• What is EGFR?
  • EGFR in Lung Cancer
  • EGFR c.2573T>G (L858R)
  • Clinical Trials

EGFR

Epidermal growth factor receptor (EGFR) belongs to a family of receptor tyrosine kinases (RTKs) that include EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The binding of ligands, such as epidermal growth factor (EGF), induces a conformational change that facilitates receptor homo- or heterodimer formation, thereby resulting in activation of EGFR tyrosine kinase activity. Activated EGFR then phosphorylates its substrates, resulting in activation of multiple downstream pathways within the cell, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure 1).

mapk-pk13.png

Figure 1.
Schematic of EGFR signaling pathway. Growth factor binding to EGFR results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2013. EGFR. My Cancer Genome http://www.mycancergenome.org/content/disease/lung-cancer/egfr/?tab=0 (Updated October 16).

Last Updated: October 16, 2013

EGFR Mutations in Non-Small Cell Lung Cancer (NSCLC)

Approximately 10% of patients with NSCLC in the US and 35% in East Asia have tumor associated EGFR mutations (Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004). These mutations occur within EGFR exons 18–21, which encodes a portion of the EGFR kinase domain (Figure 1). EGFR mutations are usually heterozygous, with the mutant allele also showing gene amplification (Soh et al. 2009). Approximately 90% of these mutations are exon 19 deletions or exon 21 L858R point mutations (Ladanyi and Pao 2008). These mutations increase the kinase activity of EGFR, leading to hyperactivation of downstream pro-survival signaling pathways (Sordella et al. 2004).

Regardless of ethnicity, EGFR mutations are more often found in tumors from female never smokers (defined as less than 100 cigarettes in a patient's lifetime) with adenocarcinoma histology (Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004). However, EGFR mutations can also be found in other subsets of NSCLC, including in former and current smokers as well as in other histologies.

In the vast majority of cases, EGFR mutations are non-overlapping with other oncogenic mutations found in NSCLC (e.g., KRAS mutations, ALK rearrangements, etc.).

egfr-nsclc.png

Figure 1.
Schematic of EGFR mutations. Exons 18–21 of the EGFR kinase domain are depicted. Mutations above the schematic are associated with sensitivity to EGFR TKIs. Mutations listed below the schematic are associated with EGFR TKI resistance.
NOTE: a While most exon 20 insertions are associated with decreased EGFR TKI sensitivity, the EGFR A763_Y764insFQEA mutation is an exception and has been associated in retrospective studies with increased EGFR TKI sensitivity (Yasuda et al. 2013).

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2014. EGFR Mutations in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome http://www.mycancergenome.org/content/disease/lung-cancer/egfr/ (Updated June 18).

Last Updated: June 18, 2014

EGFR c.2573T>G (L858R) Mutation in Non-Small Cell Lung Cancer

Properties
Location of mutation Kinase domain (exon 21)
Frequency of EGFR mutations in NSCLC ~10% in the USA
~35% in Asia
(Lynch et al. 2004; Paez et al. 2004; Pao et al. 2004)
Frequency of EGFR L858R mutations in EGFR-mutated NSCLC 43% (Mitsudomi and Yatabe 2010)
Implications for Targeted Therapeutics
Response to EGFR TKIs Confers increased sensitivitya
Response to anti-EGFR antibodies Currently no role for EGFR mutation in predicting response in NSCLC

The L858R mutation results in an amino acid substitution at position 858 in EGFR, from a leucine (L) to an arginine (R). This mutation occurs within exon 21, which encodes part of the kinase domain, and occurs with a frequency of approximately 43% in E GFR mutant lung tumors (Mitsudomi and Yatabe 2010).

a Multiple EGFR tyrosine kinase inhibitors (TKIs) have been developed or are in development:

  • First-generation: Gefitinib (Iressa) and erlotinib (Tarceva). Icotinib is another reversible inhibitor like gefitinib and erlotinib that was recently developed and is available only in China.
  • Second-generation: Afatinib (Gilotrif), dacomitinib, neratinib. These are irreversible inhibitors with activity against both EGFR and other ERBB family members.
  • Third-generation: CO-1686, AZD9291. These are mutant-selective as they were designed to target mutant EGFR better than wildtype EGFR, while the agents above were originally designed to target wildtype EGFR.

