Cancer Research and Treatment

Original Articles

Lung and Thoracic cancer

Tumor Microenvironment Modulation by Neoadjuvant Erlotinib Therapy and Its Clinical Impact on Operable EGFR-Mutant Non–Small Cell Lung Cancer: Beung-Chul Ahn, Charny Park, Moon Soo Kim, Jong Mog Lee, Jin Ho Choi, Hyae Young Kim, Geon Kook Lee, Namhee Yu, Youngjoo Lee, Ji-Youn Han; Cancer Res Treat. 2024;56(1):70-80. Published online June 21, 2023; DOI: https://doi.org/10.4143/crt.2023.482

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Purpose
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have greatly improved survival in EGFR-mutant (EGFRm) non–small cell lung cancer (NSCLC); however, their effects on the tumor microenvironment (TME) are unknown. We assessed the changes induced by neoadjuvant erlotinib therapy (NE) in the TME of operable EGFRm NSCLC.
Materials and Methods
This was a single-arm phase II trial for neoadjuvant/adjuvant erlotinib therapy in patients with stage II/IIIA EGFRm NSCLC (EGFR exon 19 deletion or L858R mutations). Patients received up to 2 cycles of NE (150 mg/day) for 4 weeks, followed by surgery and adjuvant erlotinib or vinorelbine plus cisplatin therapy depending on observed NE response. TME changes were assessed based on gene expression analysis and mutation profiling.
Results
A total of 26 patients were enrolled; the median age was 61, 69% were female, 88% were stage IIIA, and 62% had L858R mutation. Among 25 patients who received NE, the objective response rate was 72% (95% confidence interval [CI], 52.4 to 85.7). The median disease-free and overall survival (OS) were 17.9 (95% CI, 10.5 to 25.4) and 84.7 months (95% CI, 49.7 to 119.8), respectively. Gene set enrichment analysis in resected tissues revealed upregulation of interleukin, complement, cytokine, transforming growth factor β, and hedgehog pathways. Patients with upregulated pathogen defense, interleukins, and T-cell function pathways at baseline exhibited partial response to NE and longer OS. Patients with upregulated cell cycle pathways at baseline exhibited stable/progressive disease after NE and shorter OS.
Conclusion
NE modulated the TME in EGFRm NSCLC. Upregulation of immune-related pathways was associated with better outcomes.

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Dual Inhibition of SYK and EGFR Overcomes Chemoresistance by Inhibiting CDC6 and Blocking DNA Replication
Jayaprakash Mandal, Tiffany Nicole Jones, Juliane Marie Liberto, Stephanie Gaillard, Tian-Li Wang, Ie-Ming Shih
Cancer Research.2024; 84(22): 3881. CrossRef

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A Randomized Phase II Study of Irinotecan Plus Cisplatin with or without Simvastatin in Ever-Smokers with Extended Disease Small Cell Lung Cancer: Youngjoo Lee, Soo-Hyun Lee, Geon Kook Lee, Eun Jin Lim, Ji-Youn Han; Cancer Res Treat. 2023;55(3):885-893. Published online March 20, 2023; DOI: https://doi.org/10.4143/crt.2023.283

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Purpose
This study evaluated whether an addition of simvastatin to chemotherapy improves survival in ever-smokers with extensive disease (ED)–small cell lung cancer (SCLC).
Materials and Methods
This is an open-label randomized phase II study conducted in National Cancer Center (Goyang, Korea). Chemonaive patients with ED-SCLC, smoking history (≥ 100 cigarettes lifetime), and Eastern Cooperative Oncology Group performance status of ≤ 2 were eligible. Patients were randomized to receive irinotecan plus cisplatin alone or with simvastatin (40 mg once daily orally) for a maximum of six cycles. Primary endpoint was the the 1-year survival rate.
Results
Between September 16, 2011, and September 9, 2021, 125 patients were randomly assigned to the simvastatin (n=62) or control (n=63) groups. The median smoking pack year was 40 years. There was no significant difference in the 1-year survival rate between the simvastatin and control groups (53.2% vs. 58.7%, p=0.535). The median progression-free survival and overall survival between the simvastatin arm vs. the control groups were 6.3 months vs. 6.4 months (p=0.686), and 14.4 months vs. 15.2 months, respectively (p=0.749). The incidence of grade 3-4 adverse events was 62.9% in the simvastatin group and 61.9% in the control group. In the exploratory analysis of lipid profiles, patients with hypertriglyceridemia had significantly higher 1-year survival rates than those with normal triglyceride levels (80.0% vs. 52.7%, p=0.046).
Conclusion
Addition of simvastatin to chemotherapy provided no survival benefit in ever-smokers with ED-SCLC. Hypertriglyceridemia may be associated with better prognosis in these patient population.

