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1. Introduction

Despite many advances in the latest decade, lung cancer remains the cancer with the highest mortality, estimated at 1.8 million deaths annually, worldwide (1). The latest developments concerning lung cancer treatment have changed the clinical practice by bringing important advantages to patient survival; yet, unfortunately there remains a high mortality rate, firstly due to disease aggressivity and secondly through lack of early diagnosis and screening programs. There has been a global effort to reduce the incidence of lung cancer especially through tobacco control policies but despite all of these efforts, the worldwide incidence is increasing each year; in 2018 an estimated 2 million new cases of lung cancer worldwide were reported. Tabacco smoking remains the main cause of lung cancer but there is an increased incidence also in never smokers, this being considered a distinct entity with different molecular and genetic characteristics (1,2).

Latest therapeutic developments in lung cancer treatment include targeted agents and immunotherapy, as well as different combinations with complementary mechanisms of action.

Currently, there is discussion regarding personalized cancer treatment and there is no doubt that all diagnosed patients should have a specific diagnosis which will guide the tailored therapy in the lung cancer sequential treatment. A complete diagnostic evaluation should consider, in addition to staging and histology, the molecular aberrations and genetics of the tumor tissue.

In 2006, the treatment options for advanced non-small cell lung cancer (NSCLC) included platinum combination with gemcitabine, vinorelbine or taxanes, with an overall survival (OS) of 8 to 11 months (3). Later, histology driven pemetrexed for second line and targeted agent erlotinib in the front line were included in the European Society for Medical Oncology (ESMO) Treatment Guideline recommendations (4).

The development of tyrosine kinase inhibitors (TKIs) have led to an improvement in survival for patients with EGFR mutation, this being the most studied driver mutation in adenocarcinoma and at the same time an important predictive factor for patient outcome following the treatment with TKIs. The intracellular tyrosine kinase domain of EGFR is important in the transduction of the signal inside the cell and when a mutation or alteration occurs this leads to transformation in cell growth and development. Firstly, the tumors are classified according to their response to EGFR TKIs as sensitive, less sensitive, and resistant. The development of the TKI drug class has established a diversity of tumor genotypes and the multilateralism in the tumor response and evolution to TKI treatment (5,6).

In this work, an overview is presented of the class evolution of EGFR TKIs starting with 2006, and the main studies of EGFR TKIs in lung cancer are discussed.

2. First-generation TKIs

Gefitinib was first studied in phase III clinical trials on Asian patients whereas the genetic alteration on EGFR is more frequent in this population. IPASS trial enrolled 1,217 adenocarcinoma patients not previously treated for advanced or metastatic disease, who never smoked or had been light smokers, randomized in two open-label arms to receive either gefitinib or paclitaxel-carboplatin. Patients in the chemotherapy arm received 6 cycles while the other arm received gefitinib until disease progression. The primary endpoint was progression-free survival (PFS). The enrollment began in March 2006 and the cut-off date was April 2008, meeting the non-inferiority objective of PFS. Then the biomarker analysis was performed, and 59.7% of the samples were positive for a mutation at different exon levels (53.6% exon 19 deletions, 42.5% exon 21 mutation, 4.2% exon 20, 3.8% other, with patients presenting also multiple mutations). The final subgroup analyses showed a benefit in PFS (HR, 0.48; 95% CI, 0.36-0.64; P<0.001), with an objective response rate (ORR) of 71.2% for gefitinib compared with 47.3% for paclitaxel-carboplatin (P=0.001) (7). Later, in 2011 the final overall survival data was published together with biomarker analyses showing no difference in median OS between the two arms (18.8 vs. 17.4 months, HR, -0.90, P=0.109, 95% CI, 079-1.02) independent of the mutation status. The authors of the final analysis concluded that the EGFR mutation was a strong predictive biomarker for PFS and also for the response to treatment with gefitinib while not for OS; but also mentioning the high number of patients with cross-over to alternative TKI treatments in further lines (8).

