Adjuvant chemotherapy before osimertinib in EGFR-mutated stage IB lung adenocarcinoma: a clinical dilemma

Introduction

Non-small cell lung cancer (NSCLC) accounts for approximately 25–40% of all resectable lung cancers (1,2). Despite curative resection, disease recurrence occurs in 30–55% of these patients (3,4). Adjuvant cisplatin-based chemotherapy has significantly enhanced survival outcomes for NSCLC patients. However, the absolute 5-year survival benefit from chemotherapy is modest (5.4%). Although the survival benefit of chemotherapy is well-established for patients with stage II–III disease, its role in stage IB NSCLC (<4 cm) remains uncertain (5). Several studies have demonstrated the efficacy of adjuvant chemotherapy for stage IB NSCLC patients with high-risk features, including visceral pleural invasion, lymphovascular invasion, poor to undifferentiated histology, incomplete lymph node sampling, and high-grade histologic patterns (6-8).

Epidermal growth factor receptor (EGFR) mutations are established prognostic indicators for patients with advanced lung adenocarcinoma and are associated with an increased risk of recurrence following surgery (9,10). Previous studies have demonstrated that EGFR exon 19 deletion (Del19) exhibits significantly poorer recurrence-free survival (RFS) compared to EGFR exon 21 L858R point mutation (9). Therefore, the ADAURA trial was designed to evaluate the efficacy of adjuvant chemotherapy with osimertinib in patients with completely resected EGFR-mutated, stage IB to IIIA NSCLC [as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer (AJCC)] (11). In the study, adjuvant osimertinib provided a significant overall survival (OS) benefit among patients with completely resected, EGFR-mutated, stage IB to IIIA NSCLC (12). Thus, it is important to optimize the use of chemotherapy in the era of adjuvant Osimertinib usage. Although adjuvant chemotherapy was administered to 76% of patients with stages II to IIIA disease, only 26% of stage IB patients received this treatment. Notably, disease-free survival (DFS) curves for stage IB patients demonstrated early divergence between the osimertinib and placebo arms, regardless of chemotherapy use (13). The optimal sequencing of adjuvant chemotherapy and osimertinib in stage IB EGFR-mutant adenocarcinoma remains uncertain. We assessed the clinical impact of adjuvant chemotherapy in high-risk stage IB (<4 cm) EGFR-mutant adenocarcinoma and analyzed prognostic factors for RFS and OS. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-348/rc).

Methods

Study design and participants

This retrospective study analyzed the medical records of 198 patients with pathologic T2aN0M0 stage IB (<4 cm) EGFR-mutant adenocarcinoma, per the 8th Edition tumor-node-metastasis (TNM) staging guidelines (14), from 12 university hospitals in the Yeongnam region of the Republic of Korea. Patients with high-risk factors harboring common EGFR mutations (Del19 or exon 21 L858R point mutation) diagnosed between January 2010 and January 2017 were included. Exclusion criteria included sublobar resection, absence of high-risk factors, and non-R0 resection. In total, 178 patients were included in the final analysis and categorized into adjuvant chemotherapy and non-adjuvant chemotherapy groups based on adjuvant chemotherapy use (Figure 1). Because this study analyzed the role of adjuvant chemotherapy for patients with high-risk EGFR-mutant stage IB (<4 cm) adenocarcinoma, patients who received adjuvant EGFR-tyrosine kinase inhibitors (TKIs), including adjuvant osimertinib, were excluded from the analysis.

Figure 1 Study flowchart. EGFR, epidermal growth factor receptor.

High-risk factors included visceral pleural invasion, lymphovascular invasion, micropapillary predominant pattern, and solid predominant pattern. Predominant histological patterns were classified according to the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma multidisciplinary classification (15). Computed tomography (CT) of the chest was performed every 3–6 months for the first 3 years after surgery, followed by scans every 6 months for 5 years or until death. Additional positron emission tomography-CT or brain magnetic resonance imaging was performed in cases of suspected recurrence.

