A growth receptor that is mutated in some lung cancers and overproduced in others; the first great success of targeted pills. This dossier gathers the 22 products (16 approved), 19 trials, 6 pathways and 4 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
EGFR is a receptor tyrosine kinase activating RAS-MAPK and PI3K-AKT. Exon 20 insertions need dedicated drugs.
- NSCLC (mutations)
- Colorectal (wild-type, antibody target)
- Head and neck squamous
- Glioblastoma (amplification, EGFRvIII)
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Colorectal cancer | 100% | Wild-type EGFR is the antibody target | Benefit restricted to RAS/BRAF wild-type (~40%) | Wikipedia |
| Head and neck squamous cell carcinoma | 80-90% | Overexpression by IHC | Wikipedia | |
| Glioma & glioblastoma | 40-50% | Amplification | EGFRvIII in ~25-30% | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 10-15% | Activating mutation (US/Europe) | 40-50% in East Asian adenocarcinoma | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Mutation hotspots and which drugs address them
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| Exon 19 deletions 746 to 753 | Activating | About 45% of EGFR-mutant NSCLC | In-frame deletions around E746 to A750 in the kinase beta-3/alpha-C loop; the best responders to every generation of TKI. | — | FLAURA, NEJM 2018 | |
| L858R 858 | Activating | About 40% of EGFR-mutant NSCLC | Activation-loop substitution; somewhat shorter PFS than exon 19 deletions on every TKI. | — | FLAURA, NEJM 2018 | |
| G719X / S768I / L861Q 719 | Activating | About 10% of EGFR mutations (uncommon alleles) | Exon 18, 20 and 21 point mutations; afatinib carries a label for them and osimertinib is active. | — | COSMIC: EGFR | |
| Exon 20 insertions 762 to 774 | Activating | About 4 to 10% of EGFR mutations | Insertions after the alpha-C helix that push the drug pocket shut for first- and third-generation TKIs. | Vyse and Huang, Nat Rev Clin Oncol 2019 | ||
| T790M 790 | Resistance | About 50 to 60% of progression on first- and second-generation TKIs | Gatekeeper methionine restores ATP affinity; osimertinib was designed for it. | Yu et al., Clin Cancer Res 2013 | ||
| C797S 797 | Resistance | About 7 to 15% after first-line osimertinib | Loses the cysteine osimertinib bonds to. Fourth-generation allosteric inhibitors are in trials; ADCs against EGFR, HER3 or TROP2 work regardless of genotype. | FLAURA2, NEJM 2023 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: Cancer Hotspots (MSK) · COSMIC: EGFR.
Products by modality and phase
Browse products →| Modality | Approved | Phase 3 | Phase 2 | Withdrawn or failed |
|---|---|---|---|---|
| Small molecule 7 | — | — | — | |
| Antibody 4 | — | — | ||
| Bispecific ADC 2 | — | — | ||
| Bispecific antibody 2 | — | — | ||
| Small-molecule EGFR exon 20 insertion TKI 2 | — | — | ||
| Small-molecule EGFR TKI 2 | — | — | — | |
| Small-molecule pan-ErbB TKI 2 | — | — | — | |
| Vaccine or virus 1 | — | — | — |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| BL-B01D1-307 NCT06382142 | 3 | Positive | Previously treated locally advanced or metastatic TNBC: izalontamab brengitecan vs chemotherapy | PFS and OS significantly improved at interim analysis (numbers presented ASCO 2026). | |
| PANKU-Esophagus01 (BL-B01D1-305) NCT06304974 | 3 | Positive | Recurrent or metastatic oesophageal squamous cell carcinoma after PD-(L)1 inhibitor plus platinum chemotherapy: izalontamab brengitecan vs chemotherapy of physician's choice | OS and PFS significantly improved at interim analysis; numbers per ASCO 2026 presentation. | |
