Factors associated with efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer

Abstract

The finding of epidermal growth factor receptor tyrosine kinase inhibitors, which reflects a classical process of translational research, is a critical milestone for non-small-cell lung cancer treatment. Currently, epidermal growth factor receptor tyrosine kinase inhibitors are recommended as first-line therapy for non-small-cell lung cancer patients harboring epidermal growth factor receptor–sensitive mutations. The status of epidermal growth factor receptor mutation is widely acknowledged as superior to other clinical factors, such as smoking, gender, and histological types for predicting the response to epidermal growth factor receptor tyrosine kinase inhibitors. However, recent studies have shown that the efficacy might differ in patients with the same epidermal growth factor receptor–sensitive mutations, highlighting the need to investigate the putative factors related to the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors. This article reviews the factors associated with clinical efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib and erlotinib, and analyzes their potential implications with respect to clinical application. In addition, new findings related to clinical practice with respect to epidermal growth factor receptor tyrosine kinase inhibitors efficacy were summarized in this article.

Keywords

Epidermal growth factor receptor tyrosine kinase inhibitors non-small-cell lung cancer efficacy predictors targeted therapy

Introduction

Non-small-cell lung cancer (NSCLC) remains the most common type of lung cancer^1,2 and the leading cause of cancer-related deaths worldwide. Clinically, most NSCLC patients are initially diagnosed with advanced stages, and thus, their survival outcome remains poor. The finding of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), which reflects a classical process of translational research, is an important milestone in NSCLC treatment.

Initially, clinical studies revealed that these drugs (gefitinib and erlotinib) might be effective in unselected NSCLC patients. However, significant differences were identified in the efficacy among different individuals. Factors, such as East Asian origin, female sex, adenocarcinoma histology, non-smoking status, and thyroid transcription factor-1 (TTF-1) positivity were found to be predictors of a favorable response to EGFR-TKIs in these patients.^3–5 Subsequently, mechanistic studies demonstrated that patients with the above characteristics were likely to harbor specific mutations in the tyrosine kinase domain of EGFR,^6–9 which were identified as oncogenic driver mutations.^6,7 In patients with EGFR-sensitive mutations, gefitinib showed a significantly prolonged progression-free survival (PFS) and higher response, with acceptable toxicity, as compared to the chemotherapeutic group.¹⁰ Currently, EGFR-TKIs are recommended as a first-line therapy for NSCLC patients harboring EGFR-sensitive mutations.^11,12

It is widely acknowledged that EGFR mutation status is superior to other clinical factors for predicting the response to EGFR-TKIs.^13–15 However, recent studies showed that the efficacy might differ in patients with same EGFR-sensitive mutations,¹⁶ highlighting the need for addressing the possible factors related to the efficacy of EGFR-TKIs.

This article reviews the factors associated with clinical efficacy of first-generation EGFR-TKIs, such as gefitinib and erlotinib, and analyzes their potential implications with respect to clinical applications.

EGFR-sensitive mutations

EGFR-TKIs are currently recommended as the standard first-line therapy for NSCLC patients with activated EGFR mutations^10,17,18 as an alternative in patients without such mutations. Patients who do not harbor EGFR-sensitive mutations or their mutation status is unknown, administration of EGFR-TKIs may be related to a deleterious effect regarding the objective response rate (ORR), PFS, and overall survival (OS) as compared to chemotherapy.¹⁹

Common sensitive mutations—exon 19 deletion and exon 21 L858R

A large number of mutations have been described for the EGFR gene. Approximately, 85% of lung-cancer-specific EGFR-sensitive mutations comprise the in-frame deletions in exon 19 (19del) or a point mutation in exon 21 at position 858 (21L858R), and thus, these two mutations are recognized as common sensitive mutations. Studies revealed that patients harboring 19del and 21L858R may exhibit different responses to EGFR-TKIs.^{4,8,9,20–24}

Riely et al.⁸ and Jackman et al.²² discovered that patients with 19del had a significantly longer OS as compared to the patients with an L858R mutation. Jackman et al.²² also found that specific trends were displayed toward higher response rate (RR) and improved duration to progression in patients harboring 19del, albeit these were not independently significant in a multivariate analysis. Subsequent studies revealed that patients with 19del had significantly prolonged PFS as compared to patients with L858R mutation. In a multivariate Cox regression model, the two studies also revealed that EGFR 19del was independently predictive of longer PFS. However, no significant differences in RR and OS were observed between these two mutations.^20,21

