Non-Small Cell Lung Cancer; Review of Mutations and Tyrosine Kinase Inhibitors

Dhara  Dave; Basheer  Mohammed; Janakikeerthika Dharmarpandi; Darshit  Dave; Rohit  Saralaya; Praveen  Tumula

doi:10.31487/j.AJMC.2022.01.01

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Non-Small Cell Lung Cancer; Review of Mutations and Tyrosine Kinase Inhibitors

A B S T R A C T

Lung cancer is the leading cause of cancer-related death in the United States and the incidence of this in never smokers is about 15-20% in males and about 50% in females. Non-small cell lung carcinoma (NSCLC) constitutes about 75% to 80% of these cancers and is more common than small cell lung carcinoma (SCLC) in never smokers. Treatment of NSCLC has been rapidly evolving with the discovery of targetable mutations like EGFR, and ALK. Despite this, prognosis of NSCLC remains guarded given diagnosis at an advanced stage as well as patient factors like age and comorbidities. The standard of care should include therapy customized to suit the patient. In this review article we report the first known case of checkpoint mutation seen in a patient with NSCLC and summarize the common mutations along with targeted therapy with tyrosine kinase inhibitors.

Keywords

Non-small cell lung cancer (NSCLC), tyrosine kinase inhibitors (TKIs), germline mutations, ALK mutation, CHEK2 mutation

Description

We present a case report of a patient who was a lifetime non-smoker and was found to have a rare CHEK2 mutation with non-small cell lung cancer. Hence, we present a short review of the common mutations and TKIs involved in non-small cell lung cancer.

Introduction

Lung cancer occurred in approximately 2.1 million patients in 2018 and caused an estimated 1.7 million deaths. It is the commonest cancer in both sexes combined and is the leading cause of death; however, it is the 2nd leading cause of death in females after breast cancer [1]. In the United States, there are over 230,000 new cases of lung cancer and 130,000 deaths annually [2]. Histopathologic classification of lung cancer includes small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In the past, treatment decisions were based on a simple distinction between SCLC and NSCLC however further classification of these cancers into adenocarcinoma vs squamous cell carcinoma has led to further optimization of therapy with better outcomes. Tremendous research has been dedicated over the last decade to improving the survival in these patients.

Non-small cell lung cancer is a broad term encompassing squamous cell cancer, adenocarcinoma and large cell cancer. NSCLC constitutes approximately 75-80% of all lung cancers [3]. Oncogenic mutations are mutations leading to transformation of non-cancerous tissue to cancerous tissue. The discovery of driver mutations has changed the face of management of lung cancers and led to the achievement of individually tailored therapy.

Some of the known oncogenic drivers in NSCLC include epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK), and ROS1 fusion genes among others. Increased detection of targetable mutations over the past 10 years has led to a better understanding of the biology and underlying genetic susceptibilities in patients with NSCLC.

The primary risk factor for lung cancer is smoking, accounting for about 90% of all lung cancers; however, that leaves approximately 10-20% lung cancers that occur in non-smokers. Lung cancer in never smokers (defined as those who have had less than 100 cigarettes in their lifetime) has been recognized as having a distinct epidemiology and biology which is enough to support the notion that it can be considered a separate entity. The incidence is seen to be at 15-20% incidence in males and about 50% incidence in females however the incidence varies with different geographic locations [4]. Sun et al. reported that in Asia the incidence of lung cancer in female never smokers was about 60-80% [5]. In one analysis in the United States, an estimated 19 percent of women with lung cancer had never smoked, compared with approximately 9 percent of men with the disease [6]. The incidence of SCLC in never smokers is exceedingly small hence discussions regarding lung cancer in never smokers focus for the most part on NSCLC.

In recent years, an increasing number of lung cancers have been observed in people who have never smoked tobacco (LCINS). This phenomenon is more likely to be observed among women, especially those living in Southeast Asia. Environmental conditions, such as air pollution, secondhand smoke, exposure to radon, asbestos, heavy metals, human papillomavirus, and genetic conditions are the main causes [7].

It has been postulated that lung cancer in never smokers occurs at a younger age but this has not been validated in all cohorts in Western populations. In studies from Asia, however, a younger age at diagnosis is characteristic of lung cancer in never smokers [8]. The age-adjusted incidence rate for lung cancer in never smokers, in the United States, aged 40 to 79 years ranged from 11.2 to 13.7 per 100,000 person-years for men and from 15.2 to 20.8 per 100,000 person-years for women. These incidence rates are like those for myeloma in men or cervical cancer in women in this country. By contrast, the age-adjusted rates of lung cancer in current smokers in the same cohorts were approximately 12 to 30 times higher [9]. Subtype analysis of NSCLC has come full circle now that epidermal growth factor receptors (EGFR), anaplastic lymphoma kinase (ALK), and c-ROS oncogene 1 (ROS1) mutations are not only identifiable but their targeted treatment results in responses better than that with standard chemotherapy.

The incidence of the EGFR mutation in patients with adenocarcinoma varies with ethnicity and has been seen to be about 15 to 30% in non-Asian populations while it can be as high as 60% in Asian patients [10, 11]. The ALK mutation has been seen at an incidence of about 2 to 7% in the United States. The other mutations are not as common and incidences of these mutations in adenocarcinoma have been summarized in (Table 1) below. Given the improving response to tyrosine kinase inhibitors, it has been recommended that EGFR and ALK testing should be done in all advanced-stage adenocarcinoma, mixed cancers, and in those with NSCLC in whom adenocarcinoma cannot be excluded.

Table 1: Frequency of genetic mutations in NSCLC.

