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Wei FF, Zhang J, Jia Z, Yao ZC, Chen CQ. Furmonertinib re-challenge for epidermal growth factor receptor-mutant lung adenocarcinoma after osimertinib-induced interstitial lung disease: A case report. World J Clin Oncol 2025; 16:101766. [PMID: 40130059 PMCID: PMC11866095 DOI: 10.5306/wjco.v16.i3.101766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/06/2024] [Accepted: 12/09/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Most non-small cell lung cancer patients have epidermal growth factor receptor (EGFR) activating mutations, such as exon 19 deletion and exon 21 replacement mutations. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitors approved for the treatment of lung cancer patients carrying EGFR activating mutations. Osimertinib-induced interstitial lung disease (ILD) is a rare and potentially fatal pulmonary toxic manifestation of drug therapy. At present, there is no international consensus on the risks and treatment of the osimertinib-induced ILD. CASE SUMMARY We report a case of a 56-year-old woman who was diagnosed with lung adenocarcinoma with lung hilum, mediastinal lymph nodes and brain metastases (T4N3M1c stage IVB). The patient received targeted treatment with osimertinib after radiotherapy and chemotherapy. But she developed ILD after osimertinib treatment. Following active symptomatic treatment and hormone treatment, the lung injury alleviated. The patient was retreated with furmonertinib combined with prednisone and did not experience ILD again. So far, she has survived for 14 months without disease progression. CONCLUSION Retreatment with furmonertinib under prednisone could be considered as an effective therapeutic option after risk-benefit assessment for EGFR-mutant lung adenocarcinoma patients.
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Affiliation(s)
- Fei-Fei Wei
- Department of Tumor Radiotherapy, Nanxishan Hospital of Guangxi Zhuang Autonomous Region (The Second People’s Hospital of Guangxi Zhuang Autonomous Region), Guilin 541002, Guangxi Zhuang Autonomous Region, China
| | - Jing Zhang
- Department of Oncology, People’s Hospital of Guilin, Guilin 541002, Guangxi Zhuang Autonomous Region, China
| | - Zhe Jia
- Department of Oncology, People’s Hospital of Guilin, Guilin 541002, Guangxi Zhuang Autonomous Region, China
| | - Zhi-Chao Yao
- Department of Pathematology, People’s Hospital of Guilin, Guilin 541002, Guangxi Zhuang Autonomous Region, China
| | - Chun-Qiao Chen
- Department of Oncology, People’s Hospital of Guilin, Guilin 541002, Guangxi Zhuang Autonomous Region, China
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Adegboyega FN, Anifowose LO, Hammad SF, Ghazy MA. Repurposing Antiviral Drugs as Potential Anti-EGFR Agents in NSCLC: A Structure-Based Screening and Molecular Dynamics Analysis. Chem Biodivers 2024; 21:e202400898. [PMID: 39078025 DOI: 10.1002/cbdv.202400898] [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: 04/09/2024] [Revised: 07/04/2024] [Accepted: 07/29/2024] [Indexed: 07/31/2024]
Abstract
One of the problems resulting from recurrent hyperactivated or mutant epidermal growth factor receptors (EGFR) in non-small cell lung cancer (NSCLC) is therapeutic resistance. Consequently, this leads to increased expression of oncogenic proteins and reduces the efficacy of EGFR tyrosine kinase inhibitors (TKIs). This study assessed antiviral drug efficacy as potential anti-EGFR agents for NSCLC. We used structure-based virtual screening to evaluate 66 antiviral drugs thoroughly. The top 6 antiviral drugs exhibiting impressive binding energies (i. e. surpassing a threshold of -8.5 kcal mol-1) were identified. Subsequent bioactivity analysis and ADMET profiling were performed to select the most promising candidates, followed by a molecular dynamic simulation. Among the selected antiviral regimens, dolutegravir demonstrated the highest docking score (-9.8 kcal mol-1), followed by rilpivirine and ensitrelvir, surpassing other candidates and our reference EGFR TKI. Further molecular dynamics simulations revealed promising dynamic interactions of dolutegravir, ensitrelvir, and rilpivirine with the EGFR target as compared with afatinib. Our findings highlight the repositioning potential of antiviral drugs for anti-EGFR drug discovery, supported by their robust docking scores, ADMET profiles, dynamic interactions, and binding free energies. The results open up new avenues for advanced NSCLC therapy. Further in vitro investigations are warranted to evaluate their efficacy and safety.
