Review Article

Flipped script for gefitinib: A reapproved tyrosine kinase inhibitor for first-line treatment of epidermal growth factor receptor mutation positive metastatic nonsmall cell lung cancer

J Oncol Pharm Practice 0(0) 1–12 ! The Author(s) 2016 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155216634179 opp.sagepub.com

Brian S Bogdanowicz1, Matthew A Hoch2 and Megan E Hartranft1,3

Abstract Purpose: The approval history, pharmacology, pharmacokinetics, clinical trials, efficacy, dosing recommendations, drug interactions, safety, place in therapy, and economic considerations of gefitinib are reviewed. Summary: Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer death. Platinum-based chemotherapy and tyrosine kinase inhibitors, such as erlotinib and afatinib, are recommended therapies for nonsmall cell lung cancer. The European Medicines Association based their approval of gefitinib on the randomized, multicenter Iressa Pan-Asia Study (IPASS, NCT00322452) and a single-arm study showing effectiveness in Caucasians (IFUM, NCT01203917). Both studies were recently referenced by the United States Food & Drug Administration to reapprove gefitinib for the first-line treatment of advanced nonsmall cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 substitution. Diarrhea, acneiform rash, and interstitial lung disease are known side effects of gefitinib. Conclusion: Use of gefitinib for the first-line therapy of metastatic nonsmall cell lung cancer with epidermal growth factor receptor exon 19 deletions (residues 747–750) or exon 21 substitution mutation (L858R) is well-documented and supported.

Keywords Nonsmall cell lung cancer, gefitinib, IressaÕ , ZD1839, tyrosine kinase inhibitor, lung cancer, reapproved

Introduction Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer death among men and women.1 In the United States, it is estimated that over 220,000 individuals will be newly diagnosed with lung cancer and over 150,000 will die from the malignancy in 2015.1 Frequently, symptoms are absent until advanced stages of the disease and are commonly mistaken as the result of other disorders, such as infection.2 The epidermal growth factor receptor (EGFR) is part of a larger family of transmembrane receptor tyrosine kinases involved in cell growth and proliferation.3 EGFR overexpression frequently defines cases of

nonsmall cell lung cancers (NSCLC) and stimulates tumorigenesis through dysregulation of normal cell growth.3 1 College of Pharmacy, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA 2 Department of Pharmacy, Rush University Cancer Center, North Chicago, IL, USA 3 Department of Pharmacy, Rush University Medical Center, North Chicago, IL, USA

Corresponding author: Brian S Bogdanowicz, College of Pharmacy, Rosalind Franklin University of Medicine and Science, 3125 Nebraska Court Apt B, Great Lakes, North Chicago, IL 60088, USA. Email: [email protected]

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EGFR mutations occur in roughly 10% of patients with advanced NSCLC and are significantly more common among females, Asians, never-smokers, and those with adenocarcinoma.3,4 Particularly, exon 19 deletions (residues 747–750) and exon 21 point mutations (L858R) constitute more than 90% of all EGFR kinase mutations and promote antiapoptotic signals.3 Gefitinib is a reversible inhibitor of the autophosphorylation activity of EGFR tyrosine kinases, predominantly those with the specific mutations noted above. Wild-type EGFR is also targeted by gefitinib, albeit with much lower binding affinity.5 Gefitinib has a complicated history in the United States, but with its reapproval in early 2015, the agent is poised to be a viable option for patients with specific classifications of NSCLC.

In 2009, the European Medicines Agency (EMA) approved gefitinib for advanced, mutation-positive NSCLC, based on the results of a large randomized, controlled trial in East Asian patients.15 In this trial, gefitinib significantly improved the progression-free survival of EGFR mutation-positive patients compared with paclitaxel plus carboplatin.15 As part of the approval, the EMA required a single-arm trial to confirm efficacy in Caucasian patients due to differences in drug exposure, metabolism, and toxicities when compared with Asian patients.20 Consequently, in EGFR mutation-positive patients, gefitnib produced a median progression-free survival of 9.7 months and had an objective response rate of 69.8%.20 Based primarily on these two trials, the US FDA reapproved gefitinib for first-line monotherapy in patients with EGFRmutated NSCLC on 13 July 2015.15,20,21

