Efficacy and safety of anlotinib plus EGFR tyrosine kinase inhibitors in slow- or locally progressing non-small cell lung cancer after adjuvant therapy

Introduction

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have shown significant efficacy in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations (1). However, the efficacy of EGFR-TKIs varies among patients with NSCLC, with a minority achieving complete remission and others achieving partial remission (2). The iterative upgrading of EGFR-TKIs from the first to the third generation in clinical practice addresses the issue of diminished or lost efficacy (3). Although third-generation EGFR-TKIs outperform first- and second-generation drugs in terms of efficacy and toxicity, disease progression remains inevitable due to acquired resistance, imposing a substantial economic burden on society and patients (4). Previous studies have indicated that among the resistance mechanisms of first- and second-generation EGFR-TKIs, the T790M mutation represents the most common resistance alteration, whereas the resistance mechanisms of third-generation EGFR-TKIs are more complex, primarily involving EGFR C797S mutation, bypass activation pathways such as MET amplification, activation of downstream signaling pathways, or histological transformation. After resistance develops, clinical practice often involves increasing the daily dose of the targeted drug (5), combining it with antiangiogenic agents (6), or integrating other treatment modalities as proposed in studies such as FLAURA-2 (7) and MARIPOSA (8) to improve patient survival. Due to the complex and diverse mechanisms underlying EGFR-TKI resistance, clinical exploration of more effective therapeutic strategies remains ongoing (9,10).

Angiogenesis plays a crucial role in tumor growth and metastasis, and blocking this pathway has become a successful strategy in clinical cancer treatment. Combination therapy of EGFR-TKIs with anlotinib has emerged as a potential strategy for overcoming dr ug resistance and improving treatment outcomes in patients with EGFR-positive NSCLC (11). Anlotinib is a novel oral receptor TKI targeting vascular endothelial growth factor receptor (VEGFR) 2 and 3, fibroblast growth factor receptor (FGFR) 1–4, platelet-derived growth factor receptor (PDGFR) α and β, c-Kit, and Ret (12), exhibiting potent antitumor angiogenesis effects and inhibiting malignant tumor progression (13). Studies have demonstrated that the efficacy of anlotinib was favorable in the treatment of NSCLC and anlotinib therapy prolongs progression-free survival (PFS) and overall survival (OS) (13-15). Studies indicate that combining EGFR-TKIs with anlotinib inhibits tumors via multiple signaling pathways, enhancing efficacy in patients with EGFR-positive NSCLC (6,16-18). This combination therapy has demonstrated efficacy in inhibiting tumor cell proliferation, angiogenesis, and metastasis in EGFR-driven NSCLC models, indicating its potential clinical utility in overcoming resistance to EGFR-TKIs (11).

Given the promising preclinical data, evaluating the clinical efficacy and safety of combining anlotinib with EGFR-TKIs in patients with NSCLC who have developed resistance to EGFR-TKI adjuvant therapy is particularly important. However, few studies have assessed the efficacy and safety of combining anlotinib with EGFR-TKIs in patients with NSCLC resistant to EGFR-TKI adjuvant therapy. This study aimed to evaluate the efficacy and safety of combining anlotinib with EGFR-TKIs in patients with NSCLC who have developed resistance following EGFR-TKI adjuvant therapy after surgery. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-177/rc).

Methods

Patients

This retrospective, real-world study was conducted at the First Affiliated Hospital of Zhejiang University School of Medicine and included patients who underwent surgery received EGFR-TKI adjuvant therapy and subsequently developed resistance between January 2020 and December 2023. The criteria for diagnosing resistance included elevated blood carcinoembryonic antigen (CEA) levels (19), nodule changes [emergence of new high-risk nodules (for patients with only one primary nodule) or enlargement of existing high-risk nodules (for patients with multiple high-risk ground glass nodules)] according to the response evaluation criteria in solid tumor version 1.1 (RECIST 1.1), and metastasis (lymph nodes, bone, brain, or pleura). Elevated CEA was defined as blood CEA <10.0 ng/mL followed by consecutive measurements ≥10.0 ng/mL (with intervals of at least 1 month) or blood CEA ≥10.0 ng/mL with gradual increases in consecutive measurements (with intervals of at least 1 month). All patients underwent positron emission tomography (PET)–computed tomography (CT) after diagnosing resistance.

