Medical Policy



Subject: Epidermal Growth Factor Receptor (EGFR) Testing
Document #: GENE.00006 Current Effective Date:    06/28/2017
Status: Revised Last Review Date:    05/04/2017

Description/Scope

This document addresses the use of epidermal growth factor receptor (EGFR) mutation and gene amplification testing for predicting the response to drug therapy in individuals with non-small cell lung cancer (NSCLC), and for all other indications.

Position Statement

Medically Necessary:

Analysis of mutations in the gene for the EGFR is considered medically necessary as a technique to predict treatment response for individuals with non-small cell, non-squamous cell lung cancer when treatment with EGFR tyrosine kinase inhibitor (TKI) therapy (for example, erlotinib [Tarceva® ], gefitinib [Iressa® ], or afatinib [Gilotrif® ]), is indicated for the management of individuals with an activating mutation in EGFR such as exon 19 deletions or exon 21 (L858R) substitution. 

Analysis for the T790M mutation in the gene for the EGFR receptor is considered medically necessary as a technique to predict treatment response for individuals with non-small cell, non-squamous cell lung cancer who have progressed on or after EGFR TKI therapy and treatment with osimertinib [Tagrisso™] is indicated.

Investigational and Not Medically Necessary:

Analysis of mutations in the gene for EGFR is considered investigational and not medically necessary for all other uses not specified above.

Analysis of gene amplification for EGFR is considered investigational and not medically necessary for all indications, including as a technique to predict treatment response to tyrosine kinase inhibitor therapy (for example, erlotinib [Tarceva], gefitinib [Iressa], afatinib [Gilotrif], or osimertinib [Tagrisso]) for individuals with non-small cell lung cancer.

Rationale

EGFR mutation analysis

The published literature addressing the use of EGFR mutation analysis in tumor samples consists of EGFR mutational analysis correlated with response to several tyrosine kinase inhibitor drugs (TKIs), including gefitinib, erlotinib, and afatinib.  These TKIs are used in the treatment of some lung cancers.  Given that individuals with advanced NSCLC have few treatment options, the most likely clinical application of EGFR mutational analysis would be to deselect individuals most unlikely to benefit from targeted therapy with a TKI.  Therefore, the negative predictive value (NPV) of tumor response is of greatest clinical importance.  Relevant, published studies are reviewed here, with an emphasis on the NPV.

Gefitinib (Iressa)

Han and colleagues retrospectively performed EGFR mutational analysis in 90 consecutive subjects with advanced NSCLC who had received gefitinib; all were of Asian ethnicity (Han, 2005).  Of these 90 subjects, 17 harbored EGFR mutations (18%), and 11 of these 17 subjects (64.7%) exhibited a partial remission.  In contrast, only 10 of 73 subjects (13.7%) without an EGFR mutation exhibited a partial remission.  A higher incidence of EGFR mutations has been found in those of East Asian ethnicity, and it is unclear if the results of the analysis could be generalized to a broader population.  In a similarly designed study, Mitsudomi and colleagues performed EGFR mutational analysis on 59 subjects with recurrent NSCLC treated with gefitinib (Mitsudomi, 2005).  Mutations were identified in 33 subjects (56%).  Response was assessable in 50 subjects, and among these, only 2 of 21 subjects without an EGFR mutation exhibited a response to gefitinib.

The Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 studies were randomized studies of gefitinib monotherapy versus placebo in individuals with advanced NSCLC who had received prior chemotherapy.  Another set of studies, the Iressa NSCLC Trial Assessing Combination Treatment (INTACT)-1 and INTACT-2 studies, compared single-agent chemotherapy with and without gefitinib in previously untreated individuals.  Bell and colleagues reported the results of EGFR mutational analysis on subsets of individuals from these trials (Bell, 2005).  The negative predictive value of mutational analysis for overall response was 90% in the IDEAL studies while the negative predictive value of mutational analyses was 44% in the INTACT studies.

Mok and colleagues (2009) conducted a randomized open-label study comparing gefitinib to chemotherapy in previously untreated individuals with pulmonary adenocarcinoma (2009).  In this study, 609 subjects were randomized to receive gefitinib and 608 to receive carboplatin-paclitaxel chemotherapy with the primary endpoint of progression free survival (PFS).  At the end of a 12-month follow-up period, overall PFS was 24.0% for the gefitinib group and 6.7% for the chemotherapy group (p<0.001).  In the subgroup that tested positive for an EGFR mutation (n=261), PFS was significantly longer in the gefitinib group than the chemotherapy group (p<0.001) while the EGFR negative subgroup had significantly longer PFS when treated with chemotherapy compared to gefitinib (p<0.001).  The authors concluded that the presence of an EGFR gene mutation in a tumor is a strong predictor of a better outcome with gefitinib than with carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma.

Erlotinib (Tarceva)

The National Institute of Canada Clinical Trials Group Study BR.21 randomized study compared the outcomes of erlotinib monotherapy with placebo as a salvage therapy in 731 subjects with advanced NSCLC.  Tsao and colleagues (2005) reported the results of EGFR mutational analysis in a subset of 100 subjects who received erlotinib, had successful mutational analysis, and who had evaluable disease.  Among the 19 subjects with an EGFR mutation, only 3 achieved a response (16%), while 6 of 81 subjects (7%) without an EGFR mutation had a response.  Mutational status appeared to have no significant association with responsiveness (p=0.37).