These studies revealed that a PFS or OS benefit occurred in patients with 19del versus 21L858R after treatment with EGFR-TKIs. The phenomenon suggests that mutation types of EGFR gene may have some additional implications in predicting the efficacy of EGFR-TKIs in addition to the presence or absence of EGFR mutations.²² The mutation itself could play a vital role in influencing the outcomes. This has been demonstrated in a study of patients with surgically resected, early-stage NSCLC who did not receive EGFR-TKIs.²⁵ This study also found that patients with 19del (n = 31) exhibited poor survival than those with the 21L858R (n = 31); however, p = 0.05.²⁵ Based on this study and those comparing the efficacy of different sensitive mutations in patients treated with EGFR-TKIs, we noted that the prognostic and predictive value of EGFR-TKIs might be different. Compared with 19del, 21L858R represents a better outcome in patients who do not receive EGFR-TKIs. However, patients with 19del may acquire a better efficacy from EGFR-TKIs than those with 21L858R. Thus, some unknown molecular alterations might be speculated to occur during NSCLC and EGFR-TKIs treatment.

However, studies in the East Asian populations revealed that patients with 19del and 21L858R showed a similar survival benefit of EGFR-TKIs treatment.^26,27 The results of the Iressa Pan-Asia Study (IPASS) revealed that the ORR and PFS of patients with 19del were not statistically different as compared to those with 21L858R.²⁸ WJTOG3405 and EURTAC studies obtained similar results.¹⁷ This apparent difference between North American and East Asian populations might be attributed to the type of EGFR-TKIs studied, given that all patients in the East Asian cohorts were treated with gefitinib, whereas the North American patients were treated with erlotinib or gefitinib.²⁶ In addition, we reckon that different races are likely to respond variably to EGFR-TKIs. Thus, according to existing evidence, the two EGFR mutations should be treated equally in clinical settings.

Different locations in EGFR TK domain and uncommon sensitive mutations

Other sensitive EGFR mutations, including the G719 A/C/S, L861Q mutations, and exon 19 in-frame insertions, recognized as uncommon or minor mutations, each account for ≤2% of all mutations.^25,29 Patients harboring these mutations are also sensitive to EGFR-TKIs treatment; however, the efficacy may be different from those harboring common sensitive mutations. In addition, studies also revealed that NSCLC patients with various 19del locations might acquire different efficacy when treated with EGFR-TKIs.

A study showed different PFS in patients with exon 19 18-nucleotide deletion (delL747_P753insS), 15-nucleotide deletion (delE746_A750), and mixed insertion/substitution mutations (median PFS: 6.5, 12.4, and 22.3 months, respectively; p = 0.012).³⁰ Patients harboring delE746 demonstrated better median PFS (14.2 months) than those harboring delL747 (6.5 months; p = 0.021).³⁰ A retrospective study obtained the same outcome, revealing that median PFS of delE746 was significantly longer than delL747 (11.7 vs 10.0 months, respectively; p = 0.022).³¹ In addition, 21L858R derived a longer median PFS than L861R/L861Q (11.4 vs 2.1 months, respectively; p = 0.034).³⁰ In a retrospective study, examining predictors of EGFR-TKI response in EGFR-mutant NSCLC patients, common mutations (19del and 21L858R) were found to be independent predictors of better treatment outcome (vs minor mutations, including mutations in exons 18 and 20 and unusual mutations occurring in exons 19 and 21; median PFS: 12.5 vs 4.3 months, respectively; p = 0.022).³² However, the outcomes of this study should be interpreted with caution as mutations in exons 18 and 20 may represent a resistant, instead of a sensitive, mechanism to EGFR-TKIs.

Wu et al. studied the clinical significance of uncommon EGFR mutations. In this study, 62 patients with uncommon EGFR mutations receiving gefitinib or erlotinib and their efficacy data were analyzed. The RR of EGFR-TKIs treatment was 48.4%, and the median PFS was 5.0 months.³³ Mutations on G719 and L861 composed a major part (28/62, 45%) of uncommon mutations and were associated with a favorable efficiency of EGFR-TKIs (RR: 57.1%; median PFS: 6.0 months), whereas the other uncommon mutations led to a worse response to EGFR-TKIs (RR: 20.0%; median PFS: 1.6 months).³³

Although these mutations are relatively rare as compared to 19del and 21L858R, clinicians should focus on them since NSCLC patients harboring these mutations can benefit from EGFR-TKIs. Specifically, we should note that several East Asian patients may harbor these mutations as the EGFR mutation rate of patients is relatively higher than the other groups.