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Cardiovascular/anti‐inflammatory drugs repurposed for treating or preventing cancer: A systematic review and meta‐analysis of randomized trials
David J. Benjamin, Alyson Haslam, Vinay Prasad
Cancer Medicine.2024;[Epub] CrossRef
Repurposing simvastatin in cancer treatment: an updated review on pharmacological and nanotechnological aspects
Nargis Ara, Abdul Hafeez, Shom Prakash Kushwaha
Naunyn-Schmiedeberg's Archives of Pharmacology.2024; 397(10): 7377. CrossRef
Strategies to Target Chemoradiotherapy Resistance in Small Cell Lung Cancer
Tony Yu, Benjamin H. Lok
Cancers.2024; 16(20): 3438. CrossRef
β-blockers and statins: exploring the potential off-label applications in breast, colorectal, prostate, and lung cancers
Pedro Gabriel Senger Braga, Janaína da Silva Vieira, Aline Rachel Bezerra Gurgel, Patricia Chakur Brum
Frontiers in Pharmacology.2024;[Epub] CrossRef
Statins—From Fungi to Pharmacy
Anna Sadowska, Patryk Osiński, Alicja Roztocka, Karolina Kaczmarz-Chojnacka, Ewa Zapora, Diana Sawicka, Halina Car
International Journal of Molecular Sciences.2023; 25(1): 466. CrossRef

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Lung Cancer

The Clinical Impact of Capmatinib in the Treatment of Advanced Non–Small Cell Lung Cancer with MET Exon 14 Skipping Mutation or Gene Amplification: Wonyoung Choi, Seog-Yun Park, Youngjoo Lee, Kun Young Lim, Minjoung Park, Geon Kook Lee, Ji-Youn Han; Cancer Res Treat. 2021;53(4):1024-1032. Published online January 29, 2021; DOI: https://doi.org/10.4143/crt.2020.1331

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Purpose
Capmatinib, an oral MET kinase inhibitor, has demonstrated its efficacy against non–small cell lung cancer (NSCLC) with MET dysregulation. We investigated its clinical impact in advanced NSCLC with MET exon 14 skipping mutation (METex14) or gene amplification.
Materials and Methods
Patients who participated in the screening of a phase II study of capmatinib for advanced NSCLC were enrolled in this study. MET gene copy number (GCN), protein expression, and METex14 were analyzed and the patients’ clinical outcome were retrospectively reviewed.
Results
A total of 72 patients were included in this analysis (group A: GCN ≥ 10 or METex14, n=14; group B: others, n=58). Among them, 13 patients were treated with capmatinib (group A, n=8; group B, n=5), and the overall response rate was 50% for group A, and 0% for group B. In all patients, the median overall survival (OS) was 20.2 months (95% confidence interval [CI], 6.9 to not applicable [NA]) for group A, and 11.3 months (95% CI, 8.2 to 20.3) for group B (p=0.457). However, within group A, median OS was 21.5 months (95% CI, 20.8 to NA) for capmatinib-treated, and 7.5 months (95% CI, 3.2 to NA) for capmatinib-untreated patients (p=0.025). Among all capmatinib-untreated patients (n=59), group A showed a trend towards worse OS to group B (median OS, 7.5 months vs. 11.3 months; p=0.123).
Conclusion
Our data suggest that capmatinib is a new compelling treatment for NSCLC with MET GCN ≥ 10 or METex14 based on the improved survival within these patients.

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Exploring Cellular Plasticity and Resistance Mechanisms in Lung Cancer: Innovations and Emerging Therapies
Caiyu Jiang, Shenglong Xie, Kegang Jia, Gang Feng, Xudong Ren, Youyu Wang
Journal of Pharmaceutical Analysis.2025; : 101179. CrossRef
EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma
Ann-Katrin Piper, Chelsea Penney, Jacqueline Holliday, Gary Tincknell, Yafeng Ma, Sarbar Napaki, Klaus Pantel, Daniel Brungs, Marie Ranson
International Journal of Molecular Sciences.2024; 25(10): 5565. CrossRef
Understanding the treatment response and resistance to targeted therapies in non-small cell lung cancer: clinical insights and perspectives
Hang Zhang, Yingying Zhang, Yingying Zhu, Tian Dong, Zheng Liu
Frontiers in Oncology.2024;[Epub] CrossRef
Synthesis and bioassay of 3-Aryl -1-(pyridin-4-yl)benzo[4,5]imidazo[1,2-d][1,2,4]- triazin-4(3H)-ones as anti-cancer agents
Bassam Abu Thaher, Ihab Al-Masri, Kanan Wahedy, Rami Morjan, Saeb Aliwaini, Iman Mahmoud Al atter, Aayat Ahmed Elmabhouh, Areej khaled AL ibwaini, Saba Luay Alkhaldi, Basem Qeshta, Claus Jacob, Hans-Peter Deigner
Naunyn-Schmiedeberg's Archives of Pharmacology.2023; 396(8): 1797. CrossRef
RNA splicing alterations in lung cancer pathogenesis and therapy
Yueren Yan, Yunpeng Ren, Yufang Bao, Yongbo Wang
Cancer Pathogenesis and Therapy.2023; 1(4): 272. CrossRef
Clinicopathological characteristics of Non-Small Cell Lung Cancer (NSCLC) patients with c-MET exon 14 skipping mutation, MET overexpression and amplification
Caixia Ding, Yanyi Qiu, Juan Zhang, Wei Wei, Hongbian Gao, Yong Yuan, Xiaomin Wang
BMC Pulmonary Medicine.2023;[Epub] CrossRef
Long-Term Efficacy, Safety, and Subgroup Analysis of Savolitinib in Chinese Patients With NSCLCs Harboring MET Exon 14 Skipping Alterations
Shun Lu, Jian Fang, Xingya Li, Lejie Cao, Jianying Zhou, Qisen Guo, Zongan Liang, Ying Cheng, Liyan Jiang, Nong Yang, Zhigang Han, Jianhua Shi, Yuan Chen, Hua Xu, Helong Zhang, Gongyan Chen, Rui Ma, Sanyuan Sun, Yun Fan, Songhua Fan, Jie Yu, Puhan Lu, Xia
JTO Clinical and Research Reports.2022; 3(10): 100407. CrossRef
HPLC with Fluorescence and Photodiode Array Detection for Quantifying Capmatinib in Biological Samples: Application to In Vivo and In Vitro Studies
Aref Zayed, Sana’a A. Jaber, Jomana Al Hroot, Sahar Hawamdeh, Nehad M. Ayoub, Nidal A. Qinna
Molecules.2022; 27(23): 8582. CrossRef
Evaluation of MET alteration in EGFR-mutant non-small cell lung cancer patients treated with EGFR tyrosine kinase inhibitor from paired biopsy: A retrospective cohort study
Bo Mi Ku, Sungwon Park, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Yoon-La Choi, Myung-Ju Ahn
Precision and Future Medicine.2022; 6(4): 233. CrossRef
Targeted Treatment of Non-Small Cell Lung Cancer: Focus on Capmatinib with Companion Diagnostics
Matthew Z Guo, Kristen A Marrone, Alexander Spira, David M Waterhouse, Susan C Scott
OncoTargets and Therapy.2021; Volume 14: 5321. CrossRef

