Overcoming Resistance in EGFRm Lung Cancer

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Topics:

Clinical innovation

Disease understanding

Next generation therapeutics

Predicting clinical success 

Simon-Collett

Written by:

George Kirk,

Global Franchise Head, AstraZeneca

Epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) has been transformed by biomarker-directed therapies, yet resistance mechanisms remain a persistent challenge driving progression in advanced disease.1 At AstraZeneca, we are pioneering innovative medicines and novel combination strategies rooted in precision medicine to overcome resistance, delay progression and deliver improved outcomes for patients across lines of therapy.

A Precision Medicine Success Story – But Not the Final Chapter

One of oncology’s great precision medicine success stories came from the discovery of EGFR.2 EGFR is a kind of protein called a tyrosine kinase receptor that is involved in cell growth, division and survival.3 Mutations in the gene that produces EGFR can lead to uncontrolled cell growth and cancer.3,4,5

We learned that EGFR mutations can be “actionable biomarkers” – a measurable tumour characteristic that can be tested and targeted by treatments – in lung cancer.6 This enabled the development of EGFR-tyrosine kinase inhibitors (TKIs), therapies that block the activity of the EGFR protein and thereby may block cancer cells from growing.4 These targeted therapies have transformed the care of EGFRm NSCLC and underscored the urgency of biomarker testing at the time of diagnosis, but this story does not end there.1,7

Despite the efficacy of these biomarker-directed therapies, patients commonly develop resistance to these drugs over time, which means the treatments stop working because the tumour cells outsmart the drug, and disease progression can occur.8,9 When patients with EGFRm NSCLC invariably experienced disease progression with first- and second-generation EGFR-TKIs, researchers uncovered the T790M resistance mutation as the most common mechanism of acquired resistance, present in 50-60% of cases.8 This discovery spurred the development of third-generation medicines targeting both the initial mutations and this acquired resistance mutation.10

While this approach cemented third-generation EGFR-TKIs as the standard of care, progression remains a challenge due to various other drivers of resistance – some emerging as a result of treatment and others present from the very start.1,8,10,11 Tackling these is the next chapter in this story of scientific progress.

At AstraZeneca, we are committed to continuous innovation to improve outcomes for patients with lung cancer. That’s why we are pioneering new approaches driven by precision medicine, biomarker testing and innovative combinations that address the underlying drivers of progression – or employ novel types of treatment when no actionable biomarkers are identified.

What Drives Resistance to Third-generation EGFR-TKIs?

In first- and second-generation EGFR-TKIs, most resistance is driven by a single “on-target” mutation (T790M, a change to the EGFR protein itself); however, in third-generation EGFR-TKIs, on-target mutations are less common.1,10,12

Instead, resistance is largely driven (70-80%) by off-target, bypass pathways — alternate growth routes the tumour can switch to, allowing it to “bypass” the inhibition of the EGFR pathway and keep growing.1,10,13,14 These bypass mechanisms can coexist alongside the persistent original EGFR driver mutation, rather than replacing it.13

The most common of these is MET amplification or overexpression.10,13 Like EGFR, MET is also a tyrosine kinase receptor protein with an essential role in normal cell development.15 MET overexpression (when a cancer cell has too much of the MET protein) or amplification (when a cancer cell has extra copies of the MET gene that produces the MET protein) can lead to tumour growth and the metastatic progression of cancer cells.15,16,17,18 These develop as an acquired resistance mechanism in patients taking third-generation EGFR-TKI therapy.19,20

While far less common, MET amplification or overexpression can also be present before treatment begins, coexisting with the original EGFR mutation as an intrinsic driver of resistance to EGFR-TKI therapy.21,22

Beyond MET, there are several other mechanisms that can help a tumour bypass EGFR inhibition and some patients’ tumours may also undergo histologic transformation over time, where the cancer cells themselves change type (e.g., from NSCLC to small cell lung cancer).10,23

The Urgency of Biomarker Testing Beyond Diagnosis

Biomarker testing is just as important upon progression as it is at diagnosis.24

Testing at diagnosis identifies the initial actionable driver mutation and can also reveal co-existing drivers of resistance, like MET amplification, present at the start.25,26 Testing at progression is crucial to identify why the tumour escaped for patients who develop new resistance mechanisms over the course of treatment.25,26

Identifying the specific actionable driver of resistance (or confirming none has been found) helps clinicians match each patient to the right medicine: a therapy targeted to that mechanism of resistance, or another novel modality when no such mechanism is identified.25,27

Advancing New Approaches to Overcome Resistance

Our clinical strategy for tackling progression in advanced EGFRm NSCLC focuses on two key areas:

  1. Advancing personalised approaches using biomarker-driven therapies to address resistance to 1st-line EGFR-TKIs—whether present from the outset or developing in response to therapy
  2. Developing novel combinations to attack cancer from multiple angles and drive deeper, more durable responses

To address resistance caused by a bypass mechanism like MET, we are pioneering combination therapies that pair a targeted therapy that inhibits the driver of resistance with the therapy that maintains suppression of the initial mutation.

For those patients experiencing progression whose biomarker testing does not identify an actionable driver of resistance, we’re researching novel combinations pairing EGFR-TKI therapy with additional treatment approaches designed to work independent of specific driver mechanisms.

Tackling resistance can also begin in the 1st-line setting, before resistance even has a chance to develop.28 Our scientists continue to explore the combination of EGFR-TKIs with other types of treatment from the start, to help delay the onset of resistance and progression and improve survival.

