Afatinib and Necitumumab in EGFR-Mutant NSCLC with Acquired Resistance to Tyrosine Kinase Inhibitors
Introduction: Although tyrosine kinase inhibitors (TKIs) are effective against NSCLC harboring sensitizing EGFR gene mutations, acquired resistance is inevitable. Preclinical studies suggest that combining EGFR TKI and monoclonal antibody therapies may have activity in EGFR-mutated NSCLC that has pr...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | JTO Clinical and Research Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666364324001279 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841555707921432576 |
|---|---|
| author | Nathaniel J. Myall, MD Jennifer G. Whisenant, PhD Joel W. Neal, MD, PhD Wade T. Iams, MD Karen L. Reckamp, MD Sally York, MD, PhD Lynne D. Berry, PhD Yu Shyr, PhD Leora Horn, MD Heather A. Wakelee, MD Sukhmani K. Padda, MD |
| author_facet | Nathaniel J. Myall, MD Jennifer G. Whisenant, PhD Joel W. Neal, MD, PhD Wade T. Iams, MD Karen L. Reckamp, MD Sally York, MD, PhD Lynne D. Berry, PhD Yu Shyr, PhD Leora Horn, MD Heather A. Wakelee, MD Sukhmani K. Padda, MD |
| author_sort | Nathaniel J. Myall, MD |
| collection | DOAJ |
| description | Introduction: Although tyrosine kinase inhibitors (TKIs) are effective against NSCLC harboring sensitizing EGFR gene mutations, acquired resistance is inevitable. Preclinical studies suggest that combining EGFR TKI and monoclonal antibody therapies may have activity in EGFR-mutated NSCLC that has progressed on TKI therapy alone. Therefore, we prospectively evaluated afatinib plus necitumumab in patients with EGFR-mutated NSCLC. Methods: This was a phase 1, dose-escalation, dose-expansion trial assessing the safety and efficacy of afatinib plus necitumumab. Patients had advanced or metastatic EGFR-mutated NSCLC with progression after (1) first-generation TKI if T790M negative, (2) subsequent line third-generation TKI if T790M positive, or (3) third-generation TKI in the first-line setting. Dose-escalation followed a 3+3 design. The primary end point of dose-expansion was objective response rate. Results: A total of 22 patients with EGFR-mutated NSCLC were enrolled. The maximum tolerated dose was afatinib 40 mg oral daily plus necitumumab 600 mg intravenous on days 1 and 15 every 28 days. There were no grade 4 to 5 adverse events observed, and seven patients (32%) experienced grade 3 treatment-related adverse events (three rash; one each oral mucositis, diarrhea, headache, ventricular arrhythmia, and tachycardia). In the entire cohort, there were no responses observed, the median progression-free survival was 1.8 months, and the disease control rate was 36% but varied between the subgroups. Conclusions: Afatinib plus necitumumab was safe but had limited activity in patients with EGFR-mutated NSCLC. Biomarker studies may identify patient subgroups that are more likely to benefit. |
| format | Article |
| id | doaj-art-d3a5c40d0bc146e4b019e5b370551f68 |
| institution | Kabale University |
| issn | 2666-3643 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JTO Clinical and Research Reports |
| spelling | doaj-art-d3a5c40d0bc146e4b019e5b370551f682025-01-08T04:53:43ZengElsevierJTO Clinical and Research Reports2666-36432025-02-0162100757Afatinib and Necitumumab in EGFR-Mutant NSCLC with Acquired Resistance to Tyrosine Kinase InhibitorsNathaniel J. Myall, MD0Jennifer G. Whisenant, PhD1Joel W. Neal, MD, PhD2Wade T. Iams, MD3Karen L. Reckamp, MD4Sally York, MD, PhD5Lynne D. Berry, PhD6Yu Shyr, PhD7Leora Horn, MD8Heather A. Wakelee, MD9Sukhmani K. Padda, MD10Department of Medicine, Division of Oncology, Stanford University, Stanford, CaliforniaDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TennesseeDepartment of Medicine, Division of Oncology, Stanford University, Stanford, CaliforniaDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TennesseeDepartment of Medicine, Cedars-Sinai Medical Center, Los Angeles, CaliforniaDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TennesseeDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TennesseeDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TennesseeDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TennesseeDepartment of Medicine, Division of Oncology, Stanford University, Stanford, CaliforniaDepartment of Medicine, Division of Oncology, Stanford