Tyrosine Kinase Inhibitors for EGFR Gene Mutation-Positive Non-Small Cell Lung Cancers: An Update for Recent Advances in Therapeutics

The presence of activating gene mutations in the epidermal growth factor receptor (EGFR) of non-small cell lung cancer (NSCLC) patients is predictive (improved progression-free survival and improved response rate) when treated with small molecule tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib and afatinib. The two most common mutations that account for greater than 85% of all EGFR gene mutations, are in-frame deletions in exon 19 (LREA deletions) and point mutations in exon 21 (L858R). Exon 18 mutations occur much less frequently at about 4% of all EGFR gene mutations. Together, deletion19 and L858R gene mutations are present in about 10% of Caucasian patients and 20–40% of Asian patients with NSCLC. T790M gene mutation at exon 20 is associated with acquired resistance to EGFR TKIs. Early studies showed that activating EGFR gene mutations are most common in patients with adenocarcinoma histology, women, never smokers and those of Asian ethnicity. A recent multi-center phase III trial suggested that frontline EGFR TKI therapy with afatinib is associated with improved progressionfree survival compared to chemotherapy regardless of race. Moreover, guidelines suggest EGFR testing should be conducted in all patients with lung adenocarcinoma or mixed lung cancers with an adenocarcinoma component), regardless of characteristics such as smoking status, gender, or race. The success of targeted therapies in NSCLC patients has changed the treatment paradigm in metastatic NSCLC. However, despite a durable response of greater than a year, resistance to EGFR TKIs inevitably occurs. This mini-review describes the clinically significant EGFR gene mutations and the efficacy of small molecule EGFR TKIs as targeted therapies for these gene mutations. Therapeutic strategies to overcome resistance, including selected emerging and novel therapies are discussed. Journal of Pharmacovigilance Jo ur na l of Pharmacoilance


Introduction
Lung cancer is a leading cause of cancer death in the U.S. In 2014, an estimated 16,000 deaths are expected to occur because of the disease [1]. Lung cancer is usually diagnosed at an advanced stage and because of this, the overall five-year survival is only 15% [2]. Primary tumor in anatomic/clinical stages I to IIIA is considered respectable. Treatment option generally consists of surgery with or without adjuvant chemotherapy [3]. Tumor in the stage IIIB is no longer resectable and the treatment option is chemoradiation [4] whereas for stage IV, treatment options include chemotherapy or oral targeted therapy agents [5]. Chemotherapy typically consists of a platinum-based doublet therapy (i.e. cisplatin or carboplatin combined with agents such as gemcitabine, vinorelbine or taxanes and most recently, cisplatin-pemetrexed for non-squamous lung cancer). No regimen has proven superiority over another [6]. Common symptoms of lung cancer include weight loss, cough, dyspnea and chest pain. Symptomatic patients are more likely to have chronic obstructive pulmonary disease. Non-small cell lung cancers (NSCLC) account for about 85% of all lung cancers and they can be squamous (epithermoid) or non-squamous (including adenocarcinoma, large cell and other subtypes). Adenocarcinoma is the most common lung cancer type in the U.S. and in non-smokers [2].

EGFR Signaling Pathway
Epidermal growth factor receptor (EGFR; also known as HER1) is a 170-kDa transmembrane receptor tyrosine kinase (RTK) with an extracellular ligand-binding domain, a lipophilic transmembrane region and an intracellular regulatory domain with tyrosine kinase activity [7]. EGFR is normally found on the surface of epithelial cells and is often over-expressed in many malignancies [8,9]. In addition, somatic gene mutations in the intracellular kinase domain of the EGFR lead to ligand-independent activation of the signaling pathway, leading to constitutively activated tyrosine kinase that results in tumorigenesis [10]. In normal cells, the EGFR pathway is tightly regulated whereas loss of regulation leads to uncontrolled growth and oncogenesis [11].
EGFR is the prototypical member of a family of four RTKs, EGFR (ERB-B1, HER1), ERB-B2 (HER2/Neu), ERB-B3 (HER3) and ERB-B4 (HER4) [12]. Multiple ligands activate different family members of EGFR. Ligand binding enables homo-or heterodimerization that results in intracellular tyrosine kinase domain activation and phosphorylation. This in turn creates docking sites for a diverse set of cytoplasmic signaling molecules and results in the activation of two key intracellular signaling pathways: the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. When stimulated, RAS protein, which is the first part of the MAPK pathway, exchanges GDP for GTP and sequentially activates RAF, followed by MEK (mitogen-activated, extracellular signalregulated kinase) and MAPK. Alternatively, ligand-bound EGFR can translocate PI3K to the cell membrane and activate AKT and other downstream molecules [13]. Tumor cells can upregulate the EGFR pathway through mechanisms such as EGFR over expression, EGFR gene amplification, activating also (known as sensitizing) mutations of the receptor or any downstream proto-oncogene (e.g. RAS, RAF) that results in the constitutive activation of the pathway, leading to tumor growth and proliferation [14].