History Prior to United States Food & Drug Administration (US FDA) approval, gefitinib monotherapy was studied in hundreds of patients with advanced, chemotherapy-refractory NSCLC with only a select minority of the patients experiencing clinically significant responses.6 In 2003, primarily based on a doubleblind phase II trial, gefitinib 250 mg tablets received accelerated approval by the US FDA as monotherapy for patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.7,8 Approval was contingent upon AstraZeneca’s agreement with the FDA to conduct a randomized, placebo-controlled trial investigating gefitinib’s effect on survival in patients with advanced NSCLC who received 1–2 prior chemotherapy regimens.9 Notably, both of these early studies only considered EGFR overexpression in NSCLC, not EGFR mutations, as the basis for gefitinib treatment because the importance of mutations was not yet known.8,10 In 2004, the requested study failed to demonstrate a significant overall survival benefit with gefitinib.9,10 Upon the basis of these results, AstraZeneca suspended promotion of gefitinib, and in 2005, the US FDA restricted its access to patients who were currently benefiting or previously benefited from gefitinib, as determined by the patient’s physician.9,11 The US FDA initially elected to forego market withdrawal of gefitinib, but suggested that further clinical trials would determine the future role of the drug.11 In 2012, the US FDA withdrew gefitinib new drug application (NDA) approval.12 Over the last 10 years, additional clinical trials of gefitinib have been conducted in patients with NSCLC possessing EGFR exon 19 deletions or exon 21 substitution mutations. The results of these studies are summarized in Table 1.10,13–20

Pharmacology and pharmacokinetics Gefitinib is a quinazoline derivative tyrosine kinase inhibitor (TKI) directed against EGFR.22 Through reversible and competitive binding at the ATP-binding site of the EGFR kinase domain, gefitinib prevents dimerization of the receptor thereby halting autophosphorylation and downstream signal transduction.23,24 As demonstrated by Lynch and Paez, sensitizing mutations in the EGFR oncogene on chromosome 7, including exon 19 deletions (residues 747–750) and exon 21 point mutation (L858R), increase affinity of gefitinib for the binding site and subsequently increase clinical sensitivity.24–26 Gefitinib binding interferes with EGFinitiated cellular growth and proliferation and inhibits production of additional factors integral to tumor growth including transforming growth factor-a (TGF-a), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF).22 In pharmacokinetic studies among 17 cancer patients, a single oral dose of gefitinib 250 mg had a mean half-life of 50.5 h (range 15.6–111) with maximum serum concentration reached at a median of 3 h (range 1–8).27 Mean oral bioavailability is 60%5 with a relative increase of 32% when administered with food.27 The mean volume of distribution of gefitinib is large at 1400 L (range 830–2710), and it is approximately 90% bound to plasma proteins, including albumin and alpha-1-acid glycoprotein.27,28 Gefitinib is extensively hepatically metabolized by CYP3A4 and CYP2D6.5 Metabolism by other CYP enzymes accounts for an insignificant portion of the gefitinibelimination. The drug is a weak CYP2D6 inhibitor and has been shown to increase metoprolol AUC by 35% when administered together.29 Only 4% of gefitinib and metabolites are eliminated via the kidneys, while the majority of the dose is excreted in the feces (Table 2).5

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Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: Data from the randomized phase III INTEREST trial. J Clin Oncol 2010; 28: 744–752.

Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated nonsmall-cell lung cancer (INTEREST): A randomized phase III trial. Lancet 2008; 372: 1809–1818.