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Lung cancer

Phase II Study of Pemetrexed as a Salvage Chemotherapy for Thymidylate Synthase–Low Squamous Cell Lung Cancer: Mihong Choi, Heung Tae Kim, Ji-Youn Han, Geon Kook Lee, Soo-Hyun Lee, Kun Young Lim, Jungnam Joo, Hye Jin Won, Jin Soo Lee, Youngjoo Lee; Cancer Res Treat. 2021;53(1):87-92. Published online August 13, 2020; DOI: https://doi.org/10.4143/crt.2020.741

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Purpose
Squamous cell carcinomas (SqCC) of the lung often express high levels of thymidylate synthase (TS), which is associated with primary resistance to pemetrexed. We explored the efficacy of pemetrexed in a selected population of patients with lung SqCC with low TS expression.
Materials and Methods
In this single-arm phase II trial, we enrolled 32 previously-treated patients with advanced lung SqCC exhibiting low immunohistochemical staining for TS (i.e., in 10% or less of tumor cells). The primary endpoint was 12-week progression-free survival (PFS) rate.
Results
Of 32 patients, eight patients (25%) had an Eastern Cooperative Oncology Group performance status of 2, and seven patients (22%) had previously received three or more lines of chemotherapy. The disease control rate from pemetrexed treatment was 30%, and no objective response was observed. The 12-week PFS rate was 24.5% (95% confidence interval [CI], 13.0 to 46.1). Median PFS was 1.3 months (95% CI, 1.3 to 2.7), and median overall survival was 11.8 months (95% CI, 8.1 to not applicable). Most of adverse events were grade 1 or 2.
Conclusion
Pemetrexed demonstrated modest activity as a salvage chemotherapy in patients with advanced lung SqCC with low TS expression, although its toxicity was generally manageable.

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Bioengineered miR-7-5p modulates non–small cell lung cancer cell metabolism to improve therapy
Gavin M. Traber, Mei-Juan Tu, Su Guan, Neelu Batra, Ai-Ming Yu
Molecular Pharmacology.2025; 107(1): 100006. CrossRef

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Sequential Treatment with an Immune Checkpoint Inhibitor Followed by a Small-Molecule Targeted Agent Increases Drug-Induced Pneumonitis: Jongheon Jung, Hyae Young Kim, Dong-Gil Kim, Seog Yun Park, A Ra Ko, Ji-Youn Han, Heung Tae Kim, Jin Soo Lee, Youngjoo Lee; Cancer Res Treat. 2021;53(1):77-86. Published online August 6, 2020; DOI: https://doi.org/10.4143/crt.2020.543

Abstract PDF Supplementary Material PubReader ePub

Purpose
Immune checkpoint inhibitors (ICI) and targeted small-molecule drugs are mainstay elements of lung cancer chemotherapy. However, they are associated with development of pneumonitis, a rare, but potentially life-threatening event. We analyzed lung cancer patients treated with ICI to evaluate the effect of sequential therapeutic administration on the incidence of pneumonitis.
Materials and Methods
In this retrospective study, 242 patients were included. Serial radiologic findings taken during and immediately after ICI treatment were reviewed. Factors that increased pneumonitis and the relationship between peri-ICI chemotherapy and the development of pneumonitis were evaluated.
Results
Pneumonitis developed in 23 patients (9.5%); severe pneumonitis (grade ≥ 3) occurred in 13 of 23 patients (56%); pneumonitis-related death occurred in six. High-dose thoracic radiation (≥ 6,000 cGy) revealed a tendency toward high risk of pneumonitis (odds ratio, 2.642; 95% confidence interval, 0.932 to 7.490; p=0.068). Among 149 patients followed for ≥ 8 weeks after the final ICI dose, more patients who received targeted agents within 8-weeks post-ICI experienced pneumonitis (3/16, 18.8%) compared with patients who received cytotoxic agents (4/54, 7.4%) or no chemotherapy (4/79, 5.1%) (p=0.162). Targeted therapy was associated with earlier-onset pneumonitis than treatment with cytotoxic agents (35 vs. 62 days post-ICI, p=0.007); the resulting pneumonitis was more severe (grade ≥ 3, 100% vs. 0%, p=0.031).
Conclusion
Sequential administration of small-molecule targeted agents immediately after ICI may increase the risk of severe pneumonitis. The sequence of chemotherapy regimens that include ICI and targeted agents should be carefully planned to reduce the risk of pneumonitis in lung cancer patients.