Activating or Sensitizing Mutations of the EGFR Gene
In NSCLC patients, the most commonly found EGFR gene mutations (that account for more than 90% of all EGFR gene mutations) are present in the first four exons (i.e. exon [18][19][20][21] of the gene encoding the tyrosine kinase domain which binds to the substrate ATP. These EGFR gene mutations ( Figure 1) are: • • Exon 19 deletion (i.e. in-frame conserved deletions that encompass 4 amino acids on amino acid positions 747-750 or the "LREA" region) that occurs in 45% of patients with EGFR gene mutations. These 4 amino acids are: leucine (L), arginine (R), glutamic acid (E) and alanine (A) [15].
• • Exon 21 L858R gene mutation (a mis-sense mutation that results in a substitution of leucine with arginine at amino acid position 858) that occurs in another 40% of patients with EGFR gene mutations [16].
• • Exon 18 G719X gene mutation (a mis-sense mutation that results in the substitution of glycine with cysteine, alanine or serine at amino acid position 719) that occurs in about 4% of all EGFR gene mutated patients. Other drug-sensitizing gene mutations include point mutations at exon 21 [17].
• • T790M mutation, a secondary point mutation (developed after initial therapy with TKIs) located at exon 20 that results in substitution of methionine (T) for threonine (M) at amino acid position 790, is associated with acquired resistance to TKI therapy in 50-60% of patients with adenocarcinomas of the lung [18].
Resistance to small molecule EGFR tyrosine kinase inhibitors (TKI) can be either primary or acquired. Patients with primary resistance are refractory to upfront TKI treatment, whereas acquired or secondary resistance occurs after an initial response. Common acquired resistance mechanisms to EGFR TKIs are T790M mutation, transformation of the NSCLC to small cell lung cancer (SCLC) and the mesenchymal-epidermal transition (MET) receptor overexpression or gene amplification. Of interest, MET gene amplification is observed in 20% of resistance cases in NSCLC patients treated with gefitinib or erlotinib [18]. MET is a proto-oncogene that encodes a transmembrane tyrosine kinase receptor which binds to a ligand called the hepatocyte growth factor (HGF). The ligand-bound receptor that induces receptor dimerization, phosphorylation and PI3K activation, resulting in persistent activation of the downstream pathway that overcomes the inhibition by EGFR TKI [19]. Amplification of the MET gene is involved in the invasion, metastasis and angiogenesis of tumors [20].
In addition, less common somatic gene mutations, such as HER2 [21], HER4 [22], BRAF [23] and PIK3CA [24] are also found in the EGFR pathways. Other receptor tyrosine kinases such as AXL [25] are also implicated in the acquired resistance to EGFR TKI. Taken together, some of these EGFR gene mutations activate the EGFR signaling pathway and promote EGFR-mediated pro-survival and anti-apoptotic signals through the downstream targets. However, whether these less common gene mutations represent predictive biomarkers of interest and promising therapeutic targets in patients with EGFR-mutation positive NSCLC remain an area of ongoing research. It is possible that future targeted therapies can take advantage of these additional gene mutations in the EGFR signaling pathway. For purpose of simplicity, these downstream gene mutations are not addressed in this minireview. Interested readers are encouraged to consult further references.
In summary, both exon 19 gene deletions and exon 21 L858R gene mutations result in the activation of the tyrosine kinase domain. These mutations are associated with sensitivity (i.e. sensitizing mutations) to small molecule EGFR TKIs. These four major types of gene mutations seldom occur simultaneously. Despite the high response rate and prolonged progression-free survival in patients with EGFR gene mutations treated with first-generation EGFR TKIs (such as gefitinib and erlotinib), about 50% of these patients will develop the acquired T790M mutation [5,12,15]. The presence of a de novo T790M mutation (i.e. primary resistance to first-line EGFR TKI therapy) is predictive for poor survival outcome associated with EGFR TKIs [16][17][18].