Acronym: ISEL

Patient population: Adults with locally advanced or metastatic NSCLC previously treated with a platinum-containing regimen (maximum 2 previous regimens) recruited from Europe, Asia, North/ Central/South Americas

Intervention: Gefitinib 250 mg PO daily (n ¼ 733 ITT, 723 per-protocol, 19 Mut+) or docetaxel 75 mg/m2 IV every 21 days (n ¼ 733 ITT, 710 per-protocol, 19 Mut+)

Design: Open-label, randomized, controlled trial

Patient population: Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) not curable with surgery or radiotherapy who were refractory to or intolerant of one or two previous chemotherapy regimens and were recruited from Europe, Asia, Central and South Americas, Australia, and Canada

Exploratory: Subgroup analyses by EGFR copy number, protein expression, mutation status, and KRAS mutation status

Secondary outcomes: progression-free survival (PFS), objective response rate (ORR), quality of life (QOL measured with functional assessment of cancer therapylung, FACT-L; trial outcome index, TOI; lung cancer subset of FACT-L, LCS)

Primary outcomes: OS in overall per-protocol population and OS in high EGFR-gene-copy number ITT population

Primary analysis: Intent-to-treat, stratified (histology, smoking history, reason for chemotherapy failure, number of previous regimens, performance status, sex) log-rank test requiring 696 adenocarcinoma deaths with an assumed median survival of 5.2 months and allowing 15% treatment crossover to detect a 33% relative improvement in survival with 90% power at 95% confidence

FACT-L clinically relevant improvement 25.1 vs. 14.7% (OR 1.99, p < 0.0001)

ORR 90 vs. 82.8% (OR 1.22, p ¼ 0.33)

Secondary: Median PFS 2.2 vs. 2.7 months (HR 1.04, p ¼ 0.47)

Median OS for high EGFR copy number 8.4 vs. 7.5 months (HR 1.09, p ¼ 0.62)

Primary: Median OS for overall population 7.6 vs. 8.0 months (HR 1.020, p > 0.04 for non-inferiority)

Secondary: Median TTF in overall population 3.0 vs. 2.6 months (HR 0.82, log-rank p < 0.01)

Treatment-related AEs: 72 vs. 82% Serious AE: 4 vs. 18%, ILD 1 vs 1% Grade 3–4 AE: 9 vs. 41% AE-caused death: 1 vs. 2% AE-caused discontinue: 4 vs. 11% Common AE: Rash (49.4 vs. 10.2%), diarrhea (35 vs. 24.8%), asthenia (25 vs. 46.7%), anorexia (21.8 vs. 21.1%), nausea (20.3 vs. 26.2%), dyspnea (16.5 vs. 16.4%), dry skin (15.2 vs. 1.4%), vomiting (15 vs. 17.2%), cough (14.8 vs. 14.3%), constipation (10.8 vs. 16.9%)

Death due to AE: 5 vs. 4%

Dose interruptions due to AE: 11 vs. 5%

Serious AE: Interstitial lung disease (ILD) 1 vs. 1%

Common AE (10%): Rash (37 vs. 10%), diarrhea (27 vs. 9%), nausea (17 vs. 16%), anorexia (17 vs. 14%), vomiting (14 vs. 10%), asthenic conditions (13 vs. 13%), dry skin (11 vs. 4%), constipation (10 vs. 13%)

(continued)

-Demonstrated non-inferiority to docetaxel in patients previously treated with platinumbased therapy -No OS benefit seen in any group or subgroup -PFS benefit seen in Mut+ patients, though only a very small sample was included (n ¼ 19 in each group) -Clearly improved tolerability of gefitinib vs. docetaxel

Median OS for overall population 5.6 vs. 5.1 months (HR ¼ 0.89, log-rank p ¼ 0.087)

Secondary outcome: Time to treatment failure (TTF)

Grade 3-4 AE: 30 vs. 27%

-Study was continued for an additional 3 months to increase power despite meeting required number of events and less-than expected treatment crossover, but no significant improvement seen -Survival curves separate at 4 of 14 months, indicating log-rank test might have been a less sensitive test when compared with Cox proportional hazard, which did show statistically significant improvement, -Study authors indicated most likely cause for lack of significance was recruitment of patients who would be refractory to any treatment (i.e., too sick) -The lack of improvement in this study resulted in revocation of accelerated FDA approval Any adverse event (AE): 82 vs. 71%

Primary: Median OS for adenocarcinoma population 6.3 vs. 5.4 months (HR ¼ 0.84, log-rank p ¼ 0.089)

Primary outcome: Overall survival (OS) in (a) the adenocarcinoma population (n ¼ 812) and (b) in the overall population (n ¼ 1692).