Target	Mutation	Frequency (%)
EGFR	Exon 19 deletion and exon 21 point mutation HER2 point mutation T790M (somatic)	30-60 2-4 1-4
KRAS	Mutations in codons 12, 13, and 61	15-25
ALK	EML4-ALK	2-8
NTRK1	NTRK1 fusion	3.3
c-MET	Amplification Exon 14 skipping mutation	2-4 3-4
BRAF	V600E mutation	1-4
ROS1	ROS1	2
RET	RET fusion	1
Co-mutations		Upto 15

EGFR

Epidermal growth factor receptor (EGFR, HER-1, ERBB1) is a member of the tyrosine kinase receptor family consisting of 3 additional receptors with a similar structure: EGFR2 / HER2 / HER-2-NEU / ERBB2, EGFR3 / HER-3 / ERBB3 and ERBB4 / HER4. Several studies have shown that EGFR mutations occur with a frequency of 30% to 60% in NSCLC. Overexpression of EGFR is the main factor maintaining self-sufficiency of proliferation and maintaining the tumor phenotype in some NSCLC. Mutations and atypical expression within EGFR have been shown to influence development, progression, and acquisition of NSCLC chemoresistance. Various mechanisms contribute to EGFR overexpression including increased number of gene copies, epigenetic modifications, and activation by oncogenic viruses. Two of the commonest EGFR mutations in NSCLC are deletion in exon 19 and specific point mutation in exon 21 of codon 858. Both of which account for about 80-90% of all detected EGFR mutations. As mentioned above, certain EGFR mutations like point mutation at position T790M can lead to resistance to therapy including insensitivity to first generation kinase inhibitors such as erlotinib and gefitinib. This may be a primary mutation or appear during treatment (secondary) and may also have oncogenic potential [12]. The other receptors in the EGFR family have not been studied as extensively though it has been seen in certain studies that HER2-NEU mutations could appear in about 1.6% NSCLC. From limited studies available, it is thought that higher expression of HER2-NEU and other receptors in the family promote resistance to TKIs [12].

ALK

Genetic alterations of the anaplastic lymphoma kinase (ALK) gene have been reported in 2-7% of the patients with NSCLC, and the most common alteration of ALK is the fusion of the ALK gene with the Echinoderm microtubule-associated protein-like 4 (EML4) gene and occur more frequently in non-smokers and younger patients [13-16]. Anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase from the insulin receptor superfamily. ALK gene activation occurs by rearrangement of the chromosomes and binding the promoter region, resulting in increased transcription and protein expression. The EML4-ALK protein contains the N-terminal EML4 domain and the ALK intracellular catalytic domain. EML4 region causes constitutive dimerization of the ALK kinase domain, leading to incorrect activation of signal transduction and causing tumor cell proliferation and causing tumor cell proliferation [12].

Many rearrangement variants encode the EML4-ALK protein such as assembly of exon 13 EML4 to exon 20 ALK (E13, A20) which exist in 33% patients with this mutation in NSCLC patients while 29% of the patients were found to have the addition of exon 6 EML4 to exon 20 ALK (E6a/b, A20) [12].

The overall frequency of ALK oncogene mutation in general NSCLC patients is low, however the knowledge of clinicopathologic features enables easy identification and targeted management of these patients. Shaw et al. conducted a study in which patients were selected for genetic testing based on clinical features, including never/light smoking status and adenocarcinoma histology [16]. Thirteen percent of the overall patients had the ALK fusion gene. Among the light or never smokers, the incidence of this oncogene was 22% while the frequency was as high as 33% if the patients did not have an EGFR mutation [16].

Patients with ALK-positive lung cancer are relatively younger at onset than those without this abnormality. The two studies that were used to support the approval of crizotinib included 255 patients whose tumors contained an ALK fusion oncogene; in this database, the median age was 52 years (range, 21 to 82 years) [17, 18]. The ALK fusion oncogene in patients with NSCLC is associated with a history of never or light smoking (<10 pack-years) [19]. In the crizotinib study database of 255 patients, never-smokers and former smokers comprised 70 and 28 percent of cases, respectively [17, 18]. ALK-mediated signaling plays a role in development and progression of several cancers as is evidenced by the presence of ALK gene rearrangements in other malignancies other than NSCLC, for example, large cell anaplastic lymphoma (ALCL) and myofibroblastic tumors [12].

ROS

ROS1 is a receptor tyrosine kinase (RTK) that belongs to the same insulin receptor superfamily as ALK. The role of ROS1 is unknown however, some studies suggest that it participates in epithelial cell differentiation [12]. There is no identifiable ligand however, it has been noted that ROS1 fusion protein expression results in activation of cellular pathways involved in proliferation of cells. ROS1 gene rearrangements were originally found in glioblastomas and later discovered in NSCLC and cholangiocarcinoma alike [12].

About 2% of NSCLC has been reported to have ROS1 gene fusions and like the ALK mutations, these have been seen in younger patients and those without a history of smoking. They also seem to be mutually exclusive with other oncogenic driver genes [12].

KRAS

The four different Ras proteins, H-RAS, N-RAS, K-RAS-4A and K-RAS-4B, are encoded by three genes. RAS gene mutations are found in almost one-third of human cancers. Mutated RAS proteins preferentially bind GTP keeping the proteins active and increasing proliferation and differentiation. Other mechanisms can also activate the Ras protein, for example receptors with tyrosine kinase activity, such as EGFR and other growth factor receptors, such as PDGFR and IGFR. Continuous RAS pathway activity not only plays a role in cell proliferation but also in development of resistance to cancer therapy [13].

KRAS mutations are found in about 15% to 25% of NSCLC patients, of which 97% have exon 2 and 3 alterations (G12, G13 and Q61) [13]. Most of these mutations involve codons 12 and 13 and are mutually exclusive with EGFR or ALK alterations. KRAS mutations may be seen in never smokers but are more frequently associated with smoking [12]. Despite being a very frequent mutation in several cancers, targeted therapy towards Ras proteins have not been developed yet [13].

BRAF

BRAF is a serine–threonine protein kinase that belongs to the RAF family. BRAF signaling activates ERK and its downstream effectors which in turn control cell differentiation, proliferation, growth, and apoptosis. BRAF mutations therefore allow for autonomous cell growth via activation of MEK/ERK signaling [12].

BRAF mutations were originally described in malignant melanomas and are found in about 30% of human cancers. In NSCLC they occur at a frequency of about 1% to 4% and are more common in current or former smokers, which is unlike ALK or EGFR mutations. Just like ROS1 they are also typically mutually exclusive of other driver oncogenes and unfortunately patients with these mutations have a shorter overall survival [12]. BRAF mutations in lung cancer can be either V600E or non-V600E with prevalence of approximately 50% each. The most common non-V600E mutations include G469A, T599_V600insT, D594N, and V600_K601delinsE mutations [12].

