The Development of EGFR-TKIs: A Fight against Drug Resistance

EGFR-TKI and its role in antitumor effect

The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. In the late 20th century, scientists gradually uncovered the critical role of EGFR in tumor growth. When it bound to epidermal growth factor (EGF), it activated several key downstream signaling pathways, such as RAS-RAF-MEK-ERK and PI3K-AKT, which promoted cell proliferation and survival while inhibiting apoptosis.[1] Cancer cells often “hijack” this pathway to sustain continuous growth. Scientists proposed a revolutionary idea: if EGFR signaling could be selectively blocked, tumor growth might be effectively controlled. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) worked by blocking the EGFR protein. It achieved this by binding to the adenosine triphosphate (ATP)-binding site within the EGFR kinase domain, preventing the receptor from activating downstream signaling pathways that promote cancer cell growth and survival. This inhibition could lead to cell cycle arrest, apoptosis, and reduced tumor growth.[2],[3]  

The birth and temporary failure of gefitinib

In 2002, gefitinib was first approved in Japan, becoming the world’s first EGFR-TKI. In the next year, the U.S. Food and Drug Administration (FDA) granted accelerated approval for gefitinib to treat advanced non-small cell lung cancer (NSCLC) patients who had failed prior chemotherapy, based on the results of IDEAL 1 and IDEAL 2 trials. However, according to the large-scale phase III trials INTACT I and INTACT II in chemotherapy-naive patients with advanced NSCLC, no significant improvement in median overall survival (OS, 9.9 vs 10.9 months, p=0.4560; 9.8 vs 9.9, p=0.64, individually) and progression-free survival (5.8 vs 6.0 months, p=0.7633 in INTACT I) was observed with the addition of gefitinib to chemotherapy compared to chemotherapy alone.[4],[5]  Therefore, in 2005, the FDA tightened the indications, allowing only patients who had already benefited to continue using it and not recommending it to new patients.

The beginning of precision medicine 

So why did it happen? In 2004, Lynch et al. [6] and Paez et al. [7] found that EGFR mutations were predictive biomarkers of gefitinib sensitivity in NSCLC, and also demonstrated better clinical responses to gefitinib. Therefore, researchers gradually realized that only specific groups of NSCLC patients could benefit from gefitinib treatment. The exon 21 L858R point mutation constituted approximately 85% of all EGFR mutations. In a head-to-head trial, WJTOG3405, chemotherapy-naive advanced NSCLC patients harbouring EGFR mutations (either the exon 19 deletion or the L858R point mutation) were randomized into a chemotherapy group or a gefitinib group, and the gefitinib group had significantly longer progression-free survival (PFS) compared with the chemotherapy group, with a median PFS of 9.2 months vs. 6.3 months (p<0.0001). [8] As a result, in 2015, the FDA re-approved gefitinib as a first-line treatment for patients with metastatic NSCLC carrying EGFR exon 19 deletion or exon 21 (L858R) mutation. This approval marked the significant position of gefitinib in the field of precision medicine and highlighted the crucial role of genetic testing in guiding the treatment of lung cancer.

Incidence of Acquired resistance

The initial failure of gefitinib was not only attributed to the absence of conducting genetic screening for patients. Actually, 60% to 70% of patients would experience disease progression (acquired resistance) approximately 9 to 13 months after receiving gefitinib treatment. By 2005, it was well established that EGFR mutations such as exon 19 deletions and exon 21 L858R substitutions predicted excellent initial responses to gefitinib in patients with NSCLC. Among the patients with acquired resistance, a new secondary EGFR mutation: T790M, was observed by Pao et, al [9] , this mutation involved a substitution of threonine with methionine at position 790 in the EGFR kinase domain, and the T790M mutation increased ATP affinity at the kinase domain, which made it harder for gefitinib (which is ATP-competitive inhibitors) to effectively bind to the receptor. This is the most common acquired resistance mechanism exhibited by gefitinib. Other acquired resistance mechanisms of the first-generation EGFR-TKI were discovered gradually such as MET gene amplification and human epidermal growth factor receptor 2 (HER2) amplification. However, more than half of the patients with disease progression still face the T790M mutation. Therefore, experts have also focused the development of EGFR-TKI on conquering the T790M mutation while ensuring efficacy and safety.

Second and third generation of EGFR-TKI

Afatinib is a second-generation irreversible EGFR-TKI that was first approved by the FDA in 2013. It forms a covalent bond with the EGFR kinase domain and irreversibly inhibits not only EGFR but also other members of the HER family, such as HER2 and human epidermal growth factor receptor 4 (HER4). Compared to first-generation, afatinib provides broader inhibition and stronger suppression of EGFR signaling.[10] However, the problem of drug resistance in patients carrying the T790M mutation still failed to be solved.

