Targeted therapy for stage IA non-small cell lung cancer with EGFR mutations: a scoping review

Introduction

Lung cancer is one of the most prevalent and deadly malignant tumors worldwide. According to the International Agency for Research on Cancer (IARC), there were 2.48 million new cases and 1.82 million deaths in 2022 alone (1). Non-small cell lung cancer (NSCLC) is the most common type, accounting for approximately 85% (2). In recent years, with the widespread adoption of low-dose spiral computed tomography (CT) screening, numerous early and mid-stage NSCLC cases have been detected (3,4). Epidermal growth factor receptor (EGFR) gene mutations are common driver gene mutations in NSCLC, with approximately 10–15% of Caucasian patients and 30–40% of Asian patients carrying (5). Compared with wild-type patients, NSCLC patients with EGFR mutations have poorer prognosis and higher risk of distant metastasis (6,7). Multiple studies have demonstrated that EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are more effective than traditional chemotherapy drugs in treating EGFR-mutated NSCLC. The ADAURA and EVIDENCE studies demonstrated that, compared with placebo or adjuvant chemotherapy, postoperative adjuvant therapy with EGFR-TKIs could provide significant survival benefits for patients with stage IB–IIIA/II–IIIA EGFR-mutated NSCLC and are recommended for adjuvant therapy (8,9). The recently published NeoADAURA study also showed that neoadjuvant therapy with EGFR-TKIs significantly improved the major pathological response (MPR) rate in stage II–III B NSCLC compared to chemotherapy alone (10).

Although EGFR-TKIs have demonstrated significant clinical efficacy in targeted therapy for resectable NSCLC, there remains controversy regarding adjuvant therapy decisions for certain earlier stages of NSCLC, particularly in stage IA patients. The current mainstream view is that these tumors, due to their early stage, may not require targeted therapy. However, analysis of long-term follow-up data from numerous patients revealed that the 5-year overall survival (OS) rate for stage IA1 NSCLC patients was 92%, while it plummeted to just 77% for stage IA3 patients, with a significant number of patients still unable to achieve long-term survival after surgery (4). Additionally, with further understanding of the biological behavior of lung cancer with driver gene mutations such as EGFR, even stage IA patients still have a certain risk of recurrence after surgery. This indicates that it is crucial to pay attention to the risk of recurrence in stage IA NSCLC and to identify the treatment window in a timely manner.

Therefore, whether to initiate targeted therapy for patients with stage IA NSCLC harboring EGFR mutations has become a pressing clinical focus. This review aims to comprehensively identify and systematically summarize relevant studies to provide an overview of the current status and controversies surrounding targeted therapy for resectable stage IA NSCLC with EGFR mutations, with the goal of offering guidance for clinical decision-making and further research. We present this article in accordance with the PRISMA-ScR reporting checklist (11) (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1251/rc).

Methods

The review protocol in this study was developed a priori, based on the scoping overview framework proposed by Arksey and O’Malley (12), and was registered with the Open Science Framework (OSF; https://doi.org/10.17605/OSF.IO/65XGF).

Data source and search strategy

To comprehensively retrieve relevant evidence on topics of interest, we identified publications across nine medical databases, including PubMed, Embase, Scopus, Cochrane Library, Web of Science (WOS), China Biology Medicine Disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang Data, China Science and Technology Journal Database (VIP), as well as aggregated ongoing studies across six clinical trial registries: ClinicalTrials.gov, Chinese Clinical Trial Registry (ChiCTR), International Clinical Trials Registry Platform (ICTRP), the UK’s Clinical Study Registry (ISRCTN), European Union (EU) Clinical Trials Register, and Cochrane Central Register of Controlled Trials (CENTRAL). Our search strategy was developed collaboratively by experienced librarians and thoracic surgery clinicians, focusing on “stage IA”, “lung cancer”, and “EGFR”. It underwent thorough discussion and iterative testing to finalize the search strategy (full details in Table S1). The search was completed on June 18, 2025, with no time or language restrictions.

Eligibility criteria

We considered all studies evaluating EGFR-TKIs targeted therapy for stage IA NSCLC patients with EGFR-mutated, including adjuvant therapy, neoadjuvant therapy, sequential targeted therapy, and first-line treatment for postoperative recurrence. No restrictions were imposed on the histological subtype of NSCLC. There was no exclusion criteria based on participant characteristics (including age, gender, ethnicity, culture, or comorbidities) or study context (including geographic location or healthcare setting). No study type limitations were applied, encompassing publications, conference papers, editorials, letters, comments, and other formats. Any meaningful primary outcome was eligible. We excluded studies involving animal trials, cell experiments, purely radiological studies, interventions without EGFR mutation testing, multimodal interventions (such as targeted therapy, immunotherapy, or chemoradiotherapy) that were not clearly differentiated, studies focusing on pathology or immunology, single-case reports, clinical prediction model development, and biomarker research. Additionally, when multiple publication types existed for the same study, we selected the study with the most recent data and the largest sample size.

