Biomarkers /
EGFR G719A
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Overview
EGFR G719A is present in 0.15% of AACR GENIE cases, with lung adenocarcinoma, conventional glioblastoma multiforme, poorly differentiated non-small cell lung cancer, squamous cell lung carcinoma, and infiltrating renal pelvis and ureter urothelial carcinoma having the greatest prevalence [4].
Biomarker-Directed Therapies
EGFR G719A is a predictive biomarker for use of osimertinib, afatinib, erlotinib, gefitinib, capmatinib, crizotinib, dacomitinib, and pembrolizumab in patients.
Of the therapies with EGFR G719A as a predictive biomarker, 2 are FDA-approved and 7 have NCCN guidelines in at least one clinical setting.
Non-small cell lung carcinoma has the most therapies targeted against EGFR G719A or its related pathways [5].
Afatinib +
Non-Small Cell Lung Carcinoma -
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Biomarker Criteria:
Sample must match one or more of the following:
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Predicted Response: Primary Sensitivity |
| Clinical Setting(s): Metastatic (FDA, NCCN, ASCO) | |
| Note: Single agent (FDA, NCCN), or may be considered in combination with cetuximab after progression on afatinib, erlotinib, gefitinib, or dacomitinib, and chemotherapy (NCCN). |
Dacomitinib +
Non-Small Cell Lung Carcinoma -
Erlotinib +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match one or more of the following:
|
Predicted Response: Primary Sensitivity |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: Single agent, or in combination with bevacizumab (non-squamous only) or ramucirumab. |
Gefitinib +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match one or more of the following:
|
Predicted Response: Primary Sensitivity |
| Clinical Setting(s): Metastatic (NCCN) |
Osimertinib +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match one or more of the following: Sample must match one or more of the following: |
Predicted Response: Primary Resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: According to NCCN, mutations in KRAS have been associated with reduced responsiveness to EGFR TKI therapy. |
|
Biomarker Criteria:
Sample must match one or more of the following:
|
Predicted Response: Primary Sensitivity |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: Preferred first-line therapy, per NCCN. Also recommended as adjuvant therapy. |
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match one or more of the following: Sample must match all of the following: |
Predicted Response: Acquired Resistance |
| Clinical Setting(s): Metastatic (MCG) | |
| Note: C797S mutation can be detected in ~40% of EGFR-mutant lung cancers that have developed acquired resistance to osimertinib. |
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match one or more of the following: Sample must match all of the following: |
Predicted Response: Acquired Resistance |
| Clinical Setting(s): Metastatic (MCG) | |
| Note: C797S mutation can be detected in ~40% of EGFR-mutant lung cancers that have developed acquired resistance to osimertinib. |
Pembrolizumab +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match one or more of the following: Sample must match one or more of the following: |
Predicted Response: Primary Sensitivity |
| Clinical Setting(s): Metastatic (FDA) | |
| Note: For PD-L1 expressing tumors (Tumor Proportion Score >=1%, clone 22C3) with an EGFR or ALK alteration: FDA-approved as subsequent line of therapy following targeted therapy. However, per NCCN, data in the second-line setting suggest that subsequent pembrolizumab monotherapy is less effective in tumors with an EGFR mutation or ALK rearrangement. |
Capmatinib + Osimertinib +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match one or more of the following: Sample must match one or more of the following: |
Predicted Response: Overcomes acquired resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: To overcome resistance by secondary mutational events like MET amplification, EGFR must still be inhibited and additionally, a MET inhibitor must be added to the treatment. |
Crizotinib + Osimertinib +
Non-Small Cell Lung Carcinoma -
|
Biomarker Criteria:
Sample must match all of the following:
Sample must match all of the following: Sample must match one or more of the following: |
Predicted Response: Overcomes acquired resistance |
| Clinical Setting(s): Metastatic (NCCN) | |
| Note: To overcome resistance by secondary mutational events like MET amplification, EGFR must still be inhibited and additionally, a MET inhibitor must be added to the treatment. |
Clinical Trials
EGFR G719A serves as an inclusion eligibility criterion in 108 clinical trials, of which 64 are open and 44 are closed. Of the trials that contain EGFR G719A as an inclusion criterion, 1 is early phase 1 (0 open), 34 are phase 1 (18 open), 20 are phase 1/phase 2 (15 open), 36 are phase 2 (20 open), 4 are phase 2/phase 3 (3 open), 10 are phase 3 (7 open), 2 are phase 4 (1 open), and 1 is no phase specified (0 open).