Another study by Clark and others analyzed tumor samples from individuals who participated in the National Institute of Canada Clinical Trials Group Study BR.21 (Clark, 2006).  A total of 325 subjects from the study had evaluable tumor samples which were tested for EGFR expression via immunochemistry.  The authors report that the prognostic ability of EGFR expression status testing was not significant at any cut-off point in their study.  They concluded that selection or exclusion of individuals with NSCLC for erlotinib therapy after failure of standard therapy for advanced disease should not be based solely on EGFR expression.

In 2009, the Spanish Lung Cancer Group published the findings of a prospective case series study involving 2105 subjects from 129 institutions with stage IIIB disease with pleural effusion, or stage IV disease who were prospectively screened for EGFR mutations (Rosell, 2009b).  Individuals with tumors carrying EGFR mutations were eligible for erlotinib treatment.  The study was designed to analyze the association between EGFR mutations and the outcome of treatment with erlotinib.  EGFR mutations were found in 350 (16.6%) of all subjects.  EGFR mutations were more frequent in women (69.7%), in subjects who had never smoked (66.6%), and in those with adenocarcinoma (80.9%).  The mutations found were deletions in exon 19 (62.2%) and L858R (37.8%).  Investigators evaluated 296 subjects with tumors carrying an EGFR mutation, 79 did not receive erlotinib treatment (23 declined, 18 died prior to starting treatment, 38 began treatment subsequent to study start date).  Of the 217 subjects who received erlotinib, 197 could be evaluated.  Of the 197 subjects evaluated, 24 had a complete response, 115 had a partial response, 38 had stable disease, and 20 had progressive disease.  Median follow-up was 14 months.  Median PFS (erlotinib as first-, second-, or third-line therapy) was 14.0 months and median overall survival (OS) was 27.0 months, which is an improvement over lung cancer outcomes in trials reported previously where chemotherapy normally yields a 30% response, a 5-month PFS, and a 12-month median survival.  Multivariate analysis showed a higher probability of response with exon 19 deletion mutation (odds ratio [OR], 3.08; 95% confidence interval [CI], 1.63-5.81; p=0.001) and an age between 61 and 70 years (OR, 2.55; 95% CI, 1.32 to 4.96; p=0.006), but not with other factors.  The authors concluded that screening for EGFR mutation is warranted in women with lung cancer, in those who have never smoked, and in those with non-squamous tumors as a tool to select targeted therapy with erlotinib.

D'Angleo and colleagues (2011) conducted a study investigating the correlation of EGFR exon 19 deletions and exon 21 L858R mutations to gender and smoking status in 2142 lung adenocarcinoma samples from consecutively treated subjects.  EGFR mutations were found in 15% of tumors from former smokers, 6% from current smokers, and 52% from never smokers (p<0.001 for ever vs. never smokers).  EGFR mutations in former or current smokers represented 40% of all those detected.  EGFR mutations were found in 19% of tumors from men and 26% of tumors from women (p<0.001).  EGFR mutations in men represented 31% of all those detected.  The authors conclude that even though the mutation rate is low in men and smokers, they account for a larger portion of those with adenocarcinoma of the lung.  Thus, including these populations in routine mutation analysis when being considered for treatment with erlotinib or gefitinib, is reasonable and warranted.   

The EURTAC open-label randomized phase III study by Rosell and others (2012) compared the use of erlotinib vs. standard chemotherapy in subjects with Stage IIIB or IV NSCLC and activating EGFR mutations (exon 19 deletions and exon 21 L858R mutations).  Eighty-six subjects were randomized to receive treatment with erlotinib and 86 to receive chemotherapy.  At the pre-planned interim analysis, it was found that the study met its primary endpoint and enrollment was halted.  The mean follow-up was 18.9 months for the erlotinib group and 14.4 months for the chemotherapy group.  One subject in the erlotinib group and 2 in the standard chemotherapy group died from treatment-related causes.  The authors reported that at data cutoff, the median PFS was 9.7 months in the erlotinib group, compared with 5.2 months in the standard chemotherapy group (p<0.0001).  One-year PFS was 40% in the erlotinib group and 10% in the chemotherapy group; 2-year PFS was 11% in the erlotinib group and 0% in the standard chemotherapy group.  An analysis was conducted with subjects stratified by Eastern Cooperative Oncology Group (ECOG) performance status.  The findings indicated that for those with status 0, the estimated median PFS was 23.9 months for the erlotinib group vs. 6.0 months for the chemotherapy group (p=0.0006).  For subjects with ECOG status 1, the estimated median PFS was 8.8 months for the erlotinib group and 5.0 months in the chemotherapy group (p<0.0001).  Finally, for subjects with ECOG status 2, estimated median PFS was 8.3 months in the erlotinib group and 4.4 months in the standard chemotherapy group (p=0.191).  In the intention-to-treat population, 2 of 86 (2%) subjects in the erlotinib group had a complete response.  Partial response was noted in 48 of 86 (56%) in the erlotinib group and 13 of 87 (15%) in the standard chemotherapy group.  Neither OS nor median survival differed between groups.  This may have been explained by the fact that most subjects crossed over to erlotinib at time of progression, but further study is needed to fully understand this effect.