Study selection and data extraction

Following pilot testing of the eligibility criteria, all retrieved results were imported into the Rayyan online literature screening platform for automated duplication filtering and manual selection of studies for further research. Yafei Xie and another independent reviewer (L.X., Z.N., or Yikai Xing) initially conducted a preliminary blind screening based on titles and abstracts of the literature. After cross-checking, eligible documents proceeded to full-text to determine final inclusion. Throughout the screening process, any disagreements between reviewers were arbitrated by a third reviewer (X.M. or Z.D.) to resolve conflicts.

We developed the data extraction forms a priori for pilot testing and revised relevant items, ultimately finalizing versions for data extraction of publications and ongoing trials. The research information extracted included general study details, methods, study population, interventions, and outcome measures (full details in Appendix 1). Missing data were recorded as not applicable (NA). Data extraction followed the same protocol as study selection: intra-group blinding with third-researcher arbitration for disputes.

Evidence compilation and analysis presentation

Based on the pre-search results, we categorized the current evidence into three groups: direct evidence (studies explicitly specifying stage IA NSCLC patients with EGFR-mutated), indirect evidence (studies whose enrolled populations included our target group but did not perform stratified analysis in the results), and ongoing studies (studies whose enrolled populations included our population of interest, with evidence classification determined by whether stratified analysis for the target population is conducted upon future publication of results). Meanwhile, based on EGFR mutation frequency, we further classify EGFR mutation status into positive, classic mutations (primarily including Ex19del or L859R), non-classic mutations (primarily including T790M, L861Q, G719X, S768I, or 20INS), and wild-type. Additionally, we conducted a categorized analysis based on population classification, intervention details, and study design, with a particular focus on high-risk factors within the study populations. The synthesized evidence was presented in visual images or tabular formats.

Results

System search and selection process

Through systematic searching, we identified 3,308 records, including 2,537 published documents and 771 ongoing trials. After automated deduplication, 1,777 records remained (Figure 1). Following preliminary screening of titles and abstracts, we excluded 1,615 publications and 660 registered trials that did not meet eligibility criteria. After completing full-text screening, we retained results from 33 published clinical studies and 22 ongoing clinical trials.

Figure 1 Flow diagram of study selection process. CBM, China Biology Medicine Disc; CENTRAL, Cochrane Central Register of Controlled Trials; ChiCTR, Chinese Clinical Trial Registry; CNKI, China National Knowledge Infrastructure; EU, European Union; ICTRP, International Clinical Trials Registry Platform; ISRCTN, the UK’s Clinical Study Registry; WOS, Web of Science; VIP, China Science and Technology Journal Database.

Baseline and spatiotemporal characteristics of studies

Among the 33 published studies we identified, 12 were direct evidence sources and 21 were indirect evidence sources, as defined by our predefined criteria. The former comprised three articles (13-15), eight conference papers (16-22), and one thesis (23), encompassing eight retrospective studies and four prospective studies. Most of these were single-center studies (n=7, 58.33%) and single-arm studies (n=8, 66.67%), with the number of stage IA NSCLC participants ranging from 5 to 95 (Table 1). The latter comprised 14 articles (25-38), six conference papers (24,39-44), and one meta-analysis (45), divided into 15 retrospective studies and six prospective studies. These were predominantly single-center (n=16, 76.19%) and single-arm studies (n=11, 52.38%), with sample sizes ranging from 13 to 878 (Table 2). Additionally, among the 22 ongoing clinical trials included in the analysis, 11 were single-center (47-57) and 11 were multicenter (58-68). These comprised eight phase II trials, two phase III trials, and five phase IV trials, predominantly featuring prospective trial designs (n=21, 91.30%), with sample sizes ranging from 27 to 1,000 participants. It is noteworthy that seven of these studies were randomized controlled trials (RCTs) (Table 3).

Among the 33 studies with reported results, 24 originated from China (72.73%), 5 from America (15.15%), and 2 from Japan (6.06%) (Figure 2A,2B). Publication dates for these studies were concentrated after 2020, particularly between 2023 and 2025 (Figure 2). Among ongoing clinical trials, China remained the primary country of conduct (n=20, 86.96%). Japan has conducted a trial, while another study was being conducted as a multinational, multi-regional collaboration (Figure 2C). The peak periods for initiating these trials occurred after 2020, notably in 2022 (n=9, 39.13%) and 2024 (n=5, 21.74%) (Figure 2D).

Figure 2 Spatiotemporal distribution map of included studies. (A-C) Geographical distribution of direct evidence sources, indirect evidence sources and ongoing clinical trials. (D) Time distribution of direct evidence sources, indirect evidence sources and ongoing clinical trials.

Published studies’ findings—direct evidence sources

Direct evidence clearly established the clinical value of EGFR-TKI targeted therapy in stage IA NSCLC patients, serving as the primary reference for clinical practice. Table 1 presents brief details of the studies providing direct evidence, and full details are in tables available at https://cdn.amegroups.cn/static/public/tlcr-2025-aw-1251-1.docx.