Adjuvant chemotherapy was initiated within 6 weeks of surgery. Platinum-based dual therapy was used as adjuvant chemotherapy in accordance with the National Comprehensive Cancer Network (NCCN) guidelines for adjuvant chemotherapy and national guidelines for adjuvant chemotherapy (16). The chemotherapy cycle was every 3 weeks, but the frequency and dose were adjusted by the physician based on the patient’s PS and side effects.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional review boards of each hospital [Pusan National University Hospital (2304-018-126), Yeungnam University Medical Center (YUMC 2023-05-037), Kyungpook National University Chilgok Hospital (KNUCH 2023-08-017), Keimyung University Dongsan Medical Center (DSMC 2023-11-041), Dong-A University Hospital (DAUHIRB-23-101), Haeundae Paik Hospital (HPIRB 2023-08-001), Gyeongsang National University Changwon Hospital (GNUCH 2023-07-022), Kyungpook National University Hospital (KNUH 2023-05-005), Ulsan University Hospital (UUH 2023-04-045), Samsung Changwon Hospital (2023-05-003), Gyeongsang National University Hospital (GNUH 2023-08-014), and Inje University Busan Paik Hospital (BPIRB 2023-04-055)]. Due to the retrospective nature of the study, the requirement for written informed consent was waived.

Statistical analysis

Continuous variables are expressed as medians (ranges), whereas categorical variables are expressed as numbers (percentages). Patients were categorized into adjuvant chemotherapy and non-adjuvant chemotherapy groups based on chemotherapy use. Student’s t-test was used to compare continuous variables, whereas the Chi-squared or Fisher’s exact test was used to compare categorical variables.

RFS was defined as the time interval between surgery and the earliest occurrence of disease recurrence, death from any cause, or the last follow-up. DFS is cited only when referring to prior studies that defined their endpoints as DFS. OS was calculated from the date of surgery to the date of death. Kaplan-Meier curves were used to estimate survival probabilities, whereas the log-rank test was used for group comparisons.

Univariate and multivariate Cox regression analyses were performed to identify factors associated with recurrence or mortality. A backward elimination approach was used for the multivariate model, including variables with a univariate P<0.20. Statistical analyses were performed using SPSS version 25 (IBM Corp., Armonk, NY, USA) and R statistics. P<0.05 was considered statistically significant.

Results

Baseline characteristics

Of the 178 patients, 42 (23.6%) and 136 (76.4%) were in the adjuvant chemotherapy and non-adjuvant chemotherapy groups, respectively. No significant differences were observed in age, sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), smoking status, body mass index (BMI), or tumor size. Although a trend toward a higher Del19 rate was observed in the adjuvant chemotherapy group (64.3% vs. 48.5%), this difference was not statistically significant (P=0.08). High-risk factors, including visceral pleural invasion, lymphovascular invasion, micropapillary predominant pattern, and solid predominant pattern, were similarly distributed between the groups (Table 1).

RFS and OS

Median RFS was 55 and 97 months in the adjuvant chemotherapy and non-adjuvant chemotherapy groups, respectively (P=0.22). Notably, 2-, 5-, and 10-year RFS rates were 71.4%, 49.9%, and 35.7% for the adjuvant chemotherapy group and 78.9%, 57.3%, and 49.9% for the non-adjuvant chemotherapy group, respectively (Figure 2). The effect of adjuvant chemotherapy on RFS was not statistically significant according to age, gender, ECOG, smoking status, BMI, tumor size, type of EGFR mutation, visceral pleural invasion, lymphovascular invasion, and micropapillary/solid predominant pattern (Figure 3). Univariate analysis revealed age ≥60 years and lymphovascular invasion as risk factors for recurrence (P=0.047, P=0.03, respectively; Table 2). In univariate analysis, adjuvant chemotherapy was not significantly associated with recurrence [hazard ratio (HR) 1.345; 95% confidence interval (CI): 0.837–2.162; P=0.22]. Multivariate analysis identified age ≥60 years (HR 2.163; 95% CI: 1.232–3.796; P=0.007), lymphovascular invasion (HR 1.842; 95% CI: 1.188–3.033; P=0.02), and micropapillary/solid predominant patterns (HR 2.401; 95% CI: 1.017–5.670; P=0.046) as independent predictors of recurrence. Conversely, overweight patients (BMI ≥25 kg/m²; HR 0.591; 95% CI: 0.358–0.975; P=0.04) were associated with a lower risk of recurrence.