A similar study was conducted by Zhou and colleagues (the OPTIMAL study, 2012) that found similar results.  As with the previously mentioned Rosell study, this was an open-label, randomized phase III study that compared the use of erlotinib vs. standard chemotherapy in 154 subjects with Stage IIIB or IV NSCLC and activating EGFR mutations.  The results demonstrated that treatment with first-line erlotinib was associated with significantly longer PFS than treatment with chemotherapy.  Median PFS was 13.1 months in erlotinib-treated subjects versus 4.6 months for subjects receiving chemotherapy (p<0.0001).  Out of the 82 erlotinib group subjects, 2 (2%) achieved a complete response, compared with none of the 72 subjects on chemotherapy.  Sixty-six of 82 (80%) erlotinib subjects had a partial response compared with 26 of 72 (36%) chemotherapy subjects, giving an overall response rate of 83% (68/82) for erlotinib and 36% (26/72) for chemotherapy (p<0.0001).  At the time of publication, data for OS were not yet available.  However, the primary analysis of the available data indicated that only 16 (20%) erlotinib subjects and 12 of 72 (17%) chemotherapy subjects had died. 

In a third study, Brugger and colleagues evaluated the use of EGFR status in a randomized double-blind controlled study in 889 subjects with non-progressive, unresectable NSCLC undergoing treatment with erlotinib vs. placebo (the SATURN study, 2011).  This study also evaluated the role of EGFR status stratified by the method of testing, immunohistochemistry (IHC+ vs. IHC-) vs. fluorescent in situ hybridization (FISH+ vs. FISH-).  In the intent-to-treat analysis, erlotinib significantly improved PFS relative to placebo (p=0.001).  Additionally, erlotinib significantly extended PFS in the EGFR IHC+ population, but did not provide a statistically significant benefit in the EGFR IHC- group (n=121).  Similar results were seen with FISH testing, with erlotinib producing a significant PFS benefit in subjects with EGFR FISH+ tumors (p=0.0068), but no statistically significant benefit in those with FISH- tumors (p=0.13).  The authors also noted that erlotinib reduced the risk of progression or death by 90% in subjects with EGFR mutation positive tumors compared with placebo (median PFS, 44.6 vs. 13 weeks, respectively, p<0.001).  This data indicates that EGFR testing may have a role in selecting those individuals with unresectable NSCLC who will derive the most benefit from treatment with erlotinib.

In 2013, the U.S. Food and Drug Administration (FDA) expanded the approved indications for Tarceva (erlotinib) as "First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test."  This approval changes the way erlotinib is used and prescribed.  No longer is it used as a possible option which is considered for individuals with NSCLC and EGFR mutations, and it is now a first-line treatment whose consideration is not in doubt.  The National Comprehensive Cancer Network (NCCN) Version V5.2017 guideline for the treatment of NSCLC (2017) supports this indication.

Cetuximab (Erbitux)

In the largest, most rigorous study if its kind, Pirker and others reported on the results of the phase III FLEX (First-Line Erbitux in Lung Cancer) trial, which investigated the role of EGFR mutations on outcomes in individuals with advanced NSCLC undergoing treatment with cetuximab (2012).  They describe a study in which 1125 subjects positive for activating EGFR mutations were randomly assigned to receive either chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568).  OS was longer in the chemotherapy plus cetuximab group compared to the chemotherapy alone group for subjects with high tumor EGFR expression (p=0.011).  Median survival was 12.0 months in the chemotherapy plus cetuximab group vs. 9.6 months in the chemotherapy alone group (p=0.044), with 50% and 37% of participants alive at 1 year, and 24% and 15% alive at 2 years, respectively.  In contrast, OS was not prolonged in the chemotherapy plus cetuximab group compared with the chemotherapy alone group for those with low tumor EGFR expression (p=0.88), and a similar proportion of participants were alive at 1 year and 2 years.  PFS did not differ significantly between treatment groups for subjects in both EGFR expression groups.  This data shows a promising role for EGFR testing in individuals undergoing NSCLC treatment with cetuximab.  However, further research is warranted to better understand the benefits of such testing.

In a follow-up study of the FLEX study, Douillard (2014) tested 970 evaluable samples for EGFR mutations.  Using their results, 682 samples were classified as having low EGFR expression and 288 were classified as having high EGFR expression.  Additionally, 14% (n=133) of the overall sample of 970 tumors had mutations in EGFR exons 18 to 209.  The median survival was reported to be markedly longer in the subjects with any detected EGFR mutation when compared to those with no mutations in the chemotherapy plus cetuximab group (17.3 vs. 9.6 months) as well as in the chemotherapy alone group (19.8 vs. 9.6 months).  Additionally, PFS, time to treatment failure (TTF), and response rate were also longer in subjects with EGFR mutations in both treatment groups.

Afatinib (Gilotrif)

Afatinib is an orally available, irreversibly binding EGFR signaling blocker.  Unlike erlotinib and gefitinib which selectively inhibit EGFR, afatinib inhibits not only EGFR but also human epidermal growth factor receptor 2 (HER2) and HER4, and may have activity in subjects with acquired resistance to other TKIs. 

The efficacy and safety of afatinib was evaluated in the LUX-Lung series of studies (Katakami, 2013; Miller, 2012; Sequist, 2013; Yang, 2012, 2013).  The LUX-Lung 1 initial study was a double-blind, randomized controlled trial (RCT) involving 585 subjects with advanced NSCLC who had progressed despite previous TKI treatment with erlotinib, gefitinib, or both.  Subjects were not prospectively genotyped.  Participants were randomly assigned to undergo treatment with either afatinib (n=390) or placebo (n=195).  It was reported that 96 of 585 enrolled subjects (66% Asian, 33% white) were EGFR mutation positive.  In the EGFR positive group, the median PFS was 3.3 months in the afatinib group and 1.0 month in the placebo group (hazard ratio [HR]=0.51, p=0.009).  In the mutation negative subjects, median PFS was 2.8 months in the afatinib group and 1.8 months in the placebo group.  Interaction between treatment and EGFR mutation status was not statistically significant, possibly because of the small sample size.  Both the proportion of subjects with an objective response and the overall survival were similar with or without EGFR mutations (Miller, 2012).