Citations

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Toxicities associated with sequential or combined use of immune checkpoint inhibitors and small targeted therapies in non-small cell lung cancer: A critical review of the literature
Anne-Laure Désage, Michael Duruisseaux, Claire Lafitte, Sophie Bayle-Bleuez, Christos Chouaid, Pierre Fournel, Thomas Pierret
Cancer Treatment Reviews.2024; 129: 102805. CrossRef
Deep learning for predicting the risk of immune checkpoint inhibitor-related pneumonitis in lung cancer
M. Cheng, R. Lin, N. Bai, Y. Zhang, H. Wang, M. Guo, X. Duan, J. Zheng, Z. Qiu, Y. Zhao
Clinical Radiology.2023; 78(5): e377. CrossRef
Evaluating Pneumonitis Incidence in Patients with Non–small Cell Lung Cancer Treated with Immunotherapy and/or Chemotherapy Using Real-world and Clinical Trial Data
Qi Liu, Chenan Zhang, Yue Huang, Ruihao Huang, Shiew-Mei Huang, Erin Larkins, Liza Stapleford, Donna R. Rivera, Paul G. Kluetz, Shenggang Wang, Hao Zhu, James Weese, Elizabeth Cromartie, Mahder Teka, Sheetal Walters, Frank Wolf, Thomas D. Brown
Cancer Research Communications.2023; 3(2): 258. CrossRef
Pulmonary toxicity in driver gene positive non-small cell lung cancer therapy
Yi-Pu Zhao, Yong Long
Current Medical Research and Opinion.2022; 38(8): 1369. CrossRef
Immune checkpoint inhibitor-related pneumonitis in non-small cell lung cancer: A review
Yuxuan Hao, Xiaoye Zhang, Li Yu
Frontiers in Oncology.2022;[Epub] CrossRef
Improving Time-to-Treatment for Advanced Non-Small Cell Lung Cancer Patients through Faster Single Gene EGFR Testing Using the Idylla™ EGFR Testing Platform
Norbert Banyi, Deepu Alex, Curtis Hughesman, Kelly McNeil, Diana N. Ionescu, Carmen Ma, Stephen Yip, Barbara Melosky
Current Oncology.2022; 29(10): 7900. CrossRef
Sequential or combined immune checkpoint inhibitors and targeted therapy: Navigating uncharted waters
K. El Husseini, M. Wislez
Respiratory Medicine and Research.2021; 79: 100820. CrossRef
Multiple drugs

Reactions Weekly.2021; 1863(1): 255. CrossRef
Deep learning model enables the discovery of a novel immunotherapeutic agent regulating the kynurenine pathway
Jeong Hun Kim, Won Suk Lee, Hye Jin Lee, Hannah Yang, Seung Joon Lee, So Jung Kong, Soyeon Je, Hyun-Jin Yang, Jongsun Jung, Jaekyung Cheon, Beodeul Kang, Hong Jae Chon, Chan Kim
OncoImmunology.2021;[Epub] CrossRef

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Osimertinib in Patients with T790M-Positive Advanced Non-small Cell Lung Cancer: Korean Subgroup Analysis from Phase II Studies: Myung-Ju Ahn, Ji-Youn Han, Dong-Wan Kim, Byoung Chul Cho, Jin-Hyoung Kang, Sang-We Kim, James Chih-Hsin Yang, Tetsuya Mitsudomi, Jong Seok Lee; Cancer Res Treat. 2020;52(1):284-291. Published online July 23, 2019; DOI: https://doi.org/10.4143/crt.2019.200

Abstract PDF PubReader ePub

Purpose
Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR sensitizing mutation and EGFR T790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system (CNS) metastases. We present results of a subgroup analysis of Korean patients from the pooled data of two global phase II trials: AURA extension (NCT01802632) and AURA2 (NCT02094261).
Materials and Methods
Enrolled patients had EGFR T790M-positive NSCLC and disease progression during or after EGFR-TKI therapy. Patients received osimertinib 80 mg orally once daily until disease progression. The primary endpoint was objective response rate (ORR).
Results
In total, 66 Korean patients received osimertinib treatment with a median treatment duration of 19 months. In the evaluable-for-response population (n=62), ORR was 74% (95% confidence interval [CI], 61.5 to 84.5) and median duration of response was 9.8 months (95% CI, 7.1 to 16.8). In the full analysis set (n=66), median progression-free survival was 10.9 months (95% CI, 8.3 to 15.0; data cutoff November 1, 2016), and median overall survival was 29.2 months (95% CI, 24.8 to 35.7; data cutoff May 1, 2018). Eight patients with CNS metastases were evaluable for response, none of whom showed CNS progression. The most common adverse events were rash (53%), cough (33%), paronychia, diarrhea, and decreased appetite (each 32%).
Conclusion
Efficacy and safety profiles of osimertinib in this subgroup are consistent with the global phase II pooled population, which supports osimertinib as a recommended treatment for Korean patients with T790M positive NSCLC.