Figure 2 Kaplan-Meier curve for RFS (A) and Kaplan-Meier curve for OS (B). (A) Median RFS was 55 and 97 months in the adjuvant chemotherapy and non-adjuvant chemotherapy groups, respectively (P=0.22). (B) Median OS was 134 and 145 months in the adjuvant chemotherapy and non-adjuvant chemotherapy groups, respectively (P=0.84). OS, overall survival; RFS, recurrence-free survival.

Figure 3 Subgroup analysis of the effect of adjuvant chemotherapy on RFS. CI, confidence interval; Del19, exon 19 deletion; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HR, hazard ratio; RFS, recurrence-free survival.

Median OS was 134 and 145 months in the adjuvant chemotherapy and non-adjuvant chemotherapy groups, respectively (P=0.84). Notably, 2-, 5-, and 10-year OS rates were 97.6%, 76.0%, and 65.4% in the adjuvant chemotherapy group and 94.8%, 73.3%, and 59.5% in the non-adjuvant chemotherapy group, respectively (Figure 2). Univariate analysis revealed age ≥60 years and micropapillary/solid predominant patterns as predictors of survival (P=0.007 and P=0.02, respectively; Table 3). In univariate analysis, adjuvant chemotherapy was not significantly associated with OS (HR 1.062; 95% CI: 0.588–1.920; P=0.84). Multivariate analysis identified age ≥60 years (HR 3.121; 95% CI: 1.494–6.520; P=0.002) and micropapillary/solid predominant patterns (HR 3.718; 95% CI: 1.620–8.536; P=0.002) as independent predictors of OS.

Discussion

We evaluated the efficacy of adjuvant chemotherapy and identified prognostic factors for RFS and OS in patients with surgically resected stage IB (<4 cm) EGFR-mutant adenocarcinoma and high-risk features. Of the 178 patients, 42 (23.6%) and 136 (76.4%) were in the adjuvant chemotherapy and non-adjuvant chemotherapy groups, respectively. Our findings did not demonstrate a significant survival benefit from adjuvant chemotherapy regarding RFS or OS. Several factors were associated with increased risk of recurrence, including age ≥60 years, lymphovascular invasion, and micropapillary/solid predominant patterns. Notably, overweight patients (BMI ≥25 kg/m²) had a lower risk of recurrence. Regarding OS, age ≥60 years and micropapillary/solid predominant patterns were identified as significant prognostic factors.

The efficacy of postoperative adjuvant chemotherapy in patients with stage IB (<4 cm) NSCLC remains uncertain. Consistent with our findings of a 23.6% adjuvant chemotherapy rate, the real-world EARLY-EGFR study reported adjuvant chemotherapy administration in 22.5% of stage IB patients (AJCC 7th edition), whereas the ADAURA trial demonstrated a 26.0% rate of adjuvant platinum-based chemotherapy in stage IB patients (AJCC 8th edition) (13,17). Despite the lack of detailed patient characteristics in these studies, it is reasonable to estimate that approximately 20–30% of patients with high-risk features for recurrence receive adjuvant chemotherapy.

