Genomic co-alteration patterns are associated with differential benefit from first-line third-generation EGFR-TKI plus chemotherapy versus TKI monotherapy in advanced EGFR-mutant NSCLC
6 affiliations
- 1Department of Western Pharmacy, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei, Cangzhou, Hebei, China
- 2Department of Chemoradiotherapy and Hematology, Chengde Central Hospital, Chengde, Hebei, China
- 3Department of Hematological Oncology, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei, Cangzhou, Hebei, China
- 4Department of Interventional and Breast Medical Oncology, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei, Cangzhou, Hebei, China
- 5Department of Head, Neck and Thoracic Oncology, Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine-Hebei, Cangzhou, Hebei, China
- 6National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Abstract
Background: Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) plus pemetrexed-platinum chemotherapy are a first-line option for advanced EGFR-mutant NSCLC. However, whether benefit varies by genomic co-alteration background remains unclear. This study evaluated whether baseline co-alteration patterns are associated with differential efficacy of combined chemotherapy versus TKI monotherapy.
Methods: We retrospectively enrolled patients with advanced EGFR-mutant NSCLC receiving first-line third-generation EGFR-TKI monotherapy or combination with pemetrexed-platinum chemotherapy at two centers (2018–2025). Based on baseline NGS, patients were stratified into group A (EGFR mutation alone), group B (non-driver co-mutations), and group C (driver co-mutations). One-to-one propensity score matching (PSM) was applied. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), intracranial efficacy, and safety.
Results: Overall, 848 patients were enrolled; after PSM, 285 remained in each arm. The combination arm showed numerically longer median PFS (23.3 vs. 17.3 months; HR = 0.654; P < 0.001) and OS (41.2 vs. 33.7 months; HR = 0.750; P = 0.005). Group B derived the greatest benefit (mPFS: 23.0 vs. 15.3 months, HR = 0.554, P < 0.001; mOS: 39.9 vs. 33.1 months, HR = 0.694, P = 0.007), whereas groups A (mPFS: 26.5 vs. 22.8 months, HR = 0.833, P = 0.253) and C (mPFS: 14.5 vs. 10.2 months, HR = 0.584, P = 0.088) showed no significant differences. The treatment-by-co-alteration interaction for PFS was significant (P = 0.032). Among patients with baseline brain metastases, median intracranial PFS was numerically longer with combination therapy than with monotherapy (18.8 vs. 12.6 months; HR = 0.739, 95% CI 0.544–1.003; log-rank P = 0.047), although the difference was of borderline statistical significance. Hematologic toxicities were more frequent with combination therapy but manageable.
Conclusions: In advanced EGFR-mutant NSCLC, baseline co-alteration patterns are associated with the magnitude of benefit from first-line combined chemotherapy. Patients with non-driver co-mutations may derive greater PFS and OS benefit from TKI plus chemotherapy, whereas those with EGFR mutation alone fare well with TKI monotherapy. Given the retrospective design, biological heterogeneity within subgroups, small driver-co-mutation sample size, and non-significant OS interaction, these findings are hypothesis-generating and require prospective validation before guiding individualized treatment decisions.
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BibTeX
@article{bai2026genomic,
title = {{Genomic co-alteration patterns are associated with differential benefit from first-line third-generation EGFR-TKI plus chemotherapy versus TKI monotherapy in advanced EGFR-mutant NSCLC}},
author = {Lili Bai and Huijie Wu and Yue Jiang and Dan Ran and Ying Li and Jianxi Zhou and Teng Duan},
journal = {Frontiers in Medicine},
year = {2026},
month = oct,
doi = {10.3389/fmed.2026.1969669},
url = {https://doi.org/10.3389/fmed.2026.1969669},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Genomic co-alteration patterns are associated with differential benefit from first-line third-generation EGFR-TKI plus chemotherapy versus TKI monotherapy in advanced EGFR-mutant NSCLC
AU - Lili Bai
AU - Huijie Wu
AU - Yue Jiang
AU - Dan Ran
AU - Ying Li
AU - Jianxi Zhou
AU - Teng Duan
PY - 2026
DA - 2026/10/21
JO - Frontiers in Medicine
DO - 10.3389/fmed.2026.1969669
UR - https://doi.org/10.3389/fmed.2026.1969669
AB - Background: Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) plus pemetrexed-platinum chemotherapy are a first-line option for advanced EGFR-mutant NSCLC. However, whether benefit varies by genomic co-alteration background remains unclear. This study evaluated whether baseline co-alteration patterns are associated with differential efficacy of combined chemotherapy versus TKI monotherapy. Methods: We retrospectively enrolled patients with advanced EGFR-mutant NSCLC receiving first-line third-generation EGFR-TKI monotherapy or combination with pemetrexed-platinum chemotherapy at two centers (2018–2025). Based on baseline NGS, patients were stratified into group A (EGFR mutation alone), group B (non-driver co-mutations), and group C (driver co-mutations). One-to-one propensity score matching (PSM) was applied. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), intracranial efficacy, and safety. Results: Overall, 848 patients were enrolled; after PSM, 285 remained in each arm. The combination arm showed numerically longer median PFS (23.3 vs. 17.3 months; HR = 0.654; P < 0.001) and OS (41.2 vs. 33.7 months; HR = 0.750; P = 0.005). Group B derived the greatest benefit (mPFS: 23.0 vs. 15.3 months, HR = 0.554, P < 0.001; mOS: 39.9 vs. 33.1 months, HR = 0.694, P = 0.007), whereas groups A (mPFS: 26.5 vs. 22.8 months, HR = 0.833, P = 0.253) and C (mPFS: 14.5 vs. 10.2 months, HR = 0.584, P = 0.088) showed no significant differences. The treatment-by-co-alteration interaction for PFS was significant (P = 0.032). Among patients with baseline brain metastases, median intracranial PFS was numerically longer with combination therapy than with monotherapy (18.8 vs. 12.6 months; HR = 0.739, 95% CI 0.544–1.003; log-rank P = 0.047), although the difference was of borderline statistical significance. Hematologic toxicities were more frequent with combination therapy but manageable. Conclusions: In advanced EGFR-mutant NSCLC, baseline co-alteration patterns are associated with the magnitude of benefit from first-line combined chemotherapy. Patients with non-driver co-mutations may derive greater PFS and OS benefit from TKI plus chemotherapy, whereas those with EGFR mutation alone fare well with TKI monotherapy. Given the retrospective design, biological heterogeneity within subgroups, small driver-co-mutation sample size, and non-significant OS interaction, these findings are hypothesis-generating and require prospective validation before guiding individualized treatment decisions.
SN - 2296-858X
ER -