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Affiliation(s)
- Fikayo N Adegboyega
- Department of Biotechnology, Institute of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, New Borg El-Arab City, Alexandria, Egypt
| | - Lateef O Anifowose
- Department of Biotechnology, Institute of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, New Borg El-Arab City, Alexandria, Egypt
| | - Sherif F Hammad
- Department of Biotechnology, Institute of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, New Borg El-Arab City, Alexandria, Egypt
| | - Mohamed A Ghazy
- Department of Biotechnology, Institute of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, New Borg El-Arab City, Alexandria, Egypt
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
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Han H, Zhang X, Liu X, Zhao J, Zhang J, Zhang J, Zhu H, Jiao S, Tang H. First report of furmonertinib as a first-line treatment in advanced lung adenocarcinoma patients harboring EGFR exon 20 insertion mutations after the kinase domain αC-helix: Two case reports and a literature review. Medicine (Baltimore) 2023; 102:e36667. [PMID: 38206746 PMCID: PMC10754557 DOI: 10.1097/md.0000000000036667] [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: 09/19/2023] [Accepted: 11/23/2023] [Indexed: 01/13/2024] Open
Abstract
RATIONALE Many studies have shown that first- and second-generation epidermal growth factor receptor tyrosine kinase inhibitors are less effective in patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations. The efficacy of third-generation epidermal growth factor receptor tyrosine kinase inhibitors is still under investigation. Although new targeted tyrosine kinase inhibitors and monoclonal antibody-based agents have made significant advances in the treatment of epidermal growth factor receptor exon 20 insertion (EGFR ex20ins) mutation, the efficacy of these novel agents is not quite satisfactory. Platinum- and pemetrexed-based chemotherapy remains the standard first-line treatment for patients harboring EGFR ex20ins mutation. PATIENT CONCERNS We report for the first time 2 Chinese patients diagnosed with advanced lung adenocarcinoma with EGFR ex20ins mutations after analysis of the αC-helix sequence by next-generation sequencing. Both patients were treated with furmonertinib as the first-line therapy. INTERVENTIONS The first case included a 38-year-old female who had an EGFR ex20ins mutation (p.S768_D770dupSVD). After 1 month of treatment with furmonertinib, her symptoms of pain and cough were significantly alleviated. She achieved a partial response according to response evaluation criteria in solid tumors.[1] The final progression-free survival was 8.13 months. The second case included a 40-year-old male who had an EGFR ex20ins mutation (p.N771_P772insVal). He had a good response to furmonertinib and exhibited stable disease according to response evaluation criteria in solid tumors with a progression-free survival of 10.90 months. OUTCOMES Both patients experienced significant improvement in symptoms and prolonged survival after furmonertinib was used as first-line treatment. Side effects were limited but manageable. CONCLUSION The present study indicates that furmonertinib may be a first-line treatment option for patients with non-small cell lung cancer harboring EGFR ex20ins mutation.
