RESEARCH ARTICLE
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Secondary EGFR Mutations and MET Amplification Underlying Osimertinib Resistance in Advanced Non–Small Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Pooled Analysis

Nasser Ghaly Yousif1* ORCID , Fadhil G. Alamran2, Ahmed Atimimi3, Alaa Manea Hassan3

¹ Department of Medicine, Al Muthanna Medical College, Al Muthanna University, Iraq.
² Department of Surgery/Cardiovascular, Kufa Medical College, Kufa University, Iraq.
3 MOH, Iraq.
DOI: 10.18081/ajbm.2026.3.246

Publication History: Received 26 April 2026 • Revised 28 May 2026 • Accepted 30 June 2026 • Available online 11 August 2026
Copyright: © 2026 Yousif et al. This is an open-access article under a Creative Commons license (CC BY 4.0).
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ABSTRACT

Background

Osimertinib is the preferred first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for advanced EGFR-mutated non–small cell lung cancer (NSCLC), but acquired resistance remains inevitable and is characterized by substantial molecular heterogeneity. Secondary EGFR mutations and MET amplification are among the most clinically actionable resistance mechanisms, yet their pooled prevalence and relative contribution across treatment settings remain incompletely defined.

Method

A PRISMA 2020-compliant systematic review and pooled analysis was conducted using PubMed/MEDLINE, Embase, Scopus, Web of Science, and CENTRAL for studies published from January 2015 through March 2026. Eligible studies included adults with advanced EGFR-mutated NSCLC who developed acquired resistance to osimertinib and underwent molecular profiling. The primary outcomes were the pooled prevalence of secondary EGFR mutations and MET amplification. Random-effects models were applied, with heterogeneity assessed using Cochran Q and I² statistics. Prespecified subgroup and leave-one-out sensitivity analyses were performed.

Results

Forty-three studies were included in the qualitative synthesis, and 36 studies comprising 3,914 patients were included in the pooled quantitative analysis. Secondary EGFR mutations were detected in 34.7% of resistant cases (95% CI, 31.2%–38.4%), with EGFR C797S representing the predominant on-target alteration. MET amplification occurred in 18.6% of patients (95% CI, 15.8%–21.7%) and was the most frequent EGFR-independent bypass mechanism. MET amplification was more commonly observed after first-line osimertinib, whereas secondary EGFR mutations, particularly C797S, were more frequent after later-line osimertinib in previously T790M-positive disease. Co-occurring resistance alterations were identified in a substantial proportion of tumors, including EGFR C797S with MET amplification, MET with HER2 amplification, EGFR C797S with PIK3CA mutations, and MET amplification with KRAS alterations. Between-study heterogeneity was moderate, and sensitivity analyses demonstrated stable pooled estimates without disproportionate influence from any single study.

Conclusion

Acquired resistance to osimertinib in advanced EGFR-mutated NSCLC is driven by a complex and heterogeneous molecular landscape in which secondary EGFR mutations and MET amplification represent the principal actionable mechanisms. EGFR C797S remains the dominant on-target resistance alteration, whereas MET amplification is the leading bypass pathway. These findings support comprehensive molecular reassessment at disease progression and favor biomarker-guided combination strategies, including dual EGFR-MET inhibition and next-generation approaches targeting tertiary EGFR mutations.

Keywords: EGFR; Osimertinib; Non–small cell lung cancer; Acquired resistance; C797S; MET amplification

Recommended Citation

Yousif NG, Alamran FG, Atimimi A, Hassan AM. Secondary EGFR Mutations and MET Amplification Underlying Osimertinib Resistance in Advanced Non–Small Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Pooled Analysis. Advanced Journal of Biomedicine & Medicine. 2026;14(3):246-268. doi:10.18081/ajbm.2026.3.246

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Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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2026 Vol 14, Issue 3 Pages 246-268

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Yousif NG, Alamran FG, Atimimi A, Hassan AM (2026). Secondary EGFR Mutations and MET Amplification Underlying Osimertinib Resistance in Advanced Non–Small Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Pooled Analysis. Advanced Journal of Biomedicine & Medicine, 14(3), 246-268. https://doi.org/10.18081/ajbm.2026.3.246
Yousif NG, Alamran FG, Atimimi A, Hassan AM. " Secondary EGFR Mutations and MET Amplification Underlying Osimertinib Resistance in Advanced Non–Small Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Pooled Analysis." Advanced Journal of Biomedicine & Medicine, vol. 14, no. 3, 2026, pp. 246-268. DOI: 10.18081/ajbm.2026.3.246.
Yousif NG, Alamran FG, Atimimi A, Hassan AM. Secondary EGFR Mutations and MET Amplification Underlying Osimertinib Resistance in Advanced Non–Small Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Pooled Analysis. AJBM. 2026;14(3):246-268. DOI: 10.18081/ajbm.2026.3.246. PMID: .
Yousif NG, Alamran FG, Atimimi A, Hassan AM 2026, " Secondary EGFR Mutations and MET Amplification Underlying Osimertinib Resistance in Advanced Non–Small Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Pooled Analysis", Advanced Journal of Biomedicine & Medicine, vol. 14, no. 3, pp. 246-268.
@article{yousif2026, title={ Secondary EGFR Mutations and MET Amplification Underlying Osimertinib Resistance in Advanced Non–Small Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Pooled Analysis}, author={Yousif NG, Alamran FG, Atimimi A, Hassan AM}, journal={Advanced Journal of Biomedicine & Medicine}, volume={14}, number={3}, pages={246-268}, year={2026}, doi={10.18081/ajbm.2026.3.246} }
TY - JOUR AU - Yousif NG, Alamran FG, Atimimi A, Hassan AM TI - Secondary EGFR Mutations and MET Amplification Underlying Osimertinib Resistance in Advanced Non–Small Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Pooled Analysis JO - American Journal of Biomedicine VL - 14 IS - 3 SP - 246-268 PY - 2026 DO - 10.18081/ajbm.2026.3.246 ER -
%0 Journal Article %A Yousif NG, Alamran FG, Atimimi A, Hassan AM %T Secondary EGFR Mutations and MET Amplification Underlying Osimertinib Resistance in Advanced Non–Small Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Pooled Analysis %J American Journal of Biomedicine %V 14 %N 3 %P 246-268 %D 2026 %R 10.18081/ajbm.2026.3.246 %M
Yousif NG, Alamran FG, Atimimi A, Hassan AM (2026). Secondary EGFR Mutations and MET Amplification Underlying Osimertinib Resistance in Advanced Non–Small Cell Lung Cancer: A PRISMA-Compliant Systematic Review and Pooled Analysis. Advanced Journal of Biomedicine & Medicine, 14(3), 246-268. https://doi.org/10.18081/ajbm.2026.3.246

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