Introduction
Non-small cell lung cancer (NSCLC) accounts for 85% of all confirmed lung cancer cases in the United States (1). NSCLC is difficult to detect in the early stages and has a high degree of malignancy and invasiveness. Therefore, the majority of patients with lung cancer are diagnosed with an already locally advanced stage or metastatic lesions at first presentation. Although surgery, radiotherapy (RT), chemotherapy, and other treatments can prolong the survival time of patients with late-stage disease, the overall survival rate of NSCLC is still poor. For patients with stage IV NSCLC in the United States, the 1-year survival rate was 25.1%, with a median overall survival of only 8.2 months (2).
EGFR mutation is one of the most common types of gene mutations in NSCLC. Patients with advanced or metastatic NSCLC carrying EGFR gene mutations (such as exon 19 deletion or exon 21 point mutation) exhibit high sensitivity to EGFR tyrosine kinase inhibitors (TKIs) (3). Osimertinib is a representative third-generation EGFR-TKI that can exert marked inhibitory effects on tumor cell proliferation, invasion, and metastasis by effectively inhibiting mutant EGFR activation (3,4). Osimertinib irreversibly binds to cysteine residue 797 at the ATP binding site of EGFR. Compared with gefitinib and erlotinib, osimertinib exhibits marked antitumor activity (4) and has the ability to overcome T790M mutation-mediated drug resistance, whilst moderately inhibiting the abnormal activation state of human epidermal growth factor receptor 2 (5). In addition, osimertinib addresses the toxic side effects of second-generation EGFR-TKIs.
Thoracic RT (TRT) is an indispensable component of multimodal therapy for patients with advanced NSCLC, particularly for achieving local tumor control. Accumulating evidence suggests that the combination of local TRT with systemic therapy may be a promising strategy for patients with oligo-metastatic or oligo-progressive disease (6,7), as it may eliminate resistant tumor cells or control dominant local lesions, thereby prolonging the time to systemic treatment failure. Pre-emptive TRT before the onset of disease progression has also been proposed as an effective strategy to counteract resistance, especially that mediated by the T790M mutation (8). Furthermore, TKIs possess a radiosensitizing effect, which can enhance the antitumor efficacy of TRT and mitigate secondary drug resistance (9). However, the optimal timing and the sequencing of TRT combined with EGFR-TKIs remain subjects of considerable debate. Whilst concurrent administration may offer enhanced antitumor effects, it also carries an increased risk of severe adverse events, such as radiation pneumonitis or esophagitis, which can lead to treatment interruption. By contrast, a sequential approach may reduce toxicity, but risks compromising local control by delaying intervention (10). In addition, the majority of existing studies on this combined modality have focused on first- or second-generation EGFR-TKIs (11). Despite the existence of studies reporting improvements in progression-free survival (PFS) and overall survival (OS) as a result of the combination of TRT and earlier-generation EGFR-TKI (12), there remains a distinct lack of evidence for guiding the optimal timing of TRT in the context of third-generation osimertinib therapy. This knowledge gap highlights the need for a comprehensive investigation into the relationship between different TRT intervals and the prognosis of patients receiving osimertinib.
The aim of the present study was to investigate the relationship between different TRT intervals and the prognosis of patients with advanced lung adenocarcinoma receiving osimertinib, while exploring the optimal treatment intervals and beneficiary population for TRT.
Discussion
To the best of our knowledge, the relationship between the treatment interval for chest RT and prognosis in patients with advanced NSCLC treated with first-line osimertinib has not been sufficiently analyzed. A key novel finding of the present study is the significant impact of RT interval on prognosis and their non-linear relationship. Treatment interval was significantly associated with LPFS, PFS, and OS. In the middle intervals (40–102 days/40-104 days), the risk rapidly increased for LPFS, PFS, and OS. However, outside this threshold range, no significant change in prognostic risk was observed. In the Kaplan-Meier curve, patients treated early had a superior prognosis in terms of LPFS, PFS, and OS. These findings indicate that TRT initiation within 40 days of osimertinib commencement is associated with maximal survival benefit, whilst delays between 40 and 104 days confer a significantly elevated risk of disease progression and mortality.