RET

RET fusions occur in about 1% of NSCLC and the commonest histological subtype is adenocarcinoma. Like ALK mutations, RET mutations are associated with never-smoking status however they are usually mutually exclusive. 90% of RET mutations are KIF5B-RET fusion with fusion partners CCDC6 and NCOA4 representing the remaining 10% [12].

NRTK1 fusion mutations are seen in about 3.3% of lung adenocarcinomas. Two in-frame gene fusions characterized by rearrangements between the myosin phosphatase Rho-interacting protein gene (MPRIP-NTRK1) and CD74 gene (CD74-NTRK1) have been seen in female never smokers. NRTK1 genetic alterations are also being targeted as therapeutic targets [12].

MET

c-MET is a receptor tyrosine kinase in the MET/RON family with hepatocyte growth factor as its ligand. MET dimerization and phosphorylation occur after ligand binding, eventually recruiting signaling protein complexes including SRC, GRB2, SHC, and the p85 regulatory unit of the phosphoinositide 3-kinase, for the activation of several downstream signaling cascades [12].

Several cancers such as renal cell carcinoma and lung cancer have demonstrated aberrant c-MET signaling. Majority of lung cancers demonstrate MET exon 14 skipping mutations with and without gene amplification (3% to 4% of lung adenocarcinoma). MET gene amplification has been reported to occur in 2% to 4% of NSCLC. Increased MET expression is seen with more aggressive tumor biology and is a negative prognostic factor. Given the high frequency with which MET mutations are seen, there has been increasing interest in developing potential targets for this pathway [12].

CHEK Mutation

The role for immunotherapy in treatment of advanced-stage lung cancer is promising and rapidly evolving. Checkpoint inhibitors promote recognition of cancer cells as foreign cells by the immune system and reverse the tumor-driven inhibition of the immune system that promotes tumor growth. Clinical trials using antibodies to programmed death receptor 1 and programmed death ligand 1 have shown significant survival benefit in advanced NSCLC. The activity of the checkpoint inhibitors can be predicted to some extent by programmed death-ligand 1 (PD-L1) expression levels, but other factors play a key role as well.

In a specific analysis of patients with KRAS-mutated NSCLC, investigators found that patients with a smoking history were more likely to express PD-L1 (44 percent) versus former (20 percent) or never smokers (13 percent). Though PD-L1 expression is not the only marker of programmed cell death protein 1 checkpoint inhibitor efficacy, this does add to the data supporting mechanisms of resistance to checkpoint inhibitor therapy in those who are never smokers [20].

New immunotherapy strategies are emerging in advanced non-small cell lung cancer (NSCLC). In EMPOWER-Lung 1, among over 560 patients with advanced NSCLC with programmed death-ligand 1 (PD-L1) expression of ≥50 percent, the immune checkpoint inhibitor cemiplimab improved overall survival (OS) relative to platinum-doublet chemotherapy (median five-year OS rates of 32 versus 16 percent, respectively). Grade ≥3 toxicities were 28 percent with cemiplimab and 39 percent with chemotherapy. This data led to approval by the United States (US) Food and Drug Administration (FDA) for patients with PD-L1 high, advanced NSCLC lacking a genetic aberration in ALK, EGFR, or ROS1 [21].

In IMpower 110, in the subset of over 200 patients with advanced NSCLC and PD-L1 expression ≥50 percent, atezolizumab improved overall survival relative to platinum based chemotherapy (20 versus 13 months). Grade ≥3 adverse events occurred in approximately 30 percent of patients assigned to atezolizumab and 53 percent assigned to chemotherapy. These results led to approval by the US FDA of atezolizumab for the front-line treatment of those with advanced PD-L1 high NSCLC (PD-L1-stained ≥50 percent of tumor cells or PD-L1-stained tumor-infiltrating immune cells covering ≥10 percent of the tumor area), with no EGFR or ALK genomic alterations [22].

Duration of checkpoint inhibitor treatment in advanced non-small cell lung cancer is the subject of active study. In the CheckMate 153 trial, patients with previously treated advanced NSCLC were treated with nivolumab. Among 174 patients with stable or responding disease after one year of nivolumab, those assigned to continued treatment experienced an improvement in both median progression free survival (25 versus 9 months) and overall survival (not reached versus 33 months) relative to those assigned to observation [23]. Other preliminary data, however, suggest that discontinuation of pembrolizumab after two years may be an appropriate strategy [24]. In general, in patients with advanced NSCLC receiving a checkpoint inhibitor, we continue it until progression or unacceptable toxicity occurs, although discontinuation after two years of treatment may be a reasonable alternative.

Germline CHEK2 mutations are associated with a wide variety of cancer risks, including early-onset cancer and multiple primaries. Confirmation of the patient’s carrier status could be beneficial for the patient’s family members. The National Comprehensive Cancer Network recommends that germline CHEK2 mutation carriers undergo increased surveillance for breast and colorectal cancers. Follow-up testing should be performed on blood or saliva.

Case Presentation

Our patient is a 37 y/o female with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), asthma, depression, and seizure disorder, who is a lifetime non-smoker and presented with chest pain. Imaging revealed no demonstrated pulmonary embolism or arterial dissection. Mildly enlarged bilateral axillary nodes, unchanged per mediastinal lymphadenopathy with the largest lymph node measuring 1.7 cm, mildly progressed. Increase in size of the cavitary nodule in the right upper lobe measuring 2.3 cm on the current exam. Increase in size of pulmonary nodules in the right upper lobe and the right middle lobe the largest measuring 0.8 cm. Computed Tomography guided biopsy of the right lung mass showed well to moderately differentiated adenocarcinoma, consistent with pulmonary primary, acinar predominant with mild focal micropapillary features.