Afatinib received FDA approval in July 2013, for first-line treatment of individuals with metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.  Approval was based on improvement in PFS over chemotherapy with pemetrexed/cisplatin (PFS 11.9 vs. 6.9 months; p=0.001) in a randomized, multicenter, open-label trial of 345 subjects with EGFR mutation positive, metastatic (stage IV and Stage IIIb with pleural and/or pericardial effusion) disease (LUX-Lung 3; Sequist, 2013).  At the interim analysis, there was no significant difference in overall survival between the treatment arms.  The majority of tumor samples with an EGFR mutation had either exon 19 deletion (49%) or exon 21 L858R substitution (40%).  The remaining 11% had "other" EGFR mutations.  There were 26 afatinib-treated subjects with "other" mutations, and none of these achieved a complete response while four achieved a partial response.  Objective response rate (complete + partial) of all those treated with afatinib was 50.4% and 19.1% for those treated with chemotherapy (pemetrexed/cisplatin).  Based on the selection criteria used in this qualifying trial, the FDA incorporated the identification of specific EGFR mutations into the approved indications for this drug.  In addition, the NCCN lung cancer treatment guideline (V5.2017) recommends EGFR testing for EGFR sensitizing mutations prior to the treatment with afatinib. 

Yang and others (2015) reported on the results of a post-hoc analysis involving data from 600 participants in the LUX-Lung 2, LUX-Lung-3 and LUX-Lung 6 studies.  The authors reported on the efficacy of afatinib in subjects with uncommon EGFR mutations, stratified into the following groups: Group 1) point mutations or duplications in exons 18-21; Group 2) de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations; or Group 3) exon 20 insertions.  A total of 75 (12%) subjects had uncommon EGFR mutations, with 38 in Group 1, 14 in Group 2, 23 in Group 3.  Objective response was reported in 27 subjects in Group 1 (71.1%), 2 in Group 2 (14.3%), and 2 (8.7%) in Group 3.  Median PFS was 10.7 months in Group 1, 2.9 months in Group 2; and 2.7 months in Group 3.  Median overall survival was 19.4 months in Group 1, 14.9 months in Group 2, and 9.2 months in Group 3.  For the most frequent uncommon mutations, objective response was noted in 14 (77.8%) subjects with Gly719Xaa mutations, 9 (56.3%) subjects with Leu861Gln mutations and 8 (100%) with Ser768Ile mutations.

Osimertinib (Tagrisso)

Osimertinib is a TKI drug approved by the FDA in 2015 for the treatment of individuals with metastatic epidermal growth factor receptor (EGFR) T790M mutation positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy.  This approval is based on two unpublished single-arm studies involving 411 subjects (study 1, n=210; study 2, n=210) receiving 80 mg doses of osimertinib for T790M mutation positive NSCLC.  Of the 411 subjects, 333 were exposed to osimertinib for at least 6 months and 97 were exposed for at least 9 months.  None was exposed for 12 months.  The objective response rate in study 1 subjects was 57% and 61% for study 2.  Overall objective response rate was 59%.  Complete response rates were 0%, 1%, and 0.5% respectively.  The partial response rates were 57%, 60% and 59%, respectively.  The majority (96%) of subjects with confirmed objective responses had ongoing responses ranging from 1.1 to 5.6 months after a median duration of follow-up of 4.2 months for study 1 and 4.0 months for study 2.  In a separate dose finding part of study 1, 63 subjects with centrally confirmed T790M positive NSCLC who progressed on prior systemic therapy including an EGFR TKI, were administered osimertinib at a dose of 80 mg.  In these subjects, the Blinded Independent Central Review-confirmed objective response rate was 51% (32/63) and the median duration of response was 12.4 months from the time of first documented response.  The most common (> 20%) adverse reactions (all grades) observed were diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%).  Dose reductions occurred in 4.4% of subjects.  The most frequent adverse reactions that led to dose reductions or interruptions were: electrocardiogram QTc prolonged (2.2%) and neutropenia (1.9%).  Serious adverse reactions reported in 2% of subjects or more were pneumonia and pulmonary embolus.  There were 4 subjects (1%) who developed fatal adverse reactions of ILD/pneumonitis.  Other fatal adverse reactions occurring in more than 1 subject included pneumonia (n=4) and stroke/cerebral hemorrhage (n=2).  Discontinuation of therapy due to adverse reactions occurred in 5.6% of subjects.  The most frequent adverse reactions that led to discontinuation were interstitial lung disease (ILD)/pneumonitis and cerebrovascular accidents/infarctions.