Osimertinib is a third-generation irreversible EGFR TKI that was first approved by the FDA in 2015, for the patients with EGFR T790M mutation positive NSCLC, who have progressed on or after EGFR TKI therapy. It covalently binds to the EGFR kinase domain, effectively inhibiting both sensitizing mutations and the resistance-associated T790M mutation, overcoming the common resistance seen with first- and second-generation EGFR-TKIs. According the results from AURA3 trial [11] for patients with T790M-positive advanced NSCLC who failed EGFR-TKI treatment, The median duration of PFS was significantly longer with osimertinib than with chemotherapy (10.1 months vs. 4.4 months, P<0.001).  During the years since osimertinib was launched on the market, more studies had been carried out to expand the clinical application scope of osimertinib. In a head-to-head trial FLAURA for treatment-naïve advanced NSCLC patients [12], compared with gefinitib, osimertinib treatment showed a longer PFS (18.9 months vs. 10.2 months, P<0.001) and higher survival rate at 18 months (83% vs 71%, P=0.007). Therefore, in 2018, osimertinib was approved by the FDA as a first-line treatment for patients with metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

Summary

The superior efficacy of osimertinib compared to first-generation EGFR-TKIs, along with its ability to overcome resistance mutations, has brought new hope to patients with NSCLC. But acquired resistance eventually emerged. The most common mechanism is the EGFR C797S mutation, it is a point mutation where the amino acid cysteine (C) at position 797 in the EGFR kinase domain is substituted by serine (S). However, we must always firmly believe that one day in the future, we will overcome acquired resistance.

Reference

[1] Uribe, M. L., Marrocco, I., & Yarden, Y. (2021). EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance. Cancers, 13(11), 2748. https://doi.org/10.3390/cancers13112748 

[2] Nishihara, S., Yamaoka, T., Ishikawa, F., Higuchi, K., Hasebe, Y., Manabe, R., Kishino, Y., Kusumoto, S., Ando, K., Kuroda, Y., Ohmori, T., Sagara, H., Yoshida, H., & Tsurutani, J. (2022). Mechanisms of EGFR-TKI-Induced Apoptosis and Strategies Targeting Apoptosis in EGFR-Mutated Non-Small Cell Lung Cancer. Genes, 13(12), 2183. https://doi.org/10.3390/genes13122183 

[3] Morgillo, F. et al. (2016) ‘Mechanisms of resistance to EGFR-targeted drugs: lung cancer’, ESMO Open, 1(3), p. e000060. Available at: https://doi.org/10.1136/esmoopen-2016-000060.‌

[4] Giaccone, G., Herbst, R. S., Manegold, C., Scagliotti, G., Rosell, R., Miller, V., Natale, R. B., Schiller, J. H., Von Pawel, J., Pluzanska, A., Gatzemeier, U., Grous, J., Ochs, J. S., Averbuch, S. D., Wolf, M. K., Rennie, P., Fandi, A., & Johnson, D. H. (2004). gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 22(5), 777–784. https://doi.org/10.1200/JCO.2004.08.001 

[5] Herbst, R. S., Giaccone, G., Schiller, J. H., Natale, R. B., Miller, V., Manegold, C., Scagliotti, G., Rosell, R., Oliff, I., Reeves, J. A., Wolf, M. K., Krebs, A. D., Averbuch, S. D., Ochs, J. S., Grous, J., Fandi, A., & Johnson, D. H. (2004). gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 22(5), 785–794. https://doi.org/10.1200/JCO.2004.07.215 

[6] Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., Louis, D. N., Christiani, D. C., Settleman, J., & Haber, D. A. (2004). Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to gefitinib. New England Journal of Medicine, 350(21), 2129–2139. https://doi.org/10.1056/nejmoa040938

[7] Paez, J. G. (2004). EGFR Mutations in Lung Cancer: Correlation with Clinical Response to gefitinib Therapy. Science, 304(5676), 1497–1500. https://doi.org/10.1126/science.1099314 

[8] Mitsudomi, T., Morita, S., Yatabe, Y., Negoro, S., Okamoto, I., Tsurutani, J., Seto, T., Satouchi, M., Tada, H., Hirashima, T., Asami, K., Katakami, N., Takada, M., Yoshioka, H., Shibata, K., Kudoh, S., Shimizu, E., Saito, H., Toyooka, S., & Nakagawa, K. (2010b). gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. The Lancet Oncology, 11(2), 121–128. https://doi.org/10.1016/S1470-2045(09)70364-X 

[9] Pao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., & Varmus, H. (2005). Acquired Resistance of Lung Adenocarcinomas to gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain. PLoS Medicine, 2(3), e73. https://doi.org/10.1371/journal.pmed.0020073‌

[10] Li, D. et al. (2008) ‘BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models’, Oncogene, 27(34), pp. 4702–4711. Available at: https://doi.org/10.1038/onc.2008.109. ‌

[11] Mok, T. S., Wu, Y.-L., Ahn, M.-J., Garassino, M. C., Kim, H. R., Ramalingam, S. S., Shepherd, F. A., He, Y., Akamatsu, H., Theelen, W. S. M. E., Lee, C. K., Sebastian, M., Templeton, A., Mann, H., Marotti, M., Ghiorghiu, S., & Papadimitrakopoulou, V. A. (2017). Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. New England Journal of Medicine, 376(7), 629–640. https://doi.org/10.1056/nejmoa1612674 

[12] Soria, J.-C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H., Dechaphunkul, A., Imamura, F., Nogami, N., Kurata, T., Okamoto, I., Zhou, C., Cho, B. C., Cheng, Y., Cho, E. K., Voon, P. J., Planchard, D., Su, W.-C., Gray, J. E., & Lee, S.-M. (2018). Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer. New England Journal of Medicine, 378(2), 113–125. https://doi.org/10.1056/nejmoa1713137 

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