In 2010, the WJTOG3405 clinical trial results were published. The study included 172 patients with EGFR mutation (involving exon 19 or 21) with NSCLC [97.1% adenocarcinoma, 1.16% adenosquamous and squamous carcinoma, 1.74%, not otherwise specified (NOS)] randomly assigned to receive either gefitinib or docetaxel plus cisplatin. The results showed a median PFS of 9.2 months in the gefitinib group, respectively 6.3 months in the comparison group (HR, 0.489; 95% CI, 0.336-0.710; P<0.0001) (9). Subsequently, in 2013, the results of phase IV clinical trial IFUM were communicated and published. This study included 106 patients with EGFR mutations from a total of 1,060 screened, all Caucasians, and 64.2% never-smokers. The study intended to demonstrate gefitinib efficacy in a non-Asian origin population. The ORR was 69.8%, the disease control rate (DCR) was 90.6%, the median PFS was 9.7 months, the median OS was 19.2 months, (95% CI, 17.0-not calculable, 27% maturity) (10).

Erlotinib was studied in several clinical trials in a front-line metastatic setting, firstly on an Asiatic population, the OPTIMAL study, then EURTAC including European patients. The OPTIMAL clinical trial compared erlotinib with gemcitabine plus cisplatin and included 165 NSCLC patients harboring EGFR mutations. Patients in the erlotinib arm were treated until progression, while in the other arm the therapy was continued up to 4 cycles. Median PFS was significantly longer in the erlotinib arm (13.1 vs. 4.6 months) in comparison to the doublet arm (HR, 0.16; 95% CI, 0.10-0.26; P<0.0001) (11).

EURTAC was the first clinical trial evaluating an EGFR TKI including exclusively European patients. The inclusion started in 2007 and finished in 2011 with enrollment of 174 patients with stage IIIB/IV NSCLC with EGFR mutatations, randomized 1:1 in two open-label arms. The study compared erlotinib with standard chemotherapy: cisplatin (or carboplatin) plus either docetaxel or gemcitabine. The results favored erlotinib with a difference in median PFS of 4.5 months (9.7 vs. 5.2 months) with an HR of 0.37, 95% CI, 0.25-0.54; P<0.0001(12).

The above clinical trial results demonstrated higher efficacy of erlotinib and gefitinib in EGFR-mutated patients when compared with chemotherapy; yet, it should also be considered that the most frequent mutations were exon 19 and 21 mutations, and patients with brain metastasis were excluded. There was also a discussion regarding the past smokers' efficacy results. The EURTAC communicated HR for this subpopulation as 1.05. All the patients included in the above clinical trials in a front-line metastatic setting continued TKI treatment until disease progression, and this means that maintenance was also included.

Second-line studies involving first-generation TKIs consist of BR21 for erlotinib and phase III ISEL study including gefitinib. BR21 compared erlotinib in second-line metastatic NSCLC with a placebo. Erlotinib showed a significant difference in OS, the primary endpoint, of 6.7 vs. 4.7 months with a placebo (HR, 0.70; P<0.001) (13,14).

The ISEL study did not reach the primary endpoint, the OS in the overall population. It included 1,692 previously treated patients with NSCLC, randomized 2:1 to receive gefitinib or placebo plus best supportive care (BSC). There was no significant difference noted between the two arms concerning the median OS (5.6 vs. 5.1 months; HR, 0.89, 95% CI, 0.77-1.02; P=0.087) neither in the intent-to-treat (ITT) population nor in the adenocarcinoma subgroup (6.3 vs. 5.4 months; HR, 0.84; 95% CI, 0.68-1.03; P=0.089). Nevertheless, the preplanned analyses had positive results for never smokers (n=375; HR 0.67, P=0.012; median survival 8.9 vs. 6.1 months) and for the Asian population (n=342; HR, 0.66, P=0.01; median survival 9.5 vs. 5.5 months) (14).

3. Second-generation TKIs

The most common (90%) of the EGFR mutations include a deletion within exon 19 and Leu858Arg mutation in exon 21. Uncommon mutations include the substitution of G719X in exon 18, L861Q in exon 21, S768I in exon 20, and insertions in exon 20(14). First-generation TKIs have demonstrated activity on the level of exons 19 and 21, but not on the other uncommon alterations.

ErbB family irreversible inhibitors, afatinib and dacomitinib, represent second-generation TKIs. Clinical activity of afatinib was assessed in Lux-Lung clinical trials, demonstrating activity in some uncommon mutations but in the meantime showing less benefit on others, such as de novo T790Met or the exon 20 insertion mutation (15). Lux Lung was an extensive clinical trial program including patients from the first-line to further lines of treatment, comparing afatinib with standard chemotherapy combination or first-generation TKI. The main efficacy results of the afatinib phase III clinical studies are summarized in Table I (16-21).