Compound mutations

Kobayashi et al.³⁴ analyzed the EGFR mutation pattern in 79 NSCLC cases harboring EGFR mutations and discovered that 11 (14%) had compound mutations. Of these 11 patients, most were EGFR-sensitive mutations, such as G719X (n = 3, plus S768I or E709A), L858R (n = 4, plus L747V, R776H, T790M, or A871G), L861Q (n = 1, plus E709V), and delL747_T751 (n = 1, plus R776H).³⁴ Recently, Kim et al.³⁵ found that in lung adenocarcinoma, compound EGFR mutation was frequently detected with co-mutations of activated genes, such as anaplastic lymphoma kinase (ALK) rearrangement, BCL2L11 intron 2 deletions, KRAS c.35G>A, and PIK3CA c.1633G>A, and is associated with poor clinical outcome. The majority (12/15) of compound mutations are a combination of the uncommon mutations and typical mutations such as 19del, L858R or G719X substitutions, or exon 20 insertions, whereas the remaining 3 were combinations of rare atypical mutations. Patients with compound mutations showed shorter OS than those with simple mutations.³⁵

Cases harboring compound mutations are uncommon. Subsequent studies with a larger sample size are imperative to discover the correlation between compound EGFR-sensitive mutations and response to EGFR-TKIs.

EGFR gene copy number gain and amplification

The feasibility of using EGFR copy number (CN) to predict the efficacy of EGFR-TKIs is controversial. High EGFR CN was found to be significantly related to a better response and longer PFS and OS in NSCLC patients treated with gefitinib.³⁶ Some studies indicated that EGFR CN may serve as an adequate predictive biomarker for the efficacy of EGFR-TKIs than EGFR mutation.^37,38 However, other studies revealed that high EGFR CN could not predict survival benefits from EGFR-TKIs treatment.^39,40 The concurrence of EGFR amplification and sensitizing mutations may indicate superior survival benefits from EGFR-TKIs in lung adenocarcinoma patients.⁴¹ Previous data has shown that the EGFR amplification co-exists with EGFR mutations in lung adenocarcinomas.^42,43 The predictive value of EGFR gene CN might be driven by the co-existing EGFR mutation.²⁸

In addition, EGFR CN might be used as a predictor in wild-type EGFR mutation population treated with EGFR-TKIs. A study reported that high EGFR CN may predict the benefit of TKIs treatment in NSCLC patients with wild-type EGFR mutations.⁴⁴ Lee et al.⁴⁵ found that high EGFR gene CN might serve as a predictive marker for squamous cell lung cancer without EGFR mutation.

EGFR CN and amplification may not be applied to clinical practice as conclusions drawn from these studies are not uniform. In addition, whether EGFR amplification is homogeneously distributed within a primary tumor or both in a primary tumor and metastasis remains unknown, which limits the use of EGFR amplification as a reliable biomarker in the clinical setting.⁴⁵

Clinical and pathological factors

Cigarette smoking

Previous studies revealed that never or light smokers exhibit favorable responses to EGFR-TKIs treatment since these patients are more likely to harbor EGFR-sensitive mutations than heavy smokers.^46,47 However, in patients with EGFR mutation status, smoking was also found to be associated with EGFR-TKIs efficacy. A meta-analysis reported that non-smoking is associated with longer PFS than ever smoking after EGFR-TKIs treatment in advanced NSCLC patients with EGFR mutations.⁴⁸ The dosage of smoking may affect the EGFR-TKIs efficacy. The smoking dosage of ≥30 pack-years is an independent negative predictor of the efficacy of EGFR-TKIs in lung adenocarcinoma patients with activating EGFR mutations.¹⁶

Cigarette smoke is a complex mixture of chemicals, including various genotoxic lung carcinogens, leading to multiple carcinogenic mechanisms in smoking-related lung cancers.⁴⁹ EGFR pathway is one of the putative mechanisms of NSCLC in smoking patients; however, other mutations might also occur during the disease. EGFR-TKI might be effective in patients with EGFR mutation during the initiation of the treatment since EGFR mutation plays a dominant role. However, resistance to EGFR-TKIs may occur once the dominant carcinogenic effect of EGFR mutations is replaced by other mechanisms;⁴⁸ nevertheless, specific mechanisms remain unknown. The poor response to EGFR-TKIs in patients with a smoking history could be explained by cigarette smoking–induced EGFR post-translational changes, activation of the nicotinic acetylcholine receptor by cigarette smoking–induced EGFR-TKIs resistance, promotion of EGFR signal, and epithelial–mesenchymal transition (EMT).^50–52

Consequently, patients with a non-smoking history may acquire a favorable response to EGFR-TKIs and a longer PFS than the smokers.

