Efficacy and safety of osimertinib combined with anlotinib in EGFR-mutant non-squamous non-small cell lung cancer with gradual progression after first-line osimertinib therapy: a single-center retrospective cohort study

Introduction

Lung cancer remains a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 80–85% of all cases (1). Among NSCLC subtypes, non-squamous histology constitutes the majority, and most patients are diagnosed at an advanced stage, conferring a generally poor prognosis (2). Mutations in the epidermal growth factor receptor (EGFR) gene represent the most prevalent oncogenic drivers in NSCLC and have emerged as pivotal targets for the precision treatment of advanced disease (3). Although the clinical implementation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has substantially improved survival outcomes in patients with EGFR-mutant NSCLC, acquired drug resistance remains an inevitable challenge, ultimately leading to disease progression in the vast majority of patients (4).

Osimertinib, a third-generation EGFR-TKI, exhibits potent efficacy against the EGFR T790M resistance mutation with a favorable safety profile. It has been established as the preferred second-line therapy for patients progressing on prior EGFR-TKIs (5), and also demonstrates superior survival outcomes compared with first-generation EGFR-TKIs when administered as first-line treatment (6). Nevertheless, acquired resistance to osimertinib remains an intractable clinical hurdle despite its widespread clinical adoption (7). In current clinical practice, platinum-based chemotherapy is mostly adopted for these patients upon disease progression. However, this strategy yields limited improvement in survival and is accompanied by considerable toxicities (8). In the MARIPOSA-2 trial, the arm receiving platinum plus pemetrexed chemotherapy alone had a median progression-free survival (mPFS) of 4.2 months, with a 38% incidence of grade ≥3 adverse events (AEs) (9). In the COMPEL trial, the chemotherapy-alone arm showed a mPFS of 4.4 months, and the incidence of grade ≥3 AEs was 46% (10). Consequently, developing optimal therapeutic strategies to overcome post-osimertinib resistance, delay tumor progression, and prolong survival has become a critical focus of ongoing research (11).

Progression patterns following EGFR-TKIs resistance are heterogeneous (12). Dramatic progression is characterized by rapid enlargement of target lesions and deterioration of clinical status, which generally warrants TKI discontinuation and switching to systemic chemotherapy. Local progression is defined as disease control lasting ≥3 months under TKI therapy, with progression limited to isolated or a small number of lesions while remaining lesions stay stable. For such patients, local therapy for progressive lesions combined with maintained EGFR inhibition can be considered. Gradual progression, as defined in the present study, refers to sustained disease control of ≥6 months on prior TKI treatment, without progressive target lesions, progression occurs only in non-target lesions or new-onset lesions, accompanied by stable clinical symptoms. Under this scenario, continued TKI monotherapy or combination with other agents may be adopted. Patients within the gradual progression subgroup experience relatively indolent disease progression and may still derive benefit from ongoing targeted therapy. This feature provides a potential therapeutic window for combination regimens. Continued osimertinib after gradual progression may suppress residual EGFR-sensitive clones, while the newly added agent acts against emerging drug-resistant clones. In the COMPEL trial, for patients with non-central nervous system progression after first-line osimertinib failure, continuing osimertinib plus chemotherapy yielded a median PFS of 8.4 months (10).

Anti-angiogenic therapy, which disrupts tumor neovascularization, exerts synergistic anti-tumor activity when combined with EGFR-TKIs (13,14). Previous studies have explored this combination strategy to enhance therapeutic efficacy and delay the onset of drug resistance (15,16). Bevacizumab or ramucirumab predominantly target the extracellular vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) axis, and randomized studies of osimertinib combined with bevacizumab have not consistently demonstrated PFS benefits (17-19). Anlotinib is an oral multi-target TKI with broad inhibitory activity against VEGFR, platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and c-Kit (20,21). Preclinical resistance models indicate that anlotinib exerts dual effects of anti-angiogenesis and direct anti-tumor activity. The ALTER-0303 trial has confirmed that anlotinib significantly improves survival in patients receiving later-line treatment (22). The prospective CTONG-1803/ALTER-L001 trial (23) and the retrospective ALTER-L058 study (24) have shown that combination with anlotinib after EGFR-TKI progression prolongs patients’ PFS. Nevertheless, prior studies did not stratify populations according to progression patterns after osimertinib failure. The present study enrolled this specific subgroup of patients with gradual progression. Data regarding continued osimertinib plus anlotinib for this patient subset remain limited and warrant further exploration.

Accordingly, this study aimed to evaluate the efficacy and safety of continuing osimertinib plus anlotinib in patients with EGFR-mutant non-squamous NSCLC experiencing gradual progression after first-line osimertinib therapy, and to offer insights into clinical treatment options for patients with this specific progression pattern. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0785/rc).

