Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non‑small cell lung cancer in patients with common and rare EGFR gene mutations

  • Authors:
    • Pawel Krawczyk
    • Dariusz M. Kowalski
    • Rodryg Ramlau
    • Ewa Kalinka‑Warzocha
    • Kinga Winiarczyk
    • Katarzyna Stencel
    • Tomasz Powrózek
    • Katarzyna Reszka
    • Kamila Wojas‑Krawczyk
    • Maciej Bryl
    • Magdalena Wójcik‑Superczyńska
    • Maciej Głogowski
    • Aleksander Barinow‑Wojewódzki
    • Janusz Milanowski
    • Maciej Krzakowski
  • View Affiliations

  • Published online on: April 3, 2017     https://doi.org/10.3892/ol.2017.5980
  • Pages: 4433-4444
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Abstract

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are routinely used to treat non-small cell lung cancer (NSCLC) in patients with common activating mutations of the EGFR gene. The aim of the study was to compare the efficacies of EGFR‑TKIs in patients with common (exon 19 deletions and exon 21 p.Leu858Arg) and rare EGFR mutations. A retrospective analysis of 180 NSCLC patients with common (n=167) and rare (n=13) EGFR mutations treated with erlotinib (n=98), gefitinib (n=66) and afatinib (n=16) was performed. EGFR mutations were determined using RT‑PCR and the EntroGen EGFR Mutations Analysis kit. Partial and complete response (PR and CR), progression‑free survival (PFS), and overall survival (OS) were analyzed. Demographic and clinical factors had no impact on PFS or OS in patients treated with EGFR-TKIs. Erlotinib, gefitinib, and afatinib showed similar efficacies based on treatment response, median PFS, and OS. The type of EGFR mutation had no impact on median OS; however, median PFS was significantly longer in patients with the exon 19 deletion compared to patients with the exon 21 p.Leu858Arg substitution and rare EGFR gene mutations (P=0.013). Patients with common EGFR mutations showed significantly longer median PFS than those with rare EGFR mutations (10 vs. 5 months; P=0.009). Erlotinib, gefitinib, and afatinib show similar efficacies in NSCLC patients with both common and rare EGFR mutations. When undergoing EGFR‑TKI treatment, patients with rare EGFR mutations showed similar OS but poorer PFS. Further investigation into the associations between particular rare EGFR mutations and EGFR-TKIs treatment outcomes is required.

Introduction

Approximately 10–15% of Caucasian patients with advanced non-small cell lung cancer (NSCLC) have mutations in the epidermal growth factor receptor (EGFR) gene. Several clinical studies have demonstrated the efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for treatment of NSCLC patients with activating EGFR mutations (15). Currently, three EGFR-TKIs (erlotinib, gefitinib, and afatinib) have proven efficacy in the treatment of NSCLC in patients with common activating EGFR mutations. Erlotinib and gefitinib are reversible EGFR-TKIs, while afatinib is an irreversible EGFR-TKIs. However, despite extensive knowledge about the mechanism of action of EGFR-TKIs in NSCLC, some serious problems remain unsolved.

First of all, few prospective and randomized studies have directly compared the efficacy of the various classes of EGFR-TKIs in patients with NSCLC harboring activating EGFR mutations (68). There are the preliminary results of a single-center randomized phase II trial comparing the efficacy of gefitinib and erlotinib in second-line therapy of Asian NSCLC patients with activating EGFR mutations (6), as well as the results of the global, multi-center LUX-Lung 7 trial comparing the efficacy of afatinib and gefitinib in first-line treatment of NSCLC patients with common activating EGFR mutations (7). The results of the multinational, randomized ARCHER 1009 trial indicate that gefitinib and daconitinib have similar efficacy. However, the ARCHER 1050 phase III trial comparing the efficacy of these two drugs is ongoing (8). We have preliminary results of phase III clinical studies comparing the efficacy of third-generation inhibitors (i.e., osimertinib in the FLAURA clinical trial, ASP8273 in the SOLAR clinical trial, and rociletinib in the TIGER-1 clinical trial) and erlotinib or gefitinib in first-line treatment of NSCLC patients with EGFR mutations (see clinicaltrials.gov). In the meantime, our knowledge of the effectiveness of various EGFR-TKIs comes from a limited number of retrospective studies comparing gefitinib, erlotinib, and afatinib.