Choi et al. evaluated the clinical efficacy of adjuvant chemotherapy in stage IB (≤4 cm) NSCLC patients with high-risk features. The adjuvant chemotherapy group demonstrated significantly reduced recurrence rates (HR 0.408) and mortality risk (HR 0.176) compared to the non-adjuvant chemotherapy group. Therefore, adjuvant chemotherapy should be considered in patients with high-risk features, such as visceral pleural involvement and vascular invasion (6). Consistent with these findings, Tsutani et al. demonstrated significantly prolonged RFS (HR 0.63) and OS (HR 0.28) in patients with pathologic stage I NSCLC (AJCC 8th edition) and high risk for recurrence (pathologic T1c or T2a or lymphovascular invasion) who received adjuvant chemotherapy (18). While prior studies such as those by Choi et al. and Tsutani et al. reported a survival benefit of adjuvant chemotherapy in high-risk stage I NSCLC, our findings did not replicate this effect in EGFR-mutant stage IB patients. These discrepancies may be attributed to differences in EGFR mutation status, the definition of high-risk features, and treatment eras. Notably, our study exclusively enrolled patients with EGFR-mutant adenocarcinoma, a molecular subset that may exhibit distinct tumor biology and chemosensitivity. In contrast, previous studies either did not report EGFR status or included mixed populations. These molecular and clinical differences underscore the need to re-evaluate the benefit of chemotherapy in the era of adjuvant targeted therapy. Conversely, Park et al. evaluated the efficacy of adjuvant chemotherapy in completely resected stage IB NSCLC patients. Notably, no significant association was observed between adjuvant chemotherapy and DFS or OS. Furthermore, adjuvant chemotherapy did not confer a significant survival benefit, even among high-risk patients (defined by poorly differentiated tumors, vascular invasion, tumor size >4 cm, and visceral pleural invasion) (19).

EGFR mutations are established risk factors for recurrence in patients with NSCLC who have undergone surgery (9,10). Notably, 5-year RFS rates for patients with wild-type, Del19, and L858R EGFR mutations were 63.0%, 67.5%, and 78.2%, respectively (9). A retrospective study by Ito et al. involving 474 consecutive pathologic N0M0 lung adenocarcinoma patients who underwent curative resection revealed a significantly lower 5-year recurrence-free interval (RFI) in EGFR-positive compared to EGFR-negative patients (80.7% vs. 92.1%, P=0.04). Multivariate analysis further confirmed EGFR-positive status as an independent predictor of shorter RFI (20). Furthermore, a prior study reported significantly lower 5-year RFS rates in EGFR-mutant compared to EGFR-wild-type patients (49.6% vs. 75.6%, respectively; P<0.01) (21). Therefore, preventing recurrence with effective adjuvant chemotherapy is crucial for EGFR-mutant patients.

Consistent with previous studies in early-stage NSCLC, age ≥60, lymphovascular invasion, and micropapillary/solid predominant patterns were identified as risk factors for recurrence (6,22). Notably, we observed an inverse correlation between overweight BMI and recurrence risk, potentially indicative of an “obesity paradox”. A prior study suggested that the “obesity paradox” might be partially attributable to the limitations of BMI as a measure of obesity. A study including 513 patients with stage I and II NSCLC undergoing lobectomy used visceral fat index (VFI), derived from preoperative CT images, as a more accurate indicator of central obesity (23). Although no correlation was observed between VFI and BMI [Pearson correlation coefficient =−0.006; P=0.90, VFI was significantly associated with poorer RFS (HR 4.51, 95% CI: 0.93–21.76)]. Therefore, a cautious interpretation of the protective effects of overweight BMI on recurrence risk is warranted. Further studies are needed to validate these findings.

Post-hoc exploratory analyses within the ADAURA trial evaluated DFS according to adjuvant chemotherapy use and disease stage (IB, II, and IIIA by AJCC 7th edition) (13). Notably, 26% (57/216) of stage IB patients received adjuvant chemotherapy before randomization. A DFS benefit with osimertinib was observed in stage IB patients who did not receive adjuvant chemotherapy (HR 0.38). Moreover, the stage IB group with adjuvant chemotherapy was excluded from the analysis due to insufficient events (n<20). Among patients with stage IB disease who received osimertinib vs. placebo and had prior adjuvant chemotherapy, 81% (95% CI: 52–94%) vs. 66% (95% CI: 44–81%) remained alive and disease-free at 24 months. Conversely, among those who did not receive adjuvant chemotherapy, the corresponding rates were 90% (95% CI: 78–95%) and 74% (95% CI: 60–83%). Although direct comparison between the two groups is challenging, the observed DFS rates at 24 months do not suggest a significant benefit of adjuvant chemotherapy. Notably, the patient population in this analysis, based on AJCC 7th edition stage IB, may differ slightly from the overall study population.