In the metastatic setting, EGFR mutations are strong predictors of efficacy for the EGFR tyrosine kinase inhibitors (TKIs), including the "first-generation" drugs erlotinib (Tarceva) and gefitinib (Iressa) and the "second-generation" drug, afatinib (Gilotrif). Patients whose tumors harbor EGFR exon 19 deletions display a >50–70% radiographic response rate in prospective trials, including randomized phase III trials (Fukuoka et al. 2011; Maemondo et al. 2010; Mitsudomi et al. 2010; Mok et al. 2009; Rosell et al. 2009; Rosell et al. 2012; Sequist et al. 2013; Yang et al. 2012a, 2012b; Zhou et al. 2011). Compared to those with EGFR wild type tumors, patients with EGFR mutant tumors display a longer progression-free survival on EGFR TKI therapy than those who receive chemotherapy. Patients with metastatic EGFR mutant tumors treated with first- and second-generation EGFR TKIs have a median survival of approximately two years (Fukuoka et al. 2011; Maemondo et al. 2010; Mitsudomi et al. 2012; Mok et al. 2009; Rosell et al. 2009; Rosell et al. 2012; Sequist et al. 2013; Yang et al. 2012b; Zhou et al. 2012). Prolonged survival may also be due to the fact that patients with EGFR mutant tumors have a better prognosis in general compared to those with EGFR wild type tumors (Kosaka et al. 2009; Marks et al. 2008). Patients with EGFR mutant tumors treated with an EGFR TKI in the first-line setting may live longer than those treated in the second-line setting (30.5 months vs. 23.6 months, p=0.31) (Maemondo et al. 2010). In phase I trials, “third-generation” EGFR TKIs, such as CO-1686 and AZD9291, have demonstrated efficacy in patients with EGFR-mutant NSCLC who have progressed on prior TKI therapy (Soria et al. 2013; Ranson et al. 2013).


Reference Study Type / Phase Line of Treatment Treatment Agent Mutation Status/Group # Patients in Study Response Rate PFS (months) OS (months)
First-Generation and Reversible EGFR TKIs (Erlotinib, Gefitinib, Icotinib)
Rosell et al. 2012 Phase III (EURTAC) 1st erlotinib Exon 19 deletion and L858R mutations 86 64% 9.7 19.3
L858R mutation only subgroup 29
8.4
cisplatin/ docetaxel or gemcitabine or carboplatin/ docetaxel Exon 19 deletion and L858R mutations 87 18% 5.2 19.5
L858R mutation subgroup 29
6.0
Zhou et al. 2011; Zhou et al. 2012 Phase III (OPTIMAL) 1st erlotinib Exon 19 deletion and L858R mutations 82 83% 13.7 22.7
gemcitabine/ carboplatin Exon 19 deletion and L858R mutations 72 36% 4.6 28.9
Mok et al. 2009; Fukuoka et al. 2011 Phase III (IPASS) 1st gefitinib Exon 19 deletion, L858R, T790M, G719X, S768I, L861Q mutations 132 71% 9.5 21.6
L858R mutation only subgroup 64 61%

carboplatin/ paclitaxel Exon 19 deletion, L858R, T790M, G719X, S768I, L861Q mutations 129 47% 6.3 21.9
L858R mutation subgroup 47 53%

