Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy

Abstract

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are present in approximately 20% (in Caucasians) to 40% (in East Asians) of adenocarcinomas of the lung. Targeted therapy for these lung cancers has been established based on evidence regarding mainly common mutations; that is, exon 19 deletions (Del19) and L858R. EGFR‐tyrosine kinase inhibitors (TKI), gefitinib, erlotinib or afatinib showed high objective response rates (ORR) of approximately 60%. Several studies suggested that Del19 might be more sensitive to EGFR‐TKI than L858R. On the other hand, it has been difficult to establish evidence for other less common mutations, accounting for 12% of all EGFR mutations, because there are many variants and many studies have excluded patients with these uncommon mutations. However, recent studies revealed that these rare genotypes could be targetable if appropriate TKI are selected. For example, G719X (X denotes A, S, C and so on), Del18, E709K, insertions in exon 19 (Ins19), S768I or L861Q showed moderate sensitivities to gefitinib or erlotinb with ORR of 30%–50%. However, afatinib appeared to be especially effective for these tumors. Although Ins20s (except for insFQEA) have been regarded as resistant mutations, osimertinib may be effective for rare subtypes of them and nazartinib (EGF816) is promising for the majority of them. For the further development of targeted therapy in all EGFR mutations, it is important to precisely detect targetable mutations, to select the most appropriate TKI for each mutation, and to continue investigating in vitro studies and collecting clinical data on even rare mutations.

Frequency of Epidermal Growth Factor Receptor Mutations among Filipino Patients with Non-small Cell Lung Carcinoma in a Private Tertiary Care Setting

“…have moderate sensitivities to gefitinib or erlotinib with response rate of 30%-50%. 9 In up to 60%-80% of patients treated with TKIs, the tumor regresses dramatically, but after a median time of 9-12 months, all patients develop acquired resistance to the targeted therapy. A secondary mutation, T790M, in the exon 20 of the EGFR gene is the most frequent cause of acquired resistance, which is found in 50%-60% of relapsed cases.…”

“…For patients with EGFR T790M mutations, treatment with osimertinib may be effective and nazartinib (EGF816) is promising for the majority of them. 9 Thus, an accurate EGFR mutational analysis before initiation of treatment and repeat EGFR mutation testing at relapse, are now recommended in several clinical practice guidelines. 10 The incidence of EGFR mutations in NSCLC varies across different ethnicities.…”

Osimertinib Did Not Respond to a Pulmonary Adenocarcinoma with Triple Mutations of Epidermal Growth Factor Receptor, G719S, T790M and S768I

“…In both of these two patients, first-line erlotinib provided partial response, but only 5–7 months of PFS and 8–10 months of OS from the start of EGFR-TKIs [8]. Second, a collected and retrospective data showed that first-generation EGFR-TKI provided 42 and 53% of overall response rate for S768I single mutation and compound mutations, respectively [6]. Third, in a study of 9 patients with S768I mutation at Mayo Clinic, among 4 patients with metastatic disease treated with erlotinib, one and two patients achieved partial response and stable disease, respectively.…”

“…In this in vitro study, afatinib showed very low half maximal inhibitory concentration (IC 50 ) value to S768I mutation, but both gefitinib and erlotinib had high values of IC 50. Osimertinib was less sensitive to S768I mutation than afatinib [6, 11]. A Korean phase II trial showed that osimertinib achieved partial response in 3 patients of 8 with EGFR-TKI naïve S768I mutation (ORR, 37.5%) [12].…”

“…On the other hand, G719X and S768I point mutations are detected in approximately 3 and 1% of EGFR mutations, respectively. First generation EGFR-TKIs provided 32 and 42% of overall response rate for G719X and S768I mutations, respectively [6]. However, the clinical efficacy of osimertinib for these uncommon mutations remains unknown due to a new drug and rare mutation types.…”