Postoperative EGFR-TKIs adjuvant therapy for stage IA NSCLC with EGFR mutations

Among the direct evidence, three studies reported complete evidence of postoperative EGFR-TKI adjuvant therapy. Pennell et al. conducted a multicenter, prospective, single-arm phase II clinical trial named SELECT to evaluate the clinical efficacy of postoperative adjuvant chemoradiotherapy followed by sequential EGFR-TKI therapy in EGFR-mutant NSCLC patients (NCT00567359), and the results were reported in 2019 (14). In this study, eligible patients received oral erlotinib 150 mg, with dose reduction to 50 mg permitted due to adverse events, for a treatment duration of up to 2 years. Ultimately, among the 14 enrolled stage IA patients, 100% achieved 5-year disease-free survival (DFS).

Another two retrospective studies were published in 2023. One by Jiang et al. retraced the adjuvant treatment outcomes of patients with completely resected stage I EGFR classic mutation (13). After propensity score matching (PSM), analysis of 112 stage IA patients demonstrated significantly improved 5-year DFS in the EGFR-TKI adjuvant group (icotinib, erlotinib, and gefitinib) compared to the observation group (100.0% vs. 84.5%, P=0.007). Furthermore, adjuvant EGFR-TKI therapy demonstrated superior efficacy in high-risk patients identified through its proprietary 14-gene molecular test. Another publication was a degree thesis by Chinese scholar Chen, specifically examining postoperative EGFR-TKIs adjuvant therapy for stage IA invasive lung adenocarcinoma (23). The study demonstrated that compared to the observation group without intervention, monotherapy with EGFR-TKI (gefitinib, erlotinib, icotinib, and osimertinib) reduced the risk of postoperative recurrence and metastasis [hazard ratio (HR) =0.15; 95% confidence interval (CI): 0.03–0.87; P=0.034], significantly improving DFS (median DFS: not reached vs. 44.5; 95% CI: 16.62–72.38; P=0.03).

Additionally, eight conference papers published between 2023 and 2025 reported partial direct evidence. Geng and colleagues presented preliminary results from a multicenter, prospective, single-arm phase II clinical trial (NCT05445310) at the 2024 World Conference on Lung Cancer (WCLC) (17,61). This study aimed to evaluate the efficacy and safety of furmonertinib 80 mg/day as a 3-year postoperative adjuvant therapy for high-risk stage IA and IB NSCLC patients. High-risk factors for stage IA NSCLC included micropapillary, solid, and spread through air spaces (STAS). Results showed that among 18 patients with completely resected stage IA NSCLC enrolled between August 2022 and March 2024, none experienced disease recurrence or metastasis (DFS: 100%) following adjuvant treatment with oral furmonertinib. No treatment-related adverse events (TRAEs) of grade three or higher were observed.

Also, at the 2024 WCLC, Wu et al. reported results from a retrospective study of patients with high-risk, EGFR mutation-positive stage I NSCLC who received aumolertinib adjuvant therapy following curative resection (20). Identified high-risk factors included solid, micropapillary, or complex gland components (CGC), poorly differentiated carcinoma, visceral pleural invasion (VPI), non-EGFR co-mutations, surgical approach, smoking history, etc. Five stage IA patients received daily oral aumolertinib 110 mg postoperatively. Follow-up data demonstrated 100% 1-year DFS.

APPOINT (NCT04922138) conducted by Han et al. is a multicenter, prospective, controlled trial specifically designed to evaluate the efficacy and safety of aumolertinib as adjuvant therapy in high-risk patients with stage IA EGFR-mutant NSCLC (59). High-risk status was defined as histopathological evidence of solid, micropapillary, and/or CGC constituting ≥10%. Patients were randomized to either the aumolertinib adjuvant group (110 mg orally for 3 years) or the observation group. Preliminary results presented by investigators at the 2025 European Lung Cancer Conference (ELCC) showed that compared to 87% 1-year DFS in the 49-patient observation group, the 46 patients receiving aumolertinib adjuvant therapy achieved 100% 1-year DFS with no grade 3 or higher adverse events (18).

ASSIST (ChiCTR2200063184) is a multicenter, prospective, single-arm clinical trial conducted by Cheng et al. to explore the efficacy and safety of aumolertinib as postoperative adjuvant therapy for patients with EGFR mutation-positive stage IB and pure solid stage IA2–3 invasive NSCLC (66). Enrolled patients received daily oral aumolertinib 110 mg as adjuvant therapy for 2 years following R0 resection. Preliminary results presented at the 2025 ELCC showed 100% 2-year DFS among 45 enrolled stage IA patients, with no serious adverse events reported (16).

Scholars from The First Affiliated Hospital of Medical School of Zhejiang University subsequently published the remaining four conference papers. Among these, Wu et al. presented a single-center retrospective single-arm study at the 2023 American Society of Clinical Oncology (ASCO) annual meeting. This study retrospectively analyzed 69 patients with pathologically diagnosed classic EGFR mutation-positive stage IA2–IIIA NSCLC who also had at least one high-risk factor (micropapillary, solid, STAS, or VPI). Among them, 33 stage IA patients received daily oral 80 mg furmonertinib for 6–36 months following radical tumor resection. As of the reporting date of March 1, 2023, the 1-year DFS reached 100% (19).