Trials with EGFR G719A in the inclusion eligibility criteria most commonly target non-small cell lung carcinoma, non-squamous non-small cell lung carcinoma, lung adenocarcinoma, malignant solid tumor, and squamous cell lung carcinoma [5].
Osimertinib, pemetrexed, pembrolizumab, carboplatin, and nivolumab are the most frequent therapies in trials with EGFR G719A as an inclusion criteria [5].
Significance of EGFR G719A in Diseases
Non-Small Cell Lung Carcinoma +
EGFR is altered in 22.89% of non-small cell lung carcinoma patients with EGFR G719A present in 0.67% of all non-small cell lung carcinoma patients [4].
EGFR G719A is an inclusion criterion in 100 clinical trials for non-small cell lung carcinoma, of which 58 are open and 42 are closed. Of the trials that contain EGFR G719A and non-small cell lung carcinoma as inclusion criteria, 1 is early phase 1 (0 open), 32 are phase 1 (18 open), 20 are phase 1/phase 2 (15 open), 31 are phase 2 (15 open), 4 are phase 2/phase 3 (3 open), 9 are phase 3 (6 open), 2 are phase 4 (1 open), and 1 is no phase specified (0 open) [5].
Afatinib, erlotinib, gefitinib, capmatinib, osimertinib, crizotinib, dacomitinib, and pembrolizumab have evidence of efficacy in patients with EGFR G719A in non-small cell lung carcinoma [5].
Malignant Solid Tumor +
EGFR is altered in 7.61% of malignant solid tumor patients with EGFR G719A present in 0.13% of all malignant solid tumor patients [4].
EGFR G719A is an inclusion criterion in 10 clinical trials for malignant solid tumor, of which 8 are open and 2 are closed. Of the trials that contain EGFR G719A and malignant solid tumor as inclusion criteria, 3 are phase 1 (1 open), 2 are phase 1/phase 2 (2 open), and 5 are phase 2 (5 open) [5].
Breast Carcinoma +
EGFR is altered in 2.76% of breast carcinoma patients [4].
EGFR G719A is an inclusion criterion in 4 clinical trials for breast carcinoma, of which 4 are open and 0 are closed. Of the trials that contain EGFR G719A and breast carcinoma as inclusion criteria, 2 are phase 1 (2 open) and 2 are phase 2 (2 open) [5].
Glioblastoma +
EGFR is altered in 31.54% of glioblastoma patients with EGFR G719A present in 0.18% of all glioblastoma patients [4].
EGFR G719A is an inclusion criterion in 2 clinical trials for glioblastoma, of which 2 are open and 0 are closed. Of the trials that contain EGFR G719A and glioblastoma as inclusion criteria, 1 is phase 1 (1 open) and 1 is phase 2 (1 open) [5].
Bladder Carcinoma +
EGFR is altered in 3.84% of bladder carcinoma patients [4].
EGFR G719A is an inclusion criterion in 2 clinical trials for bladder carcinoma, of which 2 are open and 0 are closed. Of the trials that contain EGFR G719A and bladder carcinoma as inclusion criteria, 1 is phase 1 (1 open) and 1 is phase 2 (1 open) [5].
Non-Squamous Non-Small Cell Lung Carcinoma +
EGFR is altered in 25.27% of non-squamous non-small cell lung carcinoma patients with EGFR G719A present in 0.76% of all non-squamous non-small cell lung carcinoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for non-squamous non-small cell lung carcinoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and non-squamous non-small cell lung carcinoma as inclusion criteria, 1 is phase 3 (1 open) [5].
