Comparing the Efficacy of Gefitinib, Erlotinib, and Afatinib in Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor (<em>EGFR</em>) Mutations

Review Article

Austin J Lung Cancer Res. 2016; 1(1): 1003.

Comparing the Efficacy of Gefitinib, Erlotinib, and Afatinib in Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor (EGFR) Mutations

Asami K¹* and Atagi S²

¹Department of Clinical Oncology, Machida Clinic, Japan

²Department of Clinical Oncology, National Hospital Organization Kinki-chuo Chest Medical Center, Japan

*Corresponding author: Asami K, Clinical Oncology, Machida Clinic, 4F Sunwood-machida 4-15-13 Haramachida, Machida City, Tokyo, 194-0013, Japan

Received: January 22, 2015; Accepted: January 04, 2016; Published: January 06, 2016

Abstract

Gefitinib and erlotinib are reversible Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs). Compared to standard chemotherapy, both of these agents have demonstrated significantly higher response rates and are associated with prolonged survival in patients with advanced Non-Small Cell Lung Cancer (NSCLC) harboring an activating EGFR mutation such as an axon 19 deletion or an L858R mutation. These agents are recommended as firstline treatments for NSCLCs with such mutations. Afatinib belongs to a class of irreversible inhibitors of the human epidermal receptor family. Two recent largescale randomized trials demonstrated the high efficacy of afatinib as a first-line treatment for NSCLC with activating mutations of EGFR compared to standard chemotherapy.

Currently, various EGFR-TKIs including gefitinib, erlotinib, and afatinib are offered as first-line treatments in patients with advanced NSCLC harboring activating EGFR mutations. However, it is not clear if any of this EGFR-TKI should a first-line therapy advantage in these patients over the others. Herein, the latest data involving the use of these agents is reviewed.

Keywords: Afatinib; EGFR mutation; Erlotinib; Gefitinib; Non-small cell lung cancer

Abbreviations

EGFR-TKIs: Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors; NSCLC: Non-Small Cell Lung Cancer; PFS: Progression-Free Survival; RR: Response Rate; ASCO: American Society of Clinical Oncology; OS: Overall Survival; HR: Hazard Ratio; CI: Confidence Interval

Introduction

First-generation reversible Epidermal Growth Factor Receptor– Tyrosine Kinase Inhibitors (EGFR-TKIs) such as gefitinib and erlotinib have proven to be highly effective in treating Non-Small Cell Lung Cancer (NSCLC) patients harboring activating EGFR mutations such as an exon 19 deletion or an L858R mutation [1,2]. Several randomized phase III trials of gefitinib and erlotinib as firstline treatments in patients with NSCLC with the aforementioned types of mutations demonstrated significantly longer Progression- Free Survival (PFS) times, higher degrees of tumor shrinkage, better tolerability, and an extended quality of life compared to platinum doublet chemotherapy [3-6]. Based on these studies, gefitinib and erlotinib are recommended as first-line treatment agents for these types of malignancies.

Afatinib is an irreversible pan Human Epidermal Receptor (pan- HER) inhibitor that down regulates ErbB signaling by covalently binding to the kinase domain of EGFR, HER2, or HER4. Large scale randomized phase III trials that compared afatinib to standard platinum-based chemotherapy as first-line therapy demonstrated significant improvement of PFS in selected patients harboring activating EGFR mutations [7,8]. Based on the results of these trials, the United States Food and Drug Administration approved afatinib as a first-line treatment for advanced NSCLC with activating EGFR mutations. Currently, gefitinib, erlotinib, and afatinib are recommended as standard first-line therapies for this category of NSCLC. In this review, the use of these therapeutic agents are explored and compared.

Efficacy of gefitinib, erlotinib, and afatinib as first-line therapy for EGFR-mutated NSCLC

Table 1 shows the results of previous clinical studies of gefitinib, erlotinib, and afatinib as first-line treatments in treatment-naïve patients with advanced NSCLC harboring an EGFR mutation. Response Rates (RRs) and PFSs of gefitinib, erlotinib, and afatinib are 55-74% and 9-10 months, 58-83% and 9-13 months, and 58-61% and 9-11 months, respectively [3-7, 9-11]. Based on the results of previous prospective studies, these EGFR-TKIs appear to show similar efficacy in terms of RR and PFS in patients with EGFR-mutated NSCLC.

