. The pemetrexed-EGFR TKI combinations were generally associated with a higher incidence of grade 3/4 treatment-related adverse events than the single-agent regimens; however, such toxicities were clinically manageable. Future studies of pemetrexed-EGFR TKI combinations should focus on optimizing treatment strategies in patients with activating EGFR mutations.
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Affiliation(s)
| | - Tony Mok
- Department of Clinical Oncology, Prince of Wales Hospital, Sha Tin, Hong Kong
| | - Baohui Han
- Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Mauro Orlando
- Eli Lilly Interamerica, Inc, Buenos Aires, Argentina
| | - Tarun Puri
- Eli Lilly and Company (India) Pvt Ltd, Gurgaon, India
| | - Keunchil Park
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Yang H, Deng Q, Qiu Y, Huang J, Guan Y, Wang F, Xu X, Yang X. Erlotinib intercalating pemetrexed/cisplatin versus erlotinib alone in Chinese patients with brain metastases from lung adenocarcinoma: a prospective, non-randomised, concurrent controlled trial (NCT01578668). ESMO Open 2017; 2:e000112. [PMID: 29147576 PMCID: PMC5682358 DOI: 10.1136/esmoopen-2016-000112] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 12/09/2016] [Indexed: 11/04/2022] Open
Abstract
Objective Erlotinib has a synergistic effect with pemetrexed for treating non-squamous non-small-cell lung cancer. We investigated the efficacy and safety of erlotinib (E) in combination with pemetrexed/cisplatin (E-P) in Chinese patients with lung adenocarcinoma with brain metastases. Design Patients who were erlotinib-naïve or pemetrexed-naïve were assigned in parallel to receive either E or E-P. The primary endpoint was the intracranial overall response rate (ORRi). Results Sixty-nine patients with lung adenocarcinoma with brain metastases received E (n=35) or E-P (n=34) from January 2012 to November 2014. Demographics and patient characteristics were well balanced between the two groups, including epidermal growth factor receptor (EGFR) status, sex, age, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, brain metastases and number of prior treatments. ORRi in the E-P arm was superior to that in the E arm (79% vs 48%, p=0.008). Compared with E as the first-line treatment, E-P was associated with better intracranial progression-free survival (PFSi, median: 9 vs 2 months, p=0.027) and systemic PFS (median: 8 vs 2 months, p=0.006). The most frequent E-related adverse events were higher in the combination arm. No new safety signals were detected. The side effects were tolerable, and there were no drug-related deaths. Conclusion Our study suggests that the E-P combination may be effective in Chinese patients with lung adenocarcinoma with brain metastases, with improved PFS in treatment-naïve patients. Toxicities are tolerable, and there are more E-related side effects.
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Affiliation(s)
- Haihong Yang
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; State Key Laboratory of Respiratory Diseases, Guangzhou, China.
| | - Qiuhua Deng
- The Center for Translational Medicine, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yuan Qiu
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; State Key Laboratory of Respiratory Diseases, Guangzhou, China
| | - Jun Huang
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; State Key Laboratory of Respiratory Diseases, Guangzhou, China
| | - Yubao Guan
- Department of Radiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Fengnan Wang
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; State Key Laboratory of Respiratory Diseases, Guangzhou, China
| | - Xin Xu
- Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; State Key Laboratory of Respiratory Diseases, Guangzhou, China
| | - Xinyun Yang
- Department of Pharmacy, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Yang JCH, Puri T, Orlando M, Cheng Y. Reply to A. Ota et al, Y.H. Kim, and N. Van Der Steen et al. J Clin Oncol 2017; 35:694-695. [PMID: 27918723 DOI: 10.1200/jco.2016.70.6978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- James Chih-Hsin Yang
- James Chih-Hsin Yang, National Taiwan University Hospital, Taipei, Taiwan; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina; and Ying Cheng, Jilin Provincial Cancer Hospital, Changchun, China
| | - Tarun Puri
- James Chih-Hsin Yang, National Taiwan University Hospital, Taipei, Taiwan; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina; and Ying Cheng, Jilin Provincial Cancer Hospital, Changchun, China
| | - Mauro Orlando