The second serious problem related to EGFR-TKIs administration is the lack of reliable knowledge about their efficacy in patients with rare EGFR mutations. While gefitinib, erlotinib, and afatinib have proven efficacy in patients with the two major mutations in the EGFR gene (i.e., the classical Glu746-Ala750 deletion in exon 19 and the common p.Leu858Arg substitution in exon 21), their effectiveness in NSCLC cases with rare EGFR mutations remains unclear. Molecular tests based on real-time PCR techniques detect several rare EGFR mutations, including: Different substitutions in codons 709 and 719 in exon 18, substitutions and insertions in exon 20, as well as different substitutions in codons 858 and 861 in exon 21 (9). Such tests have confirmed that rare EGFR mutations occur more frequently than previously thought Results from the French National Cancer Institute network (ERMETIC-IFCT) indicated that ~10% of EGFR-mutated NSCLC patients may have rare EGFR gene mutations (10). Similarly, in our recent multicenter study in Poland, we showed that 14.77% of patients with EGFR-mutated NSCLC had rare mutations (11). Despite this, only a few retrospective analyses have investigated the efficacy of EGFR-TKIs in patients with rare EGFR mutations. Therefore, the predictive value of rare EGFR mutations for deciding on the first-line treatment option in patients with NSCLC remains unclear.

In this study, we conducted a retrospective analysis of the effectiveness of different EGFR-TKIs in NSCLC patients with common and rare EGFR mutations. To the best of our knowledge, this is the first study worldwide to compare the efficacy of erlotinib, gefitinib, and afatinib in patients with rare and common EGFR mutations.

Materials and methods

Study population

This study was approved by the Local Bioethics Committee of Medical University of Lublin. We retrospectively analyzed clinical outcomes in 180 NSCLC patients (95% with adenocarcinoma diagnosis) with different EGFR mutations, who had received erlotinib (n=98), gefitinib (n=66), or afatinib (n=16) therapy in four oncology centers in Poland (Warsaw, Lublin, Poznan, and Lodz). All patients had clinically proven recurrent or locally advanced or metastatic NSCLC. Patients with brain metastases controlled with radiotherapy or neurosurgery without intensive steroid therapy were included in the study. EGFR-TKIs were administered orally at a daily dose of 150 mg for erlotinib, 250 mg for gefitinib, and 40 mg for afatinib, and the cycle repeated every 28 days. The clinical parameters collected at the beginning of EGFR-TKIs treatment included: Age, gender, smoking status (including pack-years assessment), performance status (PS), stage of disease, pathomorphological diagnosis, line of EGFR-TKIs treatment, and information about prior surgical treatment.

Treatment was continued until progression or unacceptable toxicity. After discontinuation of EGFR-TKIs treatment, patients could receive chemotherapy or palliative radiotherapy. During this study, third-generation of EGFR-TKIs (e.g. osimertinib) have not been available in Poland. Also, therapeutic programs in Poland did not allow any possibility of switching the type of EGFR-TKIs in patients after progression on EGFR-TKIs. Five patients (2.8%) had early, no treatment-related toxicity of grade 4 and required discontinuation of EGFR-TKIs treatment. They were not included in our survival analysis.

Response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and evaluation was performed by computed tomography every 2 months of EGFR-TKIs treatment. The treatment toxicity was assessed by Common Toxicity Criteria (CTC) scale (version 4.0). Performance status was evaluated according to Eastern Cooperative Oncology Group (ECOG) scale.

EGFR gene mutations analysis

DNA was extracted from tumor tissue or tumor cells obtained during routine diagnostic or therapeutic procedures (bronchoscopy, endobronchial ultrasound-guided transbronchial needle aspiration, mediastinoscopy, or surgical resection). Formalin-fixed paraffin-embedded materials, or cytological slides containing at least 10% of tumor cells, were used for molecular examination. Mutations of the EGFR gene (NM_0,05228.3) were tested using routine real-time PCR procedures and the EntroGen EGFR Mutations Analysis kit (USA). The mutations in exons 18 to 21 were examined (Table I). Non-classical deletions in exon 19 were distinguished from the classical deletion in exon 19 by a direct sequencing method.

Table I.

Type of examined mutations in the EGFR gene.

Table I.

Type of examined mutations in the EGFR gene.

ExonType of mutations
18p.Gly719Ala (c.2156G>C), p.Gly719Ser (c.2155G>A), p.Gly719Cys (c.2155G>T)
19c.2235–2249 del 15, c.2235–2252>AAT del 18, c.2236–2253 del 18, c.2237–2251 del 15, c.223c.7–2254 del 18, c.2237–2255>T del 19, c.2236–2250 del 15, c.2238–2255 del 18, c.2238–2248>GC del 11, c.2238–2252>GCA del 15, c.2239–2247 del 9, c.2239–2253 del 15, c.2239–2256 del 18, c.2239–2248>C del 10, c.2239–2258>CA del 20, c.2240–2251 del 12, c.2240–2257 del 18, c.2240–2254 del 15, c.2239–2251>C del 13
20p.Thr790Met (c.2369C>T), p.Ser768Ile (c.2303G>T), c.2307–2308 ins GCCAGCGTG, c.2319–2320 ins CAC, c.2310–2311 ins GGT
21p.Leu858Arg (c.2573T>G), p.Leu861Gln (c.2582T>A)
Statistical analysis