Resistance to EGFR-TKI therapy isn’t the end of the story – and we’re already writing the next chapter. As we continue following the science to understand how resistance emerges over time, we’re designing novel combination strategies to help extend the effectiveness of treatment and provide more sustained outcomes.

Our ambition is to eliminate lung cancer as a cause of death. Overcoming resistance in EGFRm disease is an important part of how we intend to get there.

Topics:

Clinical innovation
Next generation therapeutics
Disease understanding
Predicting clinical success

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References

  1. Kang DH, et al. Navigating the Complexity of Resistance in Lung Cancer Therapy: Mechanisms, Organoid Models, and Strategies for Overcoming Treatment Failure. Cancers (Basel). 2024;16(23):3996.
  2. Herbst RS, et al. Looking back on the history of epidermal growth factor receptor mutations in lung cancer. Philos Trans R Soc Lond B Biol Sci. 2026;381(1957):20240506.
  3. National Cancer Institute. NCI Dictionary of Cancer Terms – EGFR. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/egfr. Accessed October 2026.
  4. National Cancer Institute. NCI Dictionary of Cancer Terms – EGFR tyrosine kinase inhibitor. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/egfr-tyrosine-kinase-inhibitor. Accessed October 2026.
  5. Dana-Farber Cancer Institute. EGFR Mutant Lung Cancer. Available at: https://www.dana-farber.org/cancer-care/types/egfr-mutant-lung-cancer. Accessed October 2026.
  6. Mukherjee P, et al. Biomarkers for targeted therapy and treatment decision making. Adv Cancer Res. 2026;170:89-138.
  7. Ellison G, et al. EGFR mutation testing in lung cancer: a review of available methods and their use for analysis of tumour tissue and cytology samples. J Clin Pathol. 2013;66(2):79-89.
  8. Westover D, et al. Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol. 2018;29(Suppl 1):i10-i19.
  9. Lung Cancer Foundation of America. Biomarkers and Why Testing is Important. Available at: https://lcfamerica.org/about-lung-cancer/diagnosis/biomarkers/. Accessed October 2026.
  10. Dempke WCM, et al. Resistance to third-generation EGFR TKIs - what can be expected from the fourth-generation? Cancer Drug Resist. 2026;9:33.
  11. Wang J, et al. Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations. Onco Targets Ther. 2016;9:3711-3726.
  12. Wu, PS, et al. EGFR-T790M Mutation–Derived Interactome Rerouted EGFR Translocation Contributing to Gefitinib Resistance in Non-Small Cell Lung Cancer. Mol Cell Proteomics. 2023;22(9):100624.
  13. Jiang Z, et al. Research progress on the role of bypass activation mechanisms in resistance to tyrosine kinase inhibitors in non-small cell lung cancer. Front Oncol. 2024;14:1447678.
  14. Wu JJ, et al. Combination Therapy With MET Tyrosine Kinase Inhibitor and EGFR Tyrosine Kinase Inhibitor in Patients With MET-Overexpressed EGFR-Mutant Lung Adenocarcinoma. JTO Clin Res Rep. 2025;6(6):100832.
  15. Uchikawa E, et al. Structural basis of the activation of c-MET receptor. Nat Commun. 2021;12(1):4074.
  16. Wang Q, et al. MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer. J Hematol Oncol. 2019;12(1):63.
  17. Baldacci S, et al. MET amplification increases the metastatic spread of EGFR-mutated NSCLC. Lung Cancer. 2018;125:57-67.
  18. Tsao MS, et al. MET (c-Met) protein overexpression is an emerging protein biomarker in non- small cell lung cancer. NPJ Precis Oncol. 2025;9:369.
  19. Suzawa K, et al. Acquired MET Exon 14 Alteration Drives Secondary Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in EGFR-Mutated Lung Cancer. JCO Precis Oncol. 2019;3:PO.19.00011.
  20. Yu D, et al. Managing Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors Through Co-Targeting MEK/ERK Signaling. Lung Cancer. 2021;12:1-10.
  21. Mi J, et al. Molecular characterization and clinical outcomes in EGFR-mutant de novo MET-overexpressed advanced non-small-cell lung cancer. ESMO Open. 2021;7(1):100347.
  22. Coleman N, et al. Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer. ESMO Open. 2021;6(6):100319.
  23. Shiba-Ishii A, et al. Histologic transformation of non‐small‐cell lung cancer in response to tyrosine kinase inhibitors: Current knowledge of genetic changes and molecular mechanisms. Cancer Sci. 2024;115(7):2138-2146.
  24. GO2 for Lung Cancer. Do I Need Another Test? The Importance of Repeat Biomarker Testing in NSCLC. Available at: https://go2.org/blog/do-i-need-another-test-the-importance-of-repeat-biomarker-testing-in-nsclc. Accessed October 2026.
  25. LUNGevity Foundation. Biomarker Testing. Available at: https://www.lungevity.org/patients-care-partners/navigating-your-diagnosis/biomarker-testing. Accessed October 2026.
  26. Walker PR, et al. Targeting EGFR mutations needs to be more precise with co-mutations. Precis Cancer Med. 2020;3:8.
  27. Saporita I, et al. Tailored strategies to overcome third-generation TKI resistance in EGFR-mutated non-small cell lung cancer. Expert Opin Ther Targets. 2026;30(7):675-691.
  28. Nan X, et al. EGFR TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Oncotarget. 2017;8(43):75712-75726.

Veeva ID: Z4-89188
Date of preparation: October 2026