| BREAKWATER NCT04607421 | 3 | Positive | First-line BRAF V600E-mutant metastatic colorectal cancer: encorafenib + cetuximab + mFOLFOX6 (or FOLFIRI) vs chemotherapy ± bevacizumab | OS 30.3 vs 15.1 months (HR 0.49); PFS 12.8 vs 7.1 months. | |
| HORIZON-Breast01 NCT05424835 | 3 | Positive | HER2+ metastatic breast cancer after trastuzumab and taxane (China): trastuzumab rezetecan (SHR-A1811) vs pyrotinib + capecitabine | PFS 30.6 vs 8.3 months, HR 0.22. | |
| ACE-Breast-02 NCT04829604 | 3 | Positive | HER2+ advanced breast cancer after trastuzumab and taxane (China): ARX788 vs lapatinib + capecitabine | PFS 11.3 vs 8.2 months, HR 0.64. | |
| LAURA NCT03521154 | 3 | Positive | Unresectable stage III EGFR-mutant NSCLC after chemoradiation: osimertinib until progression vs placebo | PFS HR 0.16. | |
| CodeBreaK 300 NCT05198934 | 3 | Positive | KRAS G12C colorectal cancer, previously treated: sotorasib + panitumumab vs standard of care | PFS HR 0.49. | |
| FLAURA2 NCT04035486 | 3 | Positive | First-line EGFR-mutant NSCLC: osimertinib + chemotherapy vs osimertinib | PFS HR 0.62; OS HR 0.77. | |
| MARIPOSA NCT04487080 | 3 | Positive | First-line EGFR-mutant NSCLC: amivantamab + lazertinib vs osimertinib | PFS HR 0.70; OS HR 0.75. | |
| PARADIGM NCT02394795 | 3 | Positive | First-line RAS wild-type metastatic colorectal cancer: panitumumab + mFOLFOX6 vs bevacizumab + mFOLFOX6 | OS 37.9 vs 34.3 months (HR 0.82) in left-sided RAS wild-type disease. | |
| ADAURA NCT02511106 | 3 | Positive | Adjuvant osimertinib 3 years after resection of stage IB-IIIA EGFR-mutant NSCLC | OS HR 0.49. | |
| COLUMBUS NCT01909453 | 3 | Positive | Advanced BRAF V600 melanoma: encorafenib + binimetinib vs vemurafenib vs encorafenib | PFS 14.9 vs 7.3 months (HR 0.54); median OS 33.6 months. | |
| ACT IV NCT01480479 | 3 | Negative | Newly diagnosed EGFRvIII+ glioblastoma with minimal residual disease: rindopepimut + temozolomide vs control (KLH) + temozolomide | OS 20.1 vs 20.0 months; no benefit. | |
| CRYSTAL & FIRE-3 | 3 | Positive | First-line metastatic colorectal cancer: FOLFIRI ± cetuximab (CRYSTAL); FOLFIRI + cetuximab vs FOLFIRI + bevacizumab (FIRE-3) | CRYSTAL KRAS-WT OS 23.5 vs 20.0 months; FIRE-3 OS 28.7 vs 25.0 months. | |
| EXTREME NCT00122460 | 3 | Positive | Untreated recurrent or metastatic HNSCC: cetuximab + platinum/5-FU vs platinum/5-FU | OS 10.1 vs 7.4 months; HR 0.80. | |
| IZABRIGHT-Breast01 NCT06926868 | 3 | Recruiting | First-line metastatic TNBC ineligible for PD-(L)1 inhibitors: iza-bren vs chemotherapy | ||
| LiGeR-HN1 NCT06525220 | 3 | Recruiting | Untreated PD-L1-positive recurrent or metastatic HNSCC: petosemtamab + pembrolizumab vs pembrolizumab | ||
| FORTIFI-HN01 NCT06788990 | 2/3 | Recruiting | Untreated PD-L1-positive, HPV-negative recurrent or metastatic HNSCC: ficerafusp alfa + pembrolizumab vs pembrolizumab | ||
| TROPION-Lung05 NCT04484142 | 2 | Positive | Actionable-genomic-alteration NSCLC after targeted therapy and platinum: datopotamab deruxtecan single arm | ORR 43.6% in EGFR-mutant disease. |
Resistance routes that involve this target
Unaddressed routes →Mutation of the cysteine that osimertinib binds covalently; abolishes drug binding while EGFR stays active.
- Fourth-generation allosteric EGFR inhibitors (in trials); amivantamab-based regimens
- ADCs that bypass genotype: Dato-DXd, HER3-DXd, iza-bren
Amplified MET signals to PI3K/MAPK independently of EGFR.