Treatment outcomes included response rate, disease control rate, progression free survival (PFS), and overall survival (OS). PFS and OS were defined as the time elapsed between the date of EGFR-TKIs treatment beginning and the date of disease progression or death, respectively. In the absence of information about the progression or death, data were classified as censored (time was calculated to the last observation). Statistical analysis was performed using Statistica 10 (Statsoft, USA) and MedCalc 10 (MedCalc Software, Belgium). A P<0.05 was considered statistically significant. Using the Fisher's exact test, we assessed the associations between clinical factors and response rate or disease control rate. The Kaplan-Meier log-rank test was used to draw a comparison curve evaluating the survival probability (PFS and OS). Cox regression model with a stepwise selection with minimum AIC factor (Akaike Information Criterion) was used to determine the influence of clinical and genetic factors on PFS and OS.

Results

Patient characteristics

The groups of patients treated with different EGFR-TKIs were comparable with respect to their demographic, clinical, and molecular factors (Table II). The median age of all patients was 67 years and 55% patients were 67 years of age or older. 71% of EGFR-TKIs treated patients were women, and 43%-non-smokers. Smokers with EGFR mutations were rather heavy smokers, with a median pack-year history of 20. Most patients had a diagnosis of adenocarcinoma (95%) and distant metastases (81%), including brain metastases (15%). NSCLC recurrence after surgery was found in 17% of patients. All patients were in very good or good performance status. EGFR-TKIs were used in the first (72%), second (24%), or third-line (3.9%) of treatment. In progression after EGFR-TKIs therapy, 41% of patients obtained palliative radiotherapy and 39% of patients received one (30%) or more (9.4%) lines of chemotherapy.

Table II.

Patients' characteristics.

Table II.

Patients' characteristics.

CharacteristicTotal (n=180)Erlotinib (n=98)Gefitinib (n=66)Afatinib (n=16)
Age
  Age (years, median ± SD)67±11.867±11.0969±13.0662±9.84
  ≥67 years (n, %)99,5552,53.142,63.65,31.25
  <67 years (n, %)81,4546,46.924,36.411,68.75
Gender
  Female (n, %)128,71.172,73.546,69.710,62.5
  Male (n, %)52,28.926,26.420,30.36,37.5
Histopathological diagnosis
  Adenocarcinoma (n, %)171,95.092,93.964,97.015,94.0
  Adenosquamous carcinoma (n, %)3,1.72,2.01,1.50,0.0
  Large cell carcinoma (n, %)2,1.11,1.00,0.01,6.0
  NOS (n, %)4,2.23,3.11,1.50,0.0
Performance status (PS)
  PS=0 (n, %)33,18.323,23,58,12.12,12.5
  PS≥1 (n, %)147,81.775,76.558,87.914,87.5
Stage of disease
  IIIB (n, %)33,18.322,22.48,12.13,18.8
  IV (n, %)147,81.776,77.658,87.913,81.2
CNS metastases
  Yes (n, %)28,15.616,16.312,18.20,0.0
  No (n, %)152,84.482,83.754,81.816,100.0
Prior surgical treatment
  Yes (n, %)31,17.214,14.313,19.74,25
  No (n, %)149,82.884,85.753,80.312,75
Smoking history
  Yes (n, %)59,32.830,30.623,34.86,37.5
  No (n, %)78,43.347,48.022,33.39,56.25
  No data (n, %)43,23.921,21.421,31.81,6.25
  Pack-years (median ± SD)20±12.420±11.1420±14.3522.5±9.91
Line of EGFR-TKI therapy
  I (n, %)129,71.753,54.163,95.513,81.2
  II or III (n, %)51,28.345,45.93,4.53,18.8
Early EGFR-TKI therapy discontinuation due to grade 3–4 toxicities
  Yes (n, %)175,97.296,9864,9715,94.0
  No (n, %)5,2.82,22,31,6.0
Chemotherapy after EGFR-TKI treatment
  Yes (n, %)71,39.438,38.828,42.45,31.3
  No (n, %)109,60.460,61.238,57.611,68.7
Palliative radiotherapy after EGFR-TKI treatment
  Yes (n, %)73,40.642,42.930,45.51,6.0
  No (n, %)107,59.456,57.136,54.515,94.0
EGFR mutations status
  Deletion in exon 19 (n, %)115,63.959,60.246,69.710,62.5
  Substitution p.Leu858Arg (n, %)52,28.932,32.716,24.24,25.0
  Rare mutations (n, %)13,7.27,7.14,6.12,12.5

Classical exon 19 deletions were found in 64% of patients, exon 21 p.Leu858Arg substitution was found in 29% of patients, and a relatively large population of patients (7.2%) had rare EGFR mutations. Among the rare EGFR mutations, insertions in exon 20 were most frequently diagnosed (23% of rare mutations), while double mutations of substitutions in codon 719 and 861 or 768 were found in two patients (15% of rare mutations). Detailed characteristics of the 13 NSCLC patients with rare EGFR gene mutations are outlined in Table II.