The inclusion criteria for patients were as follows: (I) age ≥18 and ≤75 years; (II) postoperative NSCLC; (III) genetic testing reporting EGFR exon 19 deletion or 21 L858R mutation; (IV) resistance to EGFR-TKI adjuvant therapy; (V) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and (VI) adequate organ function, including sufficient lung and heart function.

Patients with the following conditions were excluded: (I) lack of essential imaging evaluations at the study hospital; (II) presence of autoimmune diseases, infectious diseases, or other concomitant malignant tumors; (III) prior radiotherapy, chemotherapy, or immunotherapy; and (IV) previous or ongoing systemic immunosuppressive treatment.

Patient follow-up data were retrieved from the hospital’s medical record system and through telephone contact, with the latest follow-up cutoff date being March 25, 2024.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Informed consent was waived for the retrospective data. This study received approval from the Ethics Review Committee of the First Affiliated Hospital of Zhejiang University School of Medicine (No. IIT20240441A).

Treatment methods

The included patients were administered anlotinib (orally, days 1–14, once every 3 weeks, followed by a 7-day break) in addition to their original EGFR-TKI regimen. The initial dose of anlotinib (10 or 12 mg) was jointly determined by clinicians and pharmaceutical experts based on the patient’s condition. The dosage was reduced when patients experienced intolerable treatment-related adverse events (TRAEs). Patients were treated with anlotinib until progressive disease or TRAE intolerance occurred.

Efficacy and safety

The primary endpoint of this study was PFS, while secondary endpoints included 6- and 12-month PFS rates, OS, and safety. PFS was defined as the time from the initiation of anlotinib plus EGFR-TKI to disease progression [elevated blood CEA levels, nodule changes according to the RECIST 1.1, metastasis (lymph nodes, bone, brain, or pleura)] or death. OS was defined as the time from the start of anlotinib plus EGFR-TKI to death from any cause. TRAEs were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Statistical analysis

All statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA) and R software version 4.1.2 (The R Foundation for Statistical Computing), while GraphPad Prism version 9.0 (GraphPad Software, San Diego, CA, USA) was used for plotting. Categorical variables are expressed as frequencies and percentages, while continuous variables are expressed as the median and interquartile range (IQR). The Fisher exact test or Pearson chi-square test was used to compare the baseline characteristics between the groups. The Kaplan-Meier method was used to evaluate the PFS and OS, and stratified log-rank tests were applied to compare the differences between the groups. The reverse Kaplan-Meier method was used to estimate the median follow-up time. The correlation between each study variable and survival was determined using stratified Cox proportional hazard models. The statistical significance threshold was set at P<0.05.

Results

Baseline characteristics of participants

From January 2020 to December 2023, 48 patients who underwent surgery and developed resistance to adjuvant therapy with EGFR-TKIs were included in the study. The baseline characteristics of the patients are shown in Table 1. The median age of the 48 patients was 68 years, with an equal distribution of males and females, each accounting for 50%. Genetic testing reports of patient’s tumor tissue indicated that 52.1% (25/48) of the patients had the L858R mutation, while 47.9% (23/48) had exon 19 deletions. And 4 patients had concurrent TP53 mutations, 1 patient had concurrent MET mutations, 1 patient had concurrent ALK, 1 patient had concurrent HER2. After surgery, 23 (47.9%) patients received first- or second-generation EGFR-TKI treatment, and 25 (52.1%) patients received third-generation EGFR-TKI therapy. The median interval time from surgery to resistance of adjuvant therapy was 20.0 months [95% confidence interval (CI): 14.0–33.5; range, 0.0–48.0]. After EGFR-TKI adjuvant therapy, 18 (37.5%) patients exhibited elevated blood CEA levels. Six patients (12.5%) developed new high-risk nodules, and seven (14.6%) had enlargement of existing ones. Seventeen (35.4%) patients had metastases (lymphadenopathy in seven patients, bone in three, brain in three, and pleura in four). All patients underwent next-generation sequencing (NGS) in liquid biopsy after diagnosing resistance. Among patients received first- or second-generation EGFR-TKI, 6 patients (6/23, 26.1%) were found to have an EGFR T790M mutation, and the others had an unknown resistance mechanism. For patients received third-generation EGFR-TKI therapy, 3 patients (3/25, 12.0%) were found to have an EGFR C797S mutation, and the others had an unknown resistance mechanism.

