# EGFR-mutated non-small-cell lung cancer

Source: https://onco.cc/cancers/egfr-mutant-nsclc/  
OnCo record `egfr-mutant-nsclc` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

EGFR-mutated lung cancer is driven by a single faulty growth receptor and is treated first with a pill rather than chemotherapy. Osimertinib keeps the disease under control for about a year and a half on average, adding chemotherapy or the antibody amivantamab extends that further, and three years of osimertinib after surgery roughly halves the risk of death in early-stage disease.

## Summary

EGFR mutations were discovered in 2004 when three Boston groups worked out why a minority of lung cancers, mostly in never-smoking women and East Asian patients, melted away on gefitinib. The IPASS trial (2009) then showed that in mutation carriers gefitinib beat chemotherapy and in non-carriers it was worse, which made EGFR testing mandatory before first-line treatment and established the model of a driver mutation matched to a pill. Exon 19 deletions and L858R are the classical sensitising mutations; exon 20 insertions are resistant to the classical inhibitors; and uncommon mutations (G719X, L861Q, S768I) respond best to afatinib or osimertinib.

Osimertinib, designed against the T790M resistance mutation, beat gefitinib and erlotinib first line in FLAURA (2018): median progression-free survival 18.9 versus 10.2 months and overall survival 38.6 versus 31.8 months, with far less brain progression. Two trials then built on it: FLAURA2 (2023) added platinum-pemetrexed to osimertinib (progression-free survival 25.5 versus 16.7 months, hazard ratio 0.62, with the 2025 survival analysis also in favour), and MARIPOSA (2024) combined the EGFR-MET bispecific antibody amivantamab with lazertinib (23.7 versus 16.6 months, hazard ratio 0.70, and longer overall survival), at the cost of rash, nail changes and venous thrombosis. For exon 20 insertions, PAPILLON (2023) showed amivantamab plus chemotherapy beat chemotherapy (11.4 versus 6.7 months, hazard ratio 0.40) and sunvozertinib was approved in 2025 after platinum chemotherapy. After osimertinib the escape routes are MET amplification (osimertinib plus savolitinib), C797S, small-cell transformation and, most often, no identifiable mechanism, where amivantamab plus chemotherapy (MARIPOSA-2) and the TROP2 antibody-drug conjugate datopotamab deruxtecan are the options.

In early disease ADAURA (2020) showed that three years of adjuvant osimertinib after resection cut recurrence by 83 percent in stage II to IIIA (hazard ratio 0.17) and improved five-year overall survival from 78 to 88 percent, and LAURA (2024) showed that osimertinib after chemoradiation for unresectable stage III disease extended progression-free survival from 5.6 to 39.1 months. Checkpoint inhibitors work poorly in EGFR-mutated disease and are held back until targeted options are exhausted. Open questions are how to choose between the three first-line strategies, whether circulating tumour DNA clearance can guide escalation, and how to prevent rather than treat resistance.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: EGFR-mutant lung cancer; EGFR-positive NSCLC; EGFR exon 19 deletion lung cancer; EGFR L858R lung cancer; EGFR exon 20 insertion lung cancer
- Tags: subtype-page; lung
- Group: lung
- Burden: About 15 percent of lung adenocarcinomas in Europe and North America and 40 to 50 percent in East Asia carry an activating EGFR mutation; it is the commonest driver in never-smokers and in women. Exon 19 deletions and L858R make up about 85 percent of cases, exon 20 insertions about 10 percent.
- Subtypes: EGFR exon 19 deletion adenocarcinoma (about 45 percent); EGFR L858R adenocarcinoma (about 40 percent); EGFR exon 20 insertion (about 10 percent; amivantamab, sunvozertinib); Uncommon EGFR mutations (G719X, L861Q, S768I; afatinib or osimertinib); T790M or C797S after EGFR inhibitor therapy; EGFR-mutated disease transformed to small-cell lung cancer
- Biomarkers: EGFR mutation by tissue or plasma sequencing before first-line therapy (exon 19 deletion, L858R, exon 20 insertion, uncommon); T790M and C797S at progression; MET amplification at progression (fluorescence in situ hybridisation or sequencing); Circulating tumour DNA clearance during treatment (under study); Repeat biopsy at progression for small-cell transformation; PD-L1 (of limited use; checkpoint inhibitors work poorly)