Jänne and colleagues (2015) published the results of a dose finding, safety and efficacy trial involving 253 subjects with locally advanced metastatic NSCLC with either known EGFR mutation or who had prior clinical benefit on TKI therapy followed by disease progression.  A total of 31 subjects were enrolled in the dose finding portion of the study and 222 subjects participated in the safety and efficacy portion of the study.  In the dose finding study, subjects were exposed to osimertinib beginning at 20 mg once daily for a period of 21 days.  The dose was increased by 100% with each cohort until 160 mg/day and then was raised to 240 mg/day.  The authors reported that no dose-limiting toxic effects were observed, and thus no maximum dose was found.  The most common adverse events were diarrhea (47%), rash (40%), nausea (22%), and decreased appetite (21%).  Serious adverse events were observed in 22% of subjects including pneumonitis (n=6), hyperglycemia (n=6), and prolongation of QT interval (n=11).  There were 7 deaths reported; the 1 due to pneumonia was potentially drug related.  Response to treatment was evaluable in 239 subjects.  Confirmed partial or complete response was reported in 123 (51%) subjects, with 78 (33%) having stable disease, 34 (14%) with progressive disease and 4 (2%) not assessable.  The overall disease control was 85%.  EGFR mutation T790M was confirmed in 138 subjects, with objective response reported in 61% with a disease control rate of 96%.  Of the 105 subjects in the expansion cohort with confirmed response, 85% had a response rate longer than 6 months.  The median PFS was 8.2 months.  In the subjects with T790M mutations, 88% had a response greater than 6 months and a median PFS of 9.6 months.  In the subjects with no T790M mutation, 69% had a response greater than 6 months and a median PFS of 2.8 months.

In 2016, Mok and others published the results of a randomized, open-label, phase III trial involving 419 subjects with T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy.  Subjects were assigned in a 2:1 fashion to receive either oral osimertinib (n=279) or intravenous pemetrexed plus either carboplatin or cisplatin every 3 weeks for up to six cycles (controls, n=140).  Maintenance pemetrexed was allowed.  All subjects had experienced disease progression during first-line EGFR-TKI therapy.  The mean duration of treatment was 8.6 months in the osimertinib group vs. 4.8 in the control group.  Median follow-up for all subjects was 8.3 months.  The authors reported that median duration of PFS was significantly longer with osimertinib than with control treatment (10.1 months vs. 4.4 months, HR=0.30; p<0.001).  The objective response rate was significantly better in the osimertinib group vs. the control group (71% vs. 31%, OR=5.39; p<0.001).  The HR for PFS was 0.34 for subjects with EGFR exon 19 deletion, and 0.46 for those with EGFR L858R mutation.  The median duration of PFS in subjects with tumor and plasma T790M-positive status was 8.2 months in the osimertinib group vs. 4.2 in the control group (HR=0.42).  Response rates were significantly better in the osimertinib group vs. the control group (71% vs. 31%, OR=5.39).  Among 144 subjects with metastases to the central nervous system, the median duration of PFS was longer among those receiving osimertinib than those control therapy (8.5 months vs. 4.2 months, HR=0.32).  In subjects who had response to treatment, disease progression or death was lower in the osimertinib group vs. the control group (45% vs. 82%).  The proportion of subjects with adverse events of grade 3 or higher was lower with osimertinib vs. the control group (23% vs. 47%). The authors concluded that osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in participants with T790M-positive advanced NSCLC (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy.

Gene Amplification

It has been proposed that the measurement of EGFR amplification in NSCLC tumor tissue can be used for the prediction of response to TKI drug therapy.  The evidence regarding this question is currently mixed.  One study of 102 subjects with advanced NSCLC treated with gefitinib reported that EGFR gene amplification was statistically significantly associated with better drug response, disease control rate, time to progression and survival (Capuzzo, 2005).  In contrast, a study of 199 subjects with early stage NSCLC who had undergone surgical resection found no significant survival difference between subjects with or without EGFR amplification (Dacic, 2006). Another study by Tsao and colleagues (2005) evaluated 221 subjects with advanced NSCLC treated with erlotinib.  The authors reported that although responsiveness to erlotinib may be associated with EGFR gene amplification (p=0.04), increased survival was not (p=0.10).

The use of EGFR amplification testing for conditions other than NCSLC has been limited.  There have been several small studies that have investigated the use of EGFR amplification status in subjects with glioblastoma, head and neck squamous cell cancer (HNSCC), colon and gastric cancers (Cascinu, 2008; da Cunha Santos, 2010; Geyer, 2010; Laurent-Puig, 2009; Saarilahti, 2010; Srividya, 2010; Van Damme, 2010; Yung, 2010).  Several of these studies have shown some benefit from EGFR amplification testing.  However, at this time the clinical utility of such testing has not been established.

NCCN Guidelines

The NCCN guideline for the treatment of NSCLC (V5.2017) includes a category 1 recommendation for EGFR testing for the following NSCLC histologies:  adenocarcinoma, large cell, and NSCLC NOS (not otherwise specified).  The NCCN concluded that EGFR mutation testing is not routinely recommended for squamous cell carcinoma of the lung, except in never-smokers, small biopsy specimens, or the presence of mixed histology.

They also recommend the use of erlotinib or afatinib or gefitinib prior to or during first-line chemotherapy for individuals with sensitizing EFGR mutations and large cell adenocarcinoma. 

American Society of Clinical Oncology (ASCO) Publication Recommendations

ASCO published a guideline on systemic therapy for stage IV NSCLC (Masters, 2015). This guideline includes an updated recommendation that first-line use of afatinib, erlotinib, or gefitinib may be considered for individuals with a known sensitizing EGFR mutation.  For negative or unknown EGFR mutation status, cytotoxic chemotherapy is still preferred.  Additionally, for individuals with a known sensitizing EGFR mutation who received a first-line EGFR TKI and experienced disease progression after in an initial response, switching to another EFGR TKI is recommended for second-line therapy.