Caris next generation sequencing panel–ALK IHC 3+, RNA tumor fusion detected. Genetic testing profile showed a pathogenic variant in CHEK2: c.1100delC (p.T367fs) that is frequently germline. It is present in 39% of the tissue sample. BRAF-Mutation not detected. EGFR mutation not detected. ROS 1 fusion not detected. NTRK 1/2/3–fusion not detected. Tumor mutation burden is low. MET DNA tumor amplification not detected. RET RNA tumor fusion not detected.

She was diagnosed with Stage IIIB (cT3N2M0) lung adenocarcinoma based on PET-CT results and completed chemoradiation and 2 cycles of adjuvant chemotherapy. It is important to note that she had SLE and RA and was on immunosuppression which made maintenance immunotherapy with durvalumab an inconsiderable option. Restaging imaging showed no evidence of progression and it was decided that she would have continued close follow-up and in case of progression, a TKI would be considered.

Discussion

I What are the Mutations in Non-Smokers in NSCLC?

Much as the environmental and genetic risk factors for NSCLC in non-smokers are unclear, it is known that there are characteristic mutations associated with this entity. NSCLC in never-smokers has a distinct biology marked by an increased incidence of mutations in oncogenes that are now specifically targetable. Multiple studies have shown an association between lung cancer in never smokers and a family history of lung cancer, suggesting a role for genetic factors.

In a case-control study of 257 cases (including both smokers and never smokers), lung cancer was more common in those with a positive family history (OR 7.2) while in another case-control study of 316 never-smokers (including 2400 of their relatives), there was a 25 percent greater risk of lung cancer among first-degree relatives [25, 26]. Ying et al. noted that the relative risk (RR) of lung cancer associated with a positive family history, adjusted for age, gender, residence, education, and smoking, was 1.57 (95% CI 1.25-1.98) [27].

Specific mutations are noted to run in families of never smokers and the best understood so far are germline mutations in EGFR. An uncommon germline mutation was noted in a Japanese family where nine patients with lung cancer were seen over three generations. The proband was a 53-year-old woman with only 1.2 pack-years of smoking history whose mother did not have a smoking history. Both had HER2 G660D germline mutation in lung adenocarcinomas [28]. EGFR mutations represent the commonest mutations in never smokers with NSCLC and carry a higher frequency in never smokers compared to smokers.

Sonobe et al. reported an incidence of EGFR mutations in non-smokers as 83% versus 50% in smokers (p 0.008) [29]. Though they found absence of smoking to be an independent factor affecting EGFR incidence, they did not find sex to be an independent factor. This is unlike Marchetti et al. who found sex to be an independent factor affecting incidence of EGFR mutations [30].

Much as KRAS mutations are seen more commonly in smokers, an analysis of 482 lung adenocarcinomas, found that the rate of KRAS mutations was not significantly different in never smokers compared with former smokers, and current smokers (15 vs 22 vs 25 percent respectively). There was however a difference in the type of mutation as never smokers were seen to have a transition mutation (G-->A) rather than the transversion mutations known to be smoking-related (G-->T or G-->C; P < 0.0001) [31]. The EML4-ALK fusion is seen with a higher frequency in never smokers and is nearly always mutually exclusive with EGFR and KRAS mutations. Shaw et al. found that 74% of never smokers had ALK mutation compared to 26% light smokers (defined as those with 10 or less pack year history of smoking) and none in smokers [16].

Differences are also seen in the expression of several other mutations and genes in never smokers compared to smokers. As an example, TP53 mutations were found to be more common in smokers and the specific mutations were different based on smoking status. G:C to T:A transversions and A:T to G:C transitions were associated with smoking while G:C to A:T transitions were associated with never smoking. In the same study they noted no significant differences in Cox-2 expression based on smoking, and higher levels of nitrotyrosine (a marker of nitric oxide associated protein damage) in never smokers compared to smokers [32].

II Do Patients with ALK Mutations have Other Somatic or Germline Mutations?

Guidelines recommend routine testing for ALK mutation in all patients with stage IV lung adenocarcinoma, mixed tumors or those with NSCLC in whom adenocarcinoma cannot be excluded. ALK mutation testing can be performed on plasma or tissue specimens however, if not detected in plasma specimens, then tumor tissue should be tested [33].

The Lung Cancer Mutation Consortium reported 2.7% dual-positive mutations in over 1000 specimens analysed. The majority of these involved one or more of the following: ALK, MET or PIK3CA [34]. Several other retrospective analyses have demonstrated a co-occurence rate of upto 1% for EGFR and ALK. Yang et al. identified concomitant EGFR and ALK mutations at an overall frequency of 1.3% [35]. As per another large series, the frequency of dual mutations in ALK translocated NSCLC was about 4.4% when using direct sequencing and fluorescence in situ hybridization (FISH). However, this number increased to as high as 15.4% when using mutant-enriched next-generation sequencing (NGS) assays [36]. Given such variation in incidence with different assays and since the newer assays like NGS are becoming more available and the cost is going down, then it is likely that the rate of concurrent mutations is going to increase in the future [37].

The etiology behind concurrent mutations is unknown and it is also unclear as to whether these mutations arise within the same cell or if they occur in different cells due to intratumoral heterogeneity [37]. The idea behind heterogeneity within the tumor is backed by support from Bai et al. who microdissected NSCLC samples to look for intratumoral heterogeneity. They reported that upto 32.9% of the samples had a combination of EGFR-mutated and wild-type cells. The clinical significance of this was that it affected resistance to TKIs hence single point biopsies may not be optimal in deciding personalized TKI therapy [38].

III Tyrosine Kinase Inhibitors

Targeted therapy against specific proteins, that play a part in signaling transduction and metabolic pathways in cancer cells, have become an important part of treatment. They can be used alone in lung cancer however may have more effectiveness in combination with chemotherapy and/or radiotherapy, as well as immunotherapy [12].

EGFR, ALK and ROS-1 mutations contribute to about 20% of mutations in NSCLC and are the most common targets for TKIs. According to a multicenter center trial, the median survival in those patients who received targeted therapy against a driver alteration was about 3.5 years compared to 2.4 years in those who had an identifiable target but did not get targeted therapy and 2.1 years in those with no identifiable target [39].