- James Chih-Hsin Yang, National Taiwan University Hospital, Taipei, Taiwan; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina; and Ying Cheng, Jilin Provincial Cancer Hospital, Changchun, China
| | - Ying Cheng
- James Chih-Hsin Yang, National Taiwan University Hospital, Taipei, Taiwan; Tarun Puri, Eli Lilly, Gurgaon, Haryana, India; Mauro Orlando, Eli Lilly Interamérica, Buenos Aires, Argentina; and Ying Cheng, Jilin Provincial Cancer Hospital, Changchun, China
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Van Der Steen N, Rolfo CD, Pauwels P, Peters GJ, Giovannetti E. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Chemotherapy: A Glimmer of Hope? J Clin Oncol 2017; 35:692-693. [PMID: 27918717 DOI: 10.1200/jco.2016.70.1987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Nele Van Der Steen
- Nele Van Der Steen, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; and VU Medical Center, Amsterdam, the Netherlands; Christian Diego Rolfo and Patrick Pauwels, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; Godefridus J. Peters, VU Medical Center, Amsterdam, the Netherlands; and Elisa Giovannetti, VU Medical Center, Amsterdam, The Netherlands; and University of Pisa, Pisa, Italy
| | - Christian Diego Rolfo
- Nele Van Der Steen, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; and VU Medical Center, Amsterdam, the Netherlands; Christian Diego Rolfo and Patrick Pauwels, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; Godefridus J. Peters, VU Medical Center, Amsterdam, the Netherlands; and Elisa Giovannetti, VU Medical Center, Amsterdam, The Netherlands; and University of Pisa, Pisa, Italy
| | - Patrick Pauwels
- Nele Van Der Steen, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; and VU Medical Center, Amsterdam, the Netherlands; Christian Diego Rolfo and Patrick Pauwels, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; Godefridus J. Peters, VU Medical Center, Amsterdam, the Netherlands; and Elisa Giovannetti, VU Medical Center, Amsterdam, The Netherlands; and University of Pisa, Pisa, Italy
| | - Godefridus J Peters
- Nele Van Der Steen, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; and VU Medical Center, Amsterdam, the Netherlands; Christian Diego Rolfo and Patrick Pauwels, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; Godefridus J. Peters, VU Medical Center, Amsterdam, the Netherlands; and Elisa Giovannetti, VU Medical Center, Amsterdam, The Netherlands; and University of Pisa, Pisa, Italy
| | - Elisa Giovannetti
- Nele Van Der Steen, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; and VU Medical Center, Amsterdam, the Netherlands; Christian Diego Rolfo and Patrick Pauwels, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; Godefridus J. Peters, VU Medical Center, Amsterdam, the Netherlands; and Elisa Giovannetti, VU Medical Center, Amsterdam, The Netherlands; and University of Pisa, Pisa, Italy
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Koyama N, Watanabe Y, Iwai Y, Kawamura R, Miwa C, Nagai Y, Hagiwara K, Koyama S. Distinct Benefit of Overall Survival between Patients with Non-Small-Cell Lung Cancer Harboring EGFR Exon 19 Deletion and Exon 21 L858R Substitution. Chemotherapy 2017; 62:151-158. [PMID: 28110331 DOI: 10.1159/000454944] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 12/06/2016] [Indexed: 11/19/2022]
Abstract
BACKGROUND Exon 19 deletion (Del19) and exon 21 L858R substitution (L858R), which account for 90% of epidermal growth factor receptor (EGFR) mutations as common mutations, are associated with favorable outcomes with EGFR-tyrosine kinase inhibitors (TKIs) compared with other uncommon EGFR mutations in non-small-cell lung cancer (NSCLC). However, whether there are differences in overall survival (OS) between patients with these common EGFR mutations remains controversial. METHODS The subjects studied were 74 NSCLC patients with common EGFR mutations treated with gefitinib or erlotinib. Using univariate and multivariate analyses, we retrospectively compared the clinicopahological characteristics of patients harboring Del19 with those harboring L858R. RESULTS Compared with patients harboring L858R, EGFR-TKIs provided a significant OS benefit in patients harboring Del19 (p = 0.024), as well as favorable therapeutic responses (p = 0.045) and progression-free survival (PFS) benefits (p = 0.031). In multivariate analyses, Del19 was independently associated with PFS (p = 0.029) and OS (p = 0.009), whereas no parameters other than pleural dissemination at the initial treatment were associated with EGFR mutation types. CONCLUSION Del19 and L858R have distinct prognostic implications and may require individual therapeutic strategies.