Zhang et al. presented for the first time at the 2024 WLCC a single-center retrospective study of sequentially administered post-surgical EGFR-TKI adjuvant therapy in stage IA2–IIIA non-squamous NSCLC patients harboring non-classical EGFR mutations. Patients received adjuvant aumolertinib 110 mg daily for 6 months to 3 years following radical resection. Among the two enrolled stage IA patients, 1-year DFS reached 100%, with no grade three or higher TRAEs observed (22).

Ye et al. presented a single-center, retrospective single-arm study at the 2025 ELCC examining the prognosis of patients with stage I–IIIA EGFR classic mutation-positive lung adenocarcinoma who underwent surgery followed by adjuvant furmonertinib (80 mg once daily). Among the 44 enrolled stage IA2 patients, the 1-, 2-, and 3-year DFS were 97.7%, 93.2%, and 90.9%, respectively; 1-, 2-, and 3-year OS reached 100.0%, 97.7%, and 97.7%, respectively. Even among 35 stage IA3 patients, 1-, 2-, and 3-year DFS or OS all reached 100%. No serious adverse events were observed during follow-up (21).

Another retrospective multicenter study by Zhang et al., presented at the 2025 ELCC, aimed to evaluate the efficacy and safety of aumolertinib adjuvant therapy in stage IA2–IIIA NSCLC patients with EGFR classic mutation who underwent surgery and possessed high-risk factors (VPI, micropapillary, and solid). Patients received daily 110 mg aumolertinib treatment for durations ranging from one to three years. Among the 219 stage IA patients enrolled, the 3-year DFS reached 91.7%, the 4-year DFS reached 82.7%, and no serious adverse events occurred (24).

First-line EGFR-TKIs therapy for postoperative recurrence in stage IA NSCLC with EGFR mutations

One study reported the evidence of first-line EGFR-TKI therapy for postoperative recurrence. A retrospective study published by Japanese researchers in 2013 evaluated the efficacy of EGFR-TKI treatment in patients with pathologically confirmed stage IA lung adenocarcinoma [7^th edition of the tumor-node-metastasis (TNM) classification] featuring micropapillary components and EGFR classic mutation-positive who experienced postoperative recurrence (15). Among these, five patients achieved long-term survival (median survival of 64.6 months) after receiving gefitinib following postoperative recurrence, demonstrating the favorable efficacy of EGFR-TKIs for postoperative recurrence in stage IA lung adenocarcinoma patients.

Published studies’ findings—indirect evidence sources

Indirect evidence did not fully clarify the clinical value of targeted therapy with EGFR-TKIs in stage IA patients, with a lower level of evidence than direct evidence. It may serve as a secondary reference for clinical practice. Table 2 presents brief details of the studies contributing to the indirect evidence. Given space limitations, detailed descriptions are provided in tables and appendices available at https://cdn.amegroups.cn/static/public/tlcr-2025-aw-1251-2.docx.

Ongoing clinical trials

We identified 22 ongoing clinical trials that include populations of interest to us, though they do not entirely match our target population. Therefore, whether these trials will ultimately provide the clinical evidence we require—and at what level of evidence—will depend on the reporting of their final results. Table 3 presents brief details of ongoing clinical studies, with detailed descriptions provided in tables available at https://cdn.amegroups.cn/static/public/tlcr-2025-aw-1251-3.docx.

Targeted therapy for stage IA NSCLC patients with EGFR mutations

ADAURA2, a double-blind, placebo-controlled phase III clinical trial (NCT05120349) funded by AstraZeneca, spans 139 centers across 20 countries in Europe, America, and Asia (60). It aims to evaluate the efficacy of Osimertinib in stage IA2–IA3 NSCLC patients with EGFR classic mutation following radical resection. 390 patients will be randomly assigned 4–12 weeks post-surgery to receive either 40–80 mg of oral Osimertinib daily or an equivalent placebo dose. The primary endpoint is 10-year DFS. Secondary endpoints include OS, plasma drug concentrations, and the drug’s impact on patient physical function and neurological systems. The study is scheduled to conclude in November 2032.

Two other studies conducted single-center phase II clinical trials in stage IA NSCLC patients harboring classic EGFR mutations. One study led by Fang aimed to evaluate the efficacy of furmonertinib in patient ineligible for radical surgery (non-radical resection, radiotherapy, or ablation) (ChiCTR2400088570), with primary endpoints being 3-year PFS and OS (53). The other prospective, controlled trial, conducted collaboratively by Zhang et al. (ChiCTR2400089820), explored the efficacy of icotinib treatment guided by circulating tumor DNA-minimal residual disease (ctDNA-MRD) results in patients with high-risk factors (papillary, micropapillary, solid, mucinous components, and CGC) (51). Following radical resection, the intervention group received oral icotinib for up to 18 months, while the observation group received no intervention. The study aims to evaluate DFS, OS, and safety.