Adverse events

No previously undocumented TRAEs were observed in this study (Table 2). Overall, the incidence rates of any grade and grade ≥3 TRAEs were 75.0% (36/48) and 10.4% (5/48), respectively. The most common TRAEs were hypertension (17/48, 35.4%), proteinuria (15/48, 31.3%), rash (11/48, 22.9%), fatigue (5/48, 10.4%), and diarrhea (4/48, 8.3%). No new safety events were reported. Grade 1–2 TRAEs were the most common, with fewer patients experiencing grade 3 or 4 TRAEs (two cases of urine protein, two cases of hypertension, and one case of skin rash). All symptoms resolved after treatment. Dose reduction and discontinuation of anlotinib were reported in four (8.3%) and five (10.4%) patients, respectively. A summary of TRAEs is presented in Table 2.

Survival

At the time of the data cutoff (March 2024), we successfully collected follow-up information for all patients. The median follow-up time was 33.3 months (95% CI: 23.2–43.3). Thirty-three patients experienced disease progression, and twenty patients died. Thirty-three patients went on to receive next-line therapy after progression on anlotinib plus EGFR TKI. After that, all of them chose immunotherapy with or without chemotherapy. The median PFS of all patients was 9.5 months (95% CI: 4.8–14.3), with a 6-month PFS rate of 70.8% and a 12-month PFS rate of 47.9% (Figure 1A). The median OS of all patients was 31.0 months [95% CI: not reached (NR)–NR], with 6-month and 12-month rates of 91.7% and 85.4%, respectively (Figure 1B).

Figure 1 Kaplan-Meier curves of (A) PFS and (B) OS in all patients. EGFR, epidermal growth factor receptor; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

For patients previously treated with first- or second-generation EGFR-TKIs, the median PFS was 10.3 months (95% CI: 6.1–14.4), with a 6-month PFS rate of 69.6% and a 12-month PFS rate of 47.8% (Figure 2A). For patients previously treated with third-generation EGFR-TKIs, the median PFS was 7.7 months (95% CI: 4.8–10.6), with a 6-month PFS rate of 72.0% and a 12-month PFS rate of 48.0% (Figure 2A). For patients previously treated with first- or second-generation EGFR-TKIs, the median OS was NR, with a 6-month rate OS of 95.7% and a 12-month OS rate of 91.3% (Figure 2B). For patients previously treated with third-generation EGFR-TKIs, the median OS was 20.3 months (95% CI: 10.7–30.0), with a 6-month OS rate of 88.0% and a 12-month OS rate of 80.0% (Figure 2B).

Figure 2 Kaplan-Meier curves of (A) PFS and (B) OS in patients previously treated with first-/second- and third-generation EGFR-TKIs. EGFR, epidermal growth factor receptor; OS, overall survival; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

For patients with elevated blood CEA levels, the median PFS was 9.1 months (95% CI: 2.7–15.5), with a 6-month PFS rate of 72.2% and a 12-month PFS rate of 50.0% (Figure 3A). For patients with nodule changes [emergence of new high-risk nodules (for patients with only one primary nodule) or enlargement of existing nodules (for patients with multiple high-risk ground glass nodules)], the median PFS was 10.3 months (95% CI: 3.1–17.4), with a 6-month PFS rate of 61.5% and a 12-month PFS rate of 46.2% (Figure 3A). For patients with metastases (lymphadenopathy, bone, brain, or pleura), the median PFS was 9.5 months (95% CI: 5.2–13.8), with a 6-month PFS rate of 76.5% and a 12-month PFS rate of 47.1% (Figure 3A). For patients with elevated blood CEA levels, the median OS was 27.9 months (95% CI: 14.7–41.1), with 6-month OS of 88.9% and a 12-month OS rate of 77.8% (Figure 3B). For patients with nodule changes [emergence of new high-risk nodules (for patients with only one primary nodule) or enlargement of existing nodules (for patients with multiple high-risk ground glass nodules)], the median OS was 20.3 months (95% CI: NR–NR), with a 6-month OS rate of 84.6% and a 12-month OS rate of 84.6% (Figure 3B). For patients with metastases (lymph node, bone, brain, or pleura), the median OS was NR (95% CI: NR–NR), with a 6-month OS rate of 100.0% and a 12-month OS rate of 88.2% (Figure 3B).