Methods

Study design and patients

This retrospective study enrolled patients with unresectable stage III or IV EGFR-mutant non-squamous NSCLC who developed gradual progression following first-line osimertinib therapy at the Department of Medical Oncology, The First Affiliated Hospital of the University of Science and Technology of China, between January 2021 and December 2024. All patients received combination therapy with osimertinib (80 mg orally once daily) and anlotinib (10 mg orally once daily on days 1–14 of every 3-week cycle). Treatment was continued until disease progression or the occurrence of intolerable toxicity. The selection of this combination regimen was determined through shared clinical decision-making between physicians and patients during routine clinical practice, based on the patients’ baseline performance status, tumor burden and progression sites, prior treatment-related toxicities, bleeding risk, patient preference, and comprehensive physician judgment. Given the retrospective nature of this study, all eligible patients during the study period were consecutively enrolled, and no formal sample size calculation was performed. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of The First Affiliated Hospital of the University of Science and Technology of China (No. 2026-RE-396). Due to its retrospective design, the requirement for written informed consent was waived.

The inclusion criteria were as follows: (I) age ≥18 years; (II) histologically or cytologically confirmed unresectable stage III or stage IV non-squamous NSCLC; (III) presence of activating EGFR mutations (exon 19 deletion or L858R); (IV) gradual progression after first-line osimertinib, defined as prior disease control for ≥6 months with no significant progression of target lesions (progression of non-target lesions or emergence of new lesions was permitted) and no deterioration in clinical symptoms; (V) at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; and (VI) an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2.

The exclusion criteria were: (I) presence of small cell lung cancer or squamous cell carcinoma histology; (II) primary resistance to osimertinib (defined as disease control <3 months); (III) dramatic progression after first-line osimertinib, defined as prior disease control ≥3 months followed by rapid progression of target lesions and significant clinical deterioration; (IV) ECOG PS >2; and (V) contraindications to anlotinib, such as active bleeding or uncontrolled hypertension.

Data collection

Clinical data were extracted from the hospital’s electronic medical record system, including age, sex, ECOG PS, tumor stage, EGFR mutation type, and treatment response. Contrast-enhanced chest-abdominal computed tomography (CT) was performed every two cycles (approximately 6 weeks). Brain magnetic resonance imaging (MRI) and other imaging modalities for known lesions were conducted at the same interval, or whenever clinical symptoms occurred. Disease response and progression were assessed by investigators according to RECIST version 1.1. Patients were followed up monthly via hospital electronic medical records and telephone interviews to document AEs and confirm survival status. All patients were followed until death or the time-point of data lock.

Outcomes

The primary endpoint was progression-free survival (PFS), defined as the time from the date of the first dose of combination therapy to the date of disease progression or death from any cause, whichever occurred first. Secondary endpoints included PFS rates at 6 and 12 months, objective response rate (ORR), disease control rate (DCR), overall survival (OS), OS rates at 12 and 24 months, and the safety profile. The 6- and 12-month PFS rates were defined as the proportion of patients who remained progression-free and alive at 6 and 12 months from the first dose, respectively. ORR was defined as the proportion of patients achieving a complete response (CR) or partial response (PR), while DCR included those achieving CR, PR, or stable disease (SD). OS was defined as the time from the first dose to the date of death from any cause. The 12- and 24-month OS rates represented the proportion of patients alive at 12 and 24 months, respectively. AEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Statistical analysis

Continuous variables were summarized as medians with ranges, and categorical variables were presented as frequencies and percentages. Categorical variables were compared using Pearson’s χ² test or Fisher’s exact test, as appropriate. Survival curves for PFS and OS were estimated using the Kaplan-Meier method, and between-group differences were compared using the log-rank test. Given the limited sample size, multivariable Cox regression analysis was performed as an exploratory analysis. Results were reported as hazard ratios (HRs) and 95% confidence intervals (CIs). Variables entered into the multivariable model were selected based on clinical relevance and previous evidence, rather than automated statistical selection methods. The number of outcome events included in the model was reported. All variables for prognostic analyses were derived from electronic medical records. As there were no missing data among variables incorporated into the Cox regression model, imputation was not required and a complete-case analysis was conducted. All statistical analyses were performed using SPSS software (version 24.0; IBM Corp., Armonk, NY, USA). All statistical tests were two-sided, and a P value <0.05 was considered statistically significant.

Results

Patient characteristics

A total of 335 patients were screened for this study. Among them, 283 were excluded for the following reasons: ineligible histology, mismatched genetic alteration profiles, inappropriate progression patterns, ECOG PS >2, lack of measurable lesions, or contraindications to anlotinib. Ultimately, 52 patients met the inclusion criteria and were enrolled for final analysis (Figure 1). The median age of the cohort was 66 years (range, 39–82 years), comprising 23 males (44.2%) and 29 females (55.8%). Histologically, all patients (100%) were diagnosed with adenocarcinoma. The majority of patients were non-smokers [34 (65.4%)], had an ECOG PS of 0–1 [40 (76.9%)], and presented with clinical stage IV disease [33 (63.5%)]. Brain metastases were present at baseline in 16 patients (30.8%). The best overall response to prior first-line osimertinib therapy was a PR in 29 patients (55.8%) and stable disease (SD) in 23 patients (44.2%). Molecular testing was performed for all 52 patients prior to first-line osimertinib therapy. Among them, 25 patients (48.1%) harbored EGFR exon 19 deletion, and 27 patients (51.9%) had EGFR exon 21 L858R mutation. Repeat molecular testing was conducted in only 12 patients after gradual progression on osimertinib. The majority of patients declined repeat molecular testing due to refusal of invasive tissue biopsy or financial constraints. Upon gradual progression, TP53 mutation was detected in 5 patients, PIK3CA mutation in 3 patients, concurrent TP53 and PIK3CA mutations in 1 patient, and KRAS G12D mutation in 3 patients. The baseline demographic and clinicopathological characteristics are summarized in Table 1.