Response rates

Partial response (PR), complete response (CR), and disease control was achieved in 55, 3.3, and 80.5% of patients, respectively, while early progression occurred in 14.5% of patients treated with EGFR-TKIs (Table III). Demographic and clinical factors had no significant impact on the risk of NSCLC progression (Table III). Response to EGFR-TKIs was significantly (P<0.05) more frequent in patients with a deletion in exon 19 than in patients with rare mutations in EGFR gene. All patients with an insertion in exon 20 of EGFR gene showed early disease progression. All other patients with rare EGFR gene mutations (including patients with p.Ser768Ile substitution in exon 20) responded to treatment, except for a female patient with substitution at codon 747 of exon 19 and a female patient with double mutations in codons 719 and 768 in exons 18 and 20, in whom short stabilization of the disease occurred. The detailed characteristics of the response to treatment in the 13 NSCLC patients with rare EGFR gene mutations are provided in Table III.

Table III.

Response to EGFR-TKI treatment according to demographic and clinical characteristics.

Table III.

Response to EGFR-TKI treatment according to demographic and clinical characteristics.

CharacteristicPartial response+complete response (n=105)Stable disease (n=49)Progressive disease (n=26)p; χ2
Age
  ≥67 years, n=99 (n, %)57,57.525,25.317,17.20.479;1.468
  <67 years, n=81 (n, %)48,59.324,29.69,11.1
Gender
  Female, n=128 (n, %)78,60.935,27.315,11.70.247;2.796
  Male, n=52 (n, %)27,51.914,26.911,21.2
Histopathological diagnosis
  Adenocarcinoma, n=171 (n, %)99,57.947,27.525,14.60.872;0.273
  Other, n=9 (n, %)6,66.72,22.21,11.1
Performance status (PS)
  PS=0, n=33 (n, %)24,72.77,21.22,6.10.14;3.938
  PS≥1, n=147 (n, %)81,55.142,28.624,16.3
Stage of disease
  IIIB, n=33 (n, %)22,66.77,21.24,12.10.558;1.168
  IV, n=147 (n, %)83,56.542,28.522,15.0
CNS metastases
  Yes, n=28 (n, %)16750.845;0.336
  No, n=152 (n, %)894221
Prior surgical treatment
  Yes, n=31 (n, %)21,67.76,19.44,12.90.477;1.481
  No, n=149 (n, %)84,56.443,28.922,14.8
Smoking history
  Yes, n=59 (n, %)39,66.113,22.07,11.90.643;0.883
  No, n=78 (n, %)46,59.019,24.413,16.6
Line of EGFR-TKI therapy
  I, n=129 (n, %)75,58.137,28.717,13.20.649;0.865
  II or III, n=51 (n, %)30,58.812,23.59,17.6
Type of EGFR-TKI (reversible vs. irreversible)
  Erlotinib and gefitinib, n=164 (n, %)95,58.046,28.023,14.00.69;0.741
  Afatinib, n=16 (n, %)10,62.53,18.753,18.75
Type of EGFR-TKI (only reversible)
  Erlotinib, n=98 (n, %)58,59.226,26.514,14.30.87;0.278
  Gefitinib, n=66 (n, %)37,56.120,30.39,13.6
  Type of EGFR-TKI (erlotinib vs. afatinib)
  Erlotinib, n=98 (n, %)58,59.226,26.514,14.30.764;0.537
  Afatinib, n=16 (n, %)10,62.53,18.753,18.75
Type of EGFR-TKI (gefitinib vs. afatinib)
  Gefitinib, n=66 (n, %)37,56.120,30.39,13.60.626;0.936
  Afatinib, n=16 (n, %) 10,62.53,18.753,18.75
EGFR mutations status (only common)
  Deletion in exon 19, n=115 (n, %)66,57.436,31.313,11.30.302;2.396
  Substitution p.Leu858Arg, n=52 (n, %)32,61.511,21.29,17.3
EGFR mutations status (common vs. rare)
  Common mutations, n=167 (n, %)98,58.747,28.122,13.20.178;3.355
  Rare mutations, n=13 (n, %)7,53.82,15.44,30.8
EGFR mutations status (deletion in exon 19 vs. rare)
  Deletion in exon 19, n=115 (n, %)66,57.436,31.313,11.30.113;4.355
  Rare mutations, n=13 (n, %)7,53.82,15.44,30.8
EGFR mutations status (substitution p.Leu858 arg vs. rare)
  Substitution p.Leu858Arg, n=52 (n, %); 1.21832,61.511,21.29,17.30.544
Rare mutations, n=13 (n, %)7,53.82,15.44,30.8
Progression-free survival