The sensitivity of NSCLC to RT is low, and the timing of radiation therapy initiation remains a controversial issue. Previous studies have shown that the benefit of EGFR-TKI combined with RT in terms of PFS is superior compared with that of combined anti-angiogenesis therapy, chemotherapy, and any other treatment (17), in addition to being superior to EGFR-TKI alone (18). In terms of mechanism, there is evidence that the combination of EGFR-TKI and RT can significantly reduce the proportion of S-phase cells, induce apoptosis, inhibit the autophosphorylation of epidermal EGFR and downregulate the expression of Rad51 recombinase to enhance radiosensitivity (19). Similarly, induction chemotherapy before RT has a benefit on the OS of patients with NSCLC receiving RT and chemotherapy (20), which indicates the rationality of EGFR-TKI therapy combined with consolidation RT. However, Xu et al (21) enrolled 45 patients with stage III NSCLC treated with concurrent radiotherapy plus EGFR-TKIs, 20 of whom (44.4%) harbored EGFR mutations. The cohort achieved a median PFS time of 27.9 months (95% CI, 18.7–37.2) and a median OS time of 49.7 months (95% CI, 27.7–71.8). Different from this concurrent treatment strategy, the present study adopted sequential EGFR-TKI consolidation following radiotherapy and included patients with stage IV disease, who generally have poorer baseline prognostic outcomes. Despite this disadvantage at baseline, the patients still achieved promising survival outcomes, which may be explained by the longer median duration of EGFR-TKI treatment in the present cohort (28.4 vs. 14.4 months) compared with that of the cohort in the study by Xu et al (21). Previous studies found that the treatment time was positively associated with OS (21), which was also the reason for the shorter median OS time observed in the present cohort. Hu et al (22) adopted a similar treatment strategy to the present study, combining EGFR-TKIs with local consolidative radiotherapy. Nevertheless, the cohort achieved a longer median OS time than in the present study (38.0 vs. 25.6 months). This survival discrepancy was mainly attributed to differences in baseline patient characteristics, as the study only enrolled elderly patients with oligometastatic disease who carried more favorable prognostic profiles (22). Importantly, while baseline patient characteristics and EGFR-TKI treatment duration have been established as prognostic predictors for EGFR-mutant NSCLC (23), few studies have specifically investigated how the time interval between EGFR-TKI initiation and thoracic radiotherapy affects long-term survival. Although this temporal parameter has not yet been fully characterized, it bears important clinical implications for guiding the optimal sequencing of targeted therapy and radiotherapy.
The present study shows that the intervals of 40 and 102/104 days are the inflection points for the therapeutic effect of the time interval between EGFR-TKI initiation and thoracic radiotherapy. Within 40–102/104 days, the longer interval is associated with a higher probability of adverse prognostic risk. EGFR-TKI can inhibit the proliferation and survival of tumor cells while altering the immune environment (22). When the interval between EGFR-TKI and RT is short, EGFR-TKI and RT can exert synergistic effects, making the killing effect of RT on tumor cells more potent (24,25). This can explain the time trend of the RT effect observed in the present study. An interval of <30 days may be too brief to permit full TKI-mediated radiosensitization, attenuating clinical benefit. Li et al (26) observed that primary tumor radiotherapy initiated 30 days after EGFR-TKI yielded better overall survival than either earlier treatment or post-progression radiotherapy, but did not evaluate non-linear interval effects. Several lines of evidence support the rationality of the upper limit of 102/104 days for radiotherapy initiation identified. Tang et al (27) found that patients receiving single-agent EGFR-TKIs achieved a median time to therapeutic response of 2.00 months (95% CI, 1.28 to 2.92 months). For patients with stable disease, the median time to maximum tumor shrinkage was also 2.00 months, corresponding to a 95% CI of 1.42–2.58 months. These clinical observations align with another independent study confirming that effective antitumor responses can be achieved within 8 weeks after EGFR-TKI treatment initiation (27). Therefore, these published data presented above reveal that EGFR-TKIs mostly induce maximal tumor regression within the first 2 months of treatment. This temporal characteristic matches the 67-day breakpoint observed in the present restricted cubic spline analysis. Radiotherapy delayed beyond this time point correlates with an elevated risk of local disease progression. Such temporal consistency further supports the biological rationality of the present findings. Clinically, administering thoracic radiotherapy after EGFR-TKI-induced tumor shrinkage, and before the development of drug resistance and tumor regrowth, constitutes an optimal treatment window to maximize local tumor control. This appropriate time window opens 6 to 8 weeks after TKI administration and closes no later than 102 to 104 days after TKI initiation.