Citations

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Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with oncogene-addicted metastatic non-small-cell lung cancer
S.-H. Lee, J. Menis, T.M. Kim, H.R. Kim, C. Zhou, S.A. Kurniawati, K. Prabhash, H. Hayashi, D.D.-W. Lee, M.S. Imasa, Y.L. Teh, J.C.-H. Yang, T. Reungwetwattana, V. Sriuranpong, C.-E. Wu, Y. Ang, M. Sabando, M. Thiagarajan, H. Mizugaki, V. Noronha, M. Yuli
ESMO Open.2024; 9(12): 103996. CrossRef
The role of brain radiotherapy for EGFR- and ALK-positive non-small-cell lung cancer with brain metastases: a review
Valerio Nardone, Caterina Romeo, Emma D’Ippolito, Pierpaolo Pastina, Maria D’Apolito, Luigi Pirtoli, Michele Caraglia, Luciano Mutti, Giovanna Bianco, Antonella Consuelo Falzea, Rocco Giannicola, Antonio Giordano, Pierosandro Tagliaferri, Claudia Vincigue
La radiologia medica.2023; 128(3): 316. CrossRef
The Relationship Between Short-Term Surrogate Endpoint Indicators and mPFS and mOS in Clinical Trials of Malignant Tumors: A Case Study of Approved Molecular Targeted Drugs for Non-Small-Cell Lung Cancer in China
Mingjun Rui, Zijing Wang, Zhengyang Fei, Yao Wu, Yingcheng Wang, Lei Sun, Ye Shang, Hongchao Li
Frontiers in Pharmacology.2022;[Epub] CrossRef
Efficacy and Safety of SH-1028 in Patients With EGFR T790M-Positive NSCLC: A Multicenter, Single-Arm, Open-Label, Phase 2 Trial
Anwen Xiong, Shengxiang Ren, Huaimin Liu, Liyun Miao, Lei Wang, Jianhua Chen, Wei Li, Runpu Li, Xiang Wang, Zhiwei Lu, Donglin Wang, Xiaohong Wu, Zhihua Liu, Ligang Xing, Yimin Mao, Chunling Liu, Aiping Zeng, Hongrui Niu, Yingying Du, Yuping Sun, Yueyin P
Journal of Thoracic Oncology.2022; 17(10): 1216. CrossRef
Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma
Agnieszka Rybarczyk-Kasiuchnicz, Rodryg Ramlau, Katarzyna Stencel
International Journal of Molecular Sciences.2021; 22(2): 593. CrossRef

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Randomized Phase II Study of Afatinib Plus Simvastatin Versus Afatinib Alone in Previously Treated Patients with Advanced Nonadenocarcinomatous Non-small Cell Lung Cancer: Youngjoo Lee, Ki Hyeong Lee, Geon Kook Lee, Soo-Hyun Lee, Kun Young Lim, Jungnam Joo, Yun Jung Go, Jin Soo Lee, Ji-Youn Han; Cancer Res Treat. 2017;49(4):1001-1011. Published online January 13, 2017; DOI: https://doi.org/10.4143/crt.2016.546

Abstract PDF PubReader ePub

Purpose
This phase II study examined whether the addition of simvastatin to afatinib provides a clinical benefit compared with afatinib monotherapy in previously treated patients with nonadenocarcinomatous non-small cell lung cancer (NA-NSCLC).
Materials and Methods
Patientswith advancedNA-NSCLCwho progressed after one ortwo chemotherapy regimens were randomly assigned to a simvastatin (40 mg/day) plus afatinib (40 mg/day) (AS) arm or to an afatinib (A) arm. The primary endpoint was response rate (RR).
Results
Sixty-eight patients were enrolled (36 in the AS arm and 32 in the A arm). The RR was 5.7% (95% confidence interval [CI], 0.7 to 19.2) for AS and 9.4% (95% CI, 2.0 to 25.0) for A (p=0.440). In arms AS and A, the median progression-free survival (PFS) was 1.0 versus 3.6 months (p=0.240) and the overall survival was 10.0 months versus 7.0 months (p=0.930), respectively. Skin rash, stomatitis, and diarrhea were the most common adverse events in both arms. More grade 3 or 4 diarrhea was observed in arm A (18.8% vs. 5.6% in arm AS). In all patients, the median PFS for treatment including afatinib was not correlated with the status of epidermal growth factor receptor (EGFR) mutation (p=0.122), EGFR fluorescence in situ hybridization (p=0.944), or EGFR immunohistochemistry (p=0.976). However, skin rash severity was significantly related to the risk of progression for afatinib (hazard ratio for skin rash grade ≥ 2 vs. grade < 2, 0.44; 95% CI, 0.25 to 0.78; p=0.005).
Conclusion
There were no significant differences in the efficacy between AS and A arms in patients with NA-NSCLC.