Additionally, ASCO published a provisional opinion for EGFR mutation testing for individuals with advanced NSCLC considering first-line EGFR TKI treatment (Keedy, 2011).  This guideline includes the following provisional recommendation:

On the basis of the results of five phase III randomized controlled trials, patients with NSCLC who are being considered for first-line therapy with an EGFR TKI (patients who have not previously received chemotherapy or an EGFR TKI) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy.

In 2013, the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and Association for Molecular Pathology (AMP) issued a joint recommendation for the molecular testing for selection of individuals with lung cancer for EGFR and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (Lindeman, 2013).  This document included recommendations supporting the use of EGFR molecular testing for receiving TKI therapy for NSCLC.  One recommendation, based on "Expert consensus opinion," states that: "For patients with multiple, apparently separate, primary lung adenocarcinomas, each tumor may be tested but testing of multiple different areas within a single tumor is not necessary."

Background/Overview

According to the American Cancer Society, NSCLC accounts for nearly 85% of all lung cancers.  There are multiple sub-types of NSCLC that differ in size, shape, histology and molecular markers (see definitions section).  The more common subtypes include: (1) squamous cell carcinoma, which accounts for about 25% to 30% of all lung cancers; (2) adenocarcinoma, which accounts for about 40% of lung cancers; and (3) large-cell undifferentiated carcinoma, which accounts for about 10% to 15% of lung cancers.

An epidermal growth factor receptor (EGFR) is a type of tyrosine kinase receptor located on the surface of normal human cells that has been identified as a major factor in regulating cellular proliferation, differentiation, and survival.  NSCLC cells frequently have over-expressed and activated genes for EGFR, leading to an abundance or abnormal activity of these receptors on effected cells.  It is  believed that this contributes to the abnormal growth and progression of this type of cancer.  Recent research has focused on the development of EGFR-specific TKIs.

Erlotinib received FDA approval in November of 2004 as salvage therapy for advanced NSCLC, based on the results of a phase III clinical trial that demonstrated a modest survival benefit, 6.7 months median survival compared to 4.7 months in the placebo group.  Gefitinib (Iressa) was FDA approved in 2003 through the FDA's accelerated approval process, based on the initially promising results of phase II trials.  The labeled indication was limited to individuals with NSCLC who had failed two or more prior chemotherapy regimens.  However, in December of 2004, results of phase III trials became available, suggesting that gefitinib was not associated with a survival benefit.  In their press release, the FDA noted that in Phase III trials, individuals treated with erlotinib did have a very modest, but statistically significant improvement in survival, implying that this was the preferred agent.  In May of 2005, the FDA revised the labeling of gefitinib to further limit its use to individuals who were currently benefiting from the drug, or who had benefited in the past.  Afatinib received FDA approval in July 2013, for first-line treatment of individuals with metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA approved test.  The Therascreen® EGFR test was co-approved with afatanib for that analysis.  Osimertinib was approved by the FDA in 2015 for the treatment of individuals with metastatic epidermal growth factor receptor (EGFR) T790M mutation positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy. 

Another issue related to EGFR and NSCLC is gene amplification, which is defined as the presence of an increased number of copies of a specific gene fragment in a chromosome.  This is measured using a laboratory method referred to as in-situ hybridization.  Gene amplification may lead to production of increased numbers of gene copies, a process referred to as elevated gene expression.  Gene expression is measured by immunohistochemical testing.  EGFR gene amplification testing has been proposed as a predictor of clinical response to TKI drugs.

Both EGFR mutation analysis (PCR amplification and gene sequencing) and EGFR gene amplification (fluorescence in-situ hybridization or FISH) are commercially available (Genzyme Genetics Westborough, MA).  These tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA).  Pre-market approval from the FDA is not required when the assay is performed in a laboratory that observes the CLIA regulations.

Definitions

Epidermal Growth Factor Receptor (EGFR): A cell receptor that is associated with regulation of cell growth. This type of receptor is referred to as a tyrosine kinase.

Gene amplification: A genetic variation characterized by the presence of multiple copies of the same genetic code on a chromosome.

Mutation: A permanent, transmissible change in genetic material.

World Health Organization (WHO) Histologic Classification Tumours of the Lung(Travis, 2015):Malignant epithelial tumours

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

CPT  
81235 EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q)
   
ICD-10 Diagnosis  
C34.00-C34.92 Malignant neoplasm of bronchus and lung
C78.00-C78.02 Secondary malignant neoplasm of lung
Z85.118 Personal history of other malignant neoplasm of bronchus and lung

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other indications not specified as medically necessary.

When services are also Investigational and Not Medically Necessary:
When the code(s) describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT  
88365 In situ hybridization (eg, FISH), each probe [when specified as EGFR gene amplification testing]
   
ICD-10 Diagnosis  
C34.00-C34.92 Malignant neoplasm of bronchus and lung
C78.00-C78.02 Secondary malignant neoplasm of lung
Z85.118 Personal history of other malignant neoplasm of bronchus and lung
   
References

Peer Reviewed Publications:

