In EGFRm advanced NSCLC

Our understanding of tumours is evolving, and so is the research that targets them

2 out 3 patients that progress on 1st generation EGFR TKIs have the T790M mutation
2 out 3 patients that progress on 1st generation EGFR TKIs have the T790M mutation
2 out 3 patients that progress on 1st generation EGFR TKIs have the T790M mutation
2 out 3 patients that progress on 1st generation EGFR TKIs have the T790M mutation
2 out 3 patients that progress on 1st generation EGFR TKIs have the T790M mutation
2 out 3 patients that progress on 1st generation EGFR TKIs have the T790M mutation

An overview of lung cancer

  • Lung cancer has been the most common cancer globally for several decades; by 2012, there were an estimated 1.8 million new cases and 1.59 million deaths per year1
Tumour classification

The majority of lung cancers are non-small cell histology2

  • Non-small cell lung cancer (NSCLC) is divided into 2 broad histological groups: squamous and nonsquamous2
  • Squamous cell carcinomas are usually found in the center of the lung next to a bronchus, and is often linked to a history of smoking2
  • Nonsquamous histology includes the subgroups adenocarcinomas (outer parts of the lung) and large cell carcinomas (any part of the lung)2
 

Genetic alterations and abnormal gene expression contribute to pathogenesis of NSCLC3,4

Among these are EGFR-sensitising mutations (23%)3

  • Other genetic alterations include3:
    • KRAS mutations
    • ALK rearrangements
    • MET/HGFR pathway alterations
  • Approximately 30%–50% of advanced NSCLC patients in Asian populations and 7-14% in Western populations will have tumours that contain activating/sensitising mutations in EGFR (EGFRm)6-8
Tumour classification

For EGFRm advanced NSCLC patients, EGFR TKIs are a treatment option for patients*9

Most EGFRm tumours will acquire resistance to EGFR TKIs

  • Despite high initial responses with first-generation EGFR TKIs, most patients with EGFRm advanced NSCLC will develop resistance to currently available EGFR TKIs*10,11
  • A number of potential mechanisms that mediate EGFR TKI resistance have been identified: eg, development of a secondary EGFR mutation, T790M; HER2 amplification; MET amplification, PIK3CA mutation; BRAF mutation; NF1 loss; and EGFR signalling11

*Afatinib, erlotinib, and gefitinib
Defined as gefitinib and erlotinib.

Tumour classification

Acquired resistance affects patients who initially responded to first-generation EGFR TKI therapy, then stopped responding. Acquired resistance occurs in most NSCLC patients treated with first-generation EGFR TKIs.12

 

As many as 2 out of 3 cases of progression with first-generation EGFR TKIs may be related to the T790M mutation13,14

  • The main identified mechanisms of acquired resistance to first-generation EGFR TKIs can generally be classified as T790M mutations (most common), alternative pathway activations (eg, MET or HER2 amplification), or phenotypic transformations (to SCLC or EMT)15
  • Studies have reported the incidence of T790M in tumours that have developed resistance to these TKIs to range from 51% - 68%13,14,16-19
  • Currently, there are no published clinical studies that have assessed the incidence of acquired T790M-mediated resistance during treatment with afatinib; however, preclinical data and an early case report suggest that T790M-mediated resistance may also develop with this agent20,21

Studies published in the past 4 years (erlotinib, gefitinib). Primary manuscript, N≥50. Prospective tissue biopsy performed at disease progression. Primary endpoint = examining molecular mechanisms of acquired resistance; methodology reported.

Resistant Mechanisms to EGFR TKIs

Resistant Mechanisms to EGFR TKIs

  • T790M13,14,16-19
  • Other15
    • Alternative pathway activations
    • Phenotypic transformations
    • Unknown
Resistant mechanisms to EGFR TKIs

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The secondary T790M mutation is believed to result in acquired resistance to EGFR TKIs by two potential mechanisms:

1

Steric hindrance, which reduces receptor binding of reversible EGFR TKIs22

e/
ou
2

Increased binding affinity of EGFR for ATP, resulting in reduced TKI potency23

 

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The secondary T790M mutation is believed to result in acquired resistance to EGFR TKIs by two potential mechanisms:

1e/
ou
2

Obstáculo estérico, que reduz a ligação aos receptores de TKIs do EGFR reversíveis22

Afinidade de ligação aumentada do EGFR por ATP, resultando em potência reduzida do TKI23

 
 

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Tumors can be assessed to uncover T790 acquired mutations.
 

Searching for the T790M mutation

  • Patients should be monitored for radiologic or clinical progression
    • Tumours can be assessed for molecular progression to uncover additional acquired mutations
  • When patients with EGFRm status progress, prior to changing therapy, sampling and testing at progression are reasonable to identify mechanisms of acquired resistance; clinical guidelines recommend a biopsy at progression8
  • Drivers of resistance can be identified through DNA mutational analysis24

AstraZeneca is committed to advancing lung cancer research

 
 
  1. Learn more about the research on targeted therapies

References

1. GLOBOCAN 2012. http://globocan.iarc.fr. Accessed February 9, 2015. 2. American Cancer Society. Lung cancer (non-small cell). http://www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf. Published 2014. Accessed March 20, 2015. 3. Kris MG, et al.Identification of driver mutations in tumour specimens from 1,000 patients with lung adenocarcinoma: the NCI's Lung Cancer Mutation Consortium (LCMC) ASCO meeting abstract. J Clin Oncol. 2011;29(suppl):CRA7506. 4. Langer CJ. Epidermal growth factor receptor inhibition in mutation-positive non–small-cell lung cancer. is afatinib better or simply newer? J Clin Oncol.2013;27:3303-3306. 5. Cheng L,et al. Molecular pathology of lung cancer: key to personalized medicine.Mod Pathol. 2012;20:347-369. 6. Shigematsu H, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97:339-346. 7. Sekine I, et al. Emerging ethnic differences in lung cancer therapy. Br J Cancer. 2008;99:1757-1762. 8. Hirsch FR, et al. EGFR testing in lung cancer is ready for prime time. Lancet Oncol. 2009;10:432-433. 9. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-small Cell Lung Cancer v6.2015. © National Comprehensive Cancer Network,Inc 2015. All rights reserved. Accessed May 18, 2015.To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®,NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc. 10. Sequist LV, etal.Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31(27):3327-3334. 11. Mok TS,et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957. 12. Nurwidya F, et al. Molecular mechanisms contributing to resistance to tyrosine kinase-targeted therapy for non-small cell lung cancer. Cancer Biol Med. 2012;9(1):18-22. 13. Yu HA, et al. Analysis of tumour specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247. 14. Arcila ME, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011;17:1169-1180. 15. Cortot AB, Janne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respi Rev. 2014;23:356-366. 16. Oxnard GR, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumours harboring the T790M mutation. Clin Cancer Res. 2011;17:1616-1622. 17. Sun JM, et al. Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors. Lung Cancer. 2013;82:294-298. 18. Kuiper JL, et al. Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung Cancer. 2014;85:19-24. 19. Li W, et al. T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients. Lung Cancer. 2014;84:295-300. 20. Kim Y, Ko J, Cui Z, et al. The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol Cancer Ther. 2012;11(3)784-791. 21. Chmielecki J,et al.Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011;3:90ra59. 22. Kobayashi S, et al.EGFR mutation and resistance of non–small-cell lung cancer to gefitinib.N Engl J Med. 2005;352(8):786-792. 23. Yun CH, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008;105(6):2070-2075. 24. Pao W, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:225-235.