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Affiliation(s)
- Nobuyuki Koyama
- Department of Clinical Oncology, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan
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Van Der Steen N, Deben C, Deschoolmeester V, Wouters A, Lardon F, Rolfo C, Germonpré P, Giovannetti E, Peters GJ, Pauwels P. Better to be alone than in bad company: The antagonistic effect of cisplatin and crizotinib combination therapy in non-small cell lung cancer. World J Clin Oncol 2016; 7:425-432. [PMID: 28008383 PMCID: PMC5143436 DOI: 10.5306/wjco.v7.i6.425] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 09/29/2016] [Accepted: 10/25/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the potential benefit of combining the cMET inhibitor crizotinib and cisplatin we performed in vitro combination studies. METHODS We tested three different treatment schemes in four non-small cell lung cancer (NSCLC) cell lines with a different cMET/epidermal growth factor receptor genetic background by means of the sulforhodamine B assay and performed analysis with Calcusyn. RESULTS All treatment schemes showed an antagonistic effect in all cell lines, independent of the cMET status. Despite their different genetic backgrounds, all cell lines (EBC-1, HCC827, H1975 and LUDLU-1) showed antagonistic combination indexes ranging from 1.3-2.7. These results were independent of the treatment schedule. CONCLUSION These results discourage further efforts to combine cMET inhibition with cisplatin chemotherapy in NSCLC.
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Shao Y, Yu Y, Zong R, Quyang L, He H, Zhou Q, Pei C. Erlotinib has tumor inhibitory effect in human retinoblastoma cells. Biomed Pharmacother 2016; 85:479-485. [PMID: 27899256 DOI: 10.1016/j.biopha.2016.11.054] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
AIM In this study, we explored the effect of erlotinib on the development of retinoblastoma (RB) cells both in vitro and in vivo. METHOD RB cell lines, Y79 and WERI cells were treated with various concentrations of erlotinib in vitro to assess their cytotoxic profiles. In vitro proliferation, cell-cycle transition and migration were compared between RB cells treated with erlotinib and cells without erlotinib treatment. In in vivo tumorigenicity assay, mice were injected with Y79 cells and orally fed with erlotinib for 28days. The effect of erlotinib on in vivo tumor grafts was then assessed. Western blot analysis on EGFR, ERK, AKT proteins and their phosphorylated proteins was also performed to assess molecular signaling pathways of associated with erlotinib in RB cells. RESULTS In vitro erlotinib treatment induced cytotoxicity in Y79 and WERI cells in dose-dependent manner. While Y79 and WERI cells were treated with erlotinib close to EC50 concentrations for 3days, RB proliferation, cell-cycle transition and migration were all significantly inhibited. In in vivo tumorigenicity assay, oral induction of erlotinib also dramatically reduced the growth of Y79 tumor grafts. Western blot demonstrated that, in in vitro RB cells, erlotinib did not alter the protein expression levels of EGFR, ERK or AKT, but significantly reduced the expressions of phosphorylated EGFR, ERK and AKT proteins. CONCLUSION Erlotinib was shown to have tumor suppressive effect on RB growth in vitro and in vivo, possibly through the inhibition on EGFR, ERG/AKT signaling pathways.
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Affiliation(s)
- Yi Shao
- Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province clinical ophthalmology Institute, Nanchang, Jiangxi Province, 330006, China.
| | - Yao Yu
- Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province clinical ophthalmology Institute, Nanchang, Jiangxi Province, 330006, China; Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang Key Laboratory of Diabetes, Nanchang, Jiangxi Province, 330009, China
| | - Rongrong Zong
- Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian Province, 361102, China
| | - Luowa Quyang
- Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian Province, 361102, China
| | - Hui He
- Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian Province, 361102, China
| | - Qiong Zhou
- Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province clinical ophthalmology Institute, Nanchang, Jiangxi Province, 330006, China.
| | - Chonggang Pei
- Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province clinical ophthalmology Institute, Nanchang, Jiangxi Province, 330006, China.
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Abu Lila AS, Fukushima M, Huang CL, Wada H, Ishida T. Systemically Administered RNAi Molecule Sensitizes Malignant Pleural Mesotheliomal Cells to Pemetrexed Therapy. Mol Pharm 2016; 13:3955-3963. [PMID: 27740765 DOI: 10.1021/acs.molpharmaceut.6b00728] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Pemetrexed (PMX) is a key drug for the management of malignant pleural mesothelioma (MPM). However, its therapeutic efficacy is cruelly restricted in many clinical settings by the overexpression of thymidylate synthase (TS) gene. Recently, we emphasized the efficacy of locally administered shRNA designed against TS gene in enhancing the cytotoxic effect of PMX against orthotopically implanted MPM cells in tumor xenograft tumor model. Herein, we explored the efficiency of systemic, rather than local, delivery of TS RNAi molecule in sensitizing MPM cells to the cytotoxic effect of PMX. We here designed a PEG-coated TS shRNA-lipoplex (PEG-coated TS shRNA-lipoplex) for systemic injection. PEG modification efficiently delivered TS shRNA in the lipoplex to tumor tissue following intravenous administration as indicated by a significant suppression of TS expression level in tumor tissue. In addition, the combined treatment of PMX with systemic injection of PEG-coated TS shRNA-lipoplex exerted a potent antitumor activity in a s.c. xenograft tumor model, compared to a single treatment with either PMX or PEG-coated TS shRNA-lipoplex. Metastasis, or the spread, of mesothelioma substantially dedicates the effectiveness of treatment options. The systemic, in addition to local, delivery of tumor targeted anti-TS RNAi system we propose in this study might be an effective option to extend the clinical utility of PMX in treating malignant mesothelioma.