The CORIN (GASTO1003), a randomized, open-label, phase 2 trial, compared adjuvant chemotherapy with icotinib (a first-generation EGFR-TKI) with observation in patients with EGFR-mutation-positive resected stage IB NSCLC (24). Patients with completely resected, EGFR-mutant, stage IB NSCLC without adjuvant chemotherapy were randomized to receive adjuvant chemotherapy therapy with icotinib (125 mg, three times daily) for 12 months or to undergo observation until disease progression or intolerable toxicity occurred. Compared to ADAURA (25), CORIN focused solely on stage IB disease, used a first-generation EGFR-TKI for a fixed duration, and excluded patients with prior adjuvant chemotherapy; the study demonstrated a significantly longer 3-year DFS in the icotinib group (96%) compared to the observation group (86%) (HR 0.23; P=0.01). Although OS data were immature, these findings support the efficacy of 1-year EGFR-TKI therapy in EGFR-positive patients with stage IB NSCLC who have not received prior adjuvant chemotherapy.

Our study had several limitations. First, the retrospective design may introduce potential biases. A propensity score analysis may give more reliable results. However, baseline characteristics, including age, sex, ECOG PS, and high-risk factors, were comparable between the adjuvant chemotherapy and non-adjuvant chemotherapy groups, minimizing confounding variables. And, the relatively small number of patients in the chemotherapy arm (n=42) limits the statistical power to detect modest survival differences between treatment groups. Second, the lack of co-mutation testing using next-generation sequencing prevents evaluation of its potential association with disease recurrence and response to adjuvant chemotherapy. Third, although detailed information on specific adjuvant chemotherapy regimens and cycles is absent, the adherence to NCCN and national anti-cancer guidelines, typically involving four cycles of platinum-based doublet chemotherapy, is consistent with standard international practices. Lastly, it is possible that patients who received chemotherapy had more aggressive pathology, which could also affect the results.

Despite these limitations, this study is the first to provide evidence regarding the utility of adjuvant chemotherapy before osimertinib in EGFR-mutant stage IB (<4 cm) adenocarcinoma patients with high-risk factors. In addition, we analyzed risk factors for RFS and OS in a cohort of stage IB EGFR-mutant adenocarcinoma patients with long-term follow-up. While our study did not demonstrate a significant improvement in RFS or OS with adjuvant chemotherapy in stage IB (<4 cm) EGFR-mutant NSCLC, this observation—within the limitations of our sample size—raises meaningful questions about the role of chemotherapy in this subgroup, especially in the era of targeted therapy. In particular, if adjuvant osimertinib is planned, and given the uncertain or minimal added benefit of chemotherapy in this setting, it may be reasonable for clinicians to consider omitting chemotherapy for selected patients with stage IB disease, even those with high-risk features. Considering the high recurrence rate associated with EGFR-mutant stage IB adenocarcinoma, larger prospective studies are needed to identify patient subgroups that may benefit from adjuvant chemotherapy.

Conclusions

The efficacy of adjuvant chemotherapy in patients with stage IB (<4 cm) EGFR-mutant adenocarcinoma and high-risk features remains uncertain. Further prospective studies are needed to assess the role of adjuvant chemotherapy in these patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-348/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-348/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-348/prf

Funding: This work was supported by the 2024 Yeungnam University Research Grant.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-348/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional review boards of [Pusan National University Hospital (2304-018-126), Yeungnam University Medical Center (YUMC 2023-05-037), Kyungpook National University Chilgok Hospital (KNUCH 2023- 08-017), Keimyung University Dongsan Medical Center (DSMC 2023-11-041), Dong-A University Hospital (DAUHIRB-23-101), Haeundae Paik Hospital (HPIRB 2023-08-001), Gyeongsang National University Changwon Hospital (GNUCH 2023-07-022), Kyungpook National University Hospital (KNUH 2023-05-005), Ulsan University Hospital (UUH 2023-04-045), Samsung Changwon Hospital (2023-05-003), Gyeongsang National University Hospital (GNUH 2023-08-014), and Inje University Busan Paik Hospital (BPIRB 2023-04-055)]. Due to the retrospective nature of the study, the requirement for written informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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