The median PFS of patients receiving EGFR-TKIs treatment was 10 months, and 34.3% had no disease progression during observation. A comparison of the probability of PFS in NSCLC patients with EGFR gene mutations treated with erlotinib, gefitinib or afatinib is shown in Fig. 1. The median PFS was 10 months in patients treated with erlotinib, 9 months in patients treated with gefitinib, and 15 months in patients treated with afatinib (Table IV). Although patients treated with afatinib showed the longest median PFS, it was not significantly different from that observed with the other EGFR-TKIs.

Table IV.

Progression-free survival (PFS) in NSCLC patients treated with EGFR-TKIs.

Table IV.

Progression-free survival (PFS) in NSCLC patients treated with EGFR-TKIs.

Univariate analysisMultivariate analysis


CharacteristicMedian PFS (months)PHR (95% CI)PHR (95% CI)
Age
  ≥67 years100.7990.959 (0.679–1.679)0.6640.921 (0.638–1.638)
<67 years10
Gender
  Female100.0941.345 (0.914–1.914)0.1071.374 (0.935–2.935)
  Male  8
Histopathological diagnosis
  Adenocarcinoma100.9971.001 (0.468–2.468)0.5321.294 (0.579–2.579)
  Other11
Performance status (PS)
  PS=0100.3991.208 (0.785–1.785)0.8961.036 (0.611–1.611)
  PS≥110
Stage of disease
  IIIB130.1911.343 (0.879–2.879)0.2421.37 (0.811–2.811)
  IV  9
CNS metastases
  Yes  90.2561.277 (0.79–2.79)0.4211.214 (0.758–1.758)
  No10
Prior surgical treatment
  Yes160.0941.432 (0.956–2.956)0.2851.307 (0.802–2.802)
  No  9
Smoking history
  Yes  90.4481.139 (0.806–1.806)0.8591.035 (0.713–1.713)
  No10
Line of EGFR-TKI therapy
  I100.3250.841 (0.588–1.588)0.230.787 (0.533–1.533)
  II or III10
Type of EGFR-TKI (reversible vs. irreversible)
  Erlotinib and gefitinib100.5331.243 (0.648–2.648)0.4541.333 (0.63–2.63)
  Afatinib18
Type of EGFR-TKI (only reversible)
  Erlotinib100.251.219 (0.847–1.847)
  Gefitinib  9
Type of EGFR-TKI (erlotinib vs. afatinib)
  Erlotinib100.6231.191 (0.586–2.586)
  Afatinib18
Type of EGFR-TKI (gefitinib vs. afatinib)
  Gefitinib  90.4311.329 (0.655–2.655)
  Afatinib18
EGFR mutations status (only common)
  Deletion in exon 19110.0951.361 (0.909–2.909)
Substitution p.Leu858Arg  8
EGFR mutations status (deletion in exon 19 vs. rare)
  Deletion in exon 19110.00430.429 (0.099–0.099)
  Rare mutations  5
EGFR mutations status (substitution p.Leu 858Arg vs. rare)
  Substitution p.Leu858Arg  80.1150.616 (0.236–1.236)
  Rare mutations  5
EGFR mutations status (common vs. rare)
  Common mutations100.0092.155 (0.907–5.907)0.0082.437 (1.263–4.263)
  Rare mutations  5

Demographic and clinical factors had no significant impact on the PFS of patients treated with EGFR-TKIs. While, molecular factors did influence the clinical outcomes of EGFR-TKIs treatment (Table IV). Patients with common EGFR mutations showed significantly longer median PFS than patients with rare EGFR mutations (10 vs. 5 months; P=0.009). The significant difference in median PFS occurred between the group of patients with exon 19 deletion and group of patients with rare EGFR mutations (P<0.005). The median PFS was only slightly longer in patients with substitution p.Leu858Arg compared to patients with rare EGFR mutations. Moreover, insignificant (P=0.095) longer median PFS was observed in patients with exon 19 deletion than in patients with p.Leu858Arg substitution (Table IV, Fig. 2).