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Affiliation(s)
- Amr S Abu Lila
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University , Tokushima, Japan.,Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University , Zagazig 44519, Egypt.,Department of Pharmaceutics, Faculty of Pharmacy, Hail University , Hail 2440, Saudi Arabia
| | - Masakazu Fukushima
- Department of Cancer Metabolism and Therapy, Institute of Biomedical Sciences, Tokushima University , Tokushima 770-8505, Japan
| | - Cheng-Long Huang
- Department of Thoracic Surgery, Faculty of Medicine, Kyoto University , Kyoto 606-8501, Japan
| | - Hiromi Wada
- Department of Thoracic Surgery, Faculty of Medicine, Kyoto University , Kyoto 606-8501, Japan
| | - Tatsuhiro Ishida
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University , Tokushima, Japan.,Department of Cancer Metabolism and Therapy, Institute of Biomedical Sciences, Tokushima University , Tokushima 770-8505, Japan
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Avan A, Narayan R, Giovannetti E, Peters GJ. Role of Akt signaling in resistance to DNA-targeted therapy. World J Clin Oncol 2016; 7:352-369. [PMID: 27777878 PMCID: PMC5056327 DOI: 10.5306/wjco.v7.i5.352] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 06/25/2016] [Accepted: 07/29/2016] [Indexed: 02/06/2023] Open
Abstract
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.
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Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, Kim JH, Wang X, Enatsu S, Puri T, Orlando M, Yang JCH. Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations. J Clin Oncol 2016; 34:3258-3266. [DOI: 10.1200/jco.2016.66.9218] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
Purpose To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non–small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations. Patients and Methods Chemotherapy-naïve for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2:1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m2 on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-free-survival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65). Results PFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P = .014; two-sided P = .029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+G, but toxicities were manageable. Conclusion P+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation–positive patients new treatment options and improved clinical outcomes compared with the current standard of care.
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Affiliation(s)
- Ying Cheng
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Haruyasu Murakami
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Pan-Chyr Yang
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Jianxing He
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Kazuhiko Nakagawa
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Jin Hyoung Kang
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Joo-Hang Kim
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Xin Wang
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Sotaro Enatsu
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Tarun Puri
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - Mauro Orlando
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
| | - James Chih-Hsin Yang
- Ying Cheng, Jilin Provincial Cancer Hospital, Changchun; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, Guangdong; Xin Wang, Eli Lilly, Shanghai, China; Haruyasu Murakami, Shizuoka Cancer Center, Shizuoka; Kazuhiko Nakagawa, Kinki University School of Medicine, Osaka; Sotaro Enatsu, Eli Lilly Japan, Kobe, Japan; Pan-Chyr Yang and James Chih-Hsin Yang, National Taiwan University Hospital; James Chih-Hsin Yang, National Taiwan University Cancer Center, Taipei, Taiwan; Jin
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Chen YF, Hsieh MS, Wu SG, Chang YL, Yu CJ, Yang JCH, Yang PC, Shih JY. Efficacy of Pemetrexed-Based Chemotherapy in Patients with ROS1 Fusion–Positive Lung Adenocarcinoma Compared with in Patients Harboring Other Driver Mutations in East Asian Populations. J Thorac Oncol 2016; 11:1140-52. [DOI: 10.1016/j.jtho.2016.03.022] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 03/24/2016] [Accepted: 03/25/2016] [Indexed: 02/07/2023]
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Bian X, Wu P, Sha H, Qian H, Wang Q, Cheng L, Yang Y, Yang M, Liu B. Anti-EGFR-iRGD recombinant protein conjugated silk fibroin nanoparticles for enhanced tumor targeting and antitumor efficiency. Onco Targets Ther 2016; 9:3153-62. [PMID: 27313461 PMCID: PMC4892850 DOI: 10.2147/ott.s100678] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In this study, we report a novel kind of targeting with paclitaxel (PTX)-loaded silk fibroin nanoparticles conjugated with iRGD–EGFR nanobody recombinant protein (anti-EGFR-iRGD). The new nanoparticles (called A-PTX-SF-NPs) were prepared using the carbodiimide-mediated coupling procedure and their characteristics were evaluated. The cellular cytotoxicity and cellular uptake of A-PTX-SF-NPs were also investigated. The results in vivo suggested that NPs conjugated with the recombinant protein exhibited more targeting and anti-neoplastic property in cells with high EGFR expression. In the in vivo antitumor efficacy assay, the A-PTX-SF-NPs group showed slower tumor growth and smaller tumor volumes than PTX-SF-NPs in a HeLa xenograft mouse model. A real-time near-infrared fluorescence imaging study showed that A-PTX-SF-NPs could target the tumor more effectively. These results suggest that the anticancer activity and tumor targeting of A-PTX-SF-NPs were superior to those of PTX-SF-NPs and may have the potential to be used for targeted delivery for tumor therapies.