Table I Efficacy results of afatinib phase III clinical studies.

Table I

Efficacy results of afatinib phase III clinical studies.

Clinical trial (refs.)	Mutational status	Therapy	Line of treatment	Results	Statistical significance
Lux-Lung 1 phase IIB/III,	NA	Afatinib (50 mg/day)	Further lines	mOS 10.8 vs. 12 months	P=0.74, HR 1.08, 95% CI, 0.86-1.35
697 patients (16)		vs. placebo (2:1)	after erlotinib or gefitinib failure	mPFS 3.3 vs. 1.1 months	P<0.0001, HR 0.38, 95% CI, 0.31-0.48
Lux-Lung 3 phase III, open-label	EGFR mutation	Afatinib (40 mg/day) vs.	First line	mPFS 11.1 vs. 6.9 months	P=0.001, HR 0.58, 95% CI, 0.43-0.78
345 patients (17,18)		pemetrexed + cisplatin		mOS 28.2 vs. 28.2 months	P=0.39, HR 0.88, 95% CI, 0.66-1.17
Lux-Lung 6 phase III, open-label	EGFR mutation	Afatinib (40 mg/day) vs.	First line	mPFS 11.0 vs. 5.6 months	P<0.0001, HR 0.28, 95% CI, 0.20-0.39
364 Asian patients (18,19)		gemcitabine + cisplatin		mOS 23.1 vs. 23.5 months	P=0.61, HR 0.93, 95% CI, 0.72-1.22
Lux-Lung 7 phase IIb, open-label	EGFR mutation	Afatinib vs. gefitinib	First line	mPFS 11.0 vs. 10.9 months	P=0.017, HR 0.73, 95% CI, 0.57-0.95
319 patients (20,21)	(Del19 or L858R)			mOS 27.9 vs. 24.5 months	P=0.258, HR 0.83, 95% CI, 0.66-1.12

[i] EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; mPFS, median progression-free survival; mOS, median overall survival; HR, hazard ratio; CI, confidence interval.

It is to be mentioned that all the above afatinib clinical trials included patients with asymptomatic brain metastasis. In Lux-Lung 3 and Lux-Lung 6, PFS was assessed for this populational subgroup with a value superiority but without statistical significance (11.1 vs. 5.4 months; HR, 0.54; P=0.1378, respectively, 8.2 vs. 4.7 months; HR, 0.47; P=0.106). Nevertheless, a meta-analysis of the two clinical trials showed a statistical difference in PFS of 2.8 months (8.2 vs. 5.4 months) with an HR of 0.5 and P=0.0297 for brain metastasis patients (17-19,22).

Dacomitinib also a second-generation EGFR TKI showed superiority compared with gefitinib in the phase III ARCHER 1050 trial which included 452 treatment naive patients, for advanced or metastatic disease with EGFR exon 19 deletions (59%) or exon 21 L858R mutation (41%). The majority of patients were never smokers (64.8%) and 74.9% had Asian ethnicity. Patients with brain metastasis were excluded. The PFS was 14.7 vs. 9.2 months for dacomitinib, respectively, gefitinib, with an HR of 0.59 (95% CI, 0.47-0.74; P<0.001). The ORR was similar between arms and the median OS was 34.1 months in the dacomitinib and 26.8 months in the gefitinib arm, with statistical significance (P=0.0438; HR, 0.76; 95% CI, 0.582-0.993) (23).

Patients receiving previously one or two lines of chemotherapy with advanced NSCLC presenting exon 19 or 21 activating mutations, were included in the ARCHER 1028 and ARCHER 1009 studies, randomized to receive either dacomitinib or erlotinib. The pooled analysis from both clinical trials showed a median PFS of 14.6 months for the investigational arm vs. 9.6 months in the erlotinib arm (HR, 0.71; two-sided log-rank, P=0.146). The median OS was 26.6 vs. 23.2 months (unstratified HR, 0.737; 95% CI, 0.431-1.259; two-sided log-rank, P=0.265) (24).

Dacomitinib showed superiority to gefitinib in survival and similar efficacy to erlotinib in patients harboring EGFR mutation with advanced/metastatic NSCLC, whereas afatinib failed to show any benefit in OS compared to first-generation TKI.