Overall survival

Demographic, clinical, and molecular factors did not affect the median OS (27 months) in our study (Table V). One-year and two-years OS for patients treated with EGFR-TKIs was 66.3 and 26.3%, respectively. A comparison of the probability of OS in NSCLC patients with EGFR gene mutations treated with erlotinib, gefitinib or afatinib is shown in Fig. 3. The median OS was 26 months in the gefitinib and erlotinib groups, whereas in the afatinib group, the median OS had not been reached at the time of the analysis (Table V). However, these differences in OS were not statistically significant among the three treatment arms.

Table V.

Overall survival (OS) in NSCLC patients treated with EGFR-TKIs.

Table V.

Overall survival (OS) in NSCLC patients treated with EGFR-TKIs.

Univariate analysisMultivariate analysis


CharacteristicMedian OS (months)PHR (95% CI)PHR (95% CI)
Age
  ≥67 years320.4820.853 (0.536–1.536)0.3730.797 (0.485–1.485)
  <67 years25
Gender
  Female320.251.322 (0.784–2.784)0.2241.405 (0.814–2.814)
  Male23
Histopathological diagnosis
  Adenocarcinoma260.6860.815 (0.27–2.27)0.8960.929 (0.308–2.308)
  Other22
Performance status (PS)
  PS=0320.4471.263 (0.713–2.713)0.5980.82 (0.394–1.394)
  PS≥126
Stage of disease
  IIIBNot reached0.0771.829 (1.038–3.038)0.0922.013 (0.895–4.895)
  IV26
CNS metastases
  Yes230.4051.282 (0.668–2.668)0.5531.235 (0.617–2.617)
  No26
Prior surgical treatment
  Yes510.1811.477 (0.867–2.867)0.3331.39 (0.716–2.716)
  No25
Smoking history
  Yes260.7061.089 (0.692–1.692)0.8730.96 (0.581–1.581)
  No26
Line of EGFR-TKI therapy
  I260.8410.955 (0.602–1.602)0.8070.939 (0.568–1.568)
  II or III26
Type of EGFR-TKI (reversible vs. irreversible)
  Erlotinib and gefitinib260.4081.77 (0.603–5.603)0.4551.739 (0.41–7.41)
  AfatinibNot reached
  Type of EGFR-TKI (only reversible)
  Erlotinib260.3531.238 (0.768–1.768)
  Gefitinib26
  Type of EGFR-TKI (erlotinib vs afatinib)
  Erlotinib260.4181.754 (0.513–5.513)
  AfatinibNot reached
  Type of EGFR-TKI (gefitinib vs afatinib)
  Gefitinib260.4251.739 (0.497–5.497)
  AfatinibNot reached
Chemotherapy after EGFR-TKI treatment
  Yes260.6770.909 (0.576–1.576)0.6791.11 (0.679–1.679)
  No26
Palliative radiotherapy after EGFR-TKI treatment
  Yes260.4341.191 (0.757–1.757)0.80.931 (0.538–1.538)
  No32
EGFR mutations status (only common)
  Deletion in exon 19270.6041.143 (0.669–1.669)
  Substitution p.Leu858Arg26
EGFR mutations status (deletion in exon 19 vs. rare)
  Deletion in exon 19270.2010.588 (0.166–1.166)
  Rare mutations22
EGFR mutations status (substitution p.Leu858 arg vs. rare)
  Substitution p.Leu858Arg260.7990.885 (0.304–2.304)
  Rare mutations22
EGFR mutations status (common vs. rare)
  Common mutations260.2511.605 (0.576–4.576)0.311.592 (0.652–3.652)
  Rare mutations22
Adverse events

Severe, no treatment-related toxicity (grade 4) resulting in discontinuation of EGFR-TKIs treatment only occurred in five patients in our study. Afatinib and erlotinib showed significantly more frequent rash and other skin toxicities, as well as diarrhea, compared to gefitinib. All patients treated with afatinib showed mild diarrhea. Hepatotoxicity occurred only in three patients treated with gefitinib.

Discussion

This study was the first to directly compare EGFR-TKIs treatment efficacy in patients with NSCLC harboring common and rare activating EGFR mutations. Erlotinib, gefitinib, and afatinib had similar effectiveness in patients with common and rare EGFR mutations, although patients treated with afatinib had a slightly longer PFS. A relatively large proportion of our patients (7.2%) had rare EGFR gene mutations, and these patients had significantly poorer median PFS than those with common EGFR mutations (P<0.05). Moreover, patients with a rare insertion in exon 20 of EGFR gene showed early disease progression. Therefore, detection of specific EGFR mutations is important for EGFR-TKIs treatment outcomes.

