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Yuejian, Zhao J, Wu T, Zhang D. Rare exon 18 G719A and exon 21 L833V compound EGFR mutations show favorable response to Third-Generation TKI Furmonertinib: A case report and literature review. Invest New Drugs 2025; 43:425-432. [PMID: 40146384 DOI: 10.1007/s10637-025-01521-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/03/2025] [Indexed: 03/28/2025]
Abstract
EGFR exon 19 deletions and exon 21 point mutations are the most common mutations in lung adenocarcinoma, with patients deriving significant clinical benefits from EGFR tyrosine kinase inhibitors (TKIs). However, the efficacy of TKIs in rare compound EGFR mutations remains uncertain. We report a case of lung adenocarcinoma with concurrent EGFR exon 18 G719A and exon 21 L833V mutations, showing a favorable response to third-generation TKI treatment. We reported a case of a 63-year-old female patient with brain, bone, and adrenal metastases from lung adenocarcinoma. Next-generation sequencing analysis identified a rare EGFR exon 18 G719A mutation in combination with an EGFR exon 21 L833V mutation. The patient received furmonertinib as first-line treatment and achieved a sustained response lasting over 12 months. This is the first reported case highlighting the efficacy of a third-generation TKI in treating lung adenocarcinoma with this rare compound mutation. Our findings suggest that third-generation TKIs may be a viable therapeutic option for prolonging progression-free survival in this patient subset.
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Affiliation(s)
- Yuejian
- Department of Oncology, People's Hospital, Hubei University of Medicine, Xiangyang No. 1, Jiefang Road No.15, Xiangyang, Hubei, 441000, China
| | - Jijun Zhao
- Department of Oncology, People's Hospital, Hubei University of Medicine, Xiangyang No. 1, Jiefang Road No.15, Xiangyang, Hubei, 441000, China
| | - Tao Wu
- Department of Oncology, the Second Affiliated Hospital of Dalian Medical University, No. 467, Zhongshan Road, Shahekou District, Dalian, 116001, China.
| | - Dongdong Zhang
- Department of Oncology, People's Hospital, Hubei University of Medicine, Xiangyang No. 1, Jiefang Road No.15, Xiangyang, Hubei, 441000, China
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Pisapia P, Russo A, De Luca C, Pepe F, Drago F, Rolfo C, Troncone G, Malapelle U. The relevance of the reference range for EGFR testing in non-small cell lung cancer patients. Lung Cancer 2024; 198:108002. [PMID: 39509773 DOI: 10.1016/j.lungcan.2024.108002] [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: 09/03/2024] [Revised: 10/24/2024] [Accepted: 10/25/2024] [Indexed: 11/15/2024]
Abstract
INTRODUCTION Identifying mutations in the epidermal growth factor receptor (EGFR) gene is crucial for individualized treatment of non-small cell lung cancer (NSCLC) patients. Accordingly, several methodologies and instruments are now commercially available to detect these alterations. The aim of this study was to examine the performance of next generation sequencing (NGS) in detecting both common and uncommon EGFR gene mutations in advanced NSCLC patients. METHODS We retrospectively retrieved molecular data from n = 1312 advanced stage NSCLC patients tested by our NGS DNA-based panel (namely SiRe® panel) from January 2018 to December 2022. We subsequently compared the NGS results with the reference ranges of the most popular real time PCR (RT-qPCR) assays (cobas® EGFR Mutation Test v2, EasyPGX® ready EGFR, Idylla™ EGFR mutation test, and therascreen® EGFR Plus RGQ). RESULTS Overall, NGS detected n = 234 mutations in n = 192 (15.9 %) patients. Conversely, when these results were compared with the reference ranges of the four most common commercially available RT-qPCR assays, far fewer mutations were identified: n = 18 (9.4 %), n = 17 (8.9 %), n = 17 (8.9 %), and n = 18 (9.4 %) mutations. These results suggest that if patients were tested solely using RT-qPCR assays, a substantial proportion would have been ineligible for targeted therapies. CONCLUSIONS Our study highlights that NGS is able to identify a much higher number of actionable EGFR mutations than RT-qPCR approaches, thereby providing many more patients the opportunity to receive targeted EGFR treatments.
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Affiliation(s)
- Pasquale Pisapia
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Alessandro Russo
- Medical Oncology, Humanitas Istituto Clinico Catanese, Catania, Italy
| | - Caterina De Luca
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Francesco Pepe
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Francesco Drago
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Christian Rolfo
- Department of Internal Medicine, Division of Medical Oncology, The Arthur G. James Comprehensive Cancer Center, Columbus, OH, USA
| | - Giancarlo Troncone
- Department of Public Health, University of Naples Federico II, Naples, Italy.
