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Updated: Oct 16, 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
Sequential afatinib and osimertinib in patients with EGFR mutation-positive NSCLC and acquired T790M: A global
Sanjay Popat1, Hyun Ae Jung2, Shin Yup Lee3
1Lung Unit, Royal Marsden National Health Service Foundation Trust, London, United Kingdom; The Institute of Cancer Research, London, United Kingdom.
Background:
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard of care for EGFR mutation-positive non-small cell lung cancer (NSCLC). However, optimal sequence of treatment has yet to be defined. Overall survival (OS) is influenced by the availability/use of subsequent therapy after first-line treatment. Emergence of T790M is the main mechanism of resistance to afatinib and second-line osimertinib could be a treatment option in this instance.
Methods:
In this non-interventional, global study (NCT04179890), existing medical/electronic records were identified for consecutive EGFR TKI-naïve patients with EGFR mutation-positive NSCLC (Del19 or L858R) treated with first-line afatinib and second-line osimertinib in regular clinical practice (n = 191; all T790M-positive). The primary objective was time to treatment failure (TTF). Key secondary objectives were OS and objective response rate (ORR).
Results:
At the start of afatinib treatment, median age (range) was 62 years (34-88). Fifty-five percent of patients were female and 67% were Asian. ECOG PS (0/1/≥2) was 31%/57%/12%. Fourteen percent of patients had brain metastases. At the start of osimertinib treatment, ECOG PS (0/1/≥2) was 25%/61%/14% and 14% had brain metastases (rising to 29% at the end of osimertinib treatment). The source of biopsy material (solid/liquid) was 86%/3% at the start of afatinib and 54%/33% at start of osimertinib. Mutations were mainly detected with PCR methods. Overall, median TTF was 27.7 months (95% CI: 24.0-30.2) and median OS was 36.5 months (95% CI: 32.9-41.8). ORR with afatinib and osimertinib was 74% and 45%. TTF, OS and ORR were generally consistent across subgroups.
Conclusion:
Sequential afatinib and osimertinib demonstrated encouraging activity in patients with EGFR mutation-positive NSCLC and acquired T790M. Activity was observed across all subgroups, including patients with poor ECOG PS or brain metastases. ECOG PS and incidence of brain metastases remained stable prior to, and after, afatinib treatment.
Insights
Sequential treatment with afatinib and osimertinib shows promising outcomes for EGFR mutation-positive non-small cell lung cancer (NSCLC) patients who develop T790M resistance. This combination therapy offers significant time to treatment failure and overall survival benefits.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard for EGFR mutation-positive non-small cell lung cancer (NSCLC).
- Optimal treatment sequencing remains undefined, impacting overall survival (OS).
- T790M mutation is a key resistance mechanism to afatinib, suggesting osimertinib as a potential second-line option.
Purpose of the Study:
- To evaluate the efficacy of sequential afatinib followed by osimertinib in EGFR mutation-positive NSCLC patients.
- To assess time to treatment failure (TTF), overall survival (OS), and objective response rate (ORR).
- To analyze treatment outcomes across various patient subgroups.
Main Methods:
- A non-interventional, global study (NCT04179890) analyzed real-world data from 191 EGFR TKI-naïve NSCLC patients.
- Patients received first-line afatinib and second-line osimertinib, all T790M-positive.
- Primary endpoint was TTF; secondary endpoints included OS and ORR.
Main Results:
- Median TTF was 27.7 months and median OS was 36.5 months.
- Objective response rates (ORR) for afatinib and osimertinib were 74% and 45%, respectively.
- Consistent efficacy was observed across subgroups, including those with poor ECOG performance status or brain metastases.
Conclusions:
- Sequential afatinib and osimertinib demonstrate encouraging activity in EGFR mutation-positive NSCLC with acquired T790M resistance.
- The treatment sequence is effective across diverse patient populations, including those with comorbidities.
- Treatment outcomes remained stable regarding performance status and brain metastases incidence.