Examples of these drugs include:
EGFR TKIs: Eerlotinib, gefitinib, afatinib, dacomitinib, osimertinib. Table 2 below summarizes information about these TKIs.
ALK TKIs: Crizotinib, ceritinib, alectinib, lorlatinib, brigatinib
VEGFR and PDGFR TKIs: Sunitinib
Raf inhibitor: Sorafenib
MET receptor TKI: Trametinib

Table 2: Below shows a summarized detail of the approved EGFR TKIs.

TKI	Generation (Gen)	Study	Finding	S/E
Erlotinib	1st gen	OPTIMAL trial: Erlotinib versus gemcitabine + carboplatin [42] EURTAC trial: Erlotinib vs platinum-based chemotherapy doublet [43] ENSURE trial: Erlotinib or gemcitabine and cisplatin [44]	PFS 13.1 versus 4.6 months (HR 0.46, 95% CI 0.37-0.57) Response Rate 83 vs 36% PFS 9.7 versus 5.2 months (HR 0.16, 95% CI 0.10-0.26) PFS 11.0 versus 5.5 months (HR 0.34, 95% CI 0.22-0.51)	Rash, Diarrhea, LFT elevation, Nausea and vomiting
Gefitinib	1st gen	IPASS trial: gefitinib or carboplatin plus paclitaxel [45]	12-month progression-free rate 25 versus 7 percent, HR for progression 0.74 Patients with EGFR mutation had better PFS with gefitinib however those without EGFR mutation, PFS was shorter with gefitinib	Acne-like rash, diarrhea, stomatitis, elevation of liver enzymes, interstitial lung disease
Afatinib (Irreversible)	2nd gen	Phase III Lux-Lung 3 trial: Afatinib or cisplatin plus pemetrexed [46] Phase III trial Lux-Lung 6: afatinib or gemcitabine plus cisplatin [47]	12 month progression-free rate 51 versus 21 percent, HR for progression 0.58, 95% CI 0.43-0.78 PFS 11.0 versus 5.6 months	Diarrhea, rash, stomatitis, paronychia, and dry skin
Dacomitinib	2nd gen	Phase III trial ARCHER 1050: Dacomitinib versus gefitinib [48] Mok et al. [49]	At 22 months PFS was 14.7 versus 9.2 months; HR 0.59, 95% CI 0.47-0.74 At 31 months OS was 34 versus 27 months; HR 0.76, 95% CI 0.58-0.99	Grade 3-4 dermatitis, grade 3-4 diarrhea
Osimertinib	3rd gen	Phase III FLAURA trial: Osimertinib versus standard of care [50]	PFS 18.9 versus 10.2 months Response Rate 80 versus 76%	QT prolongation, reduction in EF

ALK-EML4 gene fusion positive NSCLC is highly sensitive to TKI therapy and is recommended for all patients whose tumors contain this mutation as confirmed by either fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), or immunohistochemistry (IHC).

Li et al. systematically reviewed phase I, II, and III clinical studies and discovered that ALK-inhibitors significantly improved the overall survival (OS) and progression-free survival (PFS) of non-small cell lung cancer patients. Treatment with ALK-inhibitors was specifically favoured in the patients that were positive for fusion of ALK or ROS1 genes [40].

Various phase III trials comparing ALK inhibition with first generation ALK TKI crizotinib versus chemotherapy showed prolonged progression-free survival (PFS), improved response rate and quality of life. Shaw et al. demonstrated PFS of 7.7 months versus 3.0 months for crizotinib versus pemetrexed or docetaxel (hazard ratio, 0.49; p < 0.0001) and Solomon et al. showed median survival 10.9 months versus 7.0 months for crizotinib versus pemetrexed plus either cisplatin or carboplatin (hazard ratio, 0.45; 95% confidence interval, 0.35 to 0.60; p<0.001). Subsequent trials showed PFS benefits with second-generation TKIs as well including alectinib, brigatinib and ensartinib over crizotinib [18, 41].

IV Any Role for Concurrent Targeted Therapy with Radiation?

For stage I and II disease, radiation therapy is indicated only for those with positive surgical margins after resection or for those who are not candidates for surgery [51]. About 25% to 30% cases of NSCLC are stage IIIA/B, locally advanced and with inoperable disease [52]. Adjuvant chemotherapy along with radiotherapy (RT) is recommended for better regional and systemic control of disease and is specifically indicated for those with lymph node involvement or positive margins post resection. The most common cause of mortality in patients with stage III unresectable NSCLC is distant recurrent disease. Chemo-radiation therapy (CRT) can be concurrent (cCRT), as was the case with our patient, or it could be sequential (sCRT) [52]. The median progression-free survival among patients who have been treated by CRT is around 8 months and only 20% of patients are alive at 5 years after NSCLC diagnosis [53, 54].

A greater survival benefit is seen with cCRT as compared to sCRT however, it is also associated with more side effects.
Concurrent delivery of cisplatin-based chemotherapy with thoracic radiotherapy (TRT) confers a long-term survival benefit compared with the sequential delivery of these therapies. As per this phase III trial, five-year survival was statistically significantly higher for patients treated with the concurrent regimen with once-daily TRT compared with the sequential treatment (sequential arm using cisplatin and vinblastine had 10% five-year survival [confidence interval 7 to 15%]; concurrent arm with cisplatin and vinblastine had 16% five-year survival [confidence interval 11 to 22%], concurrent arm using cisplatin and etoposide had 13% five-year survival [confidence interval 9 to 18%] [53].

In another phase III randomized study, the cCRT arm was associated with an improved response rate (84% vs. 66%), median OS (16.5 vs. 13.3 months) and 2- and 5-year survival rates (34.6% vs. 27.4% and 15.8% vs. 8.9%, respectively) compared with the sCRT arm. In this study they used cisplatin, mitomycin and vindesine as the chemotherapy regimen [55].

However, cCRT comes at the cost of increased toxicities which can lead to missed doses of chemotherapy which eventually is associated with worse outcomes. cCRT increases esophageal toxicities over sCRT or one modality alone and is also associated with higher incidence of hematologic toxicities. Rates of, grade 3 and above, thrombocytopenia, leukopenia and granulocytopenia can reach 10%, 70% and 71% of patients, respectively [56].

