Which Is Better EGFR-TKI Followed by Osimertinib: Afatinib or Gefitinib/Erlotinib?
Motohiro TamiyaAkihiro TamiyaHidekazu SuzukiKazunori MoriizumiKenji NakahamaYoshihiko TaniguchiKei KunimasaMadoka KimuraTakako InoueHanako KuharaKazumi NishinoTomonori HirashimaShinji AtagiFumio ImamuraToru Kumagai
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Abstract:
Background/Aim: Treatment with EGFR-tyrosine kinase inhibitor (TKI) shows a durable response against NSCLC harboring EGFR mutation; however, treatment resistance occurs within 1-1.5 years following first-line EGFR-TKIs [first- and second-generation (G) TKIs]. When resistant NSCLC exhibits T790M mutations, osimertinib is the standard therapy. However, intratumoral heterogeneity and clonal evolution may occur in NSCLC. Afatinib may overcome tumor heterogeneity, leading to T790M colonal purity. We aimed to determine whether NSCLC treatment with afatinib followed by osimertinib (afatinib group) provides higher therapeutic efficacy than other 1st-G EFGR-TKIs followed by osimertinib (1st-G group). Materials and Methods: This multicenter retrospective study evaluated outcomes between afatinib group and 1st-G group. We analyzed clinical data from NSCLC patients receiving osimertinib after progression following 1st- or 2nd-G EGFR-TKIs between March 28, 2016 and March 31, 2018. Patients with performance status (PS) 0-2 were enrolled to reduce bias of patients9 conditions. Results: We enrolled 111 patients treated with osimertinib. The median age was 69 (range: 39-88) years. Out of 111 patients, 33 (29.7%) were men, 100 (90%) had PS 0-1, and 35 (31.5%) were in the afatinib group. The objective RR and DCR were significantly higher in the afatinib group than in the 1st-G group [82.9% vs. 53.9% (p=0.0065); 91.4% vs. 71.1% (p=0.032)]. The median PFS tended higher in the afatinib group than in the 1st-G group (15.6 vs. 8.9 months, p=0.195). Conclusion: Afatinib followed by osimertinib may provide better outcomes for T790M-positive NSCLC than 1st-G EGFR-TKIs. Afatinib followed by osimertinib may be a therapeutic option for NSCLC harboring EGFR mutation.Keywords:
Afatinib
Osimertinib
T790M
Four epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib, gefitinib, afatinib and osimertinib, are currently available for the management of EGFR mutation-positive non-small-cell lung cancer (NSCLC), with others in development. Although tumors are exquisitely sensitive to these agents, acquired resistance is inevitable. Furthermore, emerging data indicate that first- (erlotinib and gefitinib), second- (afatinib) and third-generation (osimertinib) EGFR TKIs differ in terms of efficacy and tolerability profiles. Therefore, there is a strong imperative to optimize the sequence of TKIs in order to maximize their clinical benefit. Osimertinib has demonstrated striking efficacy as a second-line treatment option in patients with T790M-positive tumors, and also confers efficacy and tolerability advantages over first-generation TKIs in the first-line setting. However, while accrual of T790M is the most predominant mechanism of resistance to erlotinib, gefitinib and afatinib, resistance mechanisms to osimertinib have not been clearly elucidated, meaning that possible therapy options after osimertinib failure are not clear. At present, few data comparing sequential regimens in patients with EGFR mutation-positive NSCLC are available and prospective clinical trials are required. This article reviews the similarities and differences between EGFR TKIs, and discusses key considerations when assessing optimal sequential therapy with these agents for the treatment of EGFR mutation-positive NSCLC.
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Guidelines for the treatment of non-small cell lung cancer adenocarcinoma positive in epidermal growth factor mutations indicate tyrosine kinase inhibitors. There are currently three tyrosine kinase inhibitors that can be used as first line treatment: gefitinib, erlotinib and afatinib. Regarding erlotinib and afatinib dosage can be modified in the case of severe adverse effects. In the case of disease relapse investigation for T790M mutation has to be made either with re-biopsy or liquid biopsy and osimertinib has to be administered when T790M is diagnosed. Based on a case series we indicate which is the best approach for T790M mutation.
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First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for metastatic non-small-cell lung cancers (NSCLCs) that harbor sensitizing EGFR mutations (i.e. exon 19 deletions or L858R). However, acquired resistance to EGFR TKI monotherapy occurs invariably within a median time frame of one year. The most common form of biological resistance is through the selection of tumor clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. The presence of the EGFR T790M mutation negates the inhibitory activity of gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs has been identified by probing a series of covalent pyrimidine EGFR inhibitors that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant forms of EGFR versus the wild-type receptor. We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M.