  1. An N, Zhang Y, Niu H, et al. EGFR-TKIs versus taxanes agents in therapy for nonsmall-cell lung cancer patients: a PRISMA-compliant systematic review with meta-analysis and meta-regression. Medicine (Baltimore). 2016; 95(50):e5601.
  2. Asahina H, Yamazaki K, Kinoshita I, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer. 2006; 95(8):998-1004.
  3. Bell DW, Lynch TJ, Haserlat SM, et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005; 23(31):8081-8092.
  4. Brugger W, Triller N, Blasinska-Morawiec M, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol. 2011; 29(31):4113-4120.
  5. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005; 97(9):643-655.
  6. Cappuzzo F, Ligorio C, Jänne PA, et al. Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial. J Clin Oncol. 2007a; 25(16):2248-2255.
  7. Cappuzzo F, Ligorio C, Toschi L, et al. EGFR and HER2 gene copy number and response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2007b: 2(5):423-429.
  8. Cascinu S, Berardi R, Salvagni S, et al. A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation. Br J Cancer. 2008; 98(1):71-76.
  9. Clark GM, Zborowski DM, Culbertson JL, et al. Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol. 2006; 1(8):837-846.
  10. da Cunha Santos G, Dhani N, Tu D, et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010; 116(24):5599-5607.
  11. Dacic S, Flanagan M, Cieply K, et al. Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma. Am J Clin Pathol. 2006; 125(6):860-865.
  12. 12.   D'Angelo SP, Pietanza, MC, Johnson ML, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol. 2011; 29(15):2066-2070.
  13. Douillard JY, Pirker R, O'Byrne KJ, et al. Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer. J Thorac Oncol. 2014; 9(5):717-724.
  14. 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(5):744-752.
  15. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small cell lung cancer treated chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005; 23(25):5900-5909.
  16. Feld R, Sridhar SS, Shepherd FA, et al. Use of the epidermal growth factor receptor inhibitors gefitinib and erlotinib in the treatment of non-small cell lung cancer: a systematic review. J Thorac Oncol. 2006; 1(4):367-376.
  17. 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(21):2866-2874.
  18. Geyer JR, Stewart CF, Kocak M, et al. A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas. Eur J Cancer. 2010; 46(18):3287-3293.
  19. Han SW, Kim TY, Hwang PG, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2005; 23(11):2493-2501.
  20. Hirsch FR, Varella-Garcia M, Cappuzzo F, et al. Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann Oncol. 2007; 18(4):752-760.
  21. Hirsch FR, Varella-Garcia M, McCoy J, et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study. J Clin Oncol. 2005; 23(28):6838-6845.
  22. Huang SF, Liu HP, Li LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res. 2004; 10(24):8195-8203.
  23. Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol. 2006; 24(21):3340-3346.
  24. Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015; 372(18):1689-1699.
  25. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non–small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013; 31(27):3335-3341.
  26. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009; 27(35):5924-5930.
  27. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004; 350(21):2129-2139.
  28. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. N Engl J Med. 2010; 362(25):2380-2388.
  29. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012; 13(5):528-538.
  30. Mitsudomi T, Kosaka T, Endoh H, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol. 2005; 23(11):2513-2520.
  31. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010; 11(2):121–128.
  32. Mok TS, Wu Y-L, Ahn M-J, et al.; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017; 376(7):629-640.
  33. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361(10):947-957.
  34. Mok TS, Wu YL, Yu CJ, et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2009; 27(30):5080-5087.
  35. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304(5676):1497-1500.
  36. Parra HS, Cavina R, Latteri F, et al. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer. Br J Cancer. 2004; 91(2):208-212.
  37. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012; 13(1):33-42.
  38. Rosell R, Carcereny E, Gervais R, et al.; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. 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. 2012; 13(3):239-246.
  39. Rosell R, Moran T, Queralt C, et al.; Spanish Lung Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009a; 361(10):958-967.
  40. Rosell R, Perez-Roca L, Sanchez JJ, et al. Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression. PLoS One. 2009b; 4(5):e5133.
  41. Saarilahti K, Bono P, Kajanti M, et al. Phase II prospective trial of gefitinib given concurrently with cisplatin and radiotherapy in patients with locally advanced head and neck cancer. J Otolaryngol Head Neck Surg. 2010; 39(3):269-276.
  42. Sequist LV, Joshi VA, Jänne PA, et al. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist. 2007; 12(1):90-98.
  43. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31(27):3327-3334.
  44. Srividya MR, Thota B, Arivazhagan A, et al. Age-dependent prognostic effects of EGFR/p53 alterations in glioblastoma: study on a prospective cohort of 140 uniformly treated adult patients. J Clin Pathol. 2010; 63(8):687-691.
  45. Takano T, Ohe Y, Sakamoto H, et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005; 23(28):6829-6837.
  46. Tan EH, Ramlau R, Pluzanska A, et al. A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer. Ann Oncol. 2010; 21(2):217-222.
  47. Tanaka T, Matsuoka M, Sutani A, et al. Frequency of and variables associated with the EGFR mutation and its subtypes. Int J Cancer. 2010; 126(3):651-655.
  48. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 2005; 353(2):133-144.
  49. Van Damme N, Deron P, Van Roy N, et al. Epidermal growth factor receptor and K-RAS status in two cohorts of squamous cell carcinomas. BMC Cancer. 2010; 10:189.
  50. van Zandwijk N, Mathy A, Boerrigter L, et al. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann Oncol. 2007; 18(1):99-103.
  51. Wu YL, Zhong WZ, Li LY, et al. Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: a meta-analysis based on updated individual patient data from six medical centers in mainland China. J Thorac Oncol. 2007; 2(5):430-439.
  52. Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations J Clin Oncol. 2013; 31(27):3342-3350.
  53. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015; 16(7):830-838.
  54. Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012; 13(5):539-548.
  55. Yoshida K, Yatabe Y, Park JY, et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J Thorac Oncol. 2007; 2(1):22-28.
  56. Yung WK, Vredenburgh JJ, Cloughesy TF, et al. Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label study. Neuro Oncol. 2010; 12(10):1061-1070.
  57. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12(8):735-742.
  58. Zhu CQ, da Cunha Santos G, Ding K, et al.; National Cancer Institute of Canada Clinical Trials Group Study BR.21. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008; 26(26):4268-4275.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011; 29(15):2121-2127.
  2. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J Mol Diagn. 2013; 15(4):415-453.
  3. Masters GA, Temin S, Azzoli CG, et al.; American Society of Clinical Oncology Clinical Practice. Systemic therapy or stage IV non-small-cell lung Cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015; 33(30):3488-515.
  4. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. V5.2017. Updated March 16, 2017. For additional information visit the NCCN website: http://www.nccn.org/. Accessed on March 18, 2017.
  5. U.S. Food and Drug Administration (FDA). Gilotrif package insert. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf. Accessed on April 28, 2017.
  6. U.S. Food and Drug Administration (FDA). Iressa package insert. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021399s008lbl.pdf. Accessed on April 28, 2017.
  7. U.S. Food and Drug Administration (FDA). Tagrisso package insert. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208065s000lbl.pdf. Accessed on April 28, 2017.
  8. U.S. Food and Drug Administration (FDA). Tarceva package insert. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021743s018lbl.pdf. Accessed on April 28, 2017.
  9. Travis WD, Brambilla E, Nicholson AG, et al.  On behalf of the WHO Panel. The 2015 World Health Organization classification of lung tumors. Impact of genetic, clinical, and radiologic advances since the 2004 classigication. J Thorac Oncol. 2015; 10(9):1243-1260.
Websites for Additional Information
  1. American Cancer Association. Lung Cancer - Non-Small Cell. Available at: http://www.cancer.org/Cancer/LungCancer-Non-SmallCell/DetailedGuide/index. Accessed on April 28, 2017.
  2. National Cancer Institute. Non-Small Cell Cancer Treatment (PDQ® ). Available at: http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/HealthProfessional/page2. Accessed on April 28, 2017.
  3. National Library of Medicine. Medical Encyclopedia: Non-Small Cell Lung Cancer. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/007194.htm. Accessed on April 28, 2017.
Index