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Affiliation(s)
- Xinyu Bian
- Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China
| | - Puyuan Wu
- Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China
| | - Huizi Sha
- Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China
| | - Hanqing Qian
- Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China
| | - Qing Wang
- Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China
| | - Lei Cheng
- Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China
| | - Yang Yang
- Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China
| | - Mi Yang
- Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China
| | - Baorui Liu
- Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People's Republic of China
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La Monica S, Madeddu D, Tiseo M, Vivo V, Galetti M, Cretella D, Bonelli M, Fumarola C, Cavazzoni A, Falco A, Gervasi A, Lagrasta CA, Naldi N, Barocelli E, Ardizzoni A, Quaini F, Petronini PG, Alfieri R. Combination of Gefitinib and Pemetrexed Prevents the Acquisition of TKI Resistance in NSCLC Cell Lines Carrying EGFR-Activating Mutation. J Thorac Oncol 2016; 11:1051-63. [PMID: 27006151 DOI: 10.1016/j.jtho.2016.03.006] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 02/19/2016] [Accepted: 03/02/2016] [Indexed: 01/30/2023]
Abstract
INTRODUCTION Development of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors is a clinical issue in patients with epidermal growth factor receptor gene (EGFR)-mutated non-small cell lung cancer (NSCLC). The aim of this study was to investigate the potential of combining gefitinib and pemetrexed in preventing the acquisition of resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines harboring EGFR exon 19 deletion. METHODS The effect of different combinatorial schedules of gefitinib and pemetrexed on cell proliferation, cell cycle, apoptosis, and acquisition of gefitinib resistance in PC9 and HCC827 NSCLC cell lines and in PC9 xenograft models was investigated. RESULTS Simultaneous treatment with gefitinib and pemetrexed enhanced cell growth inhibition and cell death and prevented the appearance of gefitinib resistance mediated by T790M mutation or epithelial-to-mesenchymal transition (EMT) in PC9 and HCC827 cells, respectively. In PC9 cells and in PC9 xenografts the combination of gefitinib and pemetrexed, with different schedules, prevented gefitinib resistance only when pemetrexed was the first treatment, given alone or together with gefitinib. Conversely, when gefitinib alone was administered first and pemetrexed sequentially alternated, a negative interaction was observed and no prevention of gefitinib resistance was documented. The mechanisms of resistance that developed in vivo included T790M mutation and EMT. The induction of EMT was a feature of tumors treated with gefitinib when given before pemetrexed, whereas T790M was recorded only in tumors treated with gefitinib alone. CONCLUSIONS The combination of gefitinib and pemetrexed is effective in preventing gefitinib resistance; the application of intermittent treatments requires that gefitinib not be administered before pemetrexed.