Targeted Therapy against EGFR Protein and EGFR Gene Mutations
There are two types of EGFR targeted therapy: anti-EGFR monoclonal antibodies that bind to the extracellular domain of the EGFR protein and the small molecule TKIs that bind to the intracellular The EGFR gene is located in the short arm of chromosome 7. It contains 28 exons. Exons 18-21 are in the cytoplasmic tyrosine kinase domain of the EGFR receptor are commonly associated with sensitivity or resistance to EGFR TKIs when these genes are mutated. The most prevalent EGFR gene mutations are Exon 19 deletion (45%), followed by the L858R mutation in exon 21 (40%). Exon 18 mutations (G719 S/C/A) account for approximately 4% of the overall gene mutations. All gene mutations shown above are associated with sensitivity and hence they are predictive biomarkers for response to EGFR TKIs. T790M accounts for approximately 1% of primary resistance to EGFR TKIs. Another primary resistance to EGFR TKIs is due to insertions in exon 20 (about 4% of all gene mutations, not shown in diagram). Key: G= Glycine; S=serine; C=cysteine; A=alanine; T=threonine; M=methionine; L=leucine; R=arginine; Q= glutamine. The numbers below the vertical bar of each box refers to the amino acid number of each exon. can be readily targeted by first-generation reversible EGFR TKIs such as gefitinib and erlotinib and second-generation TKI such as afatinib [27][28][29].
Erlotinib is the current EGFR TKI agent of choice in U.S. for patients with sensitizing EGFR gene mutations because of the restricted access of gefitinib. Of note, although gefitinib was shown to delay disease progression over placebo in the second and third-line settings (3.0 vs. 2.6 months, P= 0.0006) in two phase II trials, IDEAL-1 [28] and IDEAL-2 [30], the lack of overall survival benefit (5.6 vs. 5.1 months, P = 0.087) in the confirmatory phase III ISEL trial prompted the FDA's withdrawal of gefitinib's accelerated approval. Gefitinib is now restricted in patients already on this medication and continue to benefit from it (enrollment through the Iressa® Access program) whereas in Europe and Asia, it is still approved or used for locally advanced and metastatic NSCLC with activating EGFR mutations. In U.S., no new patients can be initiated with gefitinib unless they are enrolled in clinical trials.
Afatinib is a newly FDA approved second-generation reversible oral TKI agent that inhibits EGFR (HER1), HER2 and HER4 (HER3 has no intrinsic tyrosine kinase activity). It is FDA approved for the first-line treatment of metastatic non-squamous NSCLC patients with sensitizing EGFR mutations. It is worth pointing out that despite the clinical efficacy of these EGFR TKIs, almost all patients who initially responded to EGFR TKI treatment (duration of response may last for 10 -14 months) will inevitably experience disease progression and become refractory to TKI therapy [20,29]. Preclinical studies of afatinib demonstrated that it was more effective than erlotinib and gefitinib in inhibiting the tumors harboring the L858R and T790M mutants [31]. Additionally, it retained significant in vitro and in vivo activity against the T790M mutations [32]. However, how much of this pharmacologic activity translates to clinical benefit currently remains unknown.
It is important to point out that the first-generation reversible TKIs such as gefitinib and erlotinib do not bind to EGFR receptors with T790M gene mutations which may also occur in patients who have not tyrosine kinase domain with activating gene mutations. Together, these inhibitors act on a series of signaling pathways that mediate cell survival, proliferation, metastasis and angiogenesis. Of note, there is a fundamental clinical difference between anti-EGFR monoclonal antibodies and EGFR TKIs: anti-EGFR monoclonal antibodies such as cetuximab (Erbitux®, Eli Lilly and Bristol-Myers Squibb, U.S.) and panitumumab (Vectibix®, Amgen, U.S.) currently are not approved by U.S. Food and Drug Administration (FDA) indicated in the treatment of advanced or metastatic NSCLC. On the contrary, current FDAapproved EGFR TKIs for advanced NSCLC patients with activating or sensitizing EGFR gene mutations include gefitinib (Iressa®, AstraZeneca Inc.), erlotinib (Tarceva®, Genentech, U.S.) and afatinib (Gilotrif®, Boehringer Ingelheim. U.S). The comparison of each EGFR TKI in terms of FDA approved indications, adverse effects, drug/food interactions is summarized in Table 1.
According to current U.S. National Comprehensive Cancer Network (NCCN) guidelines [26], first-line treatment for advanced or metastatic non-squamous NSCLC in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (0=asymptomatic; 1=symptomatic but completely ambulatory) and negative or unknown epidermal growth factor receptor (EGFR) gene mutation is a platinumbased two-drug combination regimen. On the other hand, in nonsquamous NSCLC patients who have known or documented activating (or sensitizing) EGFR gene mutations, they benefit from first-line EGFR TKI therapy rather than chemotherapy [26].
Historically, high levels of EGFR gene expression were initially observed in metastatic NSCLC across all histology types and provided the initial impetus for early lung cancer trials targeting the EGFR pathway [12,[14][15][16][17]. EGFR gene mutations were subsequently identified in select patients after clinical benefit to EGFR TKI was observed in 2004 [10,27]. Evaluation of tumor specimens in these patients led to the identification of two common mutations in EGFR gene, the exon 19 deletion and the exon 21 L858R missense mutation, both of which received TKI therapy. These patients will not respond to initial treatment with gefitinib or erlotinib and are deemed to have primary or de novo resistance [33]. However, some studies suggest that the presence of T790M gene mutations may not necessarily imply a worse treatment outcome compared to patients without the T790 gene mutations [33][34][35]. At present, afatinib does not have the FDA labeled indication for use in patients with T790M gene mutations. Moreover, T790M gene mutation should not be regarded as a predictive biomarker for afatinib.