Design: Double-blind, randomized, placebo-controlled clinical trial

Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced nonsmall-cell lung cancer: results from a randomised placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527–1537.

Intervention: Gefitinib 250 mg PO once daily (n ¼ 1129) or placebo (n ¼ 563)

Notes

Safety

Efficacy

Outcomes/Analyses

Design

Citation

Table 1. Summary of trials evaluating gefitinib monotherapy efficacy and safety.10,13–20

Bogdanowicz et al. 3

Fukuoka M, Wu YL, Thongprasert S, et al. 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 2011; 29: 2866–2874. Acronym: IPASS

Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–957.

Acronym: INTEREST

Citation

Table 1. Continued

Design: Open-label, randomized, controlledtrial Intervention: Gefitinib 250 mg PO once daily (n ¼ 609) or six 21-day cycles of paclitaxel 200 mg/m2 IV plus carboplatin AUC 5-6 mg/ mL/min IV (n ¼ 608) Patient population: Adult non-smokers or former light smokers with stage IIIB/IV NSCLC with adenocarcinoma histology who had received no previous chemotherapy or biotherapy recruited from Hong Kong, China, Indonesia, Japan, Malaysia, the Philippines, Singapore, Taiwan, and Thailand

Design

Primary outcome: PFS Secondary outcomes: OS, ORR, QOL (FACT-L, TOI, LCS) Exploratory: Efficacy assessment of EGFR biomarker status described as EGFR copy number, protein expression, and mutation type Primary analysis: Intent-to-treat, Cox proportional-hazards model analysis requiring 944 events to demonstrate noninferiority of gefitinib with 80% power and 95% confidence including WHO performance status, smoking status, and sex as covariates with the possibility of demonstrating superiority with a closed test procedure

Primary analyses: (a) Per-protocol, unadjusted, Cox proportional hazards model analysis requiring 1169 deaths in the overall population to determine non-inferiority in OS with unreported power and 4% significance (Hochberg adjustment for multiple comparisons, non-inferiority with upper limit of 95% CI HR 150%).5 No recommendations for the dosing of gefitinib in patients with renal impairment have been made.5 Mean steady state concentrations of gefitinib are clinically unaffected by creatinine clearance (>20 mL/min).5 Case reports of gefitinib 250 mg daily used in patients with NSCLC undergoing hemodialysis or continuous ambulatory peritoneal dialysis have indicated tolerability and positive outcomes, including complete metabolic remission.34,35 In the event of overdose, withhold gefitinib, initiate supportive care, and monitor the patient until they are clinically stable.5 Dose modifications recommended for adverse drug reactions are provided in Table 3.5

Availability, storage, and preparation

Warnings and precautions

Gefitinib is available as a brown, round 250 mg tablet with ‘‘IRESSA 250’’ debossed on one side.5

Presently, there are no contraindications to gefitinib treatment, but several warnings and precautions have

Efficacy of gefitinib monotherapy in NSCLC Tumor responses, stable disease, and improvements in pulmonary disease-related symptoms for patients with NSCLC taking gefitinib were noted as early as 1999.30 Following the observation that roughly 10% of EGFR positive NSCLC patients had dramatic clinical response when treated with gefitinib, a 2004 study showed that nearly all patients (8 out of 9) with EGFR mutations responded when treated with gefitinib, as compared with no patients (0 out of 7) without EGFR mutations.6 Further, early in its history, efficacy of gefitinib was shown to be unrelated to solely the level of EGFR expression in a cancer patient.31 Subsequent studies have evaluated the effect of EGFR mutation status in either the primary group or as an analyzed subgroup. Compared with chemotherapy in a number of studies, gefitinib significantly improved progression-free survival, objective response rate, and quality of life in patients with EGFR mutations. Table 1 provides summaries of several important trials.10,13–20 At this time, there are a number of active, post-approval trials further evaluating gefitinib monotherapy, including NCT00683306.