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy
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3
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Pizzutilo EG, Agostara AG, Oresti S, Signorelli D, Stabile S, Lauricella C, Motta V, Amatu A, Ruggieri L, Brambilla M, Occhipinti M, Proto C, Giusti R, Filetti M, Genova C, Barletta G, Gelsomino F, Bennati C, Siringo M, Di Fazio GR, Russano M, Montrone M, Gariazzo E, Roca E, Bordi P, Delmonte A, Scimone A, Belluomini L, Mazzoni F, Carta A, Pelizzari G, Viscardi G, Morgillo F, Gelibter A, Gori S, Berardi R, Cortinovis D, Ardizzoni A, Veronese SM, Sartore-Bianchi A, Giannetta LG, Cerea G, Siena S. Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO). ESMO Open 2024; 9:103592. [PMID: 38878323 PMCID: PMC11233869 DOI: 10.1016/j.esmoop.2024.103592] [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: 09/20/2023] [Revised: 03/26/2024] [Accepted: 05/14/2024] [Indexed: 06/26/2024] Open
Abstract
BACKGROUND Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.
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Affiliation(s)
- E G Pizzutilo
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy.
| | - A G Agostara
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - S Oresti
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - D Signorelli
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - S Stabile
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - C Lauricella
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - V Motta
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - A Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - L Ruggieri
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - M Brambilla
- Dipartimento di Oncologia Medica, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan
| | - M Occhipinti
- Dipartimento di Oncologia Medica, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan; Department of Experimental Medicine, Sapienza University of Rome, Rome
| | - C Proto
- Dipartimento di Oncologia Medica, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan
| | - R Giusti
- Medical Oncology Unit, Sant'Andrea Hospital of Rome, Rome
| | - M Filetti
- Phase 1 Unit, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome
| | - C Genova
- UO Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa; Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Università degli Studi di Genova, Genoa
| | - G Barletta
- UO Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genoa
| | - F Gelsomino
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - C Bennati
- Ospedale S. Maria delle Croci, AUSL della Romagna, Ravenna
| | - M Siringo
- Medical Oncology Department, Umberto I - Policlinico di Roma, Rome
| | - G R Di Fazio
- Department of Medical Oncology Fondazione Policlinico Universitario Campus Bio-Medico di Roma, Rome
| | - M Russano
- Department of Medical Oncology Fondazione Policlinico Universitario Campus Bio-Medico di Roma, Rome
| | - M Montrone
- SSD Oncologia Medica per la Patologia Toracica, IRCCS Istituto Tumori "Giovanni Paolo II", Bari
| | - E Gariazzo
- Medical Oncology, Santa Maria Della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia
| | - E Roca
- Thoracic Oncology - Lung Unit, P. Pederzoli Hospital, Peschiera del Garda, Verona
| | - P Bordi
- Medical Oncology Unit, University Hospital of Parma, Parma
| | - A Delmonte
- IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" (IRST), Meldola (FC)
| | - A Scimone
- Medical Oncology Department, Centro Oncologico Ospedale Papardo, Messina
| | - L Belluomini
- Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, Verona
| | - F Mazzoni
- Oncology department, Careggi University Hospital - Florence
| | - A Carta
- Ospedale Oncologico A. Businco, Cagliari
| | - G Pelizzari
- Dipartimento di Oncologia, Azienda Sanitaria Universitaria Friuli Centrale, Udine
| | - G Viscardi
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Naples; Department of Pneumology and Oncology, AORN Ospedali dei Colli, Naples
| | - F Morgillo
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Naples
| | - A Gelibter
- Medical Oncology Department, Umberto I - Policlinico di Roma, Rome
| | - S Gori
- Medical Oncology, IRCSS Sacro Cuore Don Calabria, Negrar di Valpolicella, Verona
| | - R Berardi
- Università Politecnica delle Marche - Azienda Ospedaliero Universitaria delle Marche, Ancona
| | - D Cortinovis
- SC Oncologia Medica Fondazione IRCCS San Gerardo dei Tintori, Monza
| | - A Ardizzoni
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - S M Veronese
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - A Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy; Division of Clinical Research and Innovation, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - L G Giannetta
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - G Cerea
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - S Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
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Boukansa S, Mouhrach I, El Agy F, Bouguenouch L, Serraj M, Amara B, Ouadnouni Y, Smahi M, Alami B, Mellas N, Benbrahim Z, El Fatemi H. An epidermal growth factor receptor compound mutation of L858R with S768I in advanced non-small-cell lung cancer: a case report. J Med Case Rep 2024; 18:118. [PMID: 38494473 PMCID: PMC10946199 DOI: 10.1186/s13256-024-04422-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 01/30/2024] [Indexed: 03/19/2024] Open
Abstract
BACKGROUND In the current treatment landscape for non-small cell lung cancers, epidermal growth factor receptor-tyrosine kinase inhibitors have emerged as a well-established treatment option for patients with advanced or metastatic disease. This is particularly true for those with commonly occurring epidermal growth factor receptor mutations. However, the therapeutic efficacy of these agents for so-called rare epidermal growth factor receptor mutations, and in particular those characterized by a high degree of complexity, such as double mutations, remains a subject of clinical uncertainty. CASE PRESENTATION In this context, we present the case of a 64-year-old man of Moroccan descent, a lifelong non-smoker, diagnosed with metastatic non-small cell lung cancer characterized by a complex epidermal growth factor receptor mutation encompassing L858R and S768I. The patient subsequently underwent afatinib-based treatment, showing notable clinical results. These included a remarkable overall survival of 51 months, with a median progression-free survival of more than 39 months. CONCLUSIONS This case report is a compelling testimony to the evolving therapeutic landscape of non-small cell lung cancers, providing valuable insight into the potential therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in the realm of rare and complex epidermal growth factor receptor mutations.
