Tyrosine kinase inhibition of EGFR: a successful history of targeted therapy for NSCLC since 20 years
Authors: J. Vansteenkiste, E. Wauters
Journal: Annals of Oncology (2017)

The first-in-human dosing of the Epidermal Growth Factor Receptor tyrosine kinase inhibitor (EGFR-TKI) ZD1839 (later gefitinib) goes back to April 1998, by now almost 20 years ago. In that phase I study, the tolerability, pharmacokinetics and antitumour activity of this orally administered EGFR-TKI was studied in patients with solid malignant tumours [1.Ranson M. Hammond L.A. Ferry D. et al.ZD1839, a selective oral epidermal growth factor receptor–tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.J Clin Oncol. 2002; 20: 2240-2250Crossref PubMed Scopus (754) Google Scholar]. The first patient received 50 mg of ZD1839 once daily for 14 days, followed by 14 days off treatment. Of the 16 patients with non-small-cell lung cancer (NSCLC), 4 eventually showed objective partial responses on doses of 300–700 mg daily. These results led to two dose-finding randomised phase II studies in patients with pre-treated advanced NSCLC comparing 250 mg with 500 mg daily [2.Fukuoka M. Yano S. Giaccone G. et al.Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small cell lung cancer.J Clin Oncol. 2003; 21: 2237-2246Crossref PubMed Scopus (2860) Google Scholar, 3.Kris M.G. Natale R.B. Herbst R.S. et al.Efficacy of Gefinitib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. A Randomized Trial.JAMA. 2003; 290: 2149-2158Crossref PubMed Scopus (2488) Google Scholar]. In these studies, some remarkable objective responses along with major symptom improvement were again noted, more often in female patients, in never-smokers, in those with adenocarcinoma, or of Asian origin, and it was not well understood why. Nevertheless, this favourable outcome with an oral therapy was unprecedented in pre-treated NSCLC, and brought EGFR-TKIs to the clinical arena [4.Vansteenkiste JF. Gefitinib (Iressa): a novel treatment for non-small cell lung cancer.Expert Rev Anticancer Ther. 2004; 4: 5-17Google Scholar]. In 2004, mutations affecting the tyrosine kinase domain of EGFR were linked to these dramatic responses to gefitinib in two independent papers [5.Paez J.G. Janne P.A. Lee J.C. et al.EGFR mutations in lung cancer: correlation with clinical response to Gefitinib therapy.Science. 2004; 304: 1497-1500Crossref PubMed Scopus (8465) Google Scholar, 6.Lynch T.J. Bell D.W. Sordella R. et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to gefitinib.N Engl J Med. 2004; 350: 2129-2139Crossref PubMed Scopus (9998) Google Scholar]. The first landmark phase III trial in this setting was without any doubt the I-PASS study, which was presented by Dr Tony Mok at the annual meeting of the European Society of Medical Oncology in 2008 and was published in 2009 [7.Mok T.S. Wu Y.L. Thongprasert S. et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.N Engl J Med. 2009; 361: 947-957Crossref PubMed Scopus (7031) Google Scholar]. This trial was unique because of its inclusion criteria: the population was not selected based on a biomarker, but on clinical enrichment (South-East Asian never- or light-smokers with adenocarcinoma). As a consequence, it was possible to compare four groups of patients based on type of therapy (doublet chemotherapy versus gefitinib) and presence or absence of an activating EGFR mutation. The trial not only showed a superior progression-free survival (PFS) with gefitinib compared with doublet chemotherapy [hazard ratio (HR) 0.74; 95% CI 0.65–0.85; P < 0.001], but also convincingly demonstrated that the presence of an activating EGFR mutation was by far the best biomarker to select for EGFR-TKI therapy. In the 261 patients with a tumour harbouring EGFR mutation, PFS was significantly better with gefitinib compared with chemotherapy (HR 0.48; 95% CI 0.36–0.64; P < 0.001), while the opposite was true in the wild-type group (HR 2.85; 95% CI 2.05–3.98; P < 0.001), leading to an impressive P-value for interaction of <0.0001. The story thereafter is the topic of this supplement. The first paper by Hsu et al. is an overview of the current systemic management of EGFR mutant NSCLC. Since I-PASS, several randomized controlled trials have established the role of first-generation EGFR-TKIs as preferred first-line therapy for EGFR mutant tumours. Gefitinib and erlotinib gained global approval in this setting, while icotinib is approved in China. The second-generation drugs are different because of their irreversible binding to EGFR, and because of their broader inhibition of the different members of the human epidermal receptor (HER) family. The initial hope was that these agents were the preferred strategy in tumours with acquired resistance to first-generation TKIs, but afatinib did not meet this promise in the LUX-LUNG-1 trial [8.Miller V.A. Hirsh V. Cadranel J. et al.Afatinib versus placebo for patients with advanced, metastatic non-small cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.Lancet Oncol. 2012; 13: 528-538Abstract Full Text Full Text PDF PubMed Scopus (841) Google Scholar]. Since then, afatinib has been developed as another treatment option for first-line therapy in EGFR mutant NSCLC. In the second contribution by Westover et al., the mechanisms of acquired resistance to first- and second-generation EGFR-TKIs are elucidated. Knowledge of these mechanisms was crucial in developing rational strategies to overcome acquired drug resistance. At least 50% of tumours acquire resistance to gefitinib, erlotinib, or afatinib due to a secondary mutation within the drug target: the T790M mutation leading to altered drug binding and enzymatic activity of the mutant EGF receptor. Other mechanisms are described as well, but until now, these are more difficult to target. The third chapter by Remon et al. deals with the way third-generation EGFR-TKIs have revolutionized treatment possibilities for tumours with acquired resistance based on the secondary T790M mutation. Osimertinib was the first third-generation EGFR-TKI to receive EMA and FDA approval for stage IV EGFR mutant NSCLC with acquired T790M resistance mutation, and clinical trials with other third-generation EGFR-TKIs are currently underway. A next episode in this journey is the upfront efficacy of osimertinib, and the question whether the new-generation TKIs should be moved to first-line therapy. But, at the end of the day, acquired resistance develops to the third-generation drugs as well, and the fourth contribution by Ricordel et al. summarizes the molecular mechanisms leading to this resistance. In contrast with first- and second-generation inhibitors, a much more diversified set of resistance mechanisms to these new compounds—both target-dependent and -independent—is in place. Clinical management of these tumours is at present not established, and is based on anecdotal reports of molecular findings and therapies. The fifth and last contribution by Goldman et al. reviews the role of liquid biopsies as a surrogate for tissue EGFR testing. Molecular profiling of NSCLC is now critical not only at the time of diagnosis, but even so at each step of tumour progression due to molecular alterations in the tumour. However, obtaining tissue in each step of the patient's journey is highly challenging. Moreover, a single tissue biopsy does not capture heterogeneity present in one tumour lesion and between different lesions. So-called 'liquid biopsies', based on the analysis of circulating tumour DNA acquired from a simple blood draw, address these problems, and will probably further revolutionize the molecular diagnostics of NSCLC and the clinical therapeutic decisions for our patients. In this introductory note, we summarized the origins of EGFR-TKI-based therapy for EGFR mutant NSCLC. We sincerely hope that this Annals of Oncology Supplement will be a useful guide for each of you and contribute to an optimal care of our patients with EGFR mutated NSCLC. AstraZeneca has provided a sponsorship grant towards this independent publication.