Indication

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Table 3. Grades based on NCI CTCAE classification; resume withheld treatment with gefitinib when the adverse event fully resolves or improves to NCI CTCAE Grade 1.5 Withhold (for up to 14 days)

Discontinue

Acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever) Grade 2 or higher in ALT and/or AST elevations Grade 3 or higher diarrhea

Confirmed interstitial lung disease (ILD)

Grade 3 or higher skin reactions

Severe hepatic impairment Gastrointestinal perforation Persistent ulcerative keratitis

Signs and symptoms of severe or worsening ocular disorders including keratitis

been provided. Gefitinib is known to cause interstitial lung disease, hepatotoxicity, GI perforation, severe or persistent diarrhea, ocular disorders (including keratitis), bullous and exfoliative skin disorders (SJS, TEN), and embryo-fetal toxicity.5 Gefitinib should be withheld or discontinued if a patient begins to experience any of these disorders.5 Prescreening of relevant patient parameters (e.g. liver function) should occur before administration of gefitinib. Women of childbearing potential should be warned that gefitinib was shown to cause fetal harm in animals and should be advised to use contraception throughout treatment until 2 weeks after treatment completion.5 Women should also be advised not to breastfeed while on gefitinib because of its unknown effects.5

Safety and tolerability of gefitinib monotherapy in NSCLC Phase I studies revealed that the most frequent adverse events that occur with gefitinib are grade 1 or 2 diarrhea and acneiform rash.30 Ocular events, such as mild conjunctivitis and reversible corneal erosion, and rare occurrence of grade 3 or 4 adverse events were also noted.30 Early management of these reversible adverse events includes use of over-the-counter medication (e.g. antidiarrheals) or discontinuation of gefitinib.30 Acneiform rash mainly affects the scalp, face, upper chest, and back.36 Generally, nonsmokers, people with fair skin, people >70 years old, and males are at greater risk for developing the rash.36 For prevention, the strongest recommendation is for either doxycycline 100 mg twice daily or minocycline 100 mg daily during weeks 1–6 and 8 of EGFR inhibitor use, unless the patient has contraindications (e.g. serious allergy).36 Treatment options include these antibiotic

Table 4. Additional drug–drug interactions with gefitinib.40–51 Drug interacting with gefitinib

Level of interaction

Clozapine Thioridazine Vinorelbine Topotecan Paritaprevir Ombitasvir Dasabuvir Conivaptan Fusidic Acid Idelalisib Pazopanib

Severe Severe Major Major Major Major Major Avoid use Avoid use Avoid use Avoid use

prevention regimens or alclometasone 0.05% cream.36 A meta-analysis of 33 trials revealed that NSCLC patients receiving an EGFR TKI and experiencing skin rash had significantly less risk for disease progression (hazard ration ¼ 0.45) and longer overall survival/ less risk of death (hazard ratio ¼ 0.40) compared to those who did not experience a rash.37 Interstitial lung disease (ILD) is a serious adverse event with reported frequency as high as 5.3% and connection to several cases of death.17,18 Serum albumin 3.0 mg/dL has been shown to have significant association with incidence of ILD.38 Signs and symptoms include progressive dyspnea, cough, fever, absence of infection, and lung opacifications.38 Management consists of immediate discontinuation of gefitinib and initiation of supplemental oxygen and systemic corticosteroids.39 Table 1 provides further details regarding the presence and frequency of gefitinib-related adverse events observed during clinical trials.10,13–20

Drug interactions Critical evaluation should occur when considering use of gefitinib with drugs affecting CYP3A4 or CYP2D6 or with the drugs listed in Table 4.5,40–51 When using gefitinib, concomitant drugs that are potent CYP3A4 inducers (e.g. rifampicin, phenytoin, or tricyclic antidepressants) should be discontinued and gefitinib doses should be increased to 500 mg daily per patient tolerance without the occurrence of a serious adverse drug reaction.5 Then, 7 days after discontinuation of the strong CYP3A4 inducer, regular dosing of gefitinib should be resumed (250 mg daily).5 In a study where healthy volunteers of unspecified race were administered gefitinib 250–500 mg,