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Affiliation(s)
- Sara Boukansa
- Laboratory of Biomedical and Translational Research, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez, Morocco.
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco.
| | - Ismail Mouhrach
- Unit of Medical Genetics and Oncogenetics, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Fatima El Agy
- Laboratory of Biomedical and Translational Research, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Laila Bouguenouch
- Unit of Medical Genetics and Oncogenetics, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Mounia Serraj
- Department of Pneumology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Bouchra Amara
- Department of Pneumology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Yassine Ouadnouni
- Department of Thoracic Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Mohamed Smahi
- Department of Thoracic Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Badreeddine Alami
- Department of Radiology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Nawfel Mellas
- Department of Oncology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Zineb Benbrahim
- Department of Oncology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Hinde El Fatemi
- Laboratory of Biomedical and Translational Research, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
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Cosso F, Roviello G, Catalano M, Botteri C, Comin CE, Castiglione F, Ferrari K, Baldini E, Mini E. A case report of a lung cancer patient with two uncommon EGFR mutations and a review of the literature: two sides of the same coin. Anticancer Drugs 2024; 35:76-80. [PMID: 37067984 DOI: 10.1097/cad.0000000000001517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Lung cancer is the malignancy with the highest morbidity and mortality worldwide. Approximately 60% of non-small cell lung cancer (NSCLC) presents driver alterations most of which are targetable. Nowadays, limited clinical data are available regarding the efficacy of epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with NSCLC harboring uncommon EGFR mutations, considering their heterogeneity. Herein, we report a rare case of EGFR-mutated lung adenocarcinoma which has developed into squamous cell carcinoma with uncommon EGFR (Ex18) compound mutations and phosphatidylinositol 3-kinase mutation receiving afatinib at the forefront.
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Affiliation(s)
| | | | | | | | - Camilla Eva Comin
- Pathological Histology and Molecular Diagnostics Unit, Careggi University Hospital
| | | | - Katia Ferrari
- Respiratory Medicine Unit, Careggi University Hospital, Florence
| | - Editta Baldini
- Department of Medical Oncology, San Luca Hospital, Lucca, Italy
| | - Enrico Mini
- Department of Health Sciences, University of Florence
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6
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Le X, Nadler E, Costa DB, Heymach JV. EGFR Tyrosine Kinase Inhibitors for the Treatment of Metastatic Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Podcast. Target Oncol 2023; 18:807-817. [PMID: 37792237 PMCID: PMC10663258 DOI: 10.1007/s11523-023-00994-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2023] [Indexed: 10/05/2023]
Abstract
Supplementary file1 (MP4 21169 KB).
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Affiliation(s)
- Xiuning Le
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Eric Nadler
- Baylor University Medical Center, Dallas, TX, USA
| | - Daniel B Costa
- Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Chang H, Huang K, Tseng C, Chen Y, Lai C, Chang Y, Chen Y, Chuang H, Wang C. Survival outcomes of east Asian patients with advanced non-small cell lung cancer treated with first-line EGFR tyrosine kinase inhibitors: A network meta-analysis of real-world evidence. Thorac Cancer 2023; 14:3217-3225. [PMID: 37704454 PMCID: PMC10643793 DOI: 10.1111/1759-7714.15112] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND The comparative efficacies of different generation tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) remain largely unknown. Moreover, whether one EGFR-TKI confers superior survival remains unclear, especially in East Asians. We conducted a network meta-analysis (NMA) comparing the survival outcomes of East Asian patients with advanced NSCLC treated with first-line EGFR-TKIs. METHODS The NMA included observational real-world evidence studies on adult patients with EGFR-mutated advanced NSCLC who received first (gefitinib and erlotinib), second (afatinib), or third (osimertinib) generation EGFR-TKIs as frontline therapy. Studies were identified through an online bibliographic search of Medline articles in the PubMed, SCOPUS, Web of Science, and Cochrane Library databases. RESULTS For overall survival (OS), afatinib had significantly better hazard ratios (HRs) than osimertinib (HR: 0.46, 95% confidence interval [CI]: 0.23-0.91), gefitinib (HR: 0.56, 95% CI: 0.43-0.72), and erlotinib (HR: 0.71, 95% CI: 0.54-0.92). For progression-free survival (PFS), afatinib had significantly better HRs than gefitinib (HR: 0.45, 95% CI: 0.36-0.56) and erlotinib (HR: 0.63, 95% CI: 0.49-0.81). Moreover, afatinib was most likely to achieve the longest OS (81.3%), followed by erlotinib (13%), osimertinib, and gefitinib. Furthermore, afatinib was most likely to achieve the longest PFS (48.3%), followed by osimertinib (34.9%) and erlotinib. CONCLUSIONS This real-world evidence shows that afatinib confers better survival than other first-line EGFR-TKIs in East Asian patients with advanced NSCLC.