Lung Carcinoma +
EGFR is altered in 22.35% of lung carcinoma patients with EGFR G719A present in 0.65% of all lung carcinoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for lung carcinoma, of which 0 are open and 1 is closed. Of the trial that contains EGFR G719A and lung carcinoma as inclusion criteria, 1 is phase 1 (0 open) [5].
Anaplastic Astrocytoma +
EGFR is altered in 16.31% of anaplastic astrocytoma patients with EGFR G719A present in 0.21% of all anaplastic astrocytoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for anaplastic astrocytoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and anaplastic astrocytoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Urothelial Carcinoma +
EGFR is altered in 4.38% of urothelial carcinoma patients with EGFR G719A present in 0.1% of all urothelial carcinoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for urothelial carcinoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and urothelial carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
B-Cell Non-Hodgkin Lymphoma +
EGFR is altered in 1.63% of B-cell non-hodgkin lymphoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for B-cell non-hodgkin lymphoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and B-cell non-hodgkin lymphoma as inclusion criteria, 1 is phase 2 (1 open) [5].
Biliary Tract Carcinoma +
EGFR is altered in 2.58% of biliary tract carcinoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for biliary tract carcinoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and biliary tract carcinoma as inclusion criteria, 1 is phase 2 (1 open) [5].
Cervical Squamous Cell Carcinoma +
EGFR is altered in 2.2% of cervical squamous cell carcinoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for cervical squamous cell carcinoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and cervical squamous cell carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Head And Neck Carcinoma +
EGFR is altered in 4.29% of head and neck carcinoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for head and neck carcinoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and head and neck carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Hepatocellular Carcinoma +
EGFR is altered in 1.84% of hepatocellular carcinoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for hepatocellular carcinoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and hepatocellular carcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
High Grade Ovarian Serous Adenocarcinoma +
EGFR is altered in 1.36% of high grade ovarian serous adenocarcinoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for high grade ovarian serous adenocarcinoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and high grade ovarian serous adenocarcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Malignant Salivary Gland Neoplasm +
EGFR is altered in 0.98% of malignant salivary gland neoplasm patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for malignant salivary gland neoplasm, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and malignant salivary gland neoplasm as inclusion criteria, 1 is phase 2 (1 open) [5].
Malignant Supratentorial Neoplasm +
EGFR G719A is an inclusion criterion in 1 clinical trial for malignant supratentorial neoplasm, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and malignant supratentorial neoplasm as inclusion criteria, 1 is phase 2 (1 open) [5].
Pancreatic Adenocarcinoma +
EGFR is altered in 1.02% of pancreatic adenocarcinoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for pancreatic adenocarcinoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and pancreatic adenocarcinoma as inclusion criteria, 1 is phase 1 (1 open) [5].
Small Cell Lung Carcinoma +
EGFR is altered in 9.38% of small cell lung carcinoma patients [4].
EGFR G719A is an inclusion criterion in 1 clinical trial for small cell lung carcinoma, of which 1 is open and 0 are closed. Of the trial that contains EGFR G719A and small cell lung carcinoma as inclusion criteria, 1 is phase 2 (1 open) [5].
References
1. Hart R and Prlic A. Universal Transcript Archive Repository. Version uta_20180821. San Francisco CA: Github;2015. https://github.com/biocommons/uta
2. The UniProt Consortium. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Research. 2019;47:D506-D515.
3. Liu X, Wu C, Li C, and Boerwinkle E. dbNSFP v3.0: A one-stop database of functional predictions and annotations for human nonsynonymous and splice site SNVs. Human Mutation. 2015;37:235-241.
Liu X, Jian X, and Boerwinkle E. dbNSFP: A lightweight database of human nonsynonymous SNPs and their functional predictions. Human Mutation. 2011;32:894-899.
4. The AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discovery. 2017;7(8):818-831. Dataset Version 8. This dataset does not represent the totality of the genetic landscape; see paper for more information.
5. All assertions and clinical trial landscape data are curated from primary sources. You can read more about the curation process here.