Treatment timing—first-line or second-line

Existing data have shown that first-line EGFR-TKIs therapy in patients harboring EGFR-sensitive mutations achieves a longer PFS as compared to standard chemotherapy.^10,53–55 However, assessments on the administration of EGFR-TKIs are yet ambiguous. In unselected East Asian NSCLC patients, first-line gefitinib was found to be an independent predictor for better response,⁵⁶ whereas the OS rates did not differ significantly. In EGFR-mutant population, the RR of first-line gefitinib treatment was higher than that in the other-line patients; however, no difference in OS was observed.⁵⁶

Physicians may not be concerned about the superiority of efficacy of first-line EGFR-TKIs than that of the other-line, since EGFR-TKIs are now recommended as first-line treatment in patients harboring EGFR-sensitive mutations. Moreover, EGFR-TKIs seem to prolong the survival in patients with NSCLC after first-line or second-line chemotherapy.³⁷ In addition, it is critical for physicians to carry out adequate management of NSCLC in order to achieve maximum efficacy and longest survival. Studies have revealed that EGFR-TKIs and chemotherapy may affect each other, leading to a relatively low sensitivity to another drug.^57,58 Furthermore, numerous arguments, including assurance on drug exposure, improvement in the quality of life, better tolerance by patients with poor performance status (PS), and deferral of whole brain radiation therapy (WBRT) in patients with brain metastasis, support the general application of first-line EGFR-TKIs.⁵⁸

Moreover, some advanced NSCLC patients cannot delay the first-line therapy although their tumor specimens have been sent for EGFR detection. In this scenario, physicians can arrange the second-line EGFR-TKIs therapy if post-first-line chemotherapy disease progression occurs and if they harbor EGFR-sensitive mutations.

NKX2-1

NKX2-1, also known as TTF-1, is a lineage-survival oncogene in lung adenocarcinomas. Studies have shown that NKX2-1 positive expression is associated with EGFR mutation in lung adenocarcinomas.^59–61 Specifically, the mechanism-based study revealed that receptor tyrosine kinase–like orphan receptor 1 (ROR1), a key transcriptional target of NKX2-1, sustains a favorable balance between the pro-survival PI3K-AKT pathway and pro-apoptotic p38 signaling, playing a “sustainer role” in EGFR-mediated pro-survival signaling.⁶²

In addition, TTF-1 amplification might be a predictive marker of poor response to EGFR-TKIs in patients with recurrent tumor after surgical resection.⁶³

The TTF-1 expression could serve as a major reference when EGFR mutation status is unavailable. Notably, an overwhelming majority of TTF-1 negative lung adenocarcinomas will be negative for EGFR mutations,⁶¹ indicating that early chemotherapy can be initiated in TTF-1-negative patients with advanced lung adenocarcinomas. Thus, combining EGFR mutation status with TTF-1 expression may guide an effective clinical practice.

Serum tumor markers

Carcinoembryonic antigen

A previous study revealed that carcinoembryonic antigen (CEA) levels might be associated with the efficacy of EGFR-TKIs. Another study demonstrated that pretreatment higher CEA (>5 ng/mL) was significantly associated with a higher OS as compared to the normal levels in patients receiving erlotinib.⁶⁴ The reason maybe that lung adenocarcinoma patients with high serum CEA levels are more likely to harbor EGFR-sensitive mutations^65,66 according to the study conducted in an unselected NSCLC population and a majority were lung adenocarcinoma patients.⁶⁴ A similar conclusion was obtained in another study; however, the cutoff value for CEA levels was 20 ng/mL.⁶⁷ Nevertheless, one study conducted in unselected NSCLC reached a contrasting conclusion⁶⁸ stating that median PFS and OS in patients with a high level of CEA were shorter than those with low CEA after treatment with erlotinib⁶⁸ for reasons yet to be elucidated.