Citations

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Xin Tu, Jian Zhang, Wei Yuan, Xia Wu, Zhi Xu, Cuo Qing
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Kush K. Patel, Khosrow Kashfi
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Yoichi Morofuji, Shinsuke Nakagawa, Kenta Ujifuku, Takashi Fujimoto, Kaishi Otsuka, Masami Niwa, Keisuke Tsutsumi
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Kamal Eltayeb, Silvia La Monica, Marcello Tiseo, Roberta Alfieri, Claudia Fumarola
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Xiaoshan Su, Weijing Wu, Zhixing Zhu, Xiaoping Lin, Yiming Zeng
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Iuliu Gabriel Cocuz, Maria Elena Cocuz, Angela Repanovici, Adrian-Horațiu Sabău, Raluca Niculescu, Andreea-Cătălina Tinca, Vlad Vunvulea, Corina Eugenia Budin, Andreea Raluca Szoke, Maria Cătălina Popelea, Raluca Moraru, Titiana Cornelia Cotoi, Ovidiu Sim
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Incorporating Erlotinib or Irinotecan Plus Cisplatin into Chemoradiotherapy for Stage III Non-small Cell Lung Cancer According to EGFR Mutation Status: Youngjoo Lee, Ji-Youn Han, Sung Ho Moon, Byung-Ho Nam, Kun Young Lim, Geon Kook Lee, Heung Tae Kim, Tak Yun, Hye Jin An, Jin Soo Lee; Cancer Res Treat. 2017;49(4):981-989. Published online January 6, 2017; DOI: https://doi.org/10.4143/crt.2016.522

Abstract PDF Supplementary Material PubReader ePub

Purpose
Concurrent chemoradiotherapy (CCRT) is the standard care for stage III non-small cell lung cancer (NSCLC) patients; however, a more effective regimen is needed to improve the outcome by better controlling occult metastases. We conducted two parallel randomized phase II studies to incorporate erlotinib or irinotecan-cisplatin (IP) into CCRT for stage III NSCLC depending on epidermal growth factor receptor (EGFR) mutation status.
Materials and Methods
Patients with EGFR-mutant tumors were randomized to receive three cycles of erlotinib first and then either CCRT with erlotinib followed by erlotinib (arm A) or CCRT with IP only (arm B). Patients with EGFR unknown or wild-type tumors were randomized to receive either three cycles of IP before (arm C) or after CCRT with IP (arm D).
Results
Seventy-three patients were screened and the study was closed early because of slow accrual after 59 patients were randomized. Overall, there were seven patients in arm A, five in arm B, 22 in arm C, and 25 in arm D. The response rate was 71.4% and 80.0% for arm A and B, and 70.0% and 73.9% for arm C and D. The median overall survival (OS) was 39.3 months versus 31.2 months for arm A and B (p=0.442), and 16.3 months versus 25.3 months for arm C and D (p=0.050). Patients with sensitive EGFR mutations had significantly longer OS than EGFR-wild patients (74.8 months vs. 25.3 months, p=0.034). There were no unexpected toxicities.
Conclusion
Combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC. EGFR-mutant patients appear to be a distinct subset with longer survival.

