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Updated: Oct 23, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Real-world implementation of sequential targeted therapies for EGFR-mutated lung cancer
Nikolaus Magios1, Farastuk Bozorgmehr1, Anna-Lena Volckmar2
1Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg.
Background:
Epidermal growth factor receptor-mutated (EGFR+) non-small-cell lung cancer (NSCLC) patients failing tyrosine kinase inhibitors (TKI) can benefit from next-line targeted therapies, but implementation is challenging.
Methods:
EGFR+ NSCLC patients treated with first/second-generation (1G/2G) TKI at our institution with a last follow-up after osimertinib approval (February 2016), were analyzed retrospectively, and the results compared with published data under osimertinib.
Results:
A total of 207 patients received erlotinib (37%), gefitinib (16%) or afatinib (47%). The median age was 66 years, with a predominance of female (70%), never/light-smokers (69%). T790M testing was performed in 174/202 progressive cases (86%), positive in 93/174 (53%), and followed by osimertinib in 87/93 (94%). Among the 135 deceased patients, 94 (70%) received subsequent systemic treatment (43% chemotherapy, 39% osimertinib), while 30% died without, either before (4%) or after progression, due to rapid clinical deterioration (22%), patient refusal of further therapy (2%), or severe competing illness (2%). Lack of subsequent treatment was significantly (4.5x, p < 0.001) associated with lack of T790M testing, whose most frequent cause (in approximately 50% of cases) was also rapid clinical decline. Among the 127 consecutive patients with failure of 1G/2G TKI started after November 2015, 47 (37%) received osimertinib, with a median overall survival of 36 months versus 24 and 21 months for patients with alternative and no subsequent therapies (p = 0.003).
Conclusion:
Osimertinib after 1G/2G TKI failure prolongs survival, but approximately 15% and 30% of patients forego molecular retesting and subsequent treatment, respectively, mainly due to rapid clinical deterioration. This is an important remediable obstacle to sequential TKI treatment for EGFR+ NSCLC. It pertains also to other actionable resistance mechanisms emerging under 1G/2G inhibitors or osimertinib, whose rate for lack of next-line therapy is similar (approximately 35% in the FLAURA/AURA3 trials), and highlights the need for closer monitoring alongside broader profiling of TKI-treated EGFR+ NSCLC in the future.
Insights
Osimertinib extends survival in EGFR-mutated non-small-cell lung cancer patients after first/second-generation tyrosine kinase inhibitor failure. However, rapid clinical decline impedes molecular retesting and subsequent treatment in a significant patient subset.
Area of Science:
- Oncology
- Medical Genetics
- Pharmacology
Background:
- Epidermal growth factor receptor-mutated (EGFR+) non-small-cell lung cancer (NSCLC) patients often face challenges with implementing next-line targeted therapies after tyrosine kinase inhibitor (TKI) failure.
- Understanding treatment patterns and outcomes in EGFR+ NSCLC following first/second-generation (1G/2G) TKI therapy is crucial for optimizing patient care.
Purpose of the Study:
- To evaluate the efficacy of osimertinib as a subsequent therapy in EGFR+ NSCLC patients who have progressed on 1G/2G TKIs.
- To identify factors influencing the uptake of molecular retesting and subsequent treatments in this patient population.
- To assess the impact of subsequent treatment on overall survival.
Main Methods:
- Retrospective analysis of 207 EGFR+ NSCLC patients treated with 1G/2G TKIs (erlotinib, gefitinib, afatinib).
- Comparison of outcomes with published data on osimertinib treatment.
- Analysis of T790M mutation testing rates, subsequent treatment modalities, and survival data.
Main Results:
- Among 135 deceased patients, 70% received subsequent systemic treatment (43% chemotherapy, 39% osimertinib), while 30% did not, often due to rapid clinical deterioration.
- Lack of T790M testing, frequently caused by rapid clinical decline, was significantly associated with the absence of subsequent treatment.
- In patients treated after November 2015, those receiving osimertinib after 1G/2G TKI failure showed a median overall survival of 36 months, compared to 24 and 21 months for alternative or no subsequent therapies, respectively.
Conclusions:
- Osimertinib prolongs survival in EGFR+ NSCLC patients following 1G/2G TKI failure, but a substantial proportion of patients do not undergo molecular retesting or receive subsequent treatment.
- Rapid clinical deterioration is a major impediment to sequential TKI treatment, highlighting the need for improved patient monitoring and timely intervention.
- Broader molecular profiling and closer clinical monitoring are essential for managing TKI-treated EGFR+ NSCLC patients and addressing emerging resistance mechanisms.
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