University, Stanford, California; Department of Hematology/Oncology, Fox Chase Cancer Center/Temple Health, Philadelphia, Pennsylvania; Corresponding author. Address for correspondence: Sukhmani K. Padda, MD, Department of Hematology/Oncology, Fox Chase Cancer Center/Temple Health, 3401 N. Broad Street, 4th Floor ACC Building, Philadelphia, Pennsylvania 19140.Introduction: Although tyrosine kinase inhibitors (TKIs) are effective against NSCLC harboring sensitizing EGFR gene mutations, acquired resistance is inevitable. Preclinical studies suggest that combining EGFR TKI and monoclonal antibody therapies may have activity in EGFR-mutated NSCLC that has progressed on TKI therapy alone. Therefore, we prospectively evaluated afatinib plus necitumumab in patients with EGFR-mutated NSCLC. Methods: This was a phase 1, dose-escalation, dose-expansion trial assessing the safety and efficacy of afatinib plus necitumumab. Patients had advanced or metastatic EGFR-mutated NSCLC with progression after (1) first-generation TKI if T790M negative, (2) subsequent line third-generation TKI if T790M positive, or (3) third-generation TKI in the first-line setting. Dose-escalation followed a 3+3 design. The primary end point of dose-expansion was objective response rate. Results: A total of 22 patients with EGFR-mutated NSCLC were enrolled. The maximum tolerated dose was afatinib 40 mg oral daily plus necitumumab 600 mg intravenous on days 1 and 15 every 28 days. There were no grade 4 to 5 adverse events observed, and seven patients (32%) experienced grade 3 treatment-related adverse events (three rash; one each oral mucositis, diarrhea, headache, ventricular arrhythmia, and tachycardia). In the entire cohort, there were no responses observed, the median progression-free survival was 1.8 months, and the disease control rate was 36% but varied between the subgroups. Conclusions: Afatinib plus necitumumab was safe but had limited activity in patients with EGFR-mutated NSCLC. Biomarker studies may identify patient subgroups that are more likely to benefit.http://www.sciencedirect.com/science/article/pii/S2666364324001279Dual EGFR inhibitionPhase I trialLung cancerEGFR-mutated |
| spellingShingle | Nathaniel J. Myall, MD Jennifer G. Whisenant, PhD Joel W. Neal, MD, PhD Wade T. Iams, MD Karen L. Reckamp, MD Sally York, MD, PhD Lynne D. Berry, PhD Yu Shyr, PhD Leora Horn, MD Heather A. Wakelee, MD Sukhmani K. Padda, MD Afatinib and Necitumumab in EGFR-Mutant NSCLC with Acquired Resistance to Tyrosine Kinase Inhibitors JTO Clinical and Research Reports Dual EGFR inhibition Phase I trial Lung cancer EGFR-mutated |
| title | Afatinib and Necitumumab in EGFR-Mutant NSCLC with Acquired Resistance to Tyrosine Kinase Inhibitors |
| title_full | Afatinib and Necitumumab in EGFR-Mutant NSCLC with Acquired Resistance to Tyrosine Kinase Inhibitors |
| title_fullStr | Afatinib and Necitumumab in EGFR-Mutant NSCLC with Acquired Resistance to Tyrosine Kinase Inhibitors |
| title_full_unstemmed | Afatinib and Necitumumab in EGFR-Mutant NSCLC with Acquired Resistance to Tyrosine Kinase Inhibitors |
| title_short | Afatinib and Necitumumab in EGFR-Mutant NSCLC with Acquired Resistance to Tyrosine Kinase Inhibitors |
| title_sort | afatinib and necitumumab in egfr mutant nsclc with acquired resistance to tyrosine kinase inhibitors |
| topic | Dual EGFR inhibition Phase I trial Lung cancer EGFR-mutated |
| url | http://www.sciencedirect.com/science/article/pii/S2666364324001279 |
| work_keys_str_mv | AT nathanieljmyallmd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors AT jennifergwhisenantphd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors AT joelwnealmdphd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors AT wadetiamsmd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors AT karenlreckampmd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors AT sallyyorkmdphd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors AT lynnedberryphd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors AT yushyrphd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors AT leorahornmd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors AT heatherawakeleemd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors AT sukhmanikpaddamd afatinibandnecitumumabinegfrmutantnsclcwithacquiredresistancetotyrosinekinaseinhibitors |