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Affiliation(s)
- Silvia La Monica
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | - Denise Madeddu
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | - Marcello Tiseo
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Valentina Vivo
- Department of Pharmacy, University of Parma, Parma, Italy
| | - Maricla Galetti
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy; Italian Workers' Compensation Authority Research Centre, University of Parma, Parma, Italy
| | - Daniele Cretella
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | - Mara Bonelli
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | - Claudia Fumarola
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | - Andrea Cavazzoni
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | - Angela Falco
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | - Andrea Gervasi
- Department of Biomedical, Biotechnological, and Translational Sciences, University of Parma, Parma, Italy
| | | | - Nadia Naldi
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | | | - Andrea Ardizzoni
- Division of Medical Oncology, Sant'Orsola-Malpighi University Hospital, Bologna, Italy
| | - Federico Quaini
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | | | - Roberta Alfieri
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
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Yang CJ, Tsai MJ, Hung JY, Liu TC, Chou SH, Lee JY, Hsu JS, Tsai YM, Huang MS, Chong IW. Pemetrexed had significantly better clinical efficacy in patients with stage IV lung adenocarcinoma with susceptible EGFR mutations receiving platinum-based chemotherapy after developing resistance to the first-line gefitinib treatment. Onco Targets Ther 2016; 9:1579-87. [PMID: 27051298 PMCID: PMC4803239 DOI: 10.2147/ott.s100164] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Increased evidences show that epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors such as gefitinib could prolong progression-free survival (PFS) compared with cytotoxic chemotherapy for metastatic lung nonsquamous cell carcinoma harboring susceptible EGFR mutation, and gefitinib was served as the first-line therapy. However, acquired resistance is inevitable, but the salvage therapies are still unclear. PATIENTS AND METHODS We designed a retrospective study of the salvage therapy and enrolled patients with stage IV lung adenocarcinoma who had mutated EGFR and developed an acquired resistance to the first-line gefitinib in two university-affiliated hospitals in Taiwan during June 2011 to December 2014. Age, sex, smoking history, EGFR gene mutation, performance statuses, response rate, PFS2 (the PFS in salvage therapy), and overall survival (OS2, the OS in salvage therapy) were recorded. RESULTS Two hundred and nine patients with mutated EGFR and who took gefitinib as first-line therapy were identified in the period, and a total of 98 patients who had been treated with salvage therapy with cytotoxic chemotherapy or erlotinib were eligible for this study. The overall response rate of second salvage therapy is 13%, and none of them received erlotinib. Patients who received chemotherapy had a trend for better PFS2 than those who received erlotinib (4.3 months vs 3.0 months, P=0.1417) but not in OS. Furthermore, patients who received platinum-based doublet had a trend for better PFS2 and a significantly better OS2 than those who received chemotherapy without platinum (PFS2: 4.9 months vs 2.6 months, P=0.0584; OS2: 16.1 months vs 6.7 months, P=0.0007). Analyses of the patients receiving platinum-based doublet showed that patients receiving pemetrexed had a significantly better PFS2 (6.4 months vs 4.1 months, P=0.0083) and a trend for better OS2 than those without pemetrexed treatment. CONCLUSION Pemetrexed-based platinum chemotherapy may be the most optimal therapy in acquired resistance to gefitinib. Further prospective randomized controlled study is needed urgently.
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Affiliation(s)
- Chih-Jen Yang
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Ju Tsai
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jen-Yu Hung
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ta-Chih Liu
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Shah-Hwa Chou
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Division of Chest Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jui-Ying Lee
- Division of Chest Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jui-Sheng Hsu
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ying-Ming Tsai
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Shyan Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Inn-Wen Chong
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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Santarpia M, Rolfo C, Peters GJ, Leon LG, Giovannetti E. On the pharmacogenetics of non-small cell lung cancer treatment. Expert Opin Drug Metab Toxicol 2016; 12:307-317. [PMID: 26761638 DOI: 10.1517/17425255.2016.1141894] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 01/11/2016] [Indexed: 11/05/2022]
Abstract
Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches.