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Abstract The impact of different first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)s to the clinical efficacy of osimertinib in EGFR -mutant non-small-cell lung cancer (NSCLC) patients with acquired T790M was still unclear. We enrolled 733 advanced EGFR -mutant NSCLC patients with gefitinib, erlotinib or afatinib as first-line EGFR-TKIs treatment for analysis. 373 patients received re-biopsies after progressive disease to first-line EGFR-TKIs treatment, and the total positive rate of T790M was 51.7%. 151 patients who harbored T790M received osimertinib as subsequent treatment. Among them, the median progression-free survival (PFS) of first-line EGFR-TKI (PFS1) was 14.0 months, and the median PFS of osimertinib (PFS2) was 10.1 months. The median PFS1 + PFS2 was 27.5 months, and the median overall survival from first-line EGFR-TKI was 61.3 months. Concerning different first-line EGFR-TKIs, the median PFS2 was 10.9 months in the gefitinib group, 10.0 months in the erlotinib group, and 6.7 months in the afatinib group (p = 0.534). The median PFS1 + PFS2 was 27.7 months, 26.8 months and 24.0 months in the gefitinib, erlotinib, and afatinib group, respectively (p = 0.575). In conclusion, both first-generation and second-generation EGFR-TKIs sequential osimertinib treatment provided good clinical efficacy in advanced EGFR -mutant NSCLC patients with acquired T790M mutation.
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Non-small cell lung cancer (NSCLC) driven by activating mutations in epidermal growth factor receptor (EGFR) constitutes up to 10% of NSCLC cases. According to the NCCN recommendations, all patients (with the exception of smoking patients with squamous cell lung cancer) should be screened for the presence of activating EGFR mutations, i.e. deletion in exon 19 or point mutation L858R in exon 21, in order to select the group that benefits from EGFR tyrosine kinase inhibitors (EGFR TKIs) treatment. Among approved agents there are the 1st generation reversible EGFR TKIs, erlotinib and gefitinib, and the 2nd generation irreversible EGFR TKI, afatinib. The objective response rates to these drugs in randomised clinical trials were in the range of 56-74%, and median time to progression 9-13 months. The most common determinant of resistance to these drugs is the clonal expansion of cancer cells with T790M mutation (Thr790Met) in exon 20 of EGFR. Osimertinib (Tagrisso™), a 3rd generation, irreversible EGFR tyrosine kinase inhibitor, constitutes a novel, highly efficacious treatment for NSCLC patients progressing on EGFR TKIs with T790M mutation confirmed as the resistance mechanism. Resistance mutation can be determined in tissue or liquid biopsy obtained after progression on EGFR TKIs. Osimertinib has a favourable toxicity profile, with mild rash and diarrhoea being the most common. In this article, we present three cases that were successfully treated with osimertinib after progression on 1st and 2nd generation EGFR TKIs.
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Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the treatment of choice for patients with advanced stage non-small cell lung cancer (NSCLC) harboring EGFR sensitizing mutations (1,2). Before osimertinib, a third-generation EGFR-TKI, is recommended as the preferred agent in the first-line treatment in these patients, earlier generation TKIs such as erlotinib, gefitinib and afatinib, were the drug options available.
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Abstract Background Epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) are recommended as first‐line treatment in non‐small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. The sequential use of different EGFR‐TKIs has been reported to demonstrate improvement in overall survival of NSCLC patients with EGFR mutations. There are limited reports on comparisons between regimens with first‐line use of afatinib, gefitinib or erlotinib, followed by osimertinib upon disease progression with acquired T790M mutation. Methods A retrospective cohort study of Chinese patients with metastatic NSCLC harboring EGFR mutations who received first‐line gefitinib, erlotinib or afatinib treatment, followed by osimertinib upon disease progression with acquired T790M mutation, was conducted. The differences in overall survival (OS) and progression‐free survival (PFS) with first‐line EGFR‐TKI (PFS1) and time to second objective disease progression (PFS2) were compared among patients on different first‐line EGFR‐TKIs. Results Among 155 patients, 101 (65.2%), 38 (24.5%) and 16 (10.3%) patients were on first‐line gefitinib, erlotinib or afatinib, respectively. Patients treated with afatinib in the first‐line setting had significantly longer OS compared with those on gefitinib or erlotinib, while the PFS1 and PFS2 were longer for patients on afatinib but did not reach statistical significance. Conclusions First‐line afatinib, followed by osimertinib upon disease progression with T790M mutation, demonstrated significantly longer OS compared to that using other EGFR‐TKI in the first‐line setting.
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