Clinical Efficacy of TKI Therapy in Metastatic NSCLC
The place of therapy for EGFR TKIs underwent major changes in the last decade. Initial studies with gefitinib and erlotinib as single agents demonstrated biologic and clinical activity in only a relatively limited subset of unselected NSCLC patients in the second or third line setting after failure of first-line platinum-based chemotherapy [36]. For instance, erlotinib monotherapy was shown to improve progressionfree survival (2.2 vs. 1.8 months, P<0.001) and overall survival over best supportive care (6.7 vs. 4.7, P<0.001) in unselected NSCLC patients with advanced disease who had failed one or two prior lines of chemotherapy (BR 21 trial) [37].
Early studies showed that activating EGFR gene mutations are most common in patients with adenocarcinoma histology, women, never or light smokers, and those of Asian ethnicity. As a result, these patients exhibited increased response to EGFR TKIs. The overall response rate may be as high as 80% in selected patients with gene mutations and 10-20% in unselected populations. The prevalence of sensitizing EGFR mutations (mainly exon19 deletion and exon 21 L858R mutations) is approximately 20-40% among Asians and 10% among Caucasians to treatment with first-generation, reversible EGFR TKIs such as gefitinib or erlotinib. Of important note, selection of the patient population with EGFR gene mutations upfront is necessary to maintain efficacy of TKIs as the first line therapy in metastatic setting. In unselected patients in the early clinical trials, EGFR TKIs did not show additional survival benefit when added to platinum-doublet chemotherapy, nor have they shown superiority to single-agent chemotherapy in the salvage treatment setting in unselected patients [29,[37][38][39].
More questions now arise as to whether the survival benefit is restricted to Asian patients or non-smokers alone. The recent randomized, multicenter, international LUX-Lung 3 study [29] suggested that frontline or initial EGFR TKI therapy with afatinib is associated with improved progression-free survival compared to cisplatinpemetrexed chemotherapy doublet, regardless of race. In addition, in the EURTAC [38] (European Tarceva versus chemotherapy) study, erlotinib is associated with improved survival outcome in European patients. Recently, the American Society of Clinical Oncology (ASCO) endorsed the consensus guideline of several professional organizations for EGFR gene testing to all patients with lung adenocarcinoma (or mixed lung cancers with an adenocarcinoma component), regardless of characteristics such as smoking status, gender or race [39]. Current NCCN guidelines [26] recommend erlotinib as a firstline therapy agent for advanced or metastatic NSCLC patients with sensitizing mutations. Erlotinib should not be given as a first-line therapy to patients negative for these mutations or with unknown EGFR status. Afatinib is also recommended as a first-line agent for select patients with sensitizing mutations. In patients who have experienced disease progression either during or after first-line therapy, single agent docetaxel, pemetrexed or erlotinib are established second-line agents. Erlotinib is superior to best supportive care and afatinib may also be used in select patients with sensitizing EGFR mutations. Erlotinib is also recommended as third-line agent. In general, erlotinib, gefitinib, afatinib are recommended for continuation after disease progression in patients with sensitizing EGFR mutations. Erlotinib has a category two NCCN recommendation for maintenance therapy in patients without disease progression after 4-6 cycles of first-line platinum-based chemotherapy [26].