A study by Deek et al. reported a median OS of 9.6 months in patients with missed chemotherapy versus 24.3 months in those without missed chemotherapy. The main reasons to miss chemotherapy were reported to be hematologic toxicities (59%), esophagitis (17%), decline in performance status (12%) and allergic reaction (5%) [57]. Sequential CRT (sCRT) could be less toxic but OS is 6–7% less when compared to cCRT and sCRT has been used as an alternative option in elderly or low-performance patients or with severe comorbidities [53].

V Prognosis

The 5-year survival for NSCLC is reported to be about 25% which reflects the fact that most lung cancers are diagnosed at an advanced stage and that effective treatment of NSCLC is often limited by the advanced age of patients and numerous comorbidities [58]. Furthermore, advanced NSCLC treatment is often hindered by resistance to classic cytotoxic drugs.

There is no clear evidence as to whether patients with NSCLC who are never smokers have a better outcome than those with a positive smoking history. Several observational studies have been performed and the results have mixed results though most do favour better overall survival in patients who are never smokers.

A study from California included 12,000 patients and showed that smokers had a shorter survival as compared to never smokers, with hazard ratio [HR] for death 1.09, 95% CI 1.00-1.18 [59]. Another study comparing 132 never smokers with 522 current smokers, found that the five-year survival was significantly better among never smokers, even on multivariate analysis (23 versus 16 percent) [60].

A large lung cancer registry trial, which included over 15,000 Japanese and over 13,000 Caucasian patients from Southern California, demonstrated statistically significant improvement in survival for the patients with no smoking history and this was supported by another study from Japan that analysed 26,957 NSCLC patients [61]. This study from Japan reported that median overall survival was significantly longer for never smokers compared with ever smokers (30 versus 19 months) [62]. Interestingly, a study of 254 lung cancer patients showed that the five-year survival was not significantly different in never smokers compared to smokers (27 versus 31 percent, respectively) [63].

Conclusion

NSCLC is complex and has been increasing in incidence in never smokers. The use of targeted therapy has changed the treatment of NSCLC dramatically. Questions regarding choice of therapy remain intact especially in patients with rare mutations and hence we recommend customization of therapy for each patient based on age, comorbidities, and mutations.

Acknowledgement

Not Applicable.

Funding

None.

Abbreviation

NSCLC: Non-Small Cell Lung Cancer
SCLC: Small Cell Lung Cancer
TKI: Tyrosine Kinase Inhibitor
GFR: Epidermal Growth Factor Receptor
ALK: Anaplastic Lymphoma Kinase
ROS1: C-Ros Oncogene 1
LCINS: Lung Cancer in Never Smokers
ELM4: Echinoderm Microtubule-Associated Protein-like 4
ALCL: Anaplastic Large Cell Lymphoma
RTK: Receptor Tyrosine Kinase
Ras: Rat Sarcoma Virus
KRAS: Kirsten Rat Sarcoma Virus
HRAS: Harvey Rat Sarcoma Virus
N-ras: Neuroblastoma RAS Viral Oncogene Homolog
GTP: Guanosine-5’-Triphosphate
PDGFR: Platelet-Derived Growth Factor Receptor
IGFR: Insulin-like Growth Factor Receptor
RAF: Rapidly Accelerated Fibrosarcoma
MEK/MAP2K: Mitogen-Activated Protein Kinase
ERK: Extracellular-Signal-Regulated Kinase
ROS1: Reactive Oxygen Species 1
RET: Rearranged during Transfection
NRTK: Neurotrophic Receptor Tyrosine Kinase
MET: Mesenchymal-Epithelial Transition
RON: Recepteur d’Origine Nantais
SRC: Sarcoma
GRB2: Growth Factor Receptor Bound Protein 2
CHEK: Checkpoint Kinase
PD-L1: Programmed Death-Ligand 1
OS: Overall Survival
PET-CT: Positron Emission Tomography - Computed Tomography
RR: Relative Risk
TP53: Tumor Protein p53
Cox2: Cyclooxygenase-2
PIK3CA: Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha
FISH: Fluorescence In Situ Hybridization
NGS: Next Generation Sequencing
VEGFR: Vascular Endothelial Growth Factor Receptor
IHC: Immunohistochemistry
PFS: Progression Free Survival
RT: Radiotherapy
CRT: Chemo-radiation Therapy
cCRT: Concurrent Chemo-radiation Therapy
sCRT: Sequential Chemo-radiation Therapy
TRT: Thoracic Radiotherapy
HR: Hazard Ratio
CI: Confidence Interval

Article Info

Article Type

Review Article

Publication history

Received: Tue 07, Jun 2022
Accepted: Mon 20, Jun 2022
Published: Fri 01, Jul 2022

Copyright

© 2023 Dhara Dave. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
DOI: 10.31487/j.AJMC.2022.01.01

Author Info

Dhara Dave Basheer Mohammed Janakikeerthika Dharmarpandi Darshit Dave Rohit Saralaya Praveen Tumula

Corresponding Author

Dhara Dave
Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, Texas, USA

Figures & Tables

Table 1: Frequency of genetic mutations in NSCLC.

Target	Mutation	Frequency (%)
EGFR	Exon 19 deletion and exon 21 point mutation HER2 point mutation T790M (somatic)	30-60 2-4 1-4
KRAS	Mutations in codons 12, 13, and 61	15-25
ALK	EML4-ALK	2-8
NTRK1	NTRK1 fusion	3.3
c-MET	Amplification Exon 14 skipping mutation	2-4 3-4
BRAF	V600E mutation	1-4
ROS1	ROS1	2
RET	RET fusion	1
Co-mutations		Upto 15

Table 2: Below shows a summarized detail of the approved EGFR TKIs.