Figure 3 Kaplan-Meier curves of (A) PFS and (B) OS in patients with elevated blood CEA level, nodule changes [emergence of new high-risk nodules (for patients with only one primary nodule) or enlargement of existing nodules (for patients with multiple high-risk ground glass nodules)], and metastases (lymph node, bone, brain, or pleura). CEA, carcinoembryonic antigen; OS, overall survival; PFS, progression-free survival.

Univariate Cox regression analyses revealed no statistically significant correlations between these factors and PFS (Table 3). However, we found a statistically significant correlation between the EGFR mutation subtype and OS in the univariate Cox regression analyses (Table 4). We then included factors with P<0.1 in the multivariable Cox regression analyses. Compared to exon 19 deletion, the L858R mutation was associated with worse OS (HR 3.745, 95% CI: 1.411–9.943, P=0.008). The EGFR L858R mutation group had a median PFS of 7.6 months (95% CI: 6.7–8.6), while the median PFS of the EGFR exon 19 deletion mutation group was 12.7 months (95% CI: 8.6–16.8) (P=0.16) (Figure 4A). The EGFR L858R mutation group had a median OS of 18.3 months (95% CI: 15.6–21.0), while the median OS of the EGFR exon 19 deletion mutation group was not achieved (P=0.003) (Figure 4B).

Figure 4 Kaplan-Meier curves of (A) PFS and (B) OS in patients with EGFR exon 19 deletion mutation and EGFR L858R mutation. EGFR, epidermal growth factor receptor; OS, overall survival; PFS, progression-free survival.

Discussion

The standard first-line treatment for patients with NSCLC harboring EGFR mutations is monotherapy with EGFR-TKIs. Although this provides significant survival benefits to patients, most will eventually experience disease progression over time (20,21). Due to the inevitable occurrence of resistance mutations during disease progression, clinical strategies, such as switching to a newer generation of EGFR-TKIs, are usually employed for subsequent treatment. Soria et al. (22), Park et al. (23), Urata et al. (24), and Wu et al. (25) have shown that in the first-line treatment of EGFR mutation-positive NSCLC, second- or third-generation EGFR-TKIs are more effective than are first-generation EGFR-TKIs, with significantly prolonged median PFS, similar safety profiles, and a lower incidence of serious adverse events. However, previous studies have indicated that when patients become resistant to standard TKI treatment, switching to second-generation EGFR-TKIs only provides a limited improvement in efficacy. Switching to third-generation TKIs, such as osimertinib, offers clinical benefits, but resistance may reoccur, requiring alternative treatment strategies such as combination chemotherapy (26-30). The mechanisms of acquired resistance to EGFR-TKIs are complex, and delaying resistance remains a major challenge in first-line treatment with EGFR-TKIs, for which there is no standard treatment paradigm. EGFR-TKI acquired resistance is composed of on-target (EGFR dependent), off-target (EGFR independent), and unknown (31). On-target acquired resistance of first- and second-generation EGFR TKI is relatively huge, and T790M mutation is the most common and the incidence rate is 50–60% (32). On-target acquired resistance of third-generation EGFR-TKIs was approximately 10–20% and C797S mutation was the most common (10). Off-target acquired resistance included many genes other than EGFR (33). Antiangiogenic therapy plays a crucial role in the treatment of EGFR-TKI resistance. For patients with disease progression after EGFR-TKI treatment, early use of combination therapy strategies may offer superior benefit as compared to EGFR-TKI monotherapy (15,34). Xiang et al. (35) compared the efficacy of EGFR-TKI monotherapy versus EGFR-TKIs combined with anlotinib, reporting that combination therapy achieved better PFS than did EGFR-TKI monotherapy. Our study found that when patients experienced disease progression due to resistance after EGFR-TKI treatment, combination therapy with anlotinib may prevent the need for an escalation of treatment strategies, prolong the treatment window, and provide more survival opportunities.