Citations

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Targeted treatment for unresectable EGFR mutation-positive stage III non-small cell lung cancer: Emerging evidence and future perspectives
Terufumi Kato, Ignacio Casarini, Manuel Cobo, Corinne Faivre-Finn, Fiona Hegi-Johnson, Shun Lu, Mustafa Özgüroğlu, Suresh S. Ramalingam
Lung Cancer.2024; 187: 107414. CrossRef
The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC
Allison E B Chang, Andrew J Piper-Vallillo, Raymond H Mak, Michael Lanuti, Alona Muzikansky, Julia Rotow, Pasi A Jänne, Mari Mino-Kenudson, Scott Swanson, Cameron D Wright, David Kozono, Paul Marcoux, Zofia Piotrowska, Lecia V Sequist, Henning Willers
The Oncologist.2024; 29(7): 609. CrossRef
Management of Non-Metastatic Non-Small Cell Lung Cancer (NSCLC) with Driver Gene Alterations: An Evolving Scenario
Valeria Fuorivia, Ilaria Attili, Carla Corvaja, Riccardo Asnaghi, Ambra Carnevale Schianca, Pamela Trillo Aliaga, Ester Del Signore, Gianluca Spitaleri, Antonio Passaro, Filippo de Marinis
Current Oncology.2024; 31(9): 5121. CrossRef
Comparison of treatment regimens for unresectable stage III epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer
Xin Dai, Qian Xu, Lei Sheng, Xue Zhang, Miao Huang, Song Li, Kai Huang, Jiahui Chu, Jian Wang, Jisheng Li, Yanguo Liu, Jianyuan Zhou, Shulun Nie, Lian Liu
Chinese Medical Journal.2024;[Epub] CrossRef
Management of Oncogene Driven Locally Advanced Unresectable Non-small Cell Lung Cancer
Jerold Loh, Jia Li Low, Manavi Sachdeva, Peter QJ Low, Rachel Su Jen Wong, Yiqing Huang, Puey Ling Chia, Ross A Soo
Expert Review of Anticancer Therapy.2023; 23(9): 913. CrossRef
Peptide-Hydrogel Nanocomposites for Anti-Cancer Drug Delivery
Farid Hajareh Haghighi, Roya Binaymotlagh, Ilaria Fratoddi, Laura Chronopoulou, Cleofe Palocci
Gels.2023; 9(12): 953. CrossRef
Nuclear accumulation of KPNA2 impacts radioresistance through positive regulation of the PLSCR1‐STAT1 loop in lung adenocarcinoma
Wei‐Chao Liao, Tsung‐Jen Lin, Yu‐Chin Liu, Yu‐Shan Wei, Guan‐Ying Chen, Hsiang‐Pu Feng, Yi‐Feng Chang, Hsin‐Tzu Chang, Chih‐Liang Wang, Hsinag‐Cheng Chi, Chun‐I Wang, Kwang‐Huei Lin, Wei‐Ting Ou Yang, Chia‐Jung Yu
Cancer Science.2022; 113(1): 205. CrossRef
Erlotinib Versus Etoposide/Cisplatin With Radiation Therapy in Unresectable Stage III Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter, Randomized, Open-Label, Phase 2 Trial
Ligang Xing, Gang Wu, Luhua Wang, Jiancheng Li, Jianhua Wang, Zhiyong Yuan, Ming Chen, Yaping Xu, Xiaolong Fu, Zhengfei Zhu, You Lu, Chun Han, Tingyi Xia, Conghua Xie, Guang Li, Shenglin Ma, Bing Lu, Qin Lin, Guangying Zhu, Baolin Qu, Wanqi Zhu, Jinming Y
International Journal of Radiation Oncology*Biology*Physics.2021; 109(5): 1349. CrossRef
A systematic review and meta-analysis of treatment-related toxicities of curative and palliative radiation therapy in non-small cell lung cancer
M. Or, B. Liu, J. Lam, S. Vinod, W. Xuan, R. Yeghiaian-Alvandi, E. Hau
Scientific Reports.2021;[Epub] CrossRef
Tyrosine Kinase Inhibitor Therapy in Unresectable Locally Advanced NSCLC: Keep Holding Our Breaths or Time to Take a Breather?
Aruz Mesci, Theodoros Tsakiridis, Anand Swaminath
Journal of Thoracic Oncology.2021; 16(10): 1607. CrossRef
Experiences of patients with lung cancer receiving concurrent chemo-radiotherapy
Choi Eunsook, Park Sunhee
Clinical Journal of Nursing Care and Practice.2021; 5(1): 015. CrossRef
Recent advances and new insights in the management of early-stage epidermal growth factor receptor-mutated non-small-cell lung cancer
Miguel J Sotelo, José Luis García, Cesar Torres-Mattos, Héctor Milián, Carlos Carracedo, María Ángeles González-Ruiz, Xabier Mielgo-Rubio, Juan Carlos Trujillo-Reyes, Felipe Couñago
World Journal of Clinical Oncology.2021; 12(10): 912. CrossRef
PLGA nanoparticle-reinforced supramolecular peptide hydrogels for local delivery of multiple drugs with enhanced synergism
Can Wu, Chunlu Wang, Lu Sun, Keming Xu, Wenying Zhong
Soft Matter.2020; 16(46): 10528. CrossRef
Epidermal growth factor receptor tyrosine kinase inhibitors combined with thoracic radiotherapy or chemoradiotherapy for advanced or metastatic non-small cell lung cancer: A systematic review and meta-analysis of single-arm trials
Ruifeng Liu, Shihong Wei, Qiuning Zhang, Xueliang Zhang, Hongtao Luo, Jinhui Tian, Yi Li, Long Ge, Xiaohu Wang
Medicine.2019; 98(29): e16427. CrossRef
Role of Anti-EGFR Targeted Therapies in Stage III Locally Advanced Non-small Cell Lung Cancer: Give or Not to Give?
Sanjal Desai, Chul Kim, Irina Veytsman
Current Oncology Reports.2019;[Epub] CrossRef

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ERCC1 Expression-Based Randomized Phase II Study of Gemcitabine/Cisplatin Versus Irinotecan/Cisplatin in Patients with Advanced Non-small Cell Lung Cancer: Ji-Youn Han, Geon Kook Lee, Kun Young Lim, Young Ju Lee, Byung Ho Nam, Jin Soo Lee; Cancer Res Treat. 2017;49(3):678-687. Published online October 11, 2016; DOI: https://doi.org/10.4143/crt.2016.365

Abstract PDF Supplementary Material PubReader ePub

Purpose
We evaluated the clinical utility of excision repair cross-complementation group 1 (ERCC1) expression as a predictive biomarker for platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC).
Materials and Methods
Eligible patients were randomly assigned to the GP (gemcitabine 1,250 mg/m² on days 1 and 8, and cisplatin 75 mg/m² on day 1 every 3 weeks) or IP (irinotecan 65 mg/m² and cisplatin 30 mg/m² on days 1 and 8 every 3 weeks) arm. The primary goal of this study was to compare the response rate (RR) of the GP and IP arms according to the ERCC1 expression level.
Results
A total of 279 patients were randomly assigned to the GP (n=139) and IP (n=140) arms, among which 63% were ERCC1-positive and 268 patients were assessable for the RR. The GP and IP arms did not differ significantly with respect to the RR (29.8% vs. 27.0%, respectively; p=0.082), median progression-free survival (PFS; 4.5 months vs. 3.9 months, respectively; p=0.117), and overall survival (OS; 16.5 months vs. 16.7 months, respectively; p=0.313). When comparing the efficacy between the ERCC1-positive and ERCC1-negative groups, there was no significant difference in the RR (GP, 28.2% vs. 32.6%, respectively, p=0.509; IP, 30.2% vs. 21.6%, respectively, p=0.536), median PFS (GP, 4.6 months vs. 5.0 months, respectively, p=0.506; IP, 3.9 months vs. 3.7 months, respectively, p=0.748), or median OS (GP, 18.6 months vs. 11.9 months, respectively, p=0.070; IP, 17.5 months vs. 14.0 months, respectively, p=0.821).
Conclusion
Immunohistochemical analysis of the ERCC1 expression level did not differentiate the efficacy of platinum-based chemotherapy in advanced NSCLC.