Table 1: Clinical trials of the EGFR-TKIs gefitinib, erlotinib, and afatinib as first-line treatments in patients with EGFR-mutated NSCLC.





  

    
Study

    
Phase

    
Treatment

    
Number of patients

    
Age (years)

    
RR

      
(%)

    
Median PFS

      
(months)

    
Median

      
OS

      
(months)

  

  

    
Sequist [9]

    
II

    
Gefitinib

    
31*

    
Median 62

    
55

    
9.2

    
17.5

  

  

    
Douillard [10]

    
IV

      
Single-arm

    
Gefitinib

    
106†

    
Median 65

    
70

    
9.7

    
19.2

  

  

    
WJTOG3405 [3]

    
III

    
Gefitinib

    
86

    
<75

    
62

    
9.2

    
35.5

  

  

    
NEJ002 [4]

    
III

    
Gefitinib

    
114

    
<75

    
74

    
10.8

    
30.5

  

  

    
Koich [11]

    
II

    
Erlotinib

    
103‡

    
Median 65

    
78

    
11.8

    
NE

  

  

    
OPTIMAL [5]

    
III

    
Erlotinib

    
82

    
≥18

    
83

    
13.1

    
22.7

  

  

    
EURTAC [6]

    
III

    
Erlotinib

    
86

    
≥18

    
58

    
9.7

    
19.3

  

  

    
Lux-Lung 3 [7]

    
III

    
Afatinib

    
204

    
Median 62

    
61

    
11.1

    
NE

  

  

    
Lux-Lung6 [8]

    
III 

    
Afatinib 

    
242 

    
Median 58

    
67 

    
11.0

    
NE

  

  

    
Abbreviations:    EGFR-TKIs: Epidermal Growth Factor Receptor-Tyrosine-Kinase Inhibitors;    NSCLC: Non-Small Cell Lung Cancer; RR: Response Rate; OS: Overall Survival;    NE; Not Evaluated

      
*Five    patients had atypical EGFR mutation.

      
†Atypical EGFR mutations were detected in 4    patients (L861Q in two patients, G719X in the other two patients).

      
‡Two    different types of EGFR mutation    (L858R, T790M) were detected in 2 patients.

      
 

  










Table 1:  Clinical trials of the EGFR-TKIs gefitinib, erlotinib, and afatinib as first-line treatments in patients with EGFR-mutated NSCLC.

Several subset analyses or retrospective studies that compared gefitinib to erlotinib in patients with activating EGFR-mutated NSCLC determined similar efficacies for both agents. Wu et al. showed that there was no significant difference between gefitinib and erlotinib in terms of RR and PFS in patients with NSCLC harboring activating EGFR mutations in their retrospective study [12]. Among the 224 patients with advanced NSCLC treated with gefitinib or erlotinib as first-line therapy who were reviewed, activating EGFR mutations were detected in 146. The median RR and PFS with gefitinib and erlotinib was 51% and 10.5 months (n = 94), and 58% and 10.4 months (n = 52), respectively. No statistically significant difference was noted in terms of RR and PFS between patients treated with gefitinib and those treated with erlotinib. Lim et al. reported similar efficacy in patients treated with either gefitinib or erlotinib in advanced NSCLC with activating EGFR mutations [13]. One hundred twenty one pairs of gefitinib-treated and erlotinib-treated patients were matched according to sex, smoking history, Eastern Cooperative Oncology Group performance status, and the type of EGFR mutation. Of the 242 patients, 63 (26%) received EGFR-TKIs as first-line therapy. The overall RRs in patients treated with gefitinib and those treated with erlotinib were 76.9% and 74.4%, respectively (p = 0.575). There was no statistically significant difference in terms of the median PFS (11.7 months vs. 9.6 months, p = 0.056, respectively). Additionally, no significant difference was observed between patients treated with gefitinib or erlotinib as a first-line treatment in terms of RR (76.7% vs. 90%, p = 0.431, respectively) or PFS (11.7 months vs. 14.5 months, p = 0.507, respectively).