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Affiliation(s)
- Mariacarmela Santarpia
- a Medical Oncology Unit, Human Pathology Department , University of Messina , Messina , Italy
| | - Christian Rolfo
- b Department of Medical Oncology , Antwerp University Hospital , Antwerp , Belgium
| | - G J Peters
- c Department of Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands
| | - Leticia G Leon
- d Cancer Pharmacology Lab, AIRC Start-Up Unit , University of Pisa , Pisa , Italy
| | - Elisa Giovannetti
- c Department of Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands
- d Cancer Pharmacology Lab, AIRC Start-Up Unit , University of Pisa , Pisa , Italy
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Xiao BK, Yang JY, Dong JX, Ji ZS, Si HY, Wang WL, Huang RQ. Meta-analysis of seven randomized control trials to assess the efficacy and toxicity of combining EGFR-TKI with chemotherapy for patients with advanced NSCLC who failed first-line treatment. Asian Pac J Cancer Prev 2015; 16:2915-21. [PMID: 25854383 DOI: 10.7314/apjcp.2015.16.7.2915] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Some recent clinical trials have been conducted to evaluate a combination of EGFR- TKI with chemotherapy for advanced NSCLC patients as second-line therapy, but the results on the efficacy of such trials are inconsistent. The aim of this meta-analysis was to evaluate the efficacy and safety of combination of EGFR-TKI and chemotherapy for patients with advanced NSCLC who failed first-line treatment. MATERIALS AND METHODS We searched relative trials from PubMed, EMBASE, ASCO Abstracts, ESMO Abstracts, Cochrane Library and Clinical Trials.gov. Outcomes analyzed were overall response rate (ORR), progression- free survival (PFS), overall survival (OS) and major toxicity. RESULTS Seven trails eventually were included in this meta-analysis, covering 1,168 patients. The results showed that the combined regimen arm had a significant higher ORR (RR 1.76 [1.16, 2.66], p=0.007) and longer PFS (HR 0.75 [0.66-0.85], p<0.00001), but failed to show effects on OS (HR 0.88 [0.68- 1.15], p=0.36). In terms of subgroup results, continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance confered no improvement in ORR (RR 0.95 [0.68, 1.33], p=0.75) and PFS (HR 0.89[0.69, 1.15], p=0.38), and OS was even shorter (HR1.52 [1.05- 2.21], p=0.03). However, combination therapy with EGFR-TKI and chemotherapy after failure of first-line chemotherapy significantly improved the ORR (RR 2.06 [1.42, 2.99], p=0.0002), PFS (HR 0.71 [0.61, 0.82], p<0.00001) and OS (HR 0.74 [0.62- 0.88], p=0.0008), clinical benefit being restricted to combining EGFR-TKI with pemetrexed, but not docetaxel. Grade 3-4 toxicity was found at significantly higher incidence in the combined regimen arm. CONCLUSIONS Continuation of EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance should be avoided. Combination therapy of EGFR-TKI and pemetrexed for advanced NSCLC should be further investigated for prognostic and predictive factors to find the group with the highest benefit of the combination strategy.
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Affiliation(s)
- Bing-Kun Xiao
- Department of Pharmacochemistry, Institute of Radiation Medicine, Beijing, China E-mail : ,
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Xu J, Liu X, Gao H, Guo W, Tang C, Li X, Li J, Qin H, Wang W, Qu L, Wang H, Yang H, Yang L. [Sequential Treatment of Advanced Squamous Lung Cancer:
First-line Gemcitabine +/- platinum Followed by Second-line Taxanes +/- platinum Versus Reverse Sequence]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2015; 18:308-14. [PMID: 25975302 PMCID: PMC6015219 DOI: 10.3779/j.issn.1009-3419.2015.05.09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
背景与目的 吉西他滨和紫杉类药物是晚期肺鳞癌常用的化疗药物,但二者在一、二线治疗中的最佳顺序尚未明确,本研究旨在分析吉西他滨单药/或联合铂类同紫杉类药物单药/或联合铂类在一、二线治疗中不同化疗顺序的疗效及毒副作用。 方法 回顾性分析了105例Ⅲb期-Ⅳ期肺鳞癌患者,49例为一线予吉西他滨单药/或联合铂类,进展后二线予紫杉类单药/或联合铂类治疗(G-T组);56例为一线予紫杉类单药/或联合铂类,进展后二线予吉西他滨单药/或联合铂类治疗(T-G组)。主要研究终点为总生存(overall survival, OS),次要研究终点为无进展生存期(progression-free survival, PFS)、客观缓解率(objective response rate, ORR)、疾病控制率(disease control rate, DCR)及不良反应。 结果 ① G-T组与T-G组中位OS分别为为18.5个月和19.0个月(P=0.520)。②G-T组与T-G组一线化疗中位PFS1分别为5.0个月和4.0个月(P=0.584);两组二线化疗中位PFS2为2.5个月和2.7个月(P=0.432)。③G-T组与T-G组一线化疗ORR1分别为36.73%和33.92%(P=0.577),DCR1分别为79.59%和89.29%(P=0.186);二线化疗ORR2分别为4.08%和5.36%(P=0.085),DCR2分别为51.02%和66.07%(P=0.118)。④G-T组与T-G组毒副作用相似,但G-T组更易出现Ⅲ级-Ⅳ级红细胞减低(P=0.027)和血小板减低(P=0.002)。 结论 一线吉西他滨单药/或联合铂类序贯二线紫杉类单药/或联合铂类与一线紫杉类单药/或联合铂类序贯二线吉西他滨单药/或联合铂类疗效相当,不良反应可耐受,两种序贯模式均对初治晚期肺鳞癌患者有效。