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Affiliation(s)
- Huang‐Chih Chang
- Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
- Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, and Research Center for Precision Environmental MedicineKaohsiung Medical UniversityKaohsiung CityTaiwan
- Department of Occupational and Environmental MedicineKaohsiung Medical University HospitalKaohsiung CityTaiwan
| | - Kuo‐Tung Huang
- Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
| | - Chia‐Cheng Tseng
- Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
| | - Yu‐Mu Chen
- Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
| | - Chien‐Hao Lai
- Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
| | - Yu‐Ping Chang
- Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
| | - Yung‐Che Chen
- Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
- Department of Respiratory TherapyKaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineKaohsiungTaiwan
| | - Hung‐Yi Chuang
- Ph.D. Program in Environmental and Occupational Medicine, College of Medicine, and Research Center for Precision Environmental MedicineKaohsiung Medical UniversityKaohsiung CityTaiwan
- Department of Occupational and Environmental MedicineKaohsiung Medical University HospitalKaohsiung CityTaiwan
| | - Chin‐Chou Wang
- Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial HospitalChang Gung University College of MedicineKaohsiungTaiwan
- Department of Respiratory TherapyKaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineKaohsiungTaiwan
- Department of Respiratory CareChang Gung University of Science and TechnologyChiayiTaiwan
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8
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Pu X, Zhou Y, Kong Y, Chen B, Yang A, Li J, Li K, Xu Y, Wu L. Efficacy and safety of dacomitinib in treatment-naïve patients with advanced NSCLC harboring uncommon EGFR mutation: an ambispective cohort study. BMC Cancer 2023; 23:982. [PMID: 37840124 PMCID: PMC10577935 DOI: 10.1186/s12885-023-11465-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 09/29/2023] [Indexed: 10/17/2023] Open
Abstract
BACKGROUND About 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to explore the efficacy and safety of dacomitinib, a second-generation EGFR tyrosine kinase inhibitor (EGFR-TKIs), in treating uncommon EGFR-mutated advanced NSCLC. METHODS Treatment-naïve advanced NSCLC patients treated with dacomitinib at Hunan Cancer Hospital with uncommon EGFR mutations were evaluated. The primary endpoint was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. RESULT Between December 2019 and December 2021, a total of 16 patients was included. Median PFS was 14.0 (95% CI 4.32-23.7) months, and median OS was not reached. ORR was 68.8% (95% CI 41.3 to 89.0%) and DCR was 93.8% (95%CI 69.8 to 99.8%), including three achieving complete remission (CR) and eight achieving partial remission (PR). Median PFS for patients with brain metastasis was 9.0 (95%CI 6.9 to 11.1) months. Intracranial ORR was 100%, including 2 CR and 4 PR. Major treatment-related adverse events (TRAEs) included rash (87.5%), paronychia (62.5%), oral ulcers (50.0%), and diarrhea (50.0%), none of which were ≥ grade 3 TRAEs. CONCLUSIONS Dacomitinib showed good activity and manageable toxicity in NSCLC patients with uncommon EGFR mutations.
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Affiliation(s)
- Xingxiang Pu
- The Second Department of Thoracic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, People's Republic of China
| | - Yu Zhou
- The Second Department of Thoracic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, People's Republic of China
| | - Yi Kong
- The Second Department of Thoracic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, People's Republic of China
| | - Bolin Chen
- The Second Department of Thoracic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, People's Republic of China
| | - Aifang Yang
- The Department of Radiotherapy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, People's Republic of China
| | - Jia Li
- The Second Department of Thoracic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, People's Republic of China
| | - Kang Li
- The Second Department of Thoracic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, People's Republic of China
| | - Yan Xu
- The Second Department of Thoracic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, People's Republic of China
| | - Lin Wu
- The Second Department of Thoracic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410000, People's Republic of China.