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coadminstration with the CYP3A4 inducer rifampicin reduced gefitinib area under the curve (AUC) by 83%.29 Use of gefitinib with strong inhibitors of CYP3A4 (e.g. ketoconazole) is permitted, but requires closer monitoring for adverse reactions due to increased gefitinib plasma concentrations.5 When coadministered with the CYP3A4 inhibitor itraconazole, gefitinib AUC was increased by 80%.29 Due to minor CYP2D6 inhibition, gefitinib has been shown to produce slight increases in CYP2D6 substrate concentrations when given concomitantly.5 This interaction may be relevant for concomitant agents that have a narrow therapeutic index. As gefitinib is most soluble around pH 1 and solubility decreases drastically between pH 4 and pH 6, drugs that increase the pH of the stomach, such as proton pump inhibitors (PPIs), histamine H2 receptor antagonists (H2RAs), and antacids, may decrease absorption and plasma concentrations of gefitinib.5 Use of gefitinib with PPIs should be avoided, but if PPI treatment is required, give gefitinib 12 h after the previous PPI dose or 12 h before the next PPI dose.5 If a patient is taking a concomitant H2RA or antacid, give gefitinib 6 h before or 6 h after these agents.5 In patients taking concomitant warfarin with gefitinib, regular monitoring of INR or prothrombin time should be conducted due to reports of INR elevations and/or hemorrhage.5

Implications and economic considerations When patients possess EGFR exon 19 deletions or exon 21 substitution mutations, erlotinib and afatinib share the same indication as gefitinib and are alternate options for treatment.52–54 Platinum-based chemotherapy is superior to best supportive care and is recommended when patients are EGFR mutation negative or EGFR status unknown.52,55 In a recent meta-analysis by Burotto and colleagues comparing erlotinib, afatinib, and gefitinib in metastatic NSCLC, gefitinib was demonstrated as having similar efficacy (ORR, PFS, or OS) and toxicity compared to erlotinib, but similar efficacy and less toxicity (diarrhea, rash, and paronychia) compared to afatinib.56 Another recent meta-analysis by Haspinger et al.57 of erlotinib, afatinib, and gefitinib for advanced EGFR-positive NSCLC found overall response with gefitinib to be similar in comparison to erlotinib and afatinib, but to have significantly less toxicity (diarrhea, rash) compared with afatinib and significantly more hypertransaminasemia compared with erlotinib. From this perspective, gefitinib would be a reasonable alternative to erlotinib for patients with mutation specific classifications of NSCLC and preferred over afatinib in

Table 5. Gefitinib outcome comparisons with competing EGFR tyrosine kinase inhibitors.56,57 Drug

Efficacy (ORR, PFS, OS)

Toxicity (diarrhea, rash)

Afatinib (Gilotrif) Erlotinib (Tarceva)

Similar to gefitinib Similar to gefitinib

Less with gefitnib Similar to gefitinib

Table 6. Average wholesale prices for competing EGFR tyrosine kinase inhibitors.63 Drug

Dose (mg)

AWP (USD per 30 tablets)

Afatinib (Gilotrif)

20 30 40 25 100 150 250

7768.22 7768.22 7768.22 2591.45 7117.85 8050.79 8040.00

Erlotinib (Tarceva)

Gefitinib (Iressa)

order to minimize risk of adverse events (Table 5). The National Comprehensive Cancer Network guidelines suggest that gefitinib may be used in place of erlotinib.52 While the cost of treatment with EGFR tyrosine kinase inhibitors is substantial, economic analyses in several markets have supported their use for first-line therapy when compared with conventional, cytotoxic therapy for the treatment of EGFR-expressing, mutation-positive NSCLC.58–62,65 The costs of the three medications, described in Table 6 as average wholesale prices, are similar.63 However, a 2012 analysis in the United States and a 2014 analysis in Hong Kong that both utilized indirect clinical comparisons between gefitinib and erlotinib found significant preferential benefits for erlotinib.58,64

Conclusion We suggest that use of gefitinib for the first-line therapy of metastatic NSCLC with EGFR exon 19 deletions (residues 747–750) or exon 21 substitution mutation (L858R) is well-documented and supported. However, there is more clinical experience with erlotinib. Thus, use of gefitinib should be considered as an alternate when patients are very similar to those recruited into the trials mentioned herein. A prospective, randomized clinical trial comparing gefitinib to other EGFR-directed TKI therapy would help to more precisely define gefitinib’s role in advanced NSCLC.

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Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

14.

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