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Affiliation(s)
- Jing Xu
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Xiaoqing Liu
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Hongjun Gao
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Wanfeng Guo
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Chuanhao Tang
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Xiaoyan Li
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Jianjie Li
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Haifeng Qin
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Weixia Wang
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Lili Qu
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Hong Wang
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Hui Yang
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
| | - Lin Yang
- Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, China
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Wang X, Dong Y, Liang T, Zhang X, Ma K, Cui Y. [Analyzing the Sensitivity of EGFR-L861Q Mutation to TKIs and A Case Report]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2015; 18:592-8. [PMID: 26383985 PMCID: PMC6000112 DOI: 10.3779/j.issn.1009-3419.2015.09.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
背景与目的 对于伴表皮生长因子受体(epidermal growth factor receptor, EGFR)敏感型突变的晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)患者,小分子酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)的显著疗效众所周知。但对于晚期NSCLC伴EGFR-L861Q突变的患者,TKIs治疗是否敏感,治疗时机和治疗方案该如何选择,至今尚无确切的循证医学证据。本研究旨在通过分析EGFR-L861Q与敏感突变型EGFR-L858R及野生型EGFR蛋白质空间构象的差异,结合临床实例探讨晚期NSCLC伴EGFR-L861Q突变患者的最佳治疗方案。 方法 利用同源模建重建野生型EGFR、敏感突变型EGFR-L858R及突变型EGFR-L861Q蛋白质的空间构象,并分析这三种空间构象之间的差异。 结果 敏感突变型EGFR-L858R与野生型EGFR蛋白质的空间构象差异显著。突变型EGFR-L861Q与敏感突变型EGFR-L858R及野生型EGFR的蛋白质空间构象均不完全相同。在临床中,我们总结了1例晚期NSCLC伴EGFR-L861Q突变的患者,应用化疗作为一线治疗,当肿瘤不再缩小时,换用TKIs维持治疗,复查肺部计算机断层扫描(computed tomography, CT),肿瘤较前相比进一步缩小。 结论 通过对突变型EGFR-L861Q的蛋白质空间构象进行分析比对,结合临床实例,对于晚期NSCLC伴EGFR-L861Q突变的患者,一线化疗后达到疾病控制时,换用TKIs维持治疗,可能获得令人满意的临床疗效。
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Affiliation(s)
- Xingxing Wang
- Department of Medicine, Zhoushan Hospital, Zhoushan 316000, China;Department of Cancer Center, The First Hospital of Jilin University, Changchun 132000, China
| | - Yutong Dong
- Clinical Medical College of Yanbian University, Yanbian 133000, China
| | - Tingting Liang
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 132000, China
| | - Xiongji Zhang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun 132000, China
| | - Kewei Ma
- Department of Cancer Center, The First Hospital of Jilin University, Changchun 132000, China
| | - Yongsheng Cui
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun 132000, China
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Stinchcombe TE, Borghaei H, Barker SS, Treat JA, Obasaju C. Pemetrexed With Platinum Combination as a Backbone for Targeted Therapy in Non-Small-Cell Lung Cancer. Clin Lung Cancer 2015; 17:1-9. [PMID: 26340853 DOI: 10.1016/j.cllc.2015.07.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 07/01/2015] [Accepted: 07/21/2015] [Indexed: 11/29/2022]
Abstract
Standard platinum-based chemotherapy combinations for advanced non-small-cell lung cancer (NSCLC) have reached a plateau in terms of the survival benefit they offer for patients. In addition, the emerging clinical trend of tailored treatment based on patient characteristics has led to the development of therapeutic strategies that target specific cancer-related molecular pathways, including epidermal growth factor receptor (EGFR), angiogenesis, and anaplastic lymphoma kinase inhibitors. Current research is focused on combining targeted therapy with platinum-based chemotherapy in an endeavor to achieve an additional benefit in specific patient populations. Currently, pemetrexed is indicated for use in the first-line, maintenance, and second-line settings for the treatment of nonsquamous NSCLC. The combination of pemetrexed and cisplatin is well tolerated and is the approved standard first-line therapy. Thus, the pemetrexed-platinum backbone provides an attractive option for combination with targeted therapies. This review aims to summarize the current knowledge and future prospects of the use of pemetrexed-platinum as a backbone for combination with targeted therapies for NSCLC.
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Affiliation(s)
- Thomas E Stinchcombe
- Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
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