Related Experiment Video
Updated: Sep 13, 2025
Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
Clinical Outcomes of Compound EGFR Mutations in Non-Small Cell Lung Cancer: A National, Retrospective, Multicenter
Lina Atlagh1, Anne-Claire Toublanc2, Benoit Roch3
1Pneumology Department, University Hospital Center of Limoges, Limoges, France.
Background:
Compound EGFR mutations are found in a rare proportion of non-small cell lung cancer (NSCLC). Currently there is no clear recommendation regarding the best therapeutic strategy in this setting. Chemotherapy, and tyrosine kinase inhibitors (TKI) are often used as first or second line of treatment. Recently, an in vitro structure-based classification of EGFR mutations showed a promising way of predicting response to treatment (Robichaux JC, Nature 2021).
Methods:
We conducted a multicenter, retrospective, nationwide study of patients with advanced non-small cell lung cancer (NSCLC) harboring compound EGFR mutations. The common T790M mutation and exon 20 insertions were excluded. Compound EGFR mutations were structure-based classified as classical mutations and P-loop and αC-helix compressing (PACC) mutations or unclassified mutations. Clinical data and outcome of selected patients were collected. Overall survival (OS) and progression free survival (PFS) according to structure-based classification and exon-based classification were reported, overall survival being the primary objective.
Results:
Eighty-one patients were enrolled in the analysis, including 24 patients in "classical mutations" group, 36 in the PACC group, and 21 as unclassified group. Median overall survival (OS) of the population was 42 months (95% CI, 25.5-64.4), significantly different according to structure-based classification (69.5 m in unclassified group, vs 47 m in classical mutations group and 24,3 in PACC mutations group, P = .01). There was no significant difference in OS according to the type of first-line treatment in the overall population or the presence or not of a frequent mutation (L858R or Del19). The median progression free survival in the first line setting (PFS1L) was shorter in the chemotherapy group (7.1 m.; 95% CI, 1.9-12.2) than in the TKI group (12.6 m.; 95% CI, 8.6-17), P = .005. In the PACC group, PFS1L was higher in the osimertinib group compared to other treatments, HR 0.34 (95% CI, 0.12-0.99), P=.027, whereas no difference was observed in other structure-based groups.
Conclusions:
This study demonstrates that treatment with TKIs is associated with favorable outcomes in patients with compound EGFR mutations. Structure-based configuration of EGFR might also be considered when selecting a first-line TKI.
Insights
This study shows that tyrosine kinase inhibitors (TKIs) improve outcomes for non-small cell lung cancer (NSCLC) patients with compound EGFR mutations. Structure-based classification of these mutations can guide first-line TKI selection for better treatment response.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Compound Epidermal Growth Factor Receptor (EGFR) mutations are rare in non-small cell lung cancer (NSCLC).
- Optimal therapeutic strategies for NSCLC with compound EGFR mutations remain unclear.
- A novel in vitro structure-based classification of EGFR mutations shows promise for predicting treatment response.
Purpose of the Study:
- To evaluate the clinical outcomes of patients with advanced NSCLC harboring compound EGFR mutations.
- To assess the efficacy of different therapeutic strategies based on a structure-based classification of EGFR mutations.
- To determine the impact of structure-based EGFR mutation classification on overall survival (OS) and progression-free survival (PFS).
Main Methods:
- A multicenter, retrospective, nationwide study included 81 patients with advanced NSCLC and compound EGFR mutations (excluding T790M and exon 20 insertions).
- Patients' tumors were classified based on a structure-based system: classical mutations, P-loop and αC-helix compressing (PACC) mutations, or unclassified mutations.
- Overall survival (OS) and progression-free survival (PFS) were analyzed according to mutation classification and treatment received.
Main Results:
- Median OS was significantly different across structure-based groups (69.5 months for unclassified, 47 for classical, 24.3 for PACC mutations; P = .01).
- Tyrosine kinase inhibitors (TKIs) as first-line treatment resulted in longer median PFS (12.6 months) compared to chemotherapy (7.1 months; P = .005).
- In the PACC group, osimertinib showed improved PFS compared to other treatments (HR 0.34; P=.027).
Conclusions:
- Treatment with TKIs is associated with favorable outcomes in patients with compound EGFR mutations.
- Structure-based classification of EGFR mutations may aid in selecting appropriate first-line TKIs for NSCLC patients.
- This classification system offers a potential framework for personalized treatment strategies in this challenging patient population.
More Related Videos
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...