Mitsudomi et al. 2010; Mitsudomi et al. 2012 Phase III (WJTOG 3405) 1st gefitinib Exon 19 deletion and L858R mutations 58 62% 9.6 35.5 (MST)
L858R mutation only subgroup 36 NR 9.6 34.8 (MST)
cisplatin/ docetaxel Exon 19 deletion and L858R mutations 59 32% 6.6 38.8 (MST)
L858R mutation subgroup 49
6.7
Maemondo et al. 2010 Phase III (NEJ002) 1st gefitinib Exon 19 deletions, L858R, L861Q, G719A, G719C, G719S mutations 114 74% 10.8 30.5
L858R mutation only subgroup 49 67% 10.8
carboplatin/ paclitaxel Exon 19 deletions, L858R, L861Q, G719A, G719C, G719S mutations 110 31% 5.4 23.6
Shi et al. 2013 Phase III (ICOGEN) ≥2nd (no prior EGFR TKIs) icotinib Unselected NSCLC 199 27.6% 4.6 13.3
Exon 19 deletion, L858R, G719X, T790M, L861Q mutations subgroup 68
7.8 20.9
gefitinib Unselected NSCLC 196 27.2% 3.4 13.9
Exon 19 deletion, L858R, G719X, T790M, L861Q mutations subgroup 66
5.3 20.2
Second-Generation Irreversible EGFR TKIs (Afatinib, Dacomitinib, Neratinib)
Sequist et al. 2013; Yang et al. 2012b Phase III (LUX-Lung 3) 1st afatinib All EGFR mutations (NS) 230 56% 11.1
Exon 19 deletion and L858R mutations subgroup 204 61% 13.6
pemetrexed/ cisplatin All EGFR mutations (NS) 115 23% 6.9
Exon 19 deletion and L858R mutations subgroup 104 22% 6.9
Janjigian et al. 2011; Janjigian et al. 2012 Phase I ≥2nd (acquired resistance to EGFR TKIs) afatinib / cetuximab EGFR mutations (Exon 19 deletion, L858R, T790M) progressing on erlotinib or gefitinib 100 (evaluable N=60) 40% 4.7
Ramalingam et al. 2012 Phase II 2nd / 3rd dacomitinib Unselected NSCLC 94 17% 2.9 9.5
All EGFR mutations (NS) subgroup 19
7.4
erlotinib Unselected NSCLC 94 5.3% 1.9 7.4
All EGFR mutations (NS) subgroup 11
7.4
Sequist et al. 2010 Phase II 2nd – 4th (prior EGFR TKI erlotinib or gefitinib required) neratinib All EGFR mutations (NS) 91 3.4% 3.8
1st – 4th (no prior EGFR TKIs) neratinib Unselected NSCLC 28 0% 2.3
Third-Generation Mutant Selective EGFR TKIs (CO-1686, AZD9291, AP26113)
Soria et al. 2013 Phase I ≥2nd (prior EGFR TKI required) CO-1686 All EGFR mutations (NS) 45


EGFR T790M subgroup 31 (evaluable N=4) 75%

Ranson et al. 2013 Phase I (AURA) ≥ 2nd (prior EGFR TKI required) AZD9291 NSCLC progressing on prior EGFR TKI and T790M expansion cohort 27 2 confirmed PRs reported in T790M mutation positive patients

Camidge et al. 2013 Phase I Refractory AP26113 All EGFR mutations (NS) subgroup 20 (evaluable N=18) 6%

NOTE: MST = median survival time; NS = not specified; OS = overall survival; PFS = progression-free survival; PR = partial response.

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2014. EGFR c.2573T>G (L858R) Mutation in Non-Small Cell Lung Cancer. My Cancer Genome http://www.mycancergenome.org/content/disease/lung-cancer/egfr/5/ (Updated April 8).

Last Updated: April 8, 2014

EGFR-Associated Non-Small Cell Lung Cancer Clinical Trials

Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.

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Disclaimer: The information presented at MyCancerGenome.org is compiled from sources believed to be reliable. Extensive efforts have been made to make this information as accurate and as up-to-date as possible. However, the accuracy and completeness of this information cannot be guaranteed. Despite our best efforts, this information may contain typographical errors and omissions. The contents are to be used only as a guide, and health care providers should employ sound clinical judgment in interpreting this information for individual patient care.