Afatinib
EGFR
Epidermal Growth Factor Receptor
Erlotinib
Gefitinib  
Gilotrif
Iressa
Therascreen EGFR
Tarceva
Tyrosine Kinase 

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. 

Document History
Status Date Action
Revised 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.
Revised 05/03/2017 Hematology/Oncology Subcommittee review. Clarified MN statement regarding EGFR testing for individuals undergoing TKI inhibitor therapy. Updated Rationale, Definitions, and References sections.
Revised 07/27/2016 MPTAC review.

Revised

 

07/12/2016 Hematology/Oncology Subcommittee review. Clarified MN statement regarding EGFR testing for individuals undergoing TKI inhibitor therapy. Added new MN position statement regarding EGFR testing for individuals receiving osimertinib. Added osimertinib to INV and NMN statement for analysis of gene amplification. Updated Rationale and Reference sections. Removed ICD-9 codes from Coding section.
Reviewed 05/05/2016 MPTAC review.
Reviewed 05/04/2016 Hematology/Oncology Subcommittee review. Updated Rationale and Reference sections.
Reviewed 05/07/2015 MPTAC review.
Reviewed 05/06/2015 Hematology/Oncology Subcommittee review. Updated Rationale and Reference sections.
Revised 05/15/2014 MPTAC review.
Revised 05/14/2014 Hematology/Oncology Subcommittee review. Expanded medically necessary statement to address all EGFR tyrosine kinase inhibitor (TKI) drugs. Added afatinib to investigational and not medically necessary statement. Updated Rationale and Reference sections.
Reviewed 11/14/2013 MPTAC review.
Reviewed 11/13/2013 Hematology/Oncology Subcommittee review. Updated Rationale and Reference sections.
Reviewed 11/08/2012 MPTAC review.
Reviewed 11/07/2012 Hematology/Oncology Subcommittee review. Updated Rationale and Reference sections. Updated Coding section to include 01/01/2013 CPT changes.
Revised 11/17/2011 MPTAC review.
Revised 11/16/2011 Hematology/Oncology Subcommittee review. Updated reference section. Added "for all indications, including" to analysis of gene amplification investigational and not medically necessary statement. Removed "for Non-Small Cell Lung Cancer (NSCLC)" from title. Updated Rationale, Coding and Reference sections.
Reviewed 11/18/2010 MPTAC review.
Reviewed 11/17/2010 Hematology/Oncology Subcommittee review. Updated reference section. Added EGFR analysis as medically necessary to predict treatment response to erlotinib (Tarceva) or gefitinib (Iressa) in individuals with specific types of NSCLC. Updated Rationale, Background, Coding, and Reference sections.
Reviewed 11/19/2009 MPTAC review.
Reviewed 11/18/2009 Hematology/Oncology Subcommittee review. Corrected title by replacing "Epithelial" with "Epidermal". Updated reference section.
Reviewed 11/20/2008 MPTAC review.
Reviewed 11/19/2008 Hematology/Oncology Subcommittee review. Updated Rationale, Reference sections.
  02/21/2008 The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 Medical Policy and Technology Assessment Committee (MPTAC) meeting.
Reviewed 11/29/2007 MPTAC review. 
Reviewed 11/28/2007 Hematology/Oncology Subcommittee review.  Updated Rationale, Reference sections.
Reviewed 12/07/2006 MPTAC review.
Reviewed 12/06/2006 Hematology/Oncology Subcommittee review.
New 09/14/2006 MPTAC initial document development.