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Li G, Fang M, Zhou Y, Liu X, Tian P, Mei F. Afatinib overcoming resistance to icotinib and osimertinib in NSCLC with leptomeningeal metastasis in patients with acquired EGFR L858R/T790M or L858R/S768I mutations: Two case reports. Heliyon 2023; 9:e20690. [PMID: 37860534 PMCID: PMC10582297 DOI: 10.1016/j.heliyon.2023.e20690] [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: 07/07/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/21/2023] Open
Abstract
Background Advanced non-small cell lung cancer (NSCLC) is often complicated by leptomeningeal metastases (LMs), especially in patients carrying EGFR mutations. EGFR tyrosine kinase inhibitors (TKIs) are the first-line drug for patients with specific gene mutations, such as EGFR exon 19 deletion or exon 21 L858R mutation. However, after long-term TKI use, patients eventually develop drug resistance and acquire new mutations. Acquiring the EGFR T790 M mutation during TKI treatment is a marker for first/second generation TKI resistance. Osimertinib (a third-generation TKI) could overcome this resistance, especially for patients who have already developed NSCLC-LM. Treating NSCLC patients with osimertinib resistance is challenging. Our aim was to investigate whether afatinib is effective in NSCLC-LM patient who showed resistance to osimertinib. Herein, we report two patients with resistance to first- and third-generation TKIs who benefited from second-generation TKI. Case summary Case one: A 43-year-old man was diagnosed with stage 3A NSCLC with EGFR exon 19 deletion. He underwent surgery and received 4 rounds of chemotherapy (oxaliplatin combined with liposomal paclitaxel), after which the disease was controlled by icotinib (a first-generation TKI) for 4 years. Then, he showed poor drug response and bone metastasis. A liquid biopsy was carried out, and the EGFR L858R/T790 M compound mutation was found. The patient was given osimertinib (a third-generation TKI). The patient was in a stable condition for 2 years and then he developed bilateral peripheral facial palsy. Brain MRI showed enhancement in the left temporal lobe and meninges, and cerebrospinal fluid (CSF) cytology detected tumour cells in the CSF. NSCLC-LM was diagnosed. His performance status (PS) score was 3-4. Liquid biopsy and next-generation sequencing were performed again. Different gene mutations and copy number alterations were found this time, including EGFR L858R, but without the EGFR T790 M mutation. His disease was controlled with intrathecal methotrexate and oral afatinib (a second generation TKI). The patient has shown clinical remission (PS score: 1-2) until now, which is longer than 10 months. Case two A 50-year-old man was diagnosed with NSCLC in May 2020. He underwent one round of chemotherapy before thoracoscopic partial lobectomy of the right upper lung. Histological study of the lung tissue showed lung adenocarcinoma with the EGFR L858R mutation. Then, the disease was controlled with icotinib. One year later, he was diagnosed with NSCLC-LM. Liquid biopsy and sequencing showed an EGFR L858R/S768I compound mutation. The patient was treated with osimertinib. His condition was stable for 5 months before his central nervous system (CNS) symptoms were exacerbated. Liquid biopsy and sequencing were carried out again, and his gene mutation profile had not changed much. Then, the patient was given afatinib, and his condition has remained stable for 11 months. Conclusion Afatinib might be suitable for NSCLC-LM patients with EGFR compound mutations who show resistance to icotinib and osimertinib, since it might help overcome first- and third-generation TKI resistance.
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Affiliation(s)
- Guangrui Li
- Department of Infectious Diseases, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Mei Fang
- Department of Reproductive Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yazhu Zhou
- Department of Neurology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaocui Liu
- Department of Neurology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Neurology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei, China
| | - Panpan Tian
- Department of Neurology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Fengjun Mei
- Department of Neurology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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10
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Yang LL, Luo XZ, Xie LL, Lei XZ, Zhu J. The treatment of patients with non-small cell lung cancer carrying uncommon EGFR mutations, HER2 mutations, or brain metastases: a systematic review of pre-clinical and clinical findings for dacomitinib. Transl Cancer Res 2023; 12:2197-2211. [PMID: 37701115 PMCID: PMC10493789 DOI: 10.21037/tcr-23-95] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 07/21/2023] [Indexed: 09/14/2023]
Abstract
Background Accumulating evidence has shown that dacomitinib has potential activities for patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations, human epidermal growth factor receptor 2 (HER2) mutations, or central nervous system (CNS) metastases. Methods This study aimed to give a systematic review on its potential applications in the above settings by searching MEDLINE/PubMed, Embase, Cochrane Library, American Society of Clinical Oncology.org, European Society for Medical Oncology.org, and ClinicalTrials.gov. Results The literature search yielded 649 publications in total. According to our findings, dacomitinib exhibited promising efficacy in patients with major uncommon EGFR mutations (including G719X, S768I, and L861Q). Both EGFR exon 20 insertional mutation (Ex20ins) and HER2 Ex20ins demonstrated significant internal heterogeneity in response to dacomitinib, among which specific subtypes (including EGFR D770delinsGY, A763_Y764insFQEA, and HER2 M774delinsWLV) were highly sensitive. Other uncommon EGFR mutations including 18del and L747P have also been shown responsive to dacomitinib. Interestingly, limited studies suggested dacomitinib application on certain first or third generation tyrosine kinase inhibitors (TKIs)' resistant secondary mutations. Last but not least, both pre-clinical and clinical data indicated that dacomitinib has an encouraging intracranial tumor control ability, regardless of uncommon mutations. Conclusions Dacomitinib demonstrated good disease control on patients with NSCLC harboring major uncommon EGFR mutations and specific EGFR or HER2 mutation subtypes, and selective clinical application of dacomitinib is considerable in this setting, especially for those with intracranial metastases.