First- and second-generation EGFR-TKIs yield a median PFS between 9 and 13 months (36-41), while third-generation EGFR-TKIs yield a median PFS between 18 and 22 months (22,42). In our study, the median PFS was 9.5 months, with the median PFS of patients previously treated with first- and second-generation EGFR-TKIs being 10.3 months and that of those patients previously treated with third-generation EGFR-TKIs being 7.7 months. The median PFS yielded by the combination of anlotinib with EGFR-TKI for patients with NSCLC who developed resistance to EGFR-TKI adjuvant therapy following surgery and who were treated with the combination of anlotinib and EGFR-TKIs was similar to that of those treated with first- or second-generation EGFR-TKIs and about half of that of those treated with third-generation EGFR-TKIs. Therefore, for patients with NSCLC who develop resistance after undergoing EGFR-TKI adjuvant therapy after surgery, anlotinib plus EGFR-TKIs can prolong the treatment window. For patients previously treated with first- or second-generation EGFR-TKIs, we can delay the use of third-generation EGFR-TKIs and retain more treatment options. For patients previously treated with third-generation EGFR-TKIs, we can also delay the use of alternative treatment methods, such as chemotherapy and immunotherapy. In summary, whether using first- or second-generation EGFR-TKIs or third-generation EGFR-TKIs are applied, combining anlotinib with EGFR-TKIs can provide a greater opportunity for prolonged survival.

Our study defined resistance as an elevated blood CEA level, nodule changes [emergence of new high-risk nodules (for patients with only one primary nodule) or enlargement of existing nodules (for patients with multiple high-risk ground glass nodules)], and metastasis (lymph node, bone, brain, or pleura). We found the median PFS of patients with these three conditions of resistance was similar. The median PFS of patients with elevated blood CEA levels was 9.1 months, that for those with nodule changes [emergence of new high-risk nodules (for patients with only one primary nodule) or enlargement of existing nodules (for patients with multiple high-risk ground glass nodules)]was 10.3 months, and that for those with metastases (lymph node, bone, brain, or pleura) was 9.5 months. These results were similar to those observed for entire patient cohort. Therefore, anlotinib plus EGFR-TKIs is applicable to different manifestations of drug resistance.

This study included patients with EGFR exon 19 deletions and 21 L858R mutations. We found that the survival of patients with EGFR exon 19 deletions was better than that of patients with EGFR L858R mutations. The EGFR L858R mutation group had a median PFS of 7.6 months, whereas the median PFS of the EGFR exon 19 deletion mutation group was 12.7 months. The EGFR L858R mutation group had a median OS of 18.3 months, whereas the median OS of the EGFR exon 19 deletion group was not achieved. Therefore, anlotinib plus EGFR-TKIs may be more suitable for patients with EGFR exon 19 deletion mutations.

The toxicity observed in our study was consistent with that reported in other studies, and no new adverse events were identified (43,44). All symptoms resolved after treatment. The incidence rate of grade ≥3 TRAEs was 10.4% (two cases of urine protein, two cases of hypertension, and one case of skin rash). Dose reduction and discontinuation of anlotinib were reported in four (8.3%) and five (10.4%) patients, respectively. Our results indicated that anlotinib combined with the original EGFR-TKIs demonstrated controllable safety in patients who developed resistance after first-line EGFR-TKI treatment.

This retrospective study had some limitations, including a small sample size, a short postoperative follow-up period, and heterogeneity among patients and treatment modalities. Future research should adopt a prospective design and expand the sample size to validate these findings further, thereby enhancing the statistical power of the results and their external validity.

Conclusions

For patients with NSCLC who develop resistance to postoperative adjuvant therapy with EGFR-TKIs, the combination of anlotinib and EGFR-TKIs may provide good efficacy and manageable safety, offering these patients a longer treatment window and improved survival opportunities. However, large-scale randomized controlled trials are needed to confirm our findings.

Acknowledgments

We would like to thank the participants for their time and effort during the data collection phase. We also appreciate the support from the renowned Hu Jian Workstation in Taizhou, Zhejiang.

The abstract of this manuscript was presented as a poster at the World Conference on Lung Cancer (WCLC) in 2024 and published in the Journal of Thoracic Oncology (JTO) conference proceedings [https://www.jto.org/article/S1556-0864(24)01900-2/abstract].

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-177/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-177/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-177/prf

Funding: This study was supported by grants from the National Key Research and Development Program of China (No. 2022YFC2407303) and the Zhejiang Provincial Research Center for Lung Tum or Diagnosis and Treatment Technology (No. JBZX-202007).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-177/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 (as revised in 2013). Informed consent was waived for the retrospective data. This study received approval from the Ethics Review Committee of the First Affiliated Hospital of Zhejiang University School of Medicine (No. IIT20240441A).

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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