Targeted therapy for stage IA2–IB NSCLC patients with EGFR mutations

Four studies enrolled stage IA2–IB NSCLC patients. Chen et al. are conducting a prospective, phase IV, single-center, controlled trial (NCT06561620) evaluating adjuvant befotertinib therapy after R0 resection in patients with EGFR classic mutation-positive, MRD-positive disease who also present the following high-risk factors: micropapillary ≥15%, CGC ≥20%, lymphovascular invasion (LVI), STAS, pleural invasion, or low differentiation (50). The primary endpoint is 3-year DFS. ASSIST by Cheng et al. was previously described (66). Zhou et al. continue to evaluate the utility of MRD monitoring for icotinib adjuvant therapy in EGFR classic mutation-positive NSCLC patients containing solid components in ground-glass opacity (GGO) (67). This multicenter RCT (ChiCTR2300070717) assigns the intervention group to oral icotinib 125 mg three times daily for 2 years, while the observation group receives no intervention. The primary endpoint is 3-year DFS. This study is scheduled for completion in December 2027. The final study is a single-center retrospective real-world study (ChiCTR2500103374) evaluating the efficacy and safety of firmonertinib as adjuvant therapy in patients with high-risk factors (solid, micropapillary, CGC ≥10%, STAS, LVI, and VPI) (56).

Targeted therapy for stage I NSCLC patients with EGFR mutations

Elven studies expanded their scope to include all stage I lung cancer patients. Among these, the APPOINT, NCT05445310, and ChiCTR2200066768 were outlined earlier (52,59,61). NCT05079022 is a prospective, single-center, single-arm trial conducted by Yang et al., also evaluating the clinical efficacy of adjuvant furmonertinib based on ctDNA-MRD in patients with EGFR classic mutation-positive following R0 resection (48). Patients with MRD positivity detected within 4 weeks post-surgery received furmonertinib: 80 mg orally once daily for 3 years or until disease progression or drug toxicity. The primary endpoint was clearance of ctDNA. Wu et al. conducted a multicenter RCT named MOTION-NSCLC (NCT06709274) to evaluate the efficacy of MRD as a biomarker for guiding adjuvant treatment decisions in stage I NSCLC patients (63). A total of 342 EGFR-positive and MRD-positive patients were randomized to either the Osimertinib group or the standard treatment group, with 3-year DFS as the primary endpoint.

A multicenter, single-arm clinical trial (NCT05514314) conducted by Nan et al. evaluated the impact of adjuvant icotinib on stage I lung adenocarcinoma patients with EGFR classical mutation exhibiting high recurrence risk pathological features (solid, micropapillary, CGC >20%, LVI, invasive tumor size >2 cm, and VPI) (62). Enrolled patients received icotinib 125 mg orally three times daily for 2 years or until recurrence. Primary endpoints included RFS, OS, and safety. OSTAR (NCT05686434), conducted by Yue et al., evaluates the efficacy and safety of osimertinib adjuvant therapy in completely resected high-risk (solid, micropapillary ≥10%, and STAS) stage I non-squamous NSCLC (49). Sixty-five enrolled patients will receive adjuvant osimertinib 80 mg orally daily for 3 years. Primary outcome is 3-year DFS. UPLIFT (NCT06955325) is a phase III RCT conducted by He et al. to evaluate the efficacy of personalized targeted therapy in high-risk stage I patients following R0 resection (64). High-risk factors include the following: solid, micropapillary, CGC, LVI, STAS, low differentiation, VPI, and intermediate/high risk on the 14-gene test. EGFR mutation-positive patients were randomized to either the intervention group receiving oral icotinib 125 mg three times daily or oral rezivertinib 100 mg daily for 1 year, or to the observation group receiving no intervention. The primary endpoint was 5-year DFS, with secondary endpoints including OS and TACEs. The study is projected to conclude in 2035.

A single-center RCT named ATTNE (ChiCTR1900028226), jointly conducted by Xie et al., aimed to evaluate the clinical efficacy of postoperative adjuvant EGFR-TKIs in patients with lung cancer exhibiting high-risk features (51). Stage I NSCLC patients with exhibiting at least one of the following histological subtypes: solid, micropapillary, squamous cell, or verrucous, were randomly assigned to either adjuvant targeted therapy or non-targeted therapy postoperatively. The trial compared RFS, OS, and targeted drug side effects between the two groups. The primary endpoint of this single-center, single-arm study is objective response rate (ORR). One single-center RCT (ChiCTR-IOR-16009623) conducted by Jiang et al. aimed to evaluate the clinical efficacy of targeted therapy in EGFR mutation-positive micro-papillary stage I lung cancer (57). The primary endpoint was DFS, with secondary endpoints including OS and quality of life (QOL). Another single-center retrospective study, organized by Mei et al. (ChiCTR2500098187), conducted an exploratory analysis of the clinical efficacy of EGFR-TKIs in adjuvant therapy for stage I invasive lung adenocarcinoma (55). EGFR-TKIs included multiple agents, including gefitinib, icotinib, erlotinib, osimertinib, ametinib, and vometinib. The primary outcome was OS, with RFS as a secondary endpoint.