TKI	Generation (Gen)	Study	Finding	S/E
Erlotinib	1st gen	OPTIMAL trial: Erlotinib versus gemcitabine + carboplatin [42] EURTAC trial: Erlotinib vs platinum-based chemotherapy doublet [43] ENSURE trial: Erlotinib or gemcitabine and cisplatin [44]	PFS 13.1 versus 4.6 months (HR 0.46, 95% CI 0.37-0.57) Response Rate 83 vs 36% PFS 9.7 versus 5.2 months (HR 0.16, 95% CI 0.10-0.26) PFS 11.0 versus 5.5 months (HR 0.34, 95% CI 0.22-0.51)	Rash, Diarrhea, LFT elevation, Nausea and vomiting
Gefitinib	1st gen	IPASS trial: gefitinib or carboplatin plus paclitaxel [45]	12-month progression-free rate 25 versus 7 percent, HR for progression 0.74 Patients with EGFR mutation had better PFS with gefitinib however those without EGFR mutation, PFS was shorter with gefitinib	Acne-like rash, diarrhea, stomatitis, elevation of liver enzymes, interstitial lung disease
Afatinib (Irreversible)	2nd gen	Phase III Lux-Lung 3 trial: Afatinib or cisplatin plus pemetrexed [46] Phase III trial Lux-Lung 6: afatinib or gemcitabine plus cisplatin [47]	12 month progression-free rate 51 versus 21 percent, HR for progression 0.58, 95% CI 0.43-0.78 PFS 11.0 versus 5.6 months	Diarrhea, rash, stomatitis, paronychia, and dry skin
Dacomitinib	2nd gen	Phase III trial ARCHER 1050: Dacomitinib versus gefitinib [48] Mok et al. [49]	At 22 months PFS was 14.7 versus 9.2 months; HR 0.59, 95% CI 0.47-0.74 At 31 months OS was 34 versus 27 months; HR 0.76, 95% CI 0.58-0.99	Grade 3-4 dermatitis, grade 3-4 diarrhea
Osimertinib	3rd gen	Phase III FLAURA trial: Osimertinib versus standard of care [50]	PFS 18.9 versus 10.2 months Response Rate 80 versus 76%	QT prolongation, reduction in EF

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA et al. (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68: 394-424. [Crossref]

2. Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer Statistics, 2021. CA Cancer J Clin 71: 7-33. [Crossref]

3. Da Cunha Santos G, Shepherd FA, Tsao MS (2011) EGFR mutations and lung cancer. Annu Rev Pathol 6: 49-69. [Crossref]

4. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55: 74-108. [Crossref]

5. Sun S, Schiller JH, Gazdar AF (2007) Lung cancer in never smokers--a different disease. Nat Rev Cancer 7: 778-790. [Crossref]

6. Wakelee HA, Chang ET, Gomez SL, Keegan TH, Feskanich D et al. (2007) Lung cancer incidence in never smokers. J Clin Oncol 25: 472-478. [Crossref]

7. Torok S, Hegedus B, Laszlo V, Hoda MA, Ghanim B et al. (2011) Lung cancer in never smokers. Future Oncol 7: 1195-1211. [Crossref]

8. Toh CK, Gao F, Lim WT, Leong SS, Fong KW et al. (2006) Never-smokers with lung cancer: epidemiologic evidence of a distinct disease entity. J Clin Oncol 24: 2245-2251. [Crossref]

9. Surveillance, Epidemiology, and End Results (SEER) Program Seer*Stat Database: Incidence - SEER 13 Regs Public-Use, Nov 2004 Sub for Expanded Races (1992-2002). National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch. 2005.

10. Shi Y, Au JSK, Thongprasert S, Srinivasan S, Tsai CM et al. (2014) A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 9: 154-162. [Crossref]

11. Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR et al. (2016) The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 7: 78985-78993. [Crossref]

12. Kutkowska J, Porębska I, Rapak A (2017) Non-small cell lung cancer - mutations, targeted and combination therapy. Postepy Hig Med Dosw (Online) 71: 431-445. [Crossref]

13. Park SJ, More S, Murtuza A, Woodward BD, Husain H (2017) New Targets in Non-Small Cell Lung Cancer. Hematol Oncol Clin North Am 31: 113-129. [Crossref]

14. Shukuya T, Takahashi K (2019) Germline mutations in lung cancer. Respir Investig 57: 201-206. [Crossref]

15. Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J et al. (2016) Biomarkers France contributors. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 387: 1415-1426. [Crossref]

16. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB et al. (2009) Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27: 4247-4253. [Crossref]

17. Malik SM, Maher VE, Bijwaard KE, Becker RL, Zhang L et al. (2014) U.S. Food and Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive. Clin Cancer Res 20: 2029-2034. [Crossref]

18. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L et al. (2015) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 373: 1582. [Crossref]

19. Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A et al. (2009) Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res 15: 5216-5223. [Crossref]

20. Calles A, Liao X, Sholl LM, Rodig SJ, Freeman GJ et al. (2015) Expression of PD-1 and Its Ligands, PD-L1 and PD-L2, in Smokers and Never Smokers with KRAS-Mutant Lung Cancer. J Thorac Oncol 10: 1726-1735. [Crossref]

21. Sezer A, Kilickap S, Gümüş M, Bondarenko I, Özgüroğlu M et al. (2009) Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet 397: 592-604. [Crossref]

22. Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A et al. (2020) Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med 383: 1328-1339. [Crossref]

23. Hellmann MD, Paz-Ares L, Caro RB, Zurawski B, Kim SW et al. (2019) Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med 381: 2020-2031. [Crossref]

24. Herbst RS, Garon EB, Kim DW, Cho BC, Gracia JLP et al. (2018) Long-term survival in patients (pts) with advanced NSCLC in the KEYNOTE-010 study overall and in pts who completed 2 years of pembrolizumab (pembro). Ann Oncol 29S: viii749.