Current randomized phase III studies comparing gefitinib and erlotinib for advanced NSCLC were presented at the 2014 annual meeting of American Society of Clinical Oncology (ASCO) [14]. Among the 561 patients enrolled in this study, 371 patients had an activating EGFR mutation (186 patients in the gefitinib group and 185 patients in the erlotinib group). The median PFS, time to treatment failure, and Overall Survival (OS) of gefitinib and erlotinib were 6.5, 5.6, and 22.8 months and 7.5, 5.3, and 24.5 months, respectively. No statistically significant difference was observed between patients treated with gefitinib and those treated with erlotinib in any category. However, patients with recurrence or previously treated NSCLC were enrolled in this study.

Considering the high efficacy of EGFR-TKIs in patients with advanced NSCLC harboring activating EGFR mutations, the use of these agents to treat other specific disease conditions, such as intracranial metastases that are associated with poor prognoses due to the lack of efficacious treatments other than radiotherapy, is worth considering. In previous retrospective studies and subset analyses of gefitinib and Erlotinib treatment against brain metastases in patients with NSCLC harboring EGFR mutations, investigators reported responses in these lesions that were comparable in significance to that of the primary tumor [15-18]. In their retrospective study, Lee et al. documented that erlotinib had a better control rate than gefitinib for leptomeningeal metastases in NSCLC patients [19]. Among 25 patients (14 treated with erlotinib, 11 with gefitinib) with NSCLC reviewed in their study, 17 patients had tumors with activating EGFR mutations. There was a significantly better cytological negative conversion rate of leptomeningeal cancer in patients treated with erlotinib than those treated with gefitinib (64.3% vs. 9.1%, p = 0.012). Cytological negative conversion rate of leptomeningeal cancer was defined as a rate of the absence of malignant cells in the cerebrospinal fluid three times in succession in this study. However, 9 patients had already been treated at the time the brain metastases were detected, and all patients received intra the cal chemotherapy. Thus, this study is unable to confirm the superiority of erlotinib as a first-line therapy against EGFR-mutated NSCLC with intracranial metastases compared with gefitinib. Radiation therapy has been considered a standard treatment in patients with intracranial metastases in NSCLC. A recent prospective study showed that the efficacy of erlotinib was similar to that of whole brain radiotherapy in terms of OS in patients with NSCLCs harboring EGFR mutations [20]. To the best of our knowledge, the efficacies of gefitinib or afatinib as firstline EGFR-TKI therapies for brain metastases in NSCLCs harboring EGFR mutations have not been studied.

Both the exon 19 deletion and L858 Rare activating EGFR mutations that predict active response to EGFR-TKIs and survival. However, activity of EGFR-TKIs may vary among these types of EGFR mutations. Several clinical studies reported that patients harboring an exon 19 deletion treated with EGFR-TKIs showed longer survival compared to similarly treated patients harboring an L858Rmutation [21-24]. Results of a pooled analysis of the LUX-Lung 3 and 6 trials with afatinib were presented at the ASCO annual meeting in 2014. The survival benefit of afatinib as first-line treatment was strongly apparent in patients with an exon 19 deletion mutation. In these patients, the median OS of afatinib (236 patients) and chemotherapy (119 patients) was 31.7 months and 20.7 months (HR = 0.59, 95% CI: 0.45-0.77, p = 0.0001), respectively. In patients with the L858R mutation, the median OS with afatinib (183 patients) and chemotherapy (93 patients) was 22.1 months and 26.9 months (HR = 1.26, 95% CI: 0.92-1.71, p = 0.16), respectively. Recent metaanalysis noted that the exon 19 deletion was associated with longer PFS compared to the L858R mutation in patients with NSCLC treated with EGFR-TKIs [25]. Based on the results of 6phase III trials [3-8] of EGFR-TKIs including gefitinib, erlotinib, and afatinib as first-line treatments, indirect comparison revealed longer PFS in patients with an exon 19 deletion than in those with an L858R mutation (HR= 0.59, 95% CI:0.38-0.92, p= 0.019). Additionally, direct meta-analysis based on the results of 7 prospective or retrospective studies [4,23,26-30] involving 549 patients treated with gefitinib or Erlotinib as first-line treatment showed similar results (HR = 0.75, 95% CI: 0.65-0.85, p < 0.001). On the other hand, Maemondo et al. directly compared PFS according to these two mutation types in subset analysis of the NEJ002 study [4]. The number of patients with exon 19 deletions or L858R mutations was 58 and 49, respectively, and the median PFS for each group was 11.5 vs. 10.8 months, respectively. No significant difference was noted in terms of PFS between those groups of patients (Hazard Ratio [HR] = 0.939, 95%, Confidence Interval [CI]: 0.3518- 2.5061, p = 0.9).