4. Third generation TKIs

Many patients acquire resistance during treatment with first- or second-generation of TKIs and 60% of patients develop a new mutation T790M (25). This has led to the development of new agents to overcome secondary resistance.

Osimertinib, a selective irreversible third-generation TKI, established its place on the treatment sequencing for advanced NSCLC after the positive results of the phase III clinical trials FLAURA and AURA 3 (26,27).

The AURA 3, phase III clinical trial assessed the efficacy and safety of osimertinib when compared with combination platinum-chemotherapy. It included 419 patients with locally advanced or metastatic NSCLC positive for EGFR T790M who received first-line treatment with an EGFR tyrosine kinase inhibitor, randomized 2:1. Patients in the investigational arm received 80 mg osimertinib daily and in the comparison arm, pemetrexed with cisplatin or carboplatin, on a 21-day cycle. Maintenance pemetrexed treatment was permitted and treatment beyond progression was also allowed upon the investigator's decision. In the pemetrexed group, 60% of the patients crossed over and received osimertinib (27).

The primary endpoint was PFS assessed by the investigator and the secondary ones: OS and safety data. Median PFS was 10.1 months in the osimertinib arm vs. 4.4 months in the chemotherapy arm (HR, 0.30; 95% CI, 0.23-0.41; P<0.001) (27). Osimertinib did not demonstrate a statistically significant benefit in OS, with the median OS being 26.8 with osimertinib vs. 22.5 in the chemotherapy group (HR, 0.87; 95% CI, 0.67-1.12; P=0.277). Adjusted OS for crossover in the platinum doublet arm was 15.9 months (28).

The phase 3 osimertinib registration trial FLAURA included metastatic NSCLC patients presenting an EGFR mutation on exon 19 or 21-L858R and compared osimertinib efficacy with standard EGFR TKI in the first-line metastatic setting. The study showed a significant longer PFS with osimertinib compared with erlotinib or gefitinib (18.9 vs 10.2 months; HR, 0.46; 95% CI, 0.37-0.57; P<0.001); the ORR was similar between the arms and duration of response (DOR) was 17.2 vs. 8.5 months (27). The reported OS was 38.6 months for osimertinib and 31.8 months for the other TKI arm (HR, 0.80; 95.05% CI, 0.64-1.00; P=0.046) (29).

5. TKIs: Differences in efficacy by specific mutation type (exon 19del or exon 21 L858R)

Exon 19 deletion and exon 21 single point Leu858Arg mutations are the most common mutations, accounting together for 84.6% of the total EGFR sensitizing mutations (29). These subtypes are distinct in the response to EGFR TKIs according to their specific sensitivity coming from different molecular structures. Mutation in exon 19 is an in-frame deletion of amino acids, while in exon 21 the main alteration is a single-nucleotide substitution, leucine with arginine (30). Exon 19 mutation is associated with a more favorable prognosis in terms of PFS than exon 21 L858R substitution (31-35).

A meta-analysis including 4,835 patients from 26 clinical trials in which TKIs were compared with chemotherapy regimens showed a higher risk reduction for progression in the exon 19 deletion patient subgroups compared with the exon 21 L858R mutation (HR, 0.69; 95% CI, 0.57-0.82; P<0.001) (36).

6. Conclusions

EGFR mutations are of a wide variation, the most common being the exon 19 deletion and exon 21 L858R, with a higher incidence in the Asian population than in Caucasians. First- and second-generation TKIs have demonstrated benefit in PFS but have failed to show improvement in OS. The third-generation, osimertinib, showed improved median PFS as well as median OS and became the standard of care for patients harboring an EGFR mutation in the metastatic setting.

The question to be answered refers to different TKI combination strategies to overcome resistance and furthermore to increase survival. Ongoing clinical trials may change the therapeutic approach for patients with advanced or metastatic NSCLC with EGFR mutation.

Acknowledgements

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Funding

Funding: No funding was received.

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Authors' contributions

CP and LM were responsible for collected and assessing the literature data and the original draft preparation. All authors including AIS and AG were responsible for the final review of the literature data and manuscript editing. All authors read and approved the final manuscript for publication.

Ethics approval and consent to participate

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Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Authors' information

Author CP is a PhD student at the Doctoral School, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania.

References