In addition, a retrospective study discovered that the percentage of patients with ≥20% CEA decreased after 1 month treatment of EGFR-TKIs, and were correlated with disease control rate (DCR), PFS, and OS, according to the EGFR mutational status.⁶⁵ The implication of this study regarding the outcomes of wild type/unknown group was critical as the mutation status might not be available for some patients. According to this study, the CEA response after 1 month of EGFR-TKIs therapy could be used as an early predictor of PFS in EGFR wild type/unknown NSCLC when their EGFR status is unknown. High level of pretreatment CEA may be a predictive serum marker for better response and longer survival in patients with advanced NSCLC receiving EGFR-TKIs, especially in patients with unknown EGFR mutation status or patients with squamous cell cancer.⁶⁹

With respect to patients with EGFR-sensitive mutations, higher baseline CEA was associated with poor outcomes in EGFR-mutant patients treated with first-line EGFR-TKIs.⁷⁰ This study also reported that CEA trend and normalization was a prognostic factor in EGFR-mutant patients with high baseline CEA.⁷⁰

In addition, one study found that EGFR gene mutation status was associated with high preoperative serum CEA level in NSCLC in patients in Northwest China.⁷¹

Cytokeratin-19 fragments

High pretreatment serum levels of cytokeratin-19 fragments (CYRFA21-1) were reported to be associated with poor outcomes of NSCLC patients treated with EGFR-TKIs.

In NSCLC, EGFR-mutant patients with a high CYFRA 21-1 level (>2 ng/mL) showed significantly shorter PFS as compared to those with a normal level.⁷² No significant difference in the OS was observed between the high and normal levels.⁷² One study using 3.5 ng/mL as a cutoff value for CYFRA 21-1 levels achieved a similar conclusion.⁷³ In lung adenocarcinoma subtype, low baseline CYFRA21-1 levels (<2.2 ng/mL) were found to be an independent favorable predictor for prolonged OS in both patients with EGFR mutations and no mutations.⁷⁴ In addition, the low level of pretreatment CYFRA21-1 was found to be a predictive serum marker for better response and long survival in NSCLC patients receiving EGFR-TKIs, especially in those with unknown EGFR mutation status or those with squamous cell cancer.⁶⁹

One study indicated that the third-line treatment with gefitinib necessitated further evaluation in NSCLC patients with a CYFRA 21-1 level higher than 3.5 ng/mL exhibiting a poor effect on survival.⁷⁵

Neuron-specific enolase

A higher pretreatment neuron-specific enolase (NSE) level was reported to be associated with a short survival duration following the initiation of gefitinib in non-selective NSCLC patients.⁷⁶ Data also suggested that EGFR-mutant NSCLC patients with elevated serum NSE levels (>16.3 ng/mL) had significantly short PFS and OS after EGFR-TKIs treatment.⁷⁷ A similar conclusion can be drawn in patients receiving gefitinib using a cutoff value of 13 ng/mL.⁷⁸

These findings are crucial as a transition to small cell lung cancer (SCLC), in which NSE was shown to be elevated, has been reported as one of the mechanisms in acquiring resistance to EGFR-TKIs.⁷⁹ NSE may be useful for early detection of SCLC transformation in cases resistant to EGFR-TKI therapy.⁸⁰ However, specific molecular mechanisms underlying the relationships between evaluated NSE and this transition necessitates further studies.

Other potential serum markers

Cancer antigen 242 (CA242) levels were found to be correlated with EGFR mutations in patients with lung adenocarcinomas.⁸¹ Elevated lactate dehydrogenase (LDH) levels might affect the OS of erlotinib-treated patients.⁸² A study found that pretreatment peripheral blood CD146+/CD3− cells (as circulating endothelial cells (CECs)), CD34+/CD45− cells (as endothelial progenitor cells (EPCs)), and CD133+ cells (as cancer stem cells (CSCs)) are useful predictive biomarkers of EGFR-TKIs treatment efficacy.⁸³ Fiala et al.⁸⁴ discovered that high serum level (≥10 mg/L) of C-reactive protein (CRP) was associated with poor outcome in patients with advanced-stage NSCLC treated with erlotinib. Li et al.⁸⁵ reported that serum cyclooxygenase-2 (COX-2) levels seem to be closely associated with EGFR mutations in lung adenocarcinoma and could be useful in the prediction of the efficacy of EGFR-TKIs in patients harboring an EGFR mutation. In addition, pretreatment serum surfactant protein-D (SP-D) levels in patients with NSCLC might be a new surrogate marker for predicting the response to gefitinib.⁸⁶

