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Translational Therapeutics

Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies

British Journal of Cancer volume 130, pages 135–142 (2024)Cite this article

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Abstract

Background

Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications.

Methods

This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed.

Results

Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively.

Conclusions

Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

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Fig. 1: NGS study at baseline.
Fig. 2: NGS study at PD.
Fig. 3: Overall resistance mechanisms stratified according to patients.
Fig. 4: Concordance between Tissue and Plasma at PD.

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References

  1. Hendriks LE, Kerr K, Menis J, Mok TS, Nestle U, Passaro A, et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34:339–57.

  2. Soria J-C, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR -mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378:113–25.

    Article  CAS  PubMed  Google Scholar 

  3. Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382:41–50.

    Article  CAS  PubMed  Google Scholar 

  4. Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121:725–37.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chmielecki J, Gray JE, Cheng Y, Ohe Y, Imamura F, Cho BC, et al. Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer. Nat Commun. 2023;14:1–9.

    Google Scholar 

  6. Rolfo C, Mack P, Scagliotti GV, Aggarwal C, Arcila ME, Barlesi F, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the International Association for the Study of Lung Cancer. J Thorac Oncol. 2021;16:1647–62.

    Article  CAS  PubMed  Google Scholar 

  7. Bonanno L, Dal Maso A, Pavan A, Zulato E, Calvetti L, Pasello G, et al. Liquid biopsy and non-small cell lung cancer: are we looking at the tip of the iceberg? Br J Cancer. 2022;127:383–93.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Piotrowska Z, Ahn M-J, Pang Y-K, How SH, Sang-We K, Voon PJ, et al. 360P ELIOS: A multicentre, molecular profiling study of patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC treated with first-line (1L) osimertinib. Ann Oncol. 2022;33:S1581–2.

  9. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  CAS  PubMed  Google Scholar 

  10. Tavtigian SV, Harrison SM, Boucher KM, Biesecker LG. Fitting a naturally scaled point system to the ACMG/AMP variant classification guidelines. Hum Mutat. 2020;41:1734–7.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Noonan SA, Berry L, Lu X, Gao D, Barón AE, Chesnut P, et al. Identifying the appropriate FISH criteria for defining MET copy number-driven lung adenocarcinoma through oncogene overlap analysis. J Thorac Oncol. 2016;11:1293–304.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005;97:643–55.

    Article  CAS  PubMed  Google Scholar 

  13. Li BT, Ross DS, Aisner DL, Chaft JE, Hsu M, Kako SL, et al. HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers. J Thorac Oncol. 2016;11:414.

    Article  PubMed  Google Scholar 

  14. Minari R, Leonetti A, Gnetti L, Zielli T, Ventura L, Bottarelli L, et al. Afatinib therapy in case of EGFR G724S emergence as resistance mechanism to osimertinib. Anticancer Drugs. 2021;32:758–62.

    Article  CAS  PubMed  Google Scholar 

  15. Blakely CM, Watkins TBK, Wu W, Gini B, Chabon JJ, McCoach CE, et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet. 2017;49:1693–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lu C, Kang J, Chen H-J, Tu H-Y, Zhou Q, Ye J-Y, et al. Co-occurring alterations in driver genes impact on EGFR-targeted therapy among patients with EGFR-mutant advanced non–small cell lung cancer. Ann Oncol. 2018;29:ix158–9.

    Article  Google Scholar 

  17. Roeper J, Falk M, Chalaris-Rißmann A, Lueers AC, Ramdani H, Wedeken K, et al. TP53 co-mutations in EGFR mutated patients in NSCLC stage IV: A strong predictive factor of ORR, PFS and OS in EGFR mt+ NSCLC. Oncotarget. 2020;11:250.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Labbé C, Cabanero M, Korpanty GJ, Tomasini P, Doherty MK, Mascaux C, et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Lung Cancer. 2017;111:23–9.

    Article  PubMed  Google Scholar 

  19. Molina-Vila MA, Bertran-Alamillo J, Gascó A, Mayo-de-las-Casas C, Sánchez-Ronco M, Pujantell-Pastor L, et al. Nondisruptive p53 mutations are associated with shorter survival in patients with advanced non-small cell lung cancer. Clin Cancer Res. 2014;20:4647–59.

    Article  CAS  PubMed  Google Scholar 

  20. Choudhury NJ, Marra A, Sui JSY, Flynn J, Yang S-R, Falcon CJ, et al. Molecular biomarkers of disease outcomes and mechanisms of acquired resistance to first-line osimertinib in advanced EGFR-mutant lung cancers. J Thoracic Oncol. 2023;18:463–75.

  21. Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376:629–40.

    Article  CAS  PubMed  Google Scholar 

  22. Oxnard GR, Hu Y, Mileham KF, Husain H, Costa DB, Tracy P, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M–positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 2018;4:1527–34.

    Article  PubMed  Google Scholar 

  23. Leonetti A, Minari R, Mazzaschi G, Gnetti L, la Monica S, Alfieri R, et al. Small cell lung cancer transformation as a resistance mechanism to osimertinib in epidermal growth factor receptor-mutated lung adenocarcinoma: case report and literature review. Front Oncol. 2021;11:642190.

    Article  PubMed  PubMed Central  Google Scholar 

  24. van Veggel B, Madeira R Santos JFV, Hashemi SMS, Paats MS, Monkhorst K, Heideman DAM, et al. Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer. Lung Cancer. 2020;141:9–13.