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Affiliation(s)
- Li-Li Yang
- Department of Medical Oncology, Chengdu Shangjinnanfu Hospital, West China Hospital of Sichuan University, Chengdu, China
| | - Xiao-Zhen Luo
- Department of Medical Oncology, Chengdu Shangjinnanfu Hospital, West China Hospital of Sichuan University, Chengdu, China
| | - Ling-Ling Xie
- Department of Medical Oncology, Chengdu Shangjinnanfu Hospital, West China Hospital of Sichuan University, Chengdu, China
| | - Xiao-Zhen Lei
- Department of Medical Oncology, Chengdu Shangjinnanfu Hospital, West China Hospital of Sichuan University, Chengdu, China
| | - Jiang Zhu
- Department of Medical Oncology, West China Hospital of Sichuan University, Chengdu, China
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11
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Fabrizio FP, Sparaneo A, Muscarella LA. Monitoring EGFR-lung cancer evolution: a possible beginning of a "methylation era" in TKI resistance prediction. Front Oncol 2023; 13:1137384. [PMID: 37152062 PMCID: PMC10157092 DOI: 10.3389/fonc.2023.1137384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 04/06/2023] [Indexed: 05/09/2023] Open
Abstract
The advances in scientific knowledge on biological therapies of the last two decades have impressively oriented the clinical management of non-small-cell lung cancer (NSCLC) patients. The treatment with tyrosine kinase inhibitors (TKIs) in patients harboring Epidermal Growth Factor Receptor (EGFR)-activating mutations is dramatically associated with an improvement in disease control. Anyhow, the prognosis for this selected group of patients remains unfavorable, due to the innate and/or acquired resistance to biological therapies. The methylome analysis of many tumors revealed multiple patterns of methylation at single/multiple cytosine-phosphate-guanine (CpG) sites that are linked to the modulation of several cellular pathways involved in cancer onset and progression. In lung cancer patients, ever increasing evidences also suggest that the association between DNA methylation changes at promoter/intergenic regions and the consequent alteration of gene-expression signatures could be related to the acquisition of resistance to biological therapies. Despite this intriguing hypothesis, large confirmatory studies are demanded to consolidate and finalize many preliminary observations made in this field. In this review, we will summarize the available knowledge about the dynamic role of DNA methylation in EGFR-mutated NSCLC patients.
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12
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Dong W, Wang C, Wang C, Zhao K, Ma Z, Hu S. Inconsistent clinical outcomes following afatinib treatment in NSCLC patients harboring uncommon epidermal growth factor receptor mutation. Front Oncol 2022; 12:999606. [PMID: 36425553 PMCID: PMC9680984 DOI: 10.3389/fonc.2022.999606] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/24/2022] [Indexed: 10/21/2023] Open
Abstract
Background Uncommon epidermal growth factor receptor (EGFR) mutations consist of a heterogeneous population of molecular alterations, and the available clinical data on the outcomes of patients with non-small-cell lung cancer (NSCLC) harboring uncommon EGFR mutations following afatinib treatment are limited. The purpose of this pooled analysis was to investigate the clinicopathological features of patients with uncommon EGFR mutations (um-EGFRms) along with their treatment response and survival outcomes following afatinib treatment. Methods We performed a literature search in the NCBI PubMed database to identify relevant articles and conducted this pooled analysis based on 70 studies. The relationships between patient clinical characteristics, EGFR mutation type and the response to afatinib treatment were analyzed using univariate chi-square analysis, and survival analysis was performed using the Kaplan-Meier method. Results Data from a total of 99 patients were included in the pooled analysis. The objective response rate (ORR) to treatment with afatinib was53.5%, with a median progression-free survival (mPFS) of 9.0 months. For patients administered first-line afatinib treatment, the ORR and median PFS were 73.5% and 15.6 months, respectively, which were both superior to those of patients treated with second- or later-line treatments (ORR:37.0%, p < 0.001; mPFS: 6.0months, p = 0.001). Moreover, patients with a single um-EGFRm were more likely to have a favorable response and prognosis benefit after treatment with afatinib than patients with multiple one (ORR: 63.3% vs 38.5%, p=0.017; mPFS: 15.6 months vs 6.0 months,p=0.010). Moreover, single um-EGFRm were independent predictive factors for better treatment response and superior PFS. Subgroup analysis indicated that patients harboring major um-EGFRms (i.e., L861Q, G719X, and S768I) exhibited the best treatment responses and prognoses (ORR: 74.1%, mPFS: 15.6 months), by contrast, patients harboring multiple um-EGFRms comprising 19del/L858R had the worst treatment responses and prognoses (ORR: 23.5%, mPFS: 5.6months). Conclusions Patients with um-EGFRms exhibit favorable but inconsistent responses and survival outcomes following afatinib treatment, which closely related to the mutation pattern and cooccurring partner mutant genes. Administering afatinib for the treatment of patients with um-EGFRm might be considered an effective treatment option in some circumstances, but this recommendation requires further clinical studies for verification.
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Affiliation(s)
- Wei Dong
- Department of Radiation Oncology, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Congjie Wang
- Department of Pulmonary and Critical Care Medicine, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Chunsheng Wang
- Department of Radiation Oncology, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Kewei Zhao
- Department of Radiation Oncology, Yantai Yuhuangding Hospital, Yantai, Shandong, China
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhao Ma
- Department of Radiation Oncology, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Shanliang Hu
- Department of Radiation Oncology, Yantai Yuhuangding Hospital, Yantai, Shandong, China
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Li HS, Wang SZ, Xu HY, Yan X, Zhang JY, Lei SY, Li T, Hao XZ, Zhang T, Yang GJ, Zhou LQ, Liu P, Wang YY, Hu XS, Xing PY, Wang Y. Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon EGFR Mutations: A Comparative Cohort Study in China (AFANDA Study). Cancers (Basel) 2022; 14:5307. [PMID: 36358728 PMCID: PMC9656097 DOI: 10.3390/cancers14215307] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/19/2022] [Accepted: 10/26/2022] [Indexed: 09/26/2023] Open
Abstract
(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.
