• What is EGFR?
  • EGFR in Lung Cancer
  • EGFR c.2369C>T (T790M)
  • 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).

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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.2369C>T (T790M) Mutation in Non-Small Cell Lung Cancer

Properties
Location of mutation Kinase domain (exon 20)
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 T790M mutations in EGFR-mutated NSCLC <5% of untreated EGFR mutant tumors (Inukai et al. 2006)
50% of EGFR mutant tumors with acquired resistance to erlotinib/gefitinib (Kobayashi et al. 2005; Pao et al. 2005)
Implications for Targeted Therapeutics
Response to EGFR TKIs Confers decreased sensitivity
Response to anti-EGFR antibodies Currently no role for EGFR mutation in predicting response in NSCLC

The T790M mutation results in an amino acid substitution at position 790 in EGFR, from a threonine (T) to a methionine (M). This mutation occurs within exon 20, which encodes part of the kinase domain.

T790M after acquired resistance to erlotinib/gefitinib

The T790M mutation can be detected as a "second-site mutation" in more than 50% of EGFR-mutant lung cancers that have developed acquired resistance to erlotinib or gefitinib (Kobayashi et al. 2005; Pao et al. 2005). Interestingly, case reports of patients who develop the T790M mutation as a mechanism of acquired resistance to EGFR TKI therapy have shown that this resistance mutation can be lost after an EGFR TKI free period. These patients then responded to a re-challenge with EGFR TKI (Sequist et al. 2011). Other reports have also shown that patients can re-respond to TKI treatment after a hiatus from targeted therapy (Watanabe et al. 2010). Whether patients should continue or discontinue an EGFR TKI after developing acquired resistance remains to be definitively determined.

Investigating third-generation EGFR TKIs and dual drug inhibition of EGFR in T790M mutant NSCLC is currently an active area of research. In phase I trials, third-generation EGFR TKIs CO-1686 and AZD9291 have demonstrated efficacy in patients who have progressed on prior TKI therapy, including cohorts of patients with EGFR T790M mutant NSCLC (Soria et al. 2013; Ranson et al. 2013). In a phase I study, a 38% response rate was reported with combination afatinib and cetuximab therapy in patients with EGFR T790M-mutant NSCLC (Janjigian et al. 2012).

T790M in untreated EGFR-mutant lung cancers

T790M is rarely (<5%) found in untreated EGFR mutant tumors using conventional testing techniques (Inukai et al. 2006). These "baseline" T790M mutations generally occur concurrently with another EGFR sensitizing mutation and have been found to be associated with decreased sensitivity to EGFR TKIs (Wu et al. 2011).

In approximately half of patients with baseline T790M mutations in their lung cancer, the T790M may be present as an underlying germline mutation. These germline T790M mutations occur infrequently (~0.5% of never smokers with lung cancer; Girard et al. 2010) and may be associated in some instances with familial cancer syndromes (Bell et al. 2005). A clinical trial is in development to better understand the relationship between baseline and germline T790M mutations and to better characterize the risks associated with carrying a germline T790M mutation (Oxnard et al. 2012​).​

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation Status/Group # Patients in Study Response Rate PFS (months) OS (months)
Miller et al. 2012 Phase IIb/III (LUX-Lung 1) 3rd–4th (acquired resistance to EGFR TKIs) afatinib + best supportive care NSCLC progressing on prior erlotinib or gefinitib 390 7% 3.3 10.8
placebo + best supportive care NSCLC progressing on prior erlotinib or gefinitib 195 <1% 1.1 12
Katakami et al. 2013 Phase II (LUX-Lung 4) 3rd–4th (acquired resistance to EGFR TKIs) afatinib NSCLC progressing on prior erlotinib or gefinitib 62 8% 4.4 19
Janjigian et al. 2011; Janjigian et al. 2012 Phase I ≥ 2nd (acquired resistance to EGFR TKIs) afatinib / cetuximab EGFR T790M 53 38%

Soria et al. 2013 Phase I ≥ 2nd (prior EGFR TKI required) CO-1686 EGFR T790M 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

NOTE: OS = overall survival; PFS = progression-free survival; PR = partial response.
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Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., Geoffrey R. Oxnard, M.D., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, G. Oxnard, W. Pao. 2014. EGFR c.2369C>T (T790M) Mutation in Non-Small Cell Lung Cancer. My Cancer Genome http://www.mycancergenome.org/content/disease/lung-cancer/egfr/4/ (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.