Combination of TKI Therapy with Chemotherapy
There was initial interest in whether combination of EGFR TKI and chemotherapy can enhance patient survival after their FDA approval in the last decade. However, four large front line trials [40][41][42][43] (Table  2) failed to demonstrate a survival advantage with the first-line use of either gefitinib or erlotinib in combination with chemotherapy. Based on the survival benefit of erlotinib in previously treated patients, there was interest in determining whether erlotinib treatment is more effective immediately following the completion of first-line chemotherapy. The Sequential Tarceva in Unresectable NSCLC (SATURN) trial [44] was designed to investigate the efficacy of maintenance erlotinib treatment until the time of progression. Erlotinib demonstrated significant improvement in overall survival in maintenance therapy.   [45] of intermittent TKI therapy with chemotherapy had suggested its preliminary efficacy but since the current standard of care still favors EGFR TKI for maintenance therapy, its role requires validation in long-term studies. Another study [46] from a single institution suggested that when patients with EGFR mutations progressed on erlotinib and when progression occurred in only a limited number of sites (<4), the same therapy or local disease control (e.g. stereotactic body radiation therapy in CNS disease) may be offered. Patients with EGFR gene mutations who have disease progression often experience disease flare-up when the EGFR TKI is discontinued [47].
In addition, studies [48][49][50] suggest that instead of first-line chemotherapy, erlotinib or gefitinib or afatinib should be the first-line systemic therapy in patients with EGFR gene mutations documented before starting first-line therapy. Progression-free survival (overall survival is not statistically significant) is improved with the use of these EGFR TKIs in patients with sensitizing or activating EGFR mutations compared to standard chemotherapy. In the recent LUX-Lung 3 trial, afatinib improved the quality of life compared to those received cisplatin/pemetrexed chemotherapy. However, in the trial, afatinib was associated with 4 deaths whereas chemotherapy had no treatmentrelated deaths [29].
To summarize, EGFR gene mutations of non-small cell lung cancer (NSCLC) patients are predictive (improved progression-free survival and response rate) when treated with EGFR TKIs such as gefitinib and erlotinib in the first-line therapy of metastatic disease compared to conventional platinum-based chemotherapy. EGFR TKIs are also used in second-, third-line or maintenance therapy.

Toxicities of EGFR TKIs
The most frequent adverse events in clinical trials of afatinib were diarrhea, rash or acne (78% -97%of patients treated in the LUX-Lung trials). Stomatitis and nail effects also appeared frequently. These toxicities were similar to those observed in erlotinib and gefitinib trials. Toxicities of afatinib could be managed by dose reductions to 40 mg or 30 mg, and only less than 10% of patients (8% in LUX-Lung 1 [51], and 9% in LUX-Lung 2 [52]) required afatinib discontinuation due to drugrelated adverse events. Side effects of gefitinib and erlotinib are usually mild to moderate, and most commonly manifest as dose-dependent skin rash and diarrhea.

Genetic Testing
In the setting of lung cancer resection specimens, EGFR testing is recommended for adenocarcinomas and mixed lung cancers with an adenocarcinoma component, regardless of histologic grade. EGFR testing is not recommended in lung cancers that lack any adenocarcinoma component. In squamous NSCLC, EGFR gene mutation testing is generally not required, but can be considered in never smokers, small biopsy specimen or mixed histology. If EGFR gene mutation is confirmed during first-line chemotherapy, patient may either: (1) complete chemotherapy; or (2) interrupt chemotherapy, start erlotinib or afatinib or (3) add erlotinib or afatinib to chemotherapy (NCCN category 2B recommendation) [26].
Various DNA mutational analyses can be used to determine the EGFR mutation status in tumor cells: direct sequencing of DNA corresponding to exon 18-21, PCR-based mutational screening assays and next generation sequencing can be used [53]. A number of central or reference laboratories offer EGFR genotyping of exons 18-21. Typical examples of FDA-approved qualitative PCR testing include: cobas® EGFR Mutation Test (Roche Molecular Diagnostics, Pleasanton, CA), therascreen EGFR RGQ PCR kit (Qiagen, Valencia, CA) and some others.