## Standard of care

- Advanced, first line (exon 19 deletion or L858R): Osimertinib alone (FLAURA), osimertinib plus platinum-pemetrexed (FLAURA2) for patients with high burden or brain metastases who can take chemotherapy, or amivantamab plus lazertinib (MARIPOSA) with prophylaxis against rash and clots. ([Osimertinib](https://onco.cc/drugs/osimertinib/), [FLAURA](https://onco.cc/trials/flaura/), [FLAURA2](https://onco.cc/trials/flaura2/), [Amivantamab](https://onco.cc/drugs/amivantamab/), [Lazertinib](https://onco.cc/drugs/lazertinib/), [Amivantamab + lazertinib (first-line EGFR NSCLC)](https://onco.cc/pairings/amivantamab-plus-lazertinib/), [MARIPOSA](https://onco.cc/trials/mariposa/), [EGFR exon 19 deletion & L858R](https://onco.cc/terms/egfr-exon19-l858r/))
- Advanced, exon 20 insertion: Amivantamab plus carboplatin-pemetrexed first line (PAPILLON); sunvozertinib after platinum chemotherapy. ([Amivantamab](https://onco.cc/drugs/amivantamab/), [A Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Characterized by Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions](https://onco.cc/trials/nct04538664/), [Sunvozertinib](https://onco.cc/drugs/sunvozertinib/), [Assessing an Oral EGFR Inhibitor, Sunvozertinib in Patients Who Have Advanced Non-small Cell Lung Cancer With EGFR or HER2 Mutation (WU-KONG1)](https://onco.cc/trials/nct03974022/), [EGFR exon 20 insertion](https://onco.cc/terms/egfr-exon20-insertion/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/))
- Advanced, after osimertinib: Biopsy or plasma test for the mechanism: osimertinib plus savolitinib for MET amplification; otherwise amivantamab plus platinum chemotherapy (MARIPOSA-2), platinum-pemetrexed, or datopotamab deruxtecan after chemotherapy; platinum-etoposide for small-cell transformation. ([Amivantamab](https://onco.cc/drugs/amivantamab/), [A Study of Amivantamab and Lazertinib in Combination With Platinum-Based Chemotherapy Compared With Platinum-Based Chemotherapy in Patients With Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non- Small Cell Lung Cancer After Osimertinib Failure](https://onco.cc/trials/nct04988295/), [Savolitinib](https://onco.cc/drugs/savolitinib/), [Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib](https://onco.cc/trials/nct03778229/), [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [TROPION-Lung05](https://onco.cc/trials/tropion-lung05/), [MET amplification (bypass resistance)](https://onco.cc/terms/met-amplification/), [EGFR C797S](https://onco.cc/terms/c797s/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [Platinum + etoposide (EP / CE)](https://onco.cc/drugs/platinum-etoposide/))
- Resected stage IB to IIIA: Surgery, adjuvant platinum chemotherapy where indicated, then three years of osimertinib (ADAURA). ([Osimertinib](https://onco.cc/drugs/osimertinib/), [ADAURA](https://onco.cc/trials/adaura/), [Lobectomy](https://onco.cc/terms/lobectomy/), [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/))
- Unresectable stage III: Concurrent platinum chemoradiation followed by osimertinib until progression (LAURA) rather than durvalumab. ([Osimertinib](https://onco.cc/drugs/osimertinib/), [LAURA](https://onco.cc/trials/laura/), [Chemoradiation (chemoradiotherapy, CRT)](https://onco.cc/terms/chemoradiation/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/))
- Brain and leptomeningeal metastases: Osimertinib has high brain penetration and is preferred; stereotactic radiosurgery for symptomatic or large lesions; high-dose osimertinib for leptomeningeal disease. ([Osimertinib](https://onco.cc/drugs/osimertinib/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Leptomeningeal disease](https://onco.cc/terms/leptomeningeal-disease/))

## State of the art

- Three first-line strategies with osimertinib as the anchor: alone, with chemotherapy (FLAURA2) or replaced by amivantamab plus lazertinib (MARIPOSA), with overall survival gains for the combinations.
- Amivantamab plus chemotherapy (PAPILLON) and sunvozertinib for exon 20 insertions, a group that had no effective targeted drug until 2021.
- Adjuvant osimertinib (ADAURA) and post-chemoradiation osimertinib (LAURA) extend targeted therapy into curative-intent disease.
- Datopotamab deruxtecan approved in 2025 for disease that has progressed on an EGFR inhibitor and chemotherapy.

## Open problems

- No head-to-head trial compares the three first-line strategies, and the added toxicity of the combinations falls on every patient for a benefit concentrated in some.
- Most resistance to osimertinib has no identifiable mechanism and no targeted option.
- Whether adjuvant osimertinib cures more patients or delays recurrence beyond the three years of treatment is still being followed.
- Checkpoint inhibitors add little and increase pneumonitis when combined with EGFR inhibitors.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor
- Wikipedia: https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor
- NCCN Guidelines: Non-Small Cell Lung Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450