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Affiliation(s)
- Hong-Shuai Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Shou-Zheng Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Medical Oncology, Beijing Chest Hospital, Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing 101149, China
| | - Hai-Yan Xu
- Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiang Yan
- Department of Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing 100000, China
| | - Jin-Yao Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Si-Yu Lei
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Teng Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xue-Zhi Hao
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Tao Zhang
- Department of Radiotherapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100000, China
| | - Guang-Jian Yang
- Department of Respiratory Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Ji’nan 250000, China
| | - Li-Qiang Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Peng Liu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yu-Ying Wang
- Department of Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing 100000, China
| | - Xing-Sheng Hu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Pu-Yuan Xing
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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14
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Bieńkowski M, Dziadziuszko R, Jassem J. Complex EGFR mutations in non-small cell lung cancer: a distinct entity? J Thorac Dis 2022; 14:2738-2741. [PMID: 36071780 PMCID: PMC9442527 DOI: 10.21037/jtd-2022-05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 06/28/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Michał Bieńkowski
- Department of Pathomorphology, Medical University of Gdańsk, Gdańsk, Poland
| | - Rafał Dziadziuszko
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland
| | - Jacek Jassem
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland
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Luo YH, Liang KH, Huang HC, Shen CI, Chiang CL, Wang ML, Chiou SH, Chen YM. State-of-the-Art Molecular Oncology of Lung Cancer in Taiwan. Int J Mol Sci 2022; 23:ijms23137037. [PMID: 35806042 PMCID: PMC9266727 DOI: 10.3390/ijms23137037] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/14/2022] [Accepted: 06/22/2022] [Indexed: 02/05/2023] Open
Abstract
Lung cancers are life-threatening malignancies that cause great healthcare burdens in Taiwan and worldwide. The 5-year survival rate for Taiwanese patients with lung cancer is approximately 29%, an unsatisfactorily low number that remains to be improved. We first reviewed the molecular epidemiology derived from a deep proteogenomic resource in Taiwan. The nuclear factor erythroid 2-related factor 2 (NRF2)antioxidant mechanism was discovered to mediate the oncogenesis and tumor progression of lung adenocarcinoma. Additionally, DNA replication, glycolysis and stress response are positively associated with tumor stages, while cell-to-cell communication, signaling, integrin, G protein coupled receptors, ion channels and adaptive immunity are negatively associated with tumor stages. Three patient subgroups were discovered based on the clustering analysis of protein abundance in tumors. The first subgroup is associated with more advanced cancer stages and visceral pleural invasion, as well as higher mutation burdens. The second subgroup is associated with EGFR L858R mutations. The third subgroup is associated with PI3K/AKT pathways and cell cycles. Both EGFR and PI3K/AKT signaling pathways have been shown to induce NRF2 activation and tumor cell proliferation. We also reviewed the clinical evidence of patient outcomes in Taiwan given various approved targeted therapies, such as EGFR-tyrosine kinase inhibitors and anaplastic lymphoma kinase (ALK)inhibitors, in accordance with the patients’ characteristics. Somatic mutations occurred in EGFR, KRAS, HER2 and BRAF genes, and these mutations have been detected in 55.7%, 5.2%, 2.0% and 0.7% patients, respectively. The EGFR mutation is the most prevalent targetable mutation in Taiwan. EML4-ALK translocations have been found in 9.8% of patients with wild-type EGFR. The molecular profiling of advanced NSCLC is critical to optimal therapeutic decision-making. The patient characteristics, such as mutation profiles, protein expression profiles, drug-resistance profiles, molecular oncogenic mechanisms and patient subgroup systems together offer new strategies for personalized treatments and patient care.
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Affiliation(s)
- Yung-Hung Luo
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (Y.-H.L.); (H.-C.H.); (C.-I.S.); (C.-L.C.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
| | - Kung-Hao Liang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
- Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Hsu-Ching Huang
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (Y.-H.L.); (H.-C.H.); (C.-I.S.); (C.-L.C.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
| | - Chia-I Shen
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (Y.-H.L.); (H.-C.H.); (C.-I.S.); (C.-L.C.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Chi-Lu Chiang
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (Y.-H.L.); (H.-C.H.); (C.-I.S.); (C.-L.C.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Mong-Lien Wang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
- Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Shih-Hwa Chiou
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Correspondence: (S.-H.C.); (Y.-M.C.); Tel.: +886-2-28757865 (Y.-M.C.)
| | - Yuh-Min Chen
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (Y.-H.L.); (H.-C.H.); (C.-I.S.); (C.-L.C.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Correspondence: (S.-H.C.); (Y.-M.C.); Tel.: +886-2-28757865 (Y.-M.C.)
