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Updated: May 12, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Variant allele frequency as a predictor of treatment response to osimertinib in EGFR-mutated NSCLC
Walid Shalata1,2, Bilal Krayim3, Asmah Miari4
1The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Beersheba, Israel.
Background:
Osimertinib has been approved as a treatment option for epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). However, despite the identification of common mutations, there are still no additional pathological factors that can be used to predict treatment response and improvement in survival.
Methods:
This retrospective study utilized data from a multi-center registry of NSCLC patients with EGFR mutations who were treated with first-line osimertinib therapy between March 2017 and December 2024. The variant allele frequency (VAF) was evaluated as a potential predictive factor for overall survival (OS).
Results:
For the cohort of 147 patients who met eligibility requirements, the mean OS was 25.5 months (95% CI 20.28-30.75) and progression-free survival (PFS) was 21.4 months (95% CI 17.38-25.37). The mean OS was 19.7 months (95% CI 14.21-25.10) for VAF <30% and 31.4 months (95% CI 23.15-39.56) for VAF ≥30%. The mean PFS was 18.2 months (95% CI 12.94-23.46) for VAF <30% and 25.0 months (95% CI 19.14-30.94) for VAF ≥30%. In the subgroup of EGFR ex 19del the mean OS was 21.1 months (95% CI 11.04-31.25) for VAF <30% and 36.6 months (95% CI 25.61-47.50) for VAF ≥30% and for the subgroup with EGFR ex21 L858R the mean OS was 18.7 months (95% CI 12.36-25.00) for VAF <30% and 25.5 months (95% CI 13.78-37.22) for VAF ≥30%.
Conclusion:
Our study demonstrated that the VAF is a significant factor in predicting OS and PFS in EGFR mutant patients treated with osimertinib. Patients with a VAF ≥30% showed significantly improved OS and PFS compared to those with a VAF <30%. Specifically, the mean OS was longer for patients with higher VAF in both the overall cohort and in subgroups with EGFR exon 19 deletions and exon 21 L858R mutations. These findings suggest that VAF could serve as a valuable predictive biomarker for treatment outcomes in EGFR-mutated NSCLC patients, highlighting its potential role in personalizing treatment strategies.
Insights
Variant allele frequency (VAF) predicts outcomes for EGFR-mutated NSCLC patients on osimertinib. Higher VAF (≥30%) correlates with significantly improved overall survival and progression-free survival, aiding personalized treatment strategies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Osimertinib is an approved treatment for EGFR-mutated non-small cell lung cancer (NSCLC).
- Predictive biomarkers beyond common mutations are needed to optimize treatment response and survival in NSCLC patients.
- Current limitations exist in identifying pathological factors for predicting osimertinib efficacy.
Purpose of the Study:
- To evaluate the variant allele frequency (VAF) as a predictive factor for treatment outcomes in EGFR-mutated NSCLC patients receiving first-line osimertinib.
- To determine if VAF can predict overall survival (OS) and progression-free survival (PFS) in this patient cohort.
Main Methods:
- Retrospective analysis of a multi-center registry data from 147 NSCLC patients with EGFR mutations treated with first-line osimertinib (March 2017 - December 2024).
- Variant allele frequency (VAF) was assessed as a potential predictor of overall survival (OS) and progression-free survival (PFS).
Main Results:
- Patients with VAF ≥30% demonstrated significantly longer mean OS (31.4 months) and PFS (25.0 months) compared to those with VAF <30% (OS: 19.7 months, PFS: 18.2 months).
- In the EGFR exon 19 deletion subgroup, mean OS was 36.6 months for VAF ≥30% versus 21.1 months for VAF <30%.
- For the EGFR exon 21 L858R subgroup, mean OS was 25.5 months for VAF ≥30% versus 18.7 months for VAF <30%.
Conclusions:
- Variant allele frequency (VAF) is a significant predictive biomarker for OS and PFS in EGFR-mutated NSCLC patients treated with osimertinib.
- A VAF threshold of ≥30% is associated with superior treatment outcomes, suggesting its utility in personalizing NSCLC therapy.
- VAF offers a valuable tool for stratifying patients and guiding treatment decisions in EGFR-mutated NSCLC.
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