EGFR-TKIs treatment for NSCLC with activating EGFR mutations in patients who are elderly or have poor performance statuses

In the 6 aforementioned phase III trials comparing gefitinib, erlotinib, and afatinib with standard chemotherapy as first-line treatments for EGFR-mutated NSCLC, patients with Performance Status (PS) scores of 2-4 were excluded [3-8]. Additionally, elderly patients (70 years or older) were excluded in the WJOG 3405 study and the NEJ 002 study. However, previous small phase II studies showed that gefitinib as a first-line treatment in elderly patients and/ or patients with poor PS in EGFR-mutated NSCLCs showed efficacy and tolerability on par with the results of the WJOG 3405 and the NEJ 002 studies [31-33].

Although no assessment of efficacy or tolerability of erlotinib in the elderly population was conducted in either the OPTIMAL or EUROTAC studies, no negative effects such as lower response rates, shorter survivals, or the development of sever toxicities were documented. Jackman et al. reported efficacy and relatively good tolerability of erlotinib in their small phase II study for chemotherapynaïve elderly patients (70years or older) with advanced NSCLC. Among 43 patients enrolled in their study, activating EGFR mutations were detected in 9 patients, all of whom exhibited partial response or stable disease with erlotinib treatment. The TRUST study was an open-label phase IV trial of erlotinib in advanced non-selected NSCLC patients who had previously failed or were ineligible for chemotherapy or radiotherapy [34]. Among the TRUST population, 485 elderly patients (70 years or older) receiving first-line erlotinib were examined. Erlotinib-related toxicities and serious toxicities occurred in 18% and 7% of subpopulation patients, respectively. Furthermore, 27% of this subpopulation of patients required dose reductions. To the best of our knowledge, no prospective study of erlotinib in elderly patients harboring activating EGFR mutations has been conducted. Based on the results of previous phase III trials including the LUX-Lung 3 and 6, a similar efficacy for afatinib in elderly patients (65 years or older) was reported [7,8]. Meanwhile, severe treatment-related toxicities (grade 3 to 5) due to afatinib treatment were reported more commonly in patients 65 years or older.

Toxicity profile of gefitinib, erlotinib, and afatinib in patients with EGFR-mutated NSCLC

Table 2 shows severe toxicity (grade ≥3) related to treatment with gefitinib, erlotinib, and afatinib based on the results of prospective phase III trials comparing these EGFR-TKIs with standard chemotherapy as first-line treatments in patients with NSCLC harboring an activating EGFR mutation. In the recent randomized phase III study comparing gefitinib with erlotinib in previously treated NSCLC patients as described above [14], severe toxicity symptoms of rash and elevated transaminase occurred in 2.2% and 13% of patients treated with gefitinib and 18.1% and 3.3% of those treated with erlotinib, respectively. Rash and diarrhea are the most common toxicities related to EGFR-TKI treatment. These symptoms of severe toxicity were observed more in patients treated with afatinib than those treated with gefitinib or erlotinib.