    Article  PubMed  Google Scholar 

  25. Papadimitrakopoulou VA, Wu Y-L, Han J-Y, Ahn M-J, Ramalingam SS, John T, et al. Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Ann Oncol. 2018;29:viii741.

    Article  Google Scholar 

  26. Xu C, Wang W, Zhu Y, Yu Z, Zhang H, Wang H, et al. Potential resistance mechanisms using next generation sequencing from Chinese EGFR T790M+ non-small cell lung cancer patients with primary resistance to osimertinib: a multicenter study. Ann Oncol. 2019;30:ii48.

    Article  Google Scholar 

  27. Fanjat Y, Barazzutti H, Di Mauro I, Tabary-Martin L, Duranton-Tanneur V, Gimet S, et al. Molecular follow-up of first-line treatment by osimertinib in lung cancer: importance of using appropriate tools for detecting EGFR resistance mutation C797S. Cancer Genet. 2021;256–257:158–61.

    Article  PubMed  Google Scholar 

  28. Chen J, Wang J, Wu X. Primary resistance to combination therapy with first- and third-generation EGFR tyrosine kinase inhibitors of lung adenocarcinoma harboring EGFR 19Del/T790M/in trans-C797S mutations with co-occurring CTNNB1 alteration. Onco Targets Ther. 2020;13:6749–53.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zhao J, Lin G, Zhuo M, Fan Z, Miao L, Chen L, et al. Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib. Lung Cancer. 2020;141:114–8.

    Article  PubMed  Google Scholar 

  30. Soria-Comes T, Palomar-Abril V, Ureste MM, Guerola MT, Maiques ICM. Real-world data of the correlation between EGFR determination by liquid biopsy in non-squamous non-small cell lung cancer (NSCLC) and the EGFR profile in tumor biopsy. Pathol Oncol Res. 2020;26:845–51.

    Article  CAS  PubMed  Google Scholar 

  31. Prabhash K, Biswas B, Khurana S, Batra U, Biswas G, Advani SH, et al. CONCORDANCE: a real-world evidence study to evaluate the concordance of detecting epidermal growth factor receptor (EGFR) mutation by circulating tumor DNA* versus tissue biopsy in patients with metastatic non-small cell lung cancer. Indian J Cancer. 2022;59:S11–8.

    Article  PubMed  Google Scholar 

  32. Choudhury Y, Tan M-H, Shi JL, Tee A, Ngeow KC, Poh J, et al. Complementing tissue testing with plasma mutation profiling improves therapeutic decision-making for patients with lung cancer. Front Med (Lausanne). 2022;9:758464.

    Article  PubMed  Google Scholar 

  33. Garcia-Pardo M, Czarnecka K, Law JH, Salvarrey A, Fernandes R, Fan J, et al. Plasma-first: accelerating lung cancer diagnosis and molecular profiling through liquid biopsy. Ther Adv Med Oncol. 2022;14:17588359221126152.

    Article  Google Scholar 

Download references

Funding

Grant by AIRC (Italian Association for Cancer Research) to TM (grant IG2017-20074).

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Author notes

  1. These authors contributed equally: A. Leonetti, M. Verzè.

Authors and Affiliations

  1. Medical Oncology Unit, University Hospital of Parma, Parma, Italy

    A. Leonetti, M. Verzè, R. Minari, F. Perrone, P. Bordi, M. Pluchino, R. Nizzoli, G. Mazzaschi, S. Buti, D. Gasparro, A. Cosenza, L. Ferri & M. Tiseo

  2. Pathology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy

    L. Gnetti, C. Azzoni, C. A. M. Lagrasta & E. M. Silini

  3. Department of Medicine and Surgery, University of Parma, Parma, Italy

    C. Azzoni, L. Bottarelli, C. A. M. Lagrasta, G. Mazzaschi, S. Buti, M. De Filippo, L. Ampollini, S. La Monica, R. Alfieri, E. M. Silini & M. Tiseo

  4. Pulmonology & Thoracic Endoscopy Unit, University Hospital of Parma, Parma, Italy

    M. Majori

  5. Radiology Unit, University Hospital of Parma, Parma, Italy

    M. De Filippo

  6. Thoracic Surgery, University Hospital of Parma, Parma, Italy

    L. Ampollini

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Contributions

MR, AR and TM designed the study. LA, PF, BP, MG, BS and TM enrolled patients and collected the clinical data. CA and FL performed blood sampling. MM, DFM, GD and AL performed tissue sampling. MR, VM, PM, AC, BL, LC, LMS and AR conducted molecular analyses. NR, GL and SEM performed cytological and histological examinations. All the authors contributed to the writing of the manuscript and approved the submitted version.

Corresponding author

Correspondence to R. Minari.

Ethics declarations

Competing interests

LA received speakers’ fee for Astra-Zeneca, MSD, Roche, Sanofi and Takeda. LA has been on advisory board for BeiGene, Novartis and Sanofi. TM received speakers’ and consultants’ fee from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, Merck, Sanofi. TM received institutional research grants from Astra-Zeneca and Boehringer Ingelheim. AR received institutional grants from Astra-Zeneca.

Ethics approval and consent to participate

The study was approved from the Local Ethic Committee on the 11th of April, 2018 (Protocol 14033, 09/04/2018). Informed consent was obtained prior to any procedure.

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Leonetti, A., Verzè, M., Minari, R. et al. Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies. Br J Cancer 130, 135–142 (2024). https://doi.org/10.1038/s41416-023-02475-9

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