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Meta‐Analysis of ERCC1 Protein Expression and Platinum Chemosensitivity in Non‐Small‐Cell Lung Cancer
Guoping Li, Dan Cheng, Jamal A. Mahajna
Evidence-Based Complementary and Alternative Medicine.2020;[Epub] CrossRef
The role of ERCC1 and AFP gene polymorphism in hepatocellular carcinoma
Yu-Liang Huang, Jun-Rong Wu, Min Fang, Hui-Liu Zhao, Zhi-Min Liu, Jian Ye, Ling-Sha Huang, Bo Zhu
Medicine.2019; 98(14): e15090. CrossRef

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A Phase II Study of Poziotinib in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma Who Have Acquired Resistance to EGFR–Tyrosine Kinase Inhibitors: Ji-Youn Han, Ki Hyeong Lee, Sang-We Kim, Young Joo Min, Eunkyung Cho, Youngjoo Lee, Soo-Hyun Lee, Hyae Young Kim, Geon Kook Lee, Byung Ho Nam, Hyesun Han, Jina Jung, Jin Soo Lee; Cancer Res Treat. 2017;49(1):10-19. Published online May 3, 2016; DOI: https://doi.org/10.4143/crt.2016.058

Abstract PDF Supplementary Material PubReader ePub

Purpose
We examined the efficacy of poziotinib, a second-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with activating EGFR mutations, who developed acquired resistance (AR) to EGFR-TKIs.
Materials and Methods
This single-arm phase II study included EGFR-mutant lung adenocarcinoma with AR to erlotinib or gefitinib based on the Jackman criteria. Patients received poziotinib 16 mg orally once daily in a 28-day cycle. The primary endpoint was progression-free survival (PFS). Prestudy tumor biopsies and blood samples were obtained to determine resistance mechanisms.
Results
Thirty-nine patients were treated. Tumor genotyping was determined in 37 patients; 19 EGFR T790M mutations and two PIK3CAmutations were detected in the prestudy tumors, and seven T790M mutations were detected in the plasma assay. Three (8%; 95% confidence interval [CI], 2 to 21) and 17 (44%; 95% CI, 28 to 60) patients had partial response and stable disease, respectively. The median PFS and overall survival were 2.7 months (95% CI, 1.8 to 3.7) and 15.0 months (95% CI, 9.5 to not estimable), respectively. A longer PFS was observed for patients without T790M or PIK3CA mutations in tumor or plasma compared to those with these mutations (5.5 months vs. 1.8 months, p=0.003). The most frequent grade 3 adverse events were rash (59%), mucosal inflammation (26%), and stomatitis (18%). Most patients required one (n=15) or two (n=15) dose reductions.
Conclusion
Low activity of poziotinib was detected in patients with EGFR-mutant non-small cell lung cancer who developed AR to gefitinib or erlotinib, potentially because of severe-toxicityimposed dose limitation.

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A Phase II Study of Weekly Paclitaxel Plus Gemcitabine as a Second-Line Therapy in Patients with Metastatic or Recurrent Small Cell Lung Cancer: Tak Yun, Heung Tae Kim, Ji-Youn Han, Sung Jin Yoon, Hyae Young Kim, Byung-Ho Nam, Jin Soo Lee; Cancer Res Treat. 2016;48(2):465-472. Published online May 26, 2015; DOI: https://doi.org/10.4143/crt.2015.061

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Purpose
Paclitaxel (P) and gemcitabine (G) are clinically synergistic in small cell lung cancer (SCLC). We evaluated the efficacy of PG as a salvage treatment for SCLC patients whose disease progressed after a platinum-containing regimen.
Materials and Methods
Eligibility included histologically confirmed SCLC, one dimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and progressive disease after platinum-based chemotherapy. Treatment consisted of P (80 mg/m2) and G (1,000 mg/m2) on days 1 and 8 of each cycle of 21 days until disease progression.
Results
Thirty-three patients seen between December 2005 and February 2009 were selected into this study. Thirty patients (91%) had received irinotecan-platinum, and three had received etoposide-platinum. Sixteen patients (49%) had a treatment-free interval of less than 3 months. The overall response rate was 30.3% (29.4% in sensitive relapse and 31.3% in refractory relapse). The median time to progression was 12.0 weeks and median overall survival (OS) 31.0 weeks, with a 1-year OS rate of 30.3%. Toxicities were moderate and manageable with 18.2% grade (G) 4 neutropenia, 24.2% G3 thrombocytopenia, 6.1% G3 sensory neuropathy, and 3% G3 asthenia. One patient developed febrile neutropenia.
Conclusion
Second-line paclitaxel and gemcitabine were well-tolerated and moderately active in SCLC patients previously treated with platinum-based chemotherapy.

Citations

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