Targeted therapy for stage I or above patients with EGFR mutations

The remaining four trials investigated more advanced NSCLC patients. A multicenter prospective trial by Wang et al. (ChiCTR2200062836) evaluated the clinical efficacy of ctDNA-based monitoring to guide postoperative osimertinib adjuvant therapy in patients with EGFR mutation-positive stage IA–IIA NSCLC. After MRD monitoring, NSCLC patients who underwent R0 resection received either osimertinib or observation if positive, with no intervention for negative results. The primary endpoint was DFS, with secondary endpoints including QOL and clearance rate of ctDNA. One multicenter prospective trial (JPRN-UMIN000053514) by Japanese researchers Aokage et al. evaluated the clinical efficacy of adjuvant therapy following curative resection in stage IA2–IIA non-squamous NSCLC patients with EGFR-mutated (68). The targeted therapy agent was osimertinib, with DFS as the primary clinical endpoint.

NCT02283424, registered by Liu et al., is a single-center RCT designed to evaluate the clinical efficacy of icotinib as adjuvant therapy in stage I–IIIB EGFR mutation-positive lung adenocarcinoma patients following surgery (47). Eligible patients were randomized to either the intervention group receiving icotinib 125 mg orally three times daily for 2 years, or the control group receiving carboplatin and docetaxel. The primary endpoint is 5-year RFS. ADDRESS, led by He, is a multicenter, prospective real-world study primarily designed to investigate initial adjuvant treatment patterns following curative resection in stage I–III EGFR mutation-positive NSCLC patients in the real world (58). Statistical analysis of the projected 2,000 enrolled patients will reveal current treatment patterns and follow-up approaches for targeted therapies across different stages and EGFR mutation statuses, providing a macro perspective for subsequent research.

Details of EGFR-TKIs and high-risk factors

In this review, we focused on the clinical efficacy of EGFR-TKIs, which have now advanced to the third generation, resulting in a wide variety of clinically available options. We summarized the types of EGFR-TKIs used across all studies included in the analysis, with results shown in Figure 3A. First- and third-generation EGFR-TKIs predominate, with the most frequently used being first-generation icotinib and third-generation osimertinib, followed by gefitinib, aumolertinib, and erlotinib. Notably, ongoing clinical trials predominantly select third-generation EGFR-TKIs.

Figure 3 Frequency distribution of (A) EGFR-TKIs types and (B) risk factors in included studies. EGFR, epidermal growth factor receptor; EGFR-TKIs, EGFR-tyrosine kinase inhibitors.

High-risk factors for recurrence and metastasis in stage IA EGFR mutation-positive NSCLC patients remain a key focus of current research, particularly as inclusion criteria in ongoing prospective clinical trials. We compiled all high-risk factors identified across the studies included in our analysis, with results presented in Figure 3B. Among these, micropapillary, solid, CGC, STAS, MRD-positive, and LVI were the most common high-risk factors. Notably, the top three were included as patient enrollment criteria in nearly all prospective clinical studies. Additional independently identified high-risk factors included tumor budding, insufficient LND, and intermediate-/high-risk on the 14-gene test.

Discussion

Debate persists regarding whether EGFR-TKIs targeted therapy is indicated for EGFR-mutant stage IA NSCLC. Meanwhile, the latest versions of internationally authoritative guidelines, including those issued by the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), ASCO, Chinese Society of Clinical Oncology (CSCO), and China Anti-Cancer Association (CACA), do not recommend routine targeted therapy due to the lack of high-quality clinical evidence, instead advising regular follow-up and observation (69-72). This scoping review provides the first systematic analysis of the current status of targeted therapy for stage IA EGFR mutation-positive NSCLC. Through extensive searches of major publication databases and clinical trial registries, coupled with rigorous inclusion and exclusion criteria for data screening, it synthesizes both direct and indirect evidence currently available for clinical reference. Additionally, it offers a comprehensive list of ongoing clinical trials to guide future clinical practice and research, thereby enriching the knowledge base for readers.

To start with, both the publication dates and the initiation dates of ongoing clinical trials were concentrated after 2020, with the number of clinical trials reaching its peak in 2023. This indicates that whether stage IA EGFR-mutated NSCLC patients require targeted therapy has garnered significant attention from scholars within the field in recent years (Figure 1D). Additionally, China maintained an absolute advantage in terms of the number of relevant studies (Figure 1A-1C). According to data released by the National Cancer Center in 2022, China undoubtedly accounts for the largest number of lung cancer patients globally, with 1.06 million new lung cancer cases, while the EGFR mutation rate in Asia is as high as 40% (5,73). This has indirectly driven research in this area within China.