Similar to our results, a previous meta-analysis by Liang et al indicated that erlotinib, gefitinib, and afatinib have equivalent efficacy. This meta-analysis included twelve phase III global clinical trials involving 1812 NSCLC patients with activating EGFR gene mutations (12). Authors reported a 1-year PFS of 43%, compared to 34% in our study. Moreover, 1-and 2-year OS rates were 79 and 50% in Liang study, compared to 66 and 26% in our study. The slight improvement in EGFR-TKIs efficacy shown by Liang et al (12) compared to us may be due to the fact that the patients in the clinical trials were closely matched. Moreover, most clinical trials enrolled an Asian patients compared to the Caucasian population used in our study. However, the nonrandomized design of our study did not allow a reliable assessment of the efficacy of particular EGFR-TKIs.

Despite the lower efficacy of the EGFR-TKIs observed in our study, the type and severity of adverse events was similar to those described in previous clinical trials (12). For example, afatinib and erlotinib resulted in a more severe rash and diarrhea in patients compared with gefitinib. Therefore, our results in a Caucasian cohort indicate that EGFR-TKIs are effective and show similar side effect profiles to previous studies in Asian populations.

Similar to our findings, Lim et al showed no difference in PFS between the erlotinib- and gefitinib-treated groups (11.7 vs. 14.5 months; P=0.507) in a retrospective case-control study of matched Asian patients (121 pairs) with NSCLC (13). These patients were young (median age 58 years), mostly non-smokers (64%), in very good or good performance status (91%), and received EGFR-TKIs treatment mainly in the second-line (74%) Patients showed excellent overall response rates to erlotinib and gefitinib (77 and 74.5%, respectively) (13). However, Kim et al showed the drugs were not as efficient in a randomized phase II study of 96 Asian patients with advanced NSCLC: In the erlotinib- and gefitinib-treatment arms the response rates were 40 and 48%, and the median PFS was only 3.1 and 4.9 months, respectively (6). The authors concluded that the reason for treatment failure was including patients with unknown EGFR gene mutations with at least two out of three clinical factors associated with a higher incidence of EGFR gene mutations (6). Similarly, in a recent randomized phase III study of 562 pretreated patients with lung adenocarcinoma (including 401 with EGFR mutations), the response rates were 44 and 46% and the median PFS was 7.5 and 6.5 months in erlotinib- and gefitinib-treatment arms, respectively (14).

The first head-to-head comparison of afatinib and gefitinib was recently reported in the prospective phase IIb LUX-Lung 7 clinical trial (7). In this trial, 319 Caucasian and Asian NSCLC patients with common EGFR gene mutations were randomized to first-line therapy with afatinib or gefitinib (7). Afatinib showed significant improvement in PFS, with a median duration of response of 10.1 months compared to 8.4 months with gefitinib (HR=0.73; 95% CI, 0.57–0.95; P=0.0165) (7). Similarly, in our study, we found a slight improvement in PFS with afatinib (18 months) compared to the two reversible EGFR-TKIs (10 months) although this was not statistically significant (HR=1.243; 95% CI, 0.648–2.382; P=0.533). However, due to the small sample size (n=16) of the afatinib-treated group, we cannot make any definitive conclusions about the observed difference in PFS.

We found that demographic and clinical factors did not affect the effectiveness of the EGFR-TKIs treatment of patients harboring EGFR gene mutations. While some authors have emphasized the impact of patients' performance status on the effectiveness of EGFR-TKIs treatment. The differences in EGFR-TKIs effectiveness in past studies were only found when groups of patients in good and very good performance status (PS=0 or 1) were compared with groups of patients with satisfactory performance status (PS=2) (15). Such comparison was not performed in the current study (only patients with PS=0 or 1 were included). Therefore, the impact of performance status on EGFR-TKIs requires further investigation.

We found that patients with the common exon 19 deletion in EGFR had a slightly longer PFS after treatment with EGFR-TKIs than patients with exon 21 p.Leu858Arg substitution (11 vs. 8 months; P=0.095) or rare EGFR mutations (11 vs. 5 months; P<0.005). Urata et al found no significant difference in the PFS among patients with the EGFR p.Leu858Arg mutation (n=172), the EGFR exon 19 deletion (n=192), or those with rare EGFR mutations (n=25) who were treated with gefitinib and erlotinib (14). Zhang et al also showed that the patients with the exon 19 deletion in EGFR receiving first-line EGFR-TKIs had longer PFS than those with exon 21 substitution (16). Similarly, Urata et al identified patients with the EGFR exon 19 deletion subgroup had slightly longer PFS when treated with gefitinib and erlotinib than those with p.Leu858Arg mutation (14). Furthermore, analysis of two phase III trials, LUX-Lung 3 and LUX-Lung 6, indicated that the first-line afatinib compared to chemotherapy improved OS for patients with the EGFR exon 19 deletion but not for patients with p.Leu858Arg substitution (17). We found that the common EGFR mutations (exon 19 deletion and p.Leu858Arg) did not impact the OS in this study. However, we did not specifically investigate these differences in the afatinib-treated group due to the small sample size (n=16).