Table 2: Severe toxicity (grade ≥3) of gefitinib, erlotinib, and afatinib in NSCLCs harboring EGFR mutations.





  

    
Study

    
EGFR-TKI

    
Toxicity

  

  

    
Rash

    
Diarrhea

    
Fatigue

    
ILD

    
Elevated

      
transaminase

  

  

    
WJOG 3405 [3]

    
Gefitinib

    
2%

    
1%

    
2%

    
2.3%

    
14%

  

  

    
NEJ002 [4]

    
Gefitinib

    
5.3%

    
0.9%

    
2.6%

    
2.6%

    
26.3%

  

  

    
OPTIMAL [5]

    
Erlotinib

    
2%

    
1%

    
0%

    
0%

    
4%

  

  

    
EURTAC [6]

    
Erlotinib

    
13%

    
5%

    
0%

    
1%

    
2%

  

  

    
LUX-Lung 3 [7]

    
Afatinib

    
16.2%

    
14.4%

    
1.3%

    
1%

    
-

  

  

    
LUX-Lung 6 [8]

    
Afatinib

    
14.2%

    
5.4%

    
0.4%

    
0.4%

    
1.7%

  

  

    
Abbreviations:    NSCLC: Non-Small Cell Lung Cancer; EGFR: Epidermal Growth Factor Receptor; TKI:    Tyrosine-Kinase Inhibitor; ILD: Interstitial Lung Disease

      
 

  










Table 2:  Severe toxicity (grade ≥3) of gefitinib, erlotinib, and afatinib in NSCLCs
harboring EGFR mutations.

Discussion

Results from previous clinical studies show that EGFR-TKIs used in first-line treatments, including gefitinib, erlotinib, and afatinib, have shown similar efficacy as determined by RR and PFS in patients with NSCLC harboring an activating EGFR mutation. As for treatment-related toxicities, severe toxicities, especially rash and diarrhea, occurred more often in patients treated with afatinib than in those treated with gefitinib or erlotinib. Although the LUXLung 7, which is a prospective phase II study comparing afatinib with gefitinib as first-line treatments in patients with activating EGFR-mutated NSCLC, is ongoing (NCT01466660), no prospective trials comparing afatinib with erlotinib or comparing erlotinib with gefitinib as first-line treatments for these NSCLC subtypes have been conducted. Clinical data that provide direct comparisons between these EGFR-TKIs are sorely lacking.

Recently, results of an indirect and integrated study comparing several EGFR-TKIs in patients with advanced NSCLCs harboring activating EGFR mutations were published [35]. Researchers assessed and compared efficacy of gefitinib, erlotinib, afatinib, and icotinib (BPI-2009) in terms of RR, PFS, and OS. Icotinib is an oral EGFRTKI and showed similar efficacy to, and less toxicity than, gefitinib in a randomized double-blind phase III non-inferiority study [36]. The outcome of the integrated study was indirectly based on the results of 12 previous randomized phase III trials [3-8,36-41] that investigated these EGFR-TKIs in 182 cases of NSCLC harboring an EGFR mutation. The results showed that gefitinib, erlotinib, afatinib, and icotinib had equivalent efficacy in all measured outcomes with no statistically significant differences except for toxicity. The toxicity was more severe in patients treated with erlotinib or afatinib. Severe diarrhea was particularly more frequent in patients treated with afatinib compared with those treated with the other three EGFRTKIs. Additionally, this meta-analysis showed significantly more severe treatment-related toxicity involving rashes in patients treated with afatinib than in those treated with gefitinib. No other significant differences were noted with the remaining EGFR-TKIs. Treatmentrelated toxicities, especially rash and diarrhea, seem to be slightly more prevalent in patients treated with afatinib compared to gefitinib or erlotinib. Among those EGFR-TKIs, afatinib is the most recently approved agent for use in patients with advanced EGFR-mutated NSCLC. Thus, few physicians may be accustomed to managing toxicities such as rash and diarrhea in the early phases. At this time, afatinib should not be excluded from consideration as an initial treatment based solely on the slightly higher probability of developing severe toxicities compared to gefitinib or erlotinib.