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16
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Li HS, Yang GJ, Cai Y, Li JL, Xu HY, Zhang T, Zhou LQ, Wang YY, Wang JL, Hu XS, Yan X, Wang Y. Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China. Front Pharmacol 2022; 13:919652. [PMID: 35770100 PMCID: PMC9234690 DOI: 10.3389/fphar.2022.919652] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 05/18/2022] [Indexed: 11/20/2022] Open
Abstract
Objective: Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on major uncommon EGFR mutations is currently limited. Materials and methods: This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon EGFR mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1–2 months. Adverse events were assessed by CTCAE 5.0. Results: In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X (n = 24; 75%), followed by L861X (n = 10; 31.3%), and S768I (n = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1–14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4–5 adverse events (AEs) occurred, but all patients had grade 1–2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs. Conclusions: Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon EGFR mutations.
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Affiliation(s)
- Hong-Shuai Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guang-Jian Yang
- Department of Respiratory Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Ji’nan, China
| | - Yi Cai
- Independent Researcher, Ellicott City, MD, United States
| | - Jun-Ling Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hai-Yan Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li-Qiang Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu-Ying Wang
- Department of Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Jin-Liang Wang
- Department of Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xing-Sheng Hu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiang Yan
- Department of Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
- *Correspondence: Xiang Yan, ; Yan Wang,
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Xiang Yan, ; Yan Wang,
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Attili I, Passaro A, Pisapia P, Malapelle U, de Marinis F. Uncommon EGFR Compound Mutations in Non-Small Cell Lung Cancer (NSCLC): A Systematic Review of Available Evidence. Curr Oncol 2022; 29:255-266. [PMID: 35049698 PMCID: PMC8774526 DOI: 10.3390/curroncol29010024] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/15/2021] [Accepted: 01/06/2022] [Indexed: 11/16/2022] Open
Abstract
Compound epidermal growth factor receptor (EGFR) mutations represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations. We conducted a systematic review to investigate the available data on this patients' subgroup. Overall, we found a high heterogeneity in the incidence of compound mutations (4-26% of total EGFR mutant cases), which is dependent on the different testing methods adopted and the specific mutations considered. In addition, the relative incidence of distinct compound subclasses identified is reported with extreme variability in different studies. Preclinical and clinical data, excluding de novoEGFR exon 20 p.T790M compound mutations, show good responses with EGFR tyrosine kinase inhibitors (TKIs) (combined common mutations: response rate (RR) ≥ 75% with either first- or second-generation TKIs; combined common plus uncommon: RR 40-80% and 100% with first-generation TKIs and afatinib, respectively; combined uncommon: RR 20-70%, ~80% and ~75% with first-generation TKIs, afatinib and osimertinib, respectively). Overall, data are consistent in supporting the use of EGFR TKIs in treating compound EGFR mutations, taking into account different sensitivity profile of accompanying EGFR mutations for selecting the most adequate EGFR TKI for individual patients.
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Affiliation(s)
- Ilaria Attili
- Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (I.A.); (F.d.M.)
| | - Antonio Passaro
- Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (I.A.); (F.d.M.)
| | - Pasquale Pisapia
- Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; (P.P.); (U.M.)
| | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, 80131 Naples, Italy; (P.P.); (U.M.)
| | - Filippo de Marinis
- Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy; (I.A.); (F.d.M.)
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18
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Zhang Y, Shen JQ, Shao L, Chen Y, Lei L, Wang JL. Non-small-cell lung cancer with epidermal growth factor receptor L861Q-L833F compound mutation benefits from both afatinib and osimertinib: A case report. World J Clin Cases 2021; 9:8220-8225. [PMID: 34621884 PMCID: PMC8462190 DOI: 10.12998/wjcc.v9.i27.8220] [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: 05/08/2021] [Revised: 06/17/2021] [Accepted: 07/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been adopted as the standard of care for non-small cell lung cancer (NSCLC) patients harboring EGFR sensitizing mutations. Besides the two common mutations exon 19 deletion and L858R, which together comprise approximately 85% of EGFR mutations in NSCLC, rare EGFR mutations also exist, including point mutations, deletions, and insertions spanning EGFR exons 18-25. However, the responsiveness of uncommon EGFR mutations to EGFR TKIs remains elusive and attracts increasing interest. CASE SUMMARY Herein, we report a 55-year-old male patient with stage IV NSCLC harboring a rare EGFR L833F-L861Q compound mutation in cis. The patient achieved a partial response to first-line treatment with afatinib and a progression-free survival of 10 mo. After afatinib failure, the patient received multiple line treatments with chemotherapy. Upon disease progression, the heavily pretreated patient was treated with osimertinib and bevacizumab, and both lung lesion and brain metastases were stable for more than 3 mo. He had an overall survival of 25 mo. CONCLUSION Our case revealed that both afatinib and the osimertinib + bevacizumab combination demonstrated clinical efficacy in NSCLC harboring an EGFR L833F-L861Q compound mutation. The results provide more therapeutic options for patients with rare compound mutations.
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Affiliation(s)
- Yao Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China
| | - Ji-Qiao Shen
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China
| | - Lin Shao
- Burning Rock Biotech, Guangzhou 510300, Guangdong Province, China
| | - Yan Chen
- Burning Rock Biotech, Guangzhou 510300, Guangdong Province, China
| | - Lei Lei
- Burning Rock Biotech, Guangzhou 510300, Guangdong Province, China
| | - Jia-Lei Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China
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