Future of Anti-EGFR TKI Therapy with Chemotherapy
At present, combination therapy of anti-EGFR TKIs with chemotherapy in unselected NSCLC patients have not resulted in added value. In selected patients with sensitizing EGFR gene mutations, combination therapy of anti-EGFR TKIs with chemotherapy has been shown to improve survival outcome [54]. Combination therapy may be necessary in patients with a large tumor burden. In addition, treatment beyond disease progression after TKI failure with combination therapy of anti-EGFR TKI and chemotherapy has been reported, necessitating more studies into the novel combination therapies to address these acquired mechanisms of resistance [55].
Recently, a small molecule TKI, tivantinib, and the monoclonal antibody, onartuzumab, have both been evaluated in the second-line setting in EGFR-TKI naïve patients after chemotherapy failure. In the phase 3 trial, combination therapy of onartuzumab and erlotinib was not shown to improve PFS (2.7 vs. 2.6months, P=0.92) or objective response rate 8.4% vs. 9.6%, P=0.63) [56]. Despite this negative finding, many ongoing trials will likely shed some light to elucidate the additional roles of EGFR TKIs with other agents and how these agents could be sequenced to optimized treatment outcome.
Combination of EGFR TKI (e.g. erlotinib) and anti-EGFR monoclonal antibody (e.g. cetuximab) did not seem to result in survival benefit in patients who acquired resistance to first-generation EGFR TKIs [58], while in another phase Ib study [59], the combination of afatinib and cetuximab resulted in response rate in about 30% of NSCLC patients who developed T790M gene mutations. More study is apparently needed to validate the role of this dual "EGFR blockage".
Recently, two interesting trials published their preliminary results on whether EGFR TKI should be continued during disease progression. In the phase III IMPRESS trial, 265 patients from 71 centers in Europe and Asia were enrolled and randomly assigned to cisplatin/pemetrexed plus gefitinib vs. cisplatin/pemetrexed plus placebo. 65% of patients were female and mean age was about 60. Overall response rate was 31.6% for gefitinib vs 34.1% for chemotherapy, and the disease control rate was 84.2% vs 78.2%, respectively. Overall survival data have not reached during study cut-off date. The study demonstrated that EGFR TKI should not be continued beyond progression. The standard treatment at progression remains platinum-based chemotherapy [31].
On the other hand, another phase II study (Aspiration) evaluated the safety and efficacy of erlotinib before and after disease progression in untreated Asian patients with EGFR-mutated NSCLC in 150 patients. 81 of those received erlotinib with a median 1-year progression-free survival (PFS) of 9.3 months. In patients who did not receive erlotinib after disease progression, median 1-year PFS was 7.2 months. Patients with exon 19 deletion and exon 21 L858R mutations had more favorable PFS than those without. Among the 207 patients evaluated for safety, 45.4% reported grade ≥ 3 adverse events. The study suggested that even though there is a slight increase in the tumor on the assessment, if the treatment is well-tolerated, and if the patient remains asymptomatic, patient should not be switched to chemotherapy immediately, but continues until there is clear clinical progression [32]. More studies will be needed to address the place of therapy for EGFR TKI in disease progression.

Conclusion
The success of targeted agents in molecularly defined subsets of patients has radically changed the treatment paradigm of metastatic lung adenocarcinoma. It is becoming clinically relevant to re-biopsy tumor at recurrence and defines what therapeutic options are considered appropriate. To date, the most significant progress is for metastatic NSCLC patients whose tumors harbor EGFR mutations, in whom first-line treatment with EGFR TKIs led to improvement in survival outcomes compared to standard chemotherapy. As more clinical trials for EGFR TKI mature, better understanding may be gained through the use of these agents either alone or in combination with different therapeutic agents (e.g. chemotherapy) and in different sequences in improving treatment efficacy of metastatic lung adenocarcinoma.

Disclosure
No conflicts of interest to disclose.

Funding
None.