25. Schwartz AG, Yang P, Swanson GM (1996) Familial risk of lung cancer among nonsmokers and their relatives. Am J Epidemiol 144: 554-562. [Crossref]

26. Gorlova OY, Weng SF, Zhang Y, Amos CI, Spitz MR (2007) Aggregation of cancer among relatives of never-smoking lung cancer patients. Int J Cancer 121: 111-118. [Crossref]

27. Gao Y, Goldstein AM, Consonni D, Pesatori AC, Wacholder S et al. (2009) Family history of cancer and nonmalignant lung diseases as risk factors for lung cancer. Int J Cancer 125: 146-152. [Crossref]

28. Yamamoto H, Higasa K, Sakaguchi M, Shien K, Soh J et al. (2014) Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. J Natl Cancer Inst 106: djt338. [Crossref]

29. Sonobe M, Manabe T, Wada H, Tanaka F (2005) Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma. Br J Cancer 93: 355-363. [Crossref]

30. Marchetti A, Martella C, Felicioni L, Barassi F, Salvatore S et al. (2005) EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 23: 857-865. [Crossref]

31. Riely GJ, Kris MG, Rosenbaum D, Marks J, Li A et al. (2008) Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 14: 5731-5734. [Crossref]

32. Le Calvez F, Mukeria A, Hunt JD, Kelm O, Hung RJ et al. (2005) TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res 65: 5076-5083. [Crossref]

33. Weickhardt AJ, Aisner DL, Franklin WA, Varella-Garcia M, Doebele RC et al. (2013) Diagnostic assays for identification of anaplastic lymphoma kinase-positive non-small cell lung cancer. Cancer 119: 1467-77. [Crossref]

34. Sholl LM, Aisner DL, Varella-Garcia M, Berry LD, Dias-Santagata D et al. (2015) Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience. J Thorac Oncol 10: 768-777. [Crossref]

35. Yang JJ, Zhang XC, Su J, Xu CR, Zhou Q et al. (2014) Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation. Clin Cancer Res 20: 1383-1392. [Crossref]

36. Won JK, Keam B, Koh J, Cho HJ, Jeon YK et al. (2015) Concomitant ALK translocation and EGFR mutation in lung cancer: a comparison of direct sequencing and sensitive assays and the impact on responsiveness to tyrosine kinase inhibitor. Ann Oncol 26: 348-354. [Crossref]

37. Tabchi S, Kourie HR, Klastersky J (2017) Concurrent driver mutations/rearrangements in non-small-cell lung cancer. Curr Opin Oncol 29: 118-122. [Crossref]

38. Bai H, Wang Z, Wang Y, Zhuo M, Zhou Q et al. (2013) Detection and clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with advanced non-small cell lung cancer. PLoS One 8: e54170. [Crossref]

39. Johnson B, Kris M, Berry L, Kwiatkowski D, Iafrate A et al. (2013) A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 31.

40. Li G, Dai WR, Shao FC (2017) Effect of ALK-inhibitors in the treatment of non-small cell lung cancer: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci 21: 3496-3503. [Crossref]

41. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K et al. (2014) First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371: 2167-2177. [Crossref]

42. Zhou C, Wu YL, Chen G, Feng J, Liu XQ et al. (2015) Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol 26: 1877-1883. [Crossref]

43. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B et al. (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13: 239-246. [Crossref]

44. Wu YL, Zhou C, Liam CK, Wu G, Liu X et al. (2015) First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 26: 1883-1889. [Crossref]

45. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS et al. (2011) Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 29: 2866-2874. [Crossref]

46. Sequist LV, Yang JCH, Yamamoto N, O'Byrne K, Hirsh V et al. (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31: 3327-3334. [Crossref]

47. Wu YL, Zhou C, Hu CP, Feng J, Lu S et al. (2014) Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15: 213-222. [Crossref]

48. Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K et al. (2017) Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 18: 1454-1466. [Crossref]

49. Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K et al. (2018) Improvement in Overall Survival in a Randomized Study That Compared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR-Activating Mutations. J Clin Oncol 36: 2244-2250. [Crossref]

50. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B et al. (2018) Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 378: 113-125. [Crossref]

51. Armstrong JG, Minsky BD (1989) Radiation therapy for medically inoperable stage I and II non-small cell lung cancer. Cancer Treat Rev 16: 247-255. [Crossref]

52. Costa GJ, Ferreira CG, Thuler LCS (2018) Concurrent chemoradiotherapy for stage III non-small cell lung cancer: correct clinical management as the basis to move beyond. Ann Transl Med 6: S65. [Crossref]

53. Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS et al. (2011) Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103: 1452-1460. [Crossref]

54. Postmus PE, Kerr KM, Oudkerk M, Senan S, Waller DA et al. (2017) Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28: iv1-iv21. [Crossref]

55. Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y et al. (1999) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17: 2692-2699. [Crossref]

56. Verma V, Simone CB 2nd, Werner-Wasik M (2017) Acute and Late Toxicities of Concurrent Chemoradiotherapy for Locally-Advanced Non-Small Cell Lung Cancer. Cancers (Basel) 9: 120. [Crossref]

57. Deek MP, Kim S, Ahmed I, Fang BS, Zou W et al. (2018) Prognostic Impact of Missed Chemotherapy Doses During Chemoradiation Therapy for Non-Small Cell Lung Cancer. Am J Clin Oncol 41: 362-366. [Crossref]

58. American Cancer Society. Cancer Facts & Figures 2014.

59. Zell JA, Ou SHI, Ziogas A, Anton-Culver H (2005) Epidemiology of bronchioloalveolar carcinoma: improvement in survival after release of the 1999 WHO classification of lung tumors. J Clin Oncol 23: 8396-8405. [Crossref]

60. Nordquist LT, Simon GR, Cantor A, Alberts WM, Bepler G (2004) Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung. Chest 126: 347-351. [Crossref]

61. Kawaguchi T, Matsumura A, Fukai S, Tamura A, Saito R et al. (2010) Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases. J Thorac Oncol 5: 1001-1010. [Crossref]

62. Kawaguchi T, Takada M, Kubo A, Matsumura A, Fukai S et al. (2010) Performance status and smoking status are independent favorable prognostic factors for survival in non-small cell lung cancer: a comprehensive analysis of 26,957 patients with NSCLC. J Thorac Oncol 5: 620-630. [Crossref]

63. Subramanian J, Velcheti V, Gao F, Govindan R (2007) Presentation and stage-specific outcomes of lifelong never-smokers with non-small cell lung cancer (NSCLC). J Thorac Oncol 2: 827-830. [Crossref]