Currently, direct evidence regarding EGFR-TKI treatment for patients with stage IA EGFR-mutant NSCLC remains somewhat limited, with all studies focusing exclusively on postoperative adjuvant therapy. Among the four formally published studies, only the SELECT trial was prospective. However, its design targeted resectable NSCLC, with a relatively small number of patients solely at stage IA. Nevertheless, its conclusions remain instructive. The remaining three retrospective studies focused on stage IA patients and confirmed the DFS benefit of postoperative targeted therapy with EGFR-TKIs. Ongoing prospective studies NCT05445310, APPOINT, and ASSIST have reported preliminary results at various global conferences. These studies confirmed that high-risk stage IA patients undergoing R0 resection achieved 100% DFS with at least 1 year of adjuvant furmonertinib or aumolertinib therapy (with 2-year DFS reported in the latter two studies). This provides valuable guidance for clinical practice, though long-term follow-up data remains anticipated. Four conference papers focusing on early-stage NSCLC (particularly stage IA) also revealed that EGFR-TKIs drugs have demonstrated significant clinical benefits. Our innovative concept of indirect evidence effectively bridges gaps when direct evidence is scarce, offering a viable direction for clinical practice and research. Indirect evidence for adjuvant EGFR-TKI therapy still demonstrated benefit trends similar to those observed with direct evidence. Additionally, two studies provided reference for targeted therapy of postoperative residual ground-glass nodules (GGNs). Zhang et al.’s retrospective study indicated the superiority of EGFR-TKIs over chemotherapy, while preliminary results from ChiCTR2200066768 also demonstrated aumolertinib’s favorable efficacy for postoperative residual GGN in stage I patients. No standalone studies currently exist for neoadjuvant therapy in stage IA patients. Four retrospective studies provided consistent indirect evidence indicating favorable ORR benefits and significantly improved R0 resection rates following EGFR-TKI treatment. The prospective NCT03433469 trial further supported these findings with an ORR of 51.9% and a MPR rate of 14.8%. As a pioneering study on sequential EGFR therapy, NORA warrants greater attention, offering a novel approach to targeted EGFR treatment.

Although current direct evidence remains somewhat limited, the final results of ongoing clinical trials are highly anticipated. Eighteen ongoing clinical trials focus on stage I NSCLC patients, with three trials exclusively targeting stage IA patients. The findings from these prospective studies will not only supplement direct evidence, but the results of RCTs such as ADAURA2, ChiCTR2300070717, MOTION-NSCLC, UPLIFT, and ChiCTR-IOR-16009623 will provide higher-level evidence-based medical evidence. It is anticipated that as these trial results are progressively released in the future, questions regarding targeted therapy for IA-stage EGFR-mutated NSCLC will be resolved. Additionally, it should be noted that none of the studies reporting on the safety of EGFR-TKIs documented high-grade TACE events (≥ grade 3), further supporting the safety profile of EGFR-TKIs during targeted therapy.

Future directions

Clinical efficacy endpoints for EGKR-TKIs

In oncology trials, OS is widely recognized as the optimal endpoint. However, this requires a large patient cohort and extended follow-up periods, which not only delays drug development and guideline adoption but also risks bias from treatment crossover and subsequent therapies (74). Consequently, studies indicate that alternative measures such as DFS, PFS, ORR, and MPR can provide additional benefits for efficacy assessment (75). Yet the correlation between these indicators and OS in EGFR-TKIs-related research has been mixed: some have shown synchronous trends, while others failed to translate DFS improvements into OS benefits (8,76).

In the clinical trials we evaluated, both published and ongoing studies extensively employ DFS, ORR, and similar metrics to assess clinical efficacy. Moreover, the existing evidence supporting the benefits of EGFR-TKIs in stage IA patients is primarily based on DFS; there is a lack of large-sample evidence to confirm improvements in OS. Consequently, whether specific intermediate endpoints can serve as meaningful substitutes for OS and treatment effectiveness requires comprehensive post-trial evaluation to determine. Nevertheless, DFS improvement still holds significant clinical value for stage IA patients: delayed recurrence can markedly enhance postoperative QOL in patients and avoid the physical trauma of secondary treatments (e.g., chemotherapy, reoperation) caused by early recurrence; for patients who remain eligible for effective treatment after recurrence, delayed recurrence is equivalent to extending the DFS window, thereby gaining more time for subsequent therapy; and patients with certain high-risk features tend to have poor OS following recurrence, so DFS improvement may indirectly reduce the risk of recurrence-related mortality in this subgroup.

Which generation of EGFR-TKIs should we choose? How long should they be used?

With the development and market launch of third-generation EGFR-TKIs, coupled with FLAURA’s confirmation of their superior brain penetration compared to standard EGFR-TKIs, most ongoing prospective clinical trials now prioritize third-generation as the interventions (Figure 3B) (77). However, from health economics perspective, selecting third-generation imposes a significantly higher financial burden on national health insurance and patients than first-generation. Regarding clinical efficacy, the difference in the effects of third-generation vs. first-generation for stage IA patients remains unclear. However, for advanced lung cancer patients, FLAURA demonstrated that the first-line use of osimertinib did not show a significant OS benefit in Asian populations compared to the strategy of first using first-generation EGFR-TKIs and switching to Osimertinib after progression (77). A real-world study also supported this conclusion (78). Indeed, some considered the former approach to be the most cost-effective (79). Therefore, the choice of EGFR-TKIs for stage IA NSCLC patients warrants close attention from scholars, particularly in resource-limited settings.

Moreover, the duration of EGFR-TKIs therapy remains a critical question requiring resolution. A phase II clinical trial by Neal et al. demonstrated that in stage I–III NSCLC patients undergoing R0 resection, the recurrence rate was lower with 2 years of afatinib compared to 3 months (35). A retrospective analysis by Lv et al. also indicated that longer duration of treatment (over 36 months) was associated with greater benefits in DFS and OS (32). However, this clearly cannot serve as the basis for clinical decisions. Determining the threshold duration for therapeutic equivalence may require time-gradient trials to resolve.