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Affiliation(s)
- Huan Han
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Xiao Zhang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Xiao Liu
- Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Jiuzhou Zhao
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Jianbo Zhang
- Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Jianwei Zhang
- Department of Medical Iconography, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Hui Zhu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Shuyue Jiao
- Department of Respiratory Medicine, Luohe Central Hospital, Luohe, China
| | - Hong Tang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
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Wu CP, Li YC, Murakami M, Hsiao SH, Lee YC, Huang YH, Chang YT, Hung TH, Wu YS, Ambudkar SV. Furmonertinib, a Third-Generation EGFR Tyrosine Kinase Inhibitor, Overcomes Multidrug Resistance through Inhibiting ABCB1 and ABCG2 in Cancer Cells. Int J Mol Sci 2023; 24:13972. [PMID: 37762275 PMCID: PMC10531071 DOI: 10.3390/ijms241813972] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/09/2023] [Accepted: 09/10/2023] [Indexed: 09/29/2023] Open
Abstract
ATP-binding cassette transporters, including ABCB1 (P-glycoprotein) and ABCG2 (BCRP/MXR/ABCP), are pivotal in multidrug resistance (MDR) development in cancer patients undergoing conventional chemotherapy. The absence of approved therapeutic agents for multidrug-resistant cancers presents a significant challenge in effectively treating cancer. Researchers propose repurposing existing drugs to sensitize multidrug-resistant cancer cells, which overexpress ABCB1 or ABCG2, to conventional anticancer drugs. The goal of this study is to assess whether furmonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor overcomes drug resistance mediated by ABCB1 and ABCG2 transporters. Furmonertinib stands out due to its ability to inhibit drug transport without affecting protein expression. The discovery of this characteristic was validated through ATPase assays, which revealed interactions between furmonertinib and ABCB1/ABCG2. Additionally, in silico docking of furmonertinib offered insights into potential interaction sites within the drug-binding pockets of ABCB1 and ABCG2, providing a better understanding of the underlying mechanisms responsible for the reversal of MDR by this repurposed drug. Given the encouraging results, we propose that furmonertinib should be explored as a potential candidate for combination therapy in patients with tumors that have high levels of ABCB1 and/or ABCG2. This combination therapy holds the potential to enhance the effectiveness of conventional anticancer drugs and presents a promising strategy for overcoming MDR in cancer treatment.
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Affiliation(s)
- Chung-Pu Wu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan
| | - Yen-Ching Li
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Megumi Murakami
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Sung-Han Hsiao
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yun-Chieh Lee
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yang-Hui Huang
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan
| | - Yu-Tzu Chang
- Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Tai-Ho Hung
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 10507, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Yu-Shan Wu
- Department of Chemistry, Tunghai University, Taichung 40704, Taiwan
| | - Suresh V. Ambudkar
- Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
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Chen X, Zha W, Su M, Meng N, Cao S, Niu B, Qi X. Persistent response of furmonertinib plus anlotinib in a lung adenocarcinoma patient with an EGFR exon 20 insertion mutation: A case report. Front Pharmacol 2023; 14:1053805. [PMID: 36817153 PMCID: PMC9935568 DOI: 10.3389/fphar.2023.1053805] [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: 09/26/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Insertions in exon 20 represent the third most common type of EGFR mutation following in-frame deletions in exon 19 and the point mutation L858R in exon 21. They are generally associated with primary resistance to EGFR-TKIs. Although mobocertinib and amivantamab were approved for adult patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, the efficacy of these two agents was rather moderate. Therefore, other more potent targeted agents are urgently needed. Here, we report a patient with advanced lung adenocarcinoma harboring an EGFR exon 20 insertion mutation (NM_005228: exon 20: c.2316_2321dup: p.773_774dup). After experiencing platinum-based chemotherapy, this patient received a combination of furmonertinib and anlotinib and achieved lasting stable disease (SD). The treatment was well tolerated, and only mild hand-foot syndrome was reported from the patient. To the best of our knowledge, this case firstly reported the encouraging efficacy of combined furmonertinib and anlotinib in an advanced lung adenocarcinoma patient with an EGFR exon 20 insertion mutation who was previously treated with platinum-based chemotherapy. In addition, we summarize the recent literature on therapies against NSCLC with EGFR exon 20 insertion mutations. This case might provide an alternative approach for clinical oncologists.