In the present study, restricted cubic spline and piecewise regression analyses confirmed a non-linear association between the osimertinib-to-TRT interval and survival outcomes. In the present results, the mortality risk remained stable for intervals of <40 days and rose significantly for intervals between 40 and 102 days, before plateauing again for intervals >102 days. This trend may be attributed to the dynamic changes in tumor cell cycle status, immune microenvironment evolution, and clinical confounding factors. This interval-specific elevation in risk may be primarily driven by the waning of osimertinib-induced radiosensitization. Preclinical studies in EGFR-mutant NSCLC models have demonstrated that EGFR-TKI induces G1 cell cycle arrest and exerts transient radiosensitizing effects (28,29). This radiosensitization gradually diminishes with prolonged drug exposure, as surviving tumor cells restore proliferative capacity via upregulation of cyclin D1 and CDK4/6 signaling (30–32). By 40 days post-initiation, the majority of surviving tumor cells have exited G1 arrest. The upregulation of cyclin D1 and CDK4/6 signaling restores their proliferative capacity and reverses intrinsic radiosensitivity by a 2-times decrease compared with those in the first 2 weeks of the treatment period. Furthermore, this 40–102-day window corresponds to a transient immunosuppressive phase under continuous EGFR inhibition. In a phase III FLAURA trial, the proportion of immunosuppressive M2-polarised tumor-associated macrophages and regulatory T cells was found to be notably increased between 6 and 14 weeks post-osimertinib initiation (33). A 2.1-times rise in tumor cell programmed death ligand 1 (PD-L1) expression is observed at 12 weeks. Consistent with a prior finding (26), long-term single-agent EGFR-TKI exposure can progressively consolidate the tumor microenvironment into a deeply immunosuppressive state, promoting drug resistance and immune escape. Whilst RT can induce immunogenic cell death and promote antitumor immune responses (34,35), it also instantaneously upregulates immunosuppressive molecules, such as PD-L1, indoleamine 2,3-dioxygenase 1, and TGF-β, while activating regulatory T cell and myeloid-derived suppressor cell function (36). Regardless of the local radiation dose, within the 40- to 102-day window, the pre-existing immunosuppressive milieu may blunt the RT-induced abscopal effect, eliminating the synergistic benefit of combined treatment. A previous retrospective cohort study demonstrated that RT initiated within this interval was associated with a 1.8-times higher risk of early local progression relative to intervals greater than or less than this threshold, with no notable difference in grade ≥2 radiation toxicity between groups (37). The observed plateau in mortality risk for intervals >102 days likely reflects clinical confounding. Patients requiring delayed RT beyond this point typically have rapidly progressive disease or severe local symptoms. In such cases, RT is delivered for palliative symptom control rather than with curative intent, leading to an inherently poor prognosis independent of timing. Although further mechanistic validation with longitudinal immune microenvironment profiling is warranted, this interval-specific risk likely reflects the convergence of lost cell cycle-mediated radiosensitivity and transient immunosuppression. Future studies establishing multi-omic prediction models for optimal EGFR-TKI-RT interval will enable real-time individualized treatment timing to improve patient outcomes.