Patients selection: high-risk factors for recurrence

Real-world data indicate that stage IA NSCLC exhibits high heterogeneity, potentially linked to tumor biological behavior across different histopathologies. As research advances, there is growing recognition that even for stage IA EGFR-mutated NSCLC patients, targeted therapy should be reserved for high-risk individuals (Tables 1-3, Figure 3B). Jiang et al.’s retrospective study also indicated that for low-risk patients identified by the 14-gene test, there was no significant survival difference in whether targeted therapy was administered (13). In current clinical trials, micropapillary, solid, CGC, STAS, and LVI are common high-risk factors for recurrence. These are pathologically classic high-risk factors and should be prioritized for attention. Notably, ctDNA has emerged as a highly popular detection method in recent years, capable of sensitively identifying MRD post-surgery (80,81). At the 2025 WLCC, the tumor whole-genome ctDNA test Signatera Genome was reported to achieve an overall sensitivity of 90% for adenocarcinoma, reaching 100% in stage IA patients. The six clinical trials we identified also selected MRD detection positivity as an inclusion criterion for patients (48,50,54,63,65,67). The 14-gene test developed by The First Affiliated Hospital of Guangzhou Medical University to assess postoperative recurrence risk has undergone global multicenter validation (82). As a molecular-level detection method with high sensitivity, its risk stratification shown excellent accuracy, as previously described. In addition, tumor size itself, as a reference for T staging, directly determines the stage grouping of stage I NSCLC, especially for stage IA. Thus, tumor size constitutes an important high-risk factor. However, current evidence lacks data regarding the efficacy of EGFR-TKIs in more detailed subgroups of stage IA. This finding should inspire future studies to conduct elaborate subgroup analyses to provide evidence for clinical practice.

Furthermore, although no guidelines or consensus statements have been established to clarify how to guide clinical decisions on targeted therapy based on the above high-risk factors, these factors can still serve as important references for TKIs administration outside of clinical trials, based on currently available clinical evidence.

Resistance mutations and combination therapy

AURA extension analysis indicated that approximately 50% of patients with advanced EGFR-mutant NSCLC treated with first-generation EGFR-TKIs develop T790M mutations, leading to resistance (83). The development of Osimertinib effectively overcame this limitation. However, there are no definitive reports on whether T790M mutations occur widely when non-third-generation drugs are used in stage IA patients. Of course, even if the mutation is present, third-generation drugs remain available as treatment options. If other third-line drug-resistant mutations emerge, such as C797S or G796, it may be necessary to develop next-generation drugs like fourth-generation EGFR-TKIs or combine them with other agents such as cisplatin, pemetrexed, nintedanib, or trastuzumab (84-87). Clinical trials like ELIOS (NCT03239340) and ORCHARD (NCT03944772) are already exploring these approaches.

Implications for future clinical trials

Undoubtedly, the exploration of targeted therapy for high-risk EGFR-mutant stage IA patients represents an irresistible trend. As summarized earlier, we have collated the patient enrollment criteria adopted in current clinical trials; however, variations exist in the interpretation and application of these criteria across different research centers. If multicenter experts can reach a consensus and promote the core criteria set for patient selection, it will further standardize clinical trials and enhance the generalizability and extrapolation value of conclusions. In addition, the horizontal and vertical selection of EGFR-TKIs categories and the determination of treatment duration should be evaluated with consideration to both clinical efficacy and health economic value in the design of future clinical trials. For study endpoints, a composite design featuring DFS as the primary endpoint and OS as the key secondary endpoint is recommended, with the aim of providing high-quality evidence for clinical decision-making at the earliest opportunity. Finally, given the inherently high survival rate of stage IA patients, accurate sample size calculation is essential to improve the statistical power of studies and reduce costs, thereby ensuring the scientific validity of their results. This highlights the need for multicenter initiatives to report large-sample survival data of EGFR-mutant stage IA populations, which can provide core parameter references for sample size calculation in future trials.

Conclusions

We systematically reviewed the current evidence supporting targeted therapy for stage IA NSCLC patients with EGFR mutation-positive. While direct evidence remained somewhat limited, existing data still demonstrated the potential for effective treatment with EGFR-TKIs. Several ongoing clinical trials may bring promising results, such as ADAURA2, APPOINT, ChiCTR2300070717, ASSIST, MOTION-NSCLC, and UPLIFT. However, numerous questions remain to be answered, including which intermediate endpoints should be selected to accelerate guideline implementation, which types of EGFR-TKIs offer the best cost-effectiveness for adjuvant therapy, how long targeted therapy should be continued, which characteristics of patients warrant treatment, how to overcome drug resistance once it develops, and whether combination therapy is necessary as seen in advanced lung cancer patients. Although research in this field is still starting out, overall, we see a future where stage IA EGFR-mutated patients may benefit from EGFR-TKIs.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1251/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1251/coif). The authors have no conflicts of interest to declare.

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