## Connected records

- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Bispecific antibodies](https://onco.cc/technologies/bispecific-antibody/), [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [MRD / molecular residual disease testing](https://onco.cc/technologies/mrd-testing/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/)
- targets: [EGFR](https://onco.cc/targets/egfr/), [HER3](https://onco.cc/targets/her3/), [MET](https://onco.cc/targets/met/), [TROP2](https://onco.cc/targets/trop2/)
- drugs: [Afatinib](https://onco.cc/drugs/afatinib/), [Amivantamab](https://onco.cc/drugs/amivantamab/), [Befotertinib](https://onco.cc/drugs/befotertinib/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [Erlotinib](https://onco.cc/drugs/erlotinib/), [Furmonertinib](https://onco.cc/drugs/furmonertinib/), [Gefitinib](https://onco.cc/drugs/gefitinib/), [Izalontamab brengitecan](https://onco.cc/drugs/izalontamab-brengitecan/), [Lazertinib](https://onco.cc/drugs/lazertinib/), [Mobocertinib](https://onco.cc/drugs/mobocertinib/), [Osimertinib](https://onco.cc/drugs/osimertinib/), [Patritumab deruxtecan](https://onco.cc/drugs/patritumab-deruxtecan/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Platinum + etoposide (EP / CE)](https://onco.cc/drugs/platinum-etoposide/), [Savolitinib](https://onco.cc/drugs/savolitinib/), [Silevertinib](https://onco.cc/drugs/silevertinib/), [Sunvozertinib](https://onco.cc/drugs/sunvozertinib/), [Zipalertinib](https://onco.cc/drugs/zipalertinib/)
- companies: [AstraZeneca](https://onco.cc/companies/astrazeneca/), [Daiichi Sankyo](https://onco.cc/companies/daiichi-sankyo/), [Dizal Pharmaceutical](https://onco.cc/companies/dizal/), [Johnson & Johnson](https://onco.cc/companies/johnson-johnson/), [Yuhan Corporation](https://onco.cc/companies/yuhan/)
- pathways: [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Chemoradiation (chemoradiotherapy, CRT)](https://onco.cc/terms/chemoradiation/), [Driver mutation](https://onco.cc/terms/driver-mutation/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [EGFR C797S](https://onco.cc/terms/c797s/), [EGFR exon 19 deletion & L858R](https://onco.cc/terms/egfr-exon19-l858r/), [EGFR exon 20 insertion](https://onco.cc/terms/egfr-exon20-insertion/), [EGFR mutation subtypes (exon 19 deletion, L858R, exon 20 insertion, T790M)](https://onco.cc/terms/egfr-mutation-subtypes/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [Leptomeningeal disease](https://onco.cc/terms/leptomeningeal-disease/), [Lobectomy](https://onco.cc/terms/lobectomy/), [MET amplification (bypass resistance)](https://onco.cc/terms/met-amplification/), [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/), [Oncogene addiction](https://onco.cc/terms/oncogene-addiction/), [Tyrosine kinase inhibitor (TKI)](https://onco.cc/terms/tki-term/)
- trials: [A Study of Amivantamab and Lazertinib in Combination With Platinum-Based Chemotherapy Compared With Platinum-Based Chemotherapy in Patients With Epidermal Growth Factor Receptor (EGFR)-Mutated Locally Advanced or Metastatic Non- Small Cell Lung Cancer After Osimertinib Failure](https://onco.cc/trials/nct04988295/), [A Study of Combination Amivantamab and Carboplatin-Pemetrexed Therapy, Compared With Carboplatin-Pemetrexed, in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Characterized by Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertions](https://onco.cc/trials/nct04538664/), [ADAURA](https://onco.cc/trials/adaura/), [Assessing an Oral EGFR Inhibitor, Sunvozertinib in Patients Who Have Advanced Non-small Cell Lung Cancer With EGFR or HER2 Mutation (WU-KONG1)](https://onco.cc/trials/nct03974022/), [FLAURA](https://onco.cc/trials/flaura/), [FLAURA2](https://onco.cc/trials/flaura2/), [Gefitinib vs gefitinib plus pemetrexed-carboplatin in EGFR-mutant lung cancer (Tata Memorial)](https://onco.cc/trials/gefitinib-chemo-tmh/), [HERTHENA-Lung02](https://onco.cc/trials/herthena-lung02/), [LAURA](https://onco.cc/trials/laura/), [MARIPOSA](https://onco.cc/trials/mariposa/), [Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib](https://onco.cc/trials/nct03778229/), [REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors)](https://onco.cc/trials/nct05973773/), [TROPION-Lung05](https://onco.cc/trials/tropion-lung05/)
- people: [Byoung Chul Cho](https://onco.cc/people/cho-byoung-chul/), [Daniel A. Haber](https://onco.cc/people/daniel-haber/), [David Planchard](https://onco.cc/people/david-planchard/), [Jean-Charles Soria](https://onco.cc/people/jean-charles-soria/), [Lecia V. Sequist](https://onco.cc/people/lecia-sequist/), [Pasi A. Jänne](https://onco.cc/people/pasi-janne/), [Roy S. Herbst](https://onco.cc/people/roy-herbst/), [Suresh S. Ramalingam](https://onco.cc/people/suresh-ramalingam/), [Thomas J. Lynch Jr.](https://onco.cc/people/thomas-lynch/), [Tony S. K. Mok](https://onco.cc/people/tony-mok/), [Yi-Long Wu](https://onco.cc/people/wu-yi-long/)
- key papers: [ADAURA: three years of osimertinib after surgery for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-adaura-nejm-2020/), [FLAURA: osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-flaura-nejm-2018/), [MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer](https://onco.cc/key-papers/paper-mariposa-nejm-2024/)
- pairings: [Amivantamab + lazertinib (first-line EGFR NSCLC)](https://onco.cc/pairings/amivantamab-plus-lazertinib/)
- ideas: [ctDNA-guided dose holidays for lung cancer targeted therapy](https://onco.cc/ideas/idea-bio1-ctdna-adaptive-tki/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)

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