- EGFR×MET bispecific amivantamab; MET TKI + osimertinib combinations
- c-MET-directed and EGFR×c-MET bispecific ADCs
Conversion to small-cell lung cancer (RB1/TP53 co-loss) or squamous histology; EGFR mutation persists but the cell no longer depends on it.
- Re-biopsy at progression; platinum-etoposide for SCLC transformation
Relief of ERK-mediated negative feedback re-activates receptors within hours, producing new wild-type KRAS-GTP the drug cannot bind.
- Add anti-EGFR antibody in colorectal cancer (CodeBreaK 300, KRYSTAL-1)
- SHP2 or SOS1 inhibitor combinations (trials)
Pathways where it is a node
Pathway-to-drug matrix →- Chromosomal instability & aneuploidyNode: ecDNA oncogene amplification · 2 druggable nodes
Most cancers have the wrong number of chromosomes and keep shuffling them at every division. This chaos fuels evolution and drug resistance, but it also stresses the cell and can trigger immune alarms, a double edge that researchers are trying to exploit.
Which nodes have drugs → - Drug-tolerant persister cellsNode: Targeted drug or chemo · 3 druggable nodes
Even when a drug wipes out 99% of a tumour, a few cells survive without any resistance mutation: they go quiet, stop dividing, and wait. These persisters are the seed of relapse. They are hard to kill precisely because they are not doing much, but they have their own weaknesses.
Which nodes have drugs → - Lineage plasticity & neuroendocrine transformationNode: ARPI or EGFR TKI pressure · 5 druggable nodes
Under pressure from a drug that blocks its identity (the androgen receptor in prostate cancer, EGFR in lung cancer), a tumour can change what kind of cell it is, becoming a small-cell neuroendocrine cancer that no longer needs the blocked signal. It is the ultimate escape: not a new mutation in the engine, but a new engine.
Which nodes have drugs → - RAS / RAF / MEK / ERK (MAPK)Node: RTK (EGFR, ALK, RET, MET) · 3 druggable nodes
The RAS-MAPK pathway is the cell's 'divide' relay. A signal at the surface flips RAS on, which passes to RAF, MEK, and ERK, which tell the nucleus to make the cell divide. KRAS and BRAF mutations jam it in the on position.
Which nodes have drugs → - Receptor tyrosine kinase activationNode: RTK dimer (EGFR, HER2, MET) · 5 druggable nodes
Growth-factor receptors are antennas on the cell surface that pair up when a signal lands and switch on the growth relays inside. Cancers mutate, multiply, or fuse these antennas so they broadcast 'grow' with no signal at all. Most targeted drugs, antibodies and ADCs start here.
Which nodes have drugs → - Resistance routes: how a blocked pathway comes backNode: Drug blocks target · 6 druggable nodes
When a drug blocks a cancer's engine, the cancer has five ways back: change the part the drug binds, make more of it, take a side road, switch to a different engine altogether, or stop letting the drug in. Knowing which route a tumour took decides the next drug.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| cobas EGFR Mutation Test v2 Roche Molecular Systems · FDA CDx 2013 | PCR | Mutation detected (qualitative); plasma negative result should be reflexed to tissue | |
| therascreen EGFR RGQ PCR Kit QIAGEN · FDA CDx 2013 | PCR | Mutation detected (qualitative) | |
| therascreen KRAS RGQ PCR Kit QIAGEN · FDA CDx 2012 | PCR | Wild-type required for cetuximab or panitumumab (colorectal); G12C detected for sotorasib and adagrasib (NSCLC) | |
| therascreen BRAF V600E RGQ PCR Kit QIAGEN · FDA CDx 2020 | PCR | V600E detected (colorectal cancer, encorafenib plus cetuximab) | |
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| FoundationOne Liquid CDx Foundation Medicine (Roche) · FDA CDx 2020 | NGS plasma | Per companion claim: EGFR (osimertinib, erlotinib, gefitinib), ALK (alectinib), BRCA1/2 and ATM (olaparib, rucaparib), PIK3CA (alpelisib), FGFR3 (erdafitinib), NTRK and RET; negative plasma results reflex to tissue | |