Beau-Faller et al recently proved that rare EGFR gene mutations could be associated with resistance to EGFR-TKIs treatment (distal exon 20 insertions) or sensitivity to EGFR-TKIs treatment (exon 18 substitution or complex EGFR mutations) in Caucasian NSCLC patients (10). When investigating 50 NSCLC patients with rare EGFR gene mutations treated with EGFR-TKIs, they found that primary resistance to EGFR-TKIs was diagnosed in 54% of patients with exon 20 mutations, in 66% of patients with exon 18 substitutions, and in 14% of patients with more complex EGFR mutations (10). However, median OS from EGFR-TKIs was better for patients with exon 18 (22 months) than for patients with exon 20 mutations (9.5 months) (10). Our results fully agree with those of Beau-Faller et al (10) primarily finding that patients with exon 20 insertions of EGFR failed to respond to EGFR-TKIs treatment. Resistance to EGFR TKIs therapy has been associated with a Thr790Met substitution in exon 20 of EGFR (18). However, no patients with primary Thr790Met mutation were enrolled in our study. By contrast, patients with non-classical exon 19 deletions (especially deletions of greater than 15 bp) and rare substitutions (i.e., mutations in codon 858 and 861 in exon 21) had good response to EGFR-TKIs treatment (19,20). Our study confirms results indicating that rare EGFR mutations are important for EGFR-TKIs treatment outcomes (21). However, further research is required to build a database of all EGFR mutations and their individual impact on the differing EGFR-TKIs treatments.

To combat treatment resistance, third-generation EGFR-TKIs against the p.Thr790Met substitution in exon 20 of EGFR have been developed, including osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-0,674,7775 (22). Recently, osimertinib has been registered for treatment of p.Thr790Met positive patients after failure of first- or second-generations EGFR-TKIs therapy. Clinical trials on these third-generation EGFR-TKIs are currently underway. However, further research is required to develop novel inhibitors that combat resistance in some of the other rare EGFR mutations.

Our study confirms that EGFR-TKIs treatment is effective in NSCLC patients with EGFR gene mutations, irrespective of demographic and clinical factors. We found no significant differences in the effectiveness of erlotinib, gefitinib, and afatinib among our Caucasian cohort of patients. However, qualification of patients with rare EGFR gene mutations, especially those with exon 20 insertions, to EGFR-TKIs treatment requires special attention due to the varied effectiveness of EGFR-TKIs treatment in this group of patients.

Acknowledgements

We thank all participating patients and their families. We also thank Proper Medical Writing Sp. z o.o, Poland, for editorial support and linguistic corrections.

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June 2017
Volume 13 Issue 6

Print ISSN: 1792-1074
Online ISSN:1792-1082

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APA
Krawczyk, P., Kowalski, D.M., Ramlau, R., Kalinka‑Warzocha, E., Winiarczyk, K., Stencel, K. ... Krzakowski, M. (2017). Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non‑small cell lung cancer in patients with common and rare EGFR gene mutations. Oncology Letters, 13, 4433-4444. https://doi.org/10.3892/ol.2017.5980
MLA
Krawczyk, P., Kowalski, D. M., Ramlau, R., Kalinka‑Warzocha, E., Winiarczyk, K., Stencel, K., Powrózek, T., Reszka, K., Wojas‑Krawczyk, K., Bryl, M., Wójcik‑Superczyńska, M., Głogowski, M., Barinow‑Wojewódzki, A., Milanowski, J., Krzakowski, M."Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non‑small cell lung cancer in patients with common and rare EGFR gene mutations". Oncology Letters 13.6 (2017): 4433-4444.
Chicago
Krawczyk, P., Kowalski, D. M., Ramlau, R., Kalinka‑Warzocha, E., Winiarczyk, K., Stencel, K., Powrózek, T., Reszka, K., Wojas‑Krawczyk, K., Bryl, M., Wójcik‑Superczyńska, M., Głogowski, M., Barinow‑Wojewódzki, A., Milanowski, J., Krzakowski, M."Comparison of the effectiveness of erlotinib, gefitinib, and afatinib for treatment of non‑small cell lung cancer in patients with common and rare EGFR gene mutations". Oncology Letters 13, no. 6 (2017): 4433-4444. https://doi.org/10.3892/ol.2017.5980