Based on the aforementioned investigation, most available EGFR-TKI may be equally suitable for certain NSCLC patients such as those within tracranial metastases, those harboring specific EGFR mutations, and elderly patients. Erlotinib may be a reasonable option for first-line therapy in patients harboring EGFR mutations with asymptomatic brain metastases. However, previous preliminarily studies were not sufficient to conclude whether erlotinib would be more effective than gefitinib, afatinib, or radiation therapy in such patients. Thus far, no prospective study has been conducted to assess whether EGFR-TKIs are differentially efficacious in NSCLCs with exon 19 deletions compared to L858Rmutations. Previous meta-analysis showed that gefitinib or erlotinib caused longer PFS in patients with an exon 19 deletion than in those with L858R mutations. However, it remains unclear whether gefitinib or erlotinib is more effective against each type of EGFR mutation in NSCLC. On the other hand, afatinib may bring an OS benefit in the subset of patients harboring an exon 19 deletion, according to the LUX-Lung 3 and Lux-Lung 6 studies. Although these data were derived by combined analysis, they were the first to report that an EGFR-TKI had a significant OS benefit over chemotherapy when administered as a first-line treatment for EGFR-mutated NSCLC. As for NSCLC harboring an exon 19 deletion mutation, afatinib might be the more appropriate first-line agent based on its OS benefit. However, further research is needed to confirm whether patients with an exon 19 deletion and those with an L858R mutation belong to different patient populations. Additionally, more efforts are needed to investigate the mechanism of action of each EGFR-TKI agent on different types of EGFR mutations. While several previous prospective small phase II studies showed efficacy and tolerability of gefitinib and erlotinib in elderly patients (70 years or older or 75 years or older, respectively) with activating EGFR mutations, no data from prospective trials of afatinib in elderly EGFR-mutated NSCLC patients have been available. While lung and bronchus cancer is most frequently diagnosed in people aged 65 to 74 years with the median age at diagnosis being 70 years based on the Surveillance, Epidemiology, and End Results (SEER) Program (https://seer.cancer.gov/), only a low percentage of elderly patients 70 years or older were enrolled in large-scale phase III trials for NSCLC. Therefore, those treated with new protocol therapies may not be represented in the whole elderly patient population. Seventy years or older may be considered the boundary age of cell senescence after which the rate of age-related changes increase [42]. Moreover, many elderly patients with NSCLC have comorbidity with other diseases such as obstructive pulmonary disease, decreased heart function, impaired renal function, etc. Thus, elderly NSCLC patients ought not to be considered in the same population as younger patients. Clinical studies to assess tolerability for EGFR-TKI therapy (other than performance status) are needed in elderly patients with advanced NSCLC who are disqualified from chemotherapy. Two prospective phase II studies of afatinib in elderly patients with NSCLC harboring EGFR mutations are ongoing (UMIN000015834, UMIN000014820).

Conclusion

There are no data providing direct comparisons between afatinib, gefitinib, and erlotinib as first-line therapies. It has not been demonstrated which EGFR-TKI is optimal as a first-line therapy for activating EGFR-mutated advanced NSCLC. Basedon previous investigations, gefitinib, erlotinib, and afatinib appear to provide similar efficacy in patients with NSCLC harboring activating EGFR mutations, as determined by response and survival. Some preliminary data suggested that some of these agents might be more suitable than others depending on the type of EGFR mutation, disease stage, and patient age. However, no definite evidence has been documented to confirm these observations. Future investigations may further assist physicians in choosing the appropriate EGFR-TKIs as initial-line therapies based on the disease condition, specific EGFR mutation status, and age of the patient. Until such a time, patients with EGFRmutated NSCLCs are better off being treated with whatever EGFRTKIs are readily available to their physicians.

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Citation: Asami K and Atagi S. Comparing the Efficacy of Gefitinib, Erlotinib, and Afatinib in Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor (EGFR) Mutations. Austin J Lung Cancer Res. 2016; 1(1): 1003.