| Guardant360 CDx Guardant Health · FDA CDx 2020 | NGS plasma | Per companion claim: EGFR (osimertinib), EGFR exon 20 insertions (amivantamab), KRAS G12C (sotorasib), ESR1 mutations (elacestrant), ERBB2 mutations (zongertinib); negative plasma reflexes to tissue | |
| Oncomine Dx Target Test Thermo Fisher Scientific · FDA CDx 2017 | NGS tissue | Per companion claim: BRAF V600E (dabrafenib plus trametinib), ROS1 fusions (crizotinib), EGFR (gefitinib), RET fusions (pralsetinib), MET exon 14 (tepotinib), EGFR exon 20 insertions | |
| EGFR pharmDx Agilent (Dako) · FDA CDx 2004 | IHC | Any EGFR membrane staining (historic requirement for cetuximab and panitumumab in colorectal cancer) |
Preclinical models
All models →| Cell line | Identifiers | Why it is used |
|---|---|---|
| PC-9 | CVCL_B260 · ACH-000779 | Exon 19 deletion; persister and resistance derivatives (PC-9/ER, PC-9/OR) are widely shared. |
| HCC827 | CVCL_2063 · ACH-000012 | Exon 19 deletion, amplified; MET-amplified resistant sublines (HCC827 GR). |
| NCI-H1975 | CVCL_1511 · ACH-000587 | L858R plus T790M; osimertinib-sensitive, first-generation-resistant. |
| NCI-H3255 | CVCL_6831 · ACH-000109 | L858R with amplification. |
| HCC4006 | CVCL_1269 · ACH-000066 | Exon 19 deletion; EMT-type resistance models. |
| NCI-H1650 | CVCL_1483 · ACH-000035 | Exon 19 deletion with PTEN loss; intrinsically TKI-resistant. |
| A-431 | CVCL_0037 · ACH-001328 | Vulval squamous line with massive EGFR amplification; the antibody and ADC binding standard. |
| Ba/F3 EGFR panels | not resolved | Engineered exon 20 insertion, C797S and other alleles in the IL-3-dependent Ba/F3 background. |
- EGFR L858R / T790M (tet-inducible) (CCSP-rtTA; TetO-EGFR) Politi et al., Genes Dev 2006
Open questions
All open questions →- 01
Which agent should follow osimertinib when C797S emerges: a fourth-generation TKI, amivantamab-based therapy, or an ADC that ignores genotype?
translationalindustryWhy unresolved. C797S removes the covalent anchor of every third-generation TKI. Allosteric fourth-generation inhibitors exist only in early trials, while ADCs and bispecifics work regardless of the mutation but carry different toxicities.
What would answer it. A randomised comparison at osimertinib progression stratified by resistance mechanism (C797S, MET amplification, transformation), with biopsy or ctDNA at entry.
Source: FLAURA2, NEJM 2023 - 02
Which patients need intensified first-line therapy (osimertinib plus chemotherapy, or amivantamab plus lazertinib) and which are well served by osimertinib alone?
clinicalclinicWhy unresolved. FLAURA2 and MARIPOSA improve progression-free survival at the price of toxicity, and subgroup signals (brain metastases, TP53 co-mutation, detectable ctDNA) suggest the benefit is not uniform.
What would answer it. Prospective ctDNA- or co-mutation-stratified trials, or individual-patient meta-analysis of FLAURA2 and MARIPOSA, showing who gains overall survival.
Source: MARIPOSA, NEJM 2024
Ideas and companies
Key papers and the live literature
Preprints →- BREAKWATER: encorafenib plus cetuximab with chemotherapy as first treatment for BRAF V600E-mutated colorectal cancer · New England Journal of Medicine 2025
- MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer · New England Journal of Medicine 2024
- CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer · New England Journal of Medicine 2023
- ADAURA: three years of osimertinib after surgery for EGFR-mutated lung cancer · New England Journal of Medicine 2020
- KEYNOTE-048: pembrolizumab, alone or with chemotherapy, as first treatment for recurrent or metastatic head and neck cancer · The Lancet 2019
- FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer · New England Journal of Medicine 2018
Query for this target: (TITLE:"EGFR" OR ABSTRACT:"EGFR") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about EGFR, not a curated reading list.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/egfr.json. Licence CC BY 4.0.