In the present study, the EGFR exon 21 L858R point mutation was identified as an independent prognostic factor significantly associated with OS. This finding is consistent with the general understanding that patients harboring EGFR mutations exhibit enhanced sensitivity to EGFR-TKIs (37), consequently leading to prolonged OS times compared with patients harboring wild-type EGFR (38). However, within the spectrum of common activating mutations, exon 19 deletions are generally considered to confer a superior median OS time over the L858R mutation in the setting of first-line EGFR-TKI treatment (39,40). This difference is typically mechanistically ascribed to distinct structural alterations present within the EGFR-TKI binding domain, which confer greater TKI sensitivity to the exon 19 deletion subtype (41,42).
A notable discrepancy observed in the present cohort was the lack of a significant prognostic effect of the mutation subtype on PFS, despite the strong association with OS. This difference in outcomes (PFS vs. OS) may be attributable to the established association of the L858R subtype with high-risk oncogenic features, such as a greater propensity for liver/brain metastases or concomitant TP53 co-mutation (43,44), factors that are more robustly associated with compromised OS compared with initial PFS.
Furthermore, the mechanistic rationale for combining osimertinib with ionizing radiation (IR) is robust. In vitro evidence has shown that osimertinib can synergistically enhance the antitumor activity of IR by inhibiting cellular proliferation and clonal survival, reducing IR-induced G2/M cell cycle arrest and delaying DNA damage repair in a concentration- and time-dependent manner. This synergy is also mediated by effectively blocking the phosphorylation of EGFR (Tyr1068/Tyr1173) and key downstream signaling pathways, including AKT and ERK (45). The present study established a critical time threshold for the TKI-TRT interval in the overall cohort. The observed differential impact of the L858R subtype on OS highlights the need for tailored strategies. Future large-scale, prospective investigations are therefore warranted to explore the optimal TRT initiation timing specific to individual EGFR mutation subtypes, ensuring maximized long-term clinical benefit.
The present study has several limitations. The retrospective design, single-center and relatively small sample size introduce the potential for selection bias. Although the present findings strongly suggest an optimal treatment window, the definitive establishment of the ideal combination strategy necessitates rigorous validation through larger, prospective, multi-center trials. Furthermore, despite multivariable adjustment, IPTW weighting and rigorous immortal time bias elimination, the present study remains susceptible to unmeasured confounding, among which tumor molecular heterogeneity is particularly relevant. The clonal heterogeneity of the T790M mutation and co-existing gene mutations, such as those in TP53, can accelerate the development of osimertinib resistance (46). As such molecular profiles may prompt clinicians to initiate TRT earlier while independently worsening prognosis, they act as unmeasured confounders that could create a spurious association of ‘benefits of early TRT’. Another potential source of unmeasured confounding is molecular residual disease (MRD) status, typically detected through circulating tumor DNA (ctDNA) sequencing. As MRD/ctDNA data were unavailable in the present retrospective cohort, adjustments could not be made for it. However, external evidence shows that patients with undetectable MRD have a superior prognosis (47). Such patients may be preferentially assigned to delayed TRT by their physicians. This would concentrate biologically favorable cases in the delayed-TRT arm, artificially inflating its apparent survival benefit and biasing the estimated effect of TRT timing. In addition, differences in treatment regimens that patients receive subsequently can directly affect survival, which can in turn inversely influence clinician decisions regarding the timing of TRT (48).
In summary, the interval between osimertinib initiation and TRT was an independent prognostic factor with a non-linear association with clinical outcomes. TRT delivered within 40 days was associated with optimal LPFS, PFS and OS. Between 40 and 104 days, longer intervals correlated with progressively worse outcomes. Beyond 104 days, further delay did not significantly alter prognostic risk. These findings support the integration of TRT within 40 days of osimertinib initiation.