Combination use with other therapies

Chemotherapy

The available evidence was not sufficient to support the combination use of EGFR-TKIs and chemotherapy for the first-line treatment, especially in EGFR-mutant NSCLC. One study revealed that the combination might have promising efficacy with predictable toxicities.⁸⁷ However, trials regarding the comparison between combination use and gefitinib alone are ongoing. Moreover, identifying the mode as concurrent or sequential is vital. A phase 2 study of concurrent versus sequential alternating between gefitinib and chemotherapy, which was conducted in chemotherapy-naïve patients with advanced non-squamous, EGFR-activating mutation in NSCLC, revealed that the two combination methods had similar RR and PFS. Although OS was not established, the concurrent regimens might provide better OS based on the existing data.⁸⁷

For the first-line treatment of unselected NSCLC, a synchronous combination of chemotherapy and TKIs may not be superior to chemotherapy or EGFR-TKIs alone.⁸⁸

Radiotherapy

Studies revealed that the combination use of EGFR-TKIs and radiotherapy can improve PFS and OS, primarily in patients with brain metastasis.^89,90 A mechanism study revealed that EGFR signaling inhibition can enhance tumor radiation response.⁹¹ Zhuang et al.⁹² summarized the underlying theories regarding the combination of erlotinib and WBRT into five points: (1) radiosensitizing effect of erlotinib, (2) multi-metastases need WBRT, (3) good tolerance of brain to TKI, (d) concentration of erlotinib in the cerebrospinal fluid (CSF), (5) WBRT destroys the blood–brain barrier. The review also presented some issues requiring resolution, such as treatment duration and evaluation time of efficacy. The combination use of EGFR-TKIs and WBRT may serve as a potential regimen, especially for patients with brain metastasis and EGFR-sensitive mutations. However, whether the concurrent or sequential administration of EGFR-TKIs and radiotherapy is better prerequisites further clarification.

Metformin

A retrospective study indicated that metformin and EGFR-TKIs have a synergistic effect in the treatment of diabetes mellitus type 2 (DM2) NSCLC patients harboring EGFR-activating mutations.⁹³ Patients receiving metformin and EGFR-TKIs exhibit an excellent RR, DCR, longer PFS, and OS as compared to those receiving EGFR-TKIs plus other hypoglycemic agents. A previous study from the same group revealed that metformin could sensitize EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through the inhibition of interleukin 6 (IL-6) signaling and EMT reversal.⁹⁴

Conclusion

Several factors are associated with the efficacy of first-generation EGFR-TKIs. However, this review mainly focused on the common clinical factors. The molecular factors including the absence of EGFR-sensitive mutations (for example, 19del or 21L858R), a distinct biology (existence of another oncogenic driver gene), or the baseline presence of a secondary mutation lending resistance (such as EGFR T790M) of these tumors are known to be related to the primary resistance to EGFR-TKIs,⁹⁵ while EGFR T790M, mesenchymal-to-epithelial transition (MET) amplification, hepatocyte growth factor (HGF) overexpression, transformation to SCLC, BRAF mutations, and EMT^96,97 are associated with acquired resistance. In addition, B-cell lymphoma 2 interacting mediator of cell death (BIM) deletion polymorphism, MLH1 V384D polymorphism, EGFR intron 1 (CA)n, and CYP1A1*2A and SMAD3 polymorphisms were reported to be significantly associated with efficacy to EGFR-TKIs. The relevant factors related to the efficacy of first-generation EGFR-TKIs reviewed in this article are summarized in Figure 1.

Figure 1.

Factors associated with clinical efficacy of first-generation EGFR-TKIs.

Recently, core and clinical studies regarding these factors have contributed to our extensive understanding of the relevant mechanisms and clinical applications of EGFR-TKIs. However, continued investigations are necessary to clarify the unknown and to discover new findings in the field. Currently, in the era of precise medicine, we reckon that patients should be treated based on the existing evidence and their specific condition. Factors implicating a better or poor response to EGFR-TKIs are critical references, while the personalized conditions still cannot be ignored.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by the National Nature Science Foundation of China (Grant No. 81472175) and Shanghai Municipal Commission of Health and Family Planning Key Projects (Grant No. 20134007).

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