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Affiliation(s)
- Xuesong Chen
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Wangjian Zha
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Mei Su
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Nan Meng
- ChosenMed Technology (Beijing) Co, Ltd, Beijing, China
| | - Shuliang Cao
- ChosenMed Technology (Beijing) Co, Ltd, Beijing, China
| | - Beifang Niu
- ChosenMed Technology (Beijing) Co, Ltd, Beijing, China
- Computer Network Information Center, Chinese Academy of Sciences, Beijing, China
- University of the Chinese Academy of Sciences, Beijing, China
| | - Xu Qi
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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Zhang SS, Ou SHI. Spotlight on Furmonertinib (Alflutinib, AST2818). The Swiss Army Knife (del19, L858R, T790M, Exon 20 Insertions, "uncommon-G719X, S768I, L861Q") Among the Third-Generation EGFR TKIs? LUNG CANCER (AUCKLAND, N.Z.) 2022; 13:67-73. [PMID: 36317157 PMCID: PMC9617553 DOI: 10.2147/lctt.s385437] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 09/30/2022] [Indexed: 11/05/2022]
Abstract
Osimertinib, a third-generation (3G) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is now considered the standard of care for the first-line (1L) treatment of advanced EGFR+ NSCLC due to statistically significant improved progression-free survival (PFS) and overall survival (OS) compared with first-generation (1G) treatment from the FLAURA trial. Recently two other 3G EGFR TKIs (aumolertinib and furmonertinib) have been approved in China for treatment of EGFR T790M+ NSCLC. Randomized Phase 3 trials of these two 3G EGFR TKIs have also demonstrated PFS over gefitinib respectively. Among these two Chinese home-grown, 3G EGFR TKIs, furmonertinib seems to most closely resemble osimertinib in terms of dosing regimen, efficacy and adverse events profile. In this article, we reviewed the clinical activity and adverse events of furmonertinib at 80 mg daily (approved dose), potential usage of 160 mg daily for CNS metastasis in EGFR+ NSCLC, and usage of 160 mg or 240 mg daily in EGFR exon20 insertion positive (EGFRex20ins+) NSCLC patients.
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Affiliation(s)
- Shannon S Zhang
- University of California Irvine School of Medicine, Department of Medicine, Department of Medicine, Orange, CA, USA
| | - Sai-hong Ignatius Ou
- University of California Irvine School of Medicine, Department of Medicine, Department of Medicine, Orange, CA, USA,Chao Family Comprehensive Cancer Center, Orange, CA, USA,Correspondence: Sai-hong Ignatius Ou, Chao Family Comprehensive Cancer Center, Division of Hematology and Oncology, Department of Medicine, University of California Irvine School of Medicine, 200 South Manchester Ave, Suite 400, Orange, CA, 92868, USA, Email
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[Consensus on Application of Third-generation EGFR-TKI in EGFR Mutated NSCLC
(2022 Version)]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2022; 25:627-641. [PMID: 36172727 PMCID: PMC9549424 DOI: 10.3779/j.issn.1009-3419.2022.101.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 09/02/2022] [Accepted: 09/04/2022] [Indexed: 11/05/2022]
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Zhang G, Yan B, Guo Y, Yang H, Li J. "Sandwich" Strategy to Intensify EGFR Blockade by Concurrent Tyrosine Kinase Inhibitor and Monoclonal Antibody Treatment in Highly Selected Patients. Front Oncol 2022; 12:952939. [PMID: 35903676 PMCID: PMC9321780 DOI: 10.3389/fonc.2022.952939] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 06/16/2022] [Indexed: 02/03/2023] Open
Abstract
EGFR TKIs are not curative, and targeted resistance inevitably results in therapeutic failure. Additionally, there are numerous uncommon EGFR mutations that are insensitive to EGFR TKIs, and there is a lack of clinical strategies to overcome these limitations. EGFR TKI and mAbs target EGFR at different sites, and a combination regimen for delaying/preventing resistance to targeted therapy or obtaining more intensive inhibition for uncommon mutations at cellular, animal and human levels has been explored. This review critically focuses on a combination strategy for uncommon EGFR mutation-positive NSCLC, and discuss the preclinical data, clinical implications, limitations and future prospects of the combination strategy.
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Affiliation(s)
- Guoqing Zhang
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Beibei Yan
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanan Guo
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hang Yang
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jindong Li
- Department of Thoracic Surgery and Lung Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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