Figure 1 Flowchart of patient screening and enrollment. ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor.

Efficacy analysis

At the data cutoff (September 6, 2025), the median follow-up duration was 34.8 months (95% CI: 24.6–44.8). Among the 52 patients treated with the osimertinib and anlotinib combination, gradual progression was observed in 48 patients, while 4 patients remained on therapy. Efficacy evaluation was performed for the entire cohort. No patient achieved CR, 4 patients (7.7%) achieved PR, and 41 (78.8%) achieved SD. The ORR was 7.7%, and the DCR was 86.5% (Table 2). Subgroup analyses of tumor response revealed that patients with EGFR exon 19 deletions had a significantly higher DCR than those with exon 21 L858R mutations (100% vs. 75.9%, P=0.01). Furthermore, patients who had previously achieved PR with first-line osimertinib exhibited a higher DCR compared to those whose best prior response was SD (100% vs. 69.6%, P=0.002). No significant associations were observed between DCR and other baseline characteristics, including sex, age, smoking status, ECOG PS, presence of brain metastases, or clinical stage (Figure 2).

Figure 2 Subgroup analysis of disease control rate. CI, confidence interval; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; PR, partial response; SD, stable disease.

The mPFS for the overall cohort was 9.9 months (95% CI: 4.2–12.1). The PFS rates at 6 and 12 months were 61.5% (95% CI: 47.0–73.2%) and 40.4% (95% CI: 27.1–53.3%), respectively (Figure 3A). Subgroup analyses demonstrated that patients with an ECOG PS of 0–1 had a significantly longer mPFS than those with an ECOG PS of 2 (12.1 vs. 5.5 months, P<0.001; Figure 3B). Similarly, prolonged mPFS was observed in patients without brain metastases compared to those with brain metastases (12.1 vs. 5.7 months, P=0.001; Figure 3C), and in patients who had achieved a prior PR with osimertinib compared to those with prior SD (12.1 vs. 6.9 months, P=0.03; Figure 3D). No significant differences in mPFS were identified across other subgroups (Figure 4). The univariate Cox proportional hazards regression analysis revealed that ECOG PS (HR: 3.372, 95% CI: 1.794–8.931, P<0.001), the presence of brain metastases (HR: 2.436, 95% CI: 1.818–6.497, P=0.001), and the previous response to osimertinib (HR: 1.859, 95% CI: 1.044–3.312, P=0.03) were the main factors influencing mPFS. The subsequent exploratory multivariate analysis showed that ECOG PS (HR: 3.115, 95% CI: 1.111–7.706, P<0.001) and the presence of brain metastases (HR: 2.242, 95% CI: 1.341–7.842, P=0.009) were associated with mPFS (Table 3). At the data cutoff, 22 patients (42.3%) had died, the median OS had not yet been reached. The OS rates at 12 and 24 months were 86.3% (95% CI: 73.5–93.2%) and 62.4% (95% CI: 46.9–74.5%), respectively (Figure 5).

Figure 3 Kaplan-Meier survival curves of PFS in (A) all patients, (B) patients with ECOG PS <2 and 2, (C) patients with and without brain metastases, and (D) patients with prior osimertinib treatment response of PR and SD. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; mPFS, median PFS; PFS, progression-free survival; PR, partial response; SD, stable disease.

Figure 4 Subgroup analysis of progression-free survival. CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; mPFS, median progression-free survival; PR, partial response; SD, stable disease.

Figure 5 Kaplan-Meier survival curves of overall survival in all patients. CI, confidence interval; mOS, median OS; NR, not reached; OS, overall survival.

AEs

TRAEs of any grade occurred in 78.8% (41/52) of patients, with grade ≥3 TRAEs observed in 9.6% (5/52). The most frequently reported TRAEs of any grade were diarrhea (42.3%, 22/52), hypertension (34.6%, 18/52), proteinuria (30.8%, 16/52), decreased appetite (28.8%, 15/52), and weight loss (28.8%, 15/52). Grade 1–2 events were predominantly observed, while grade ≥3 TRAEs were limited to a small number of patients, including diarrhea (n=2), hypertension (n=1), proteinuria (n=1), and rash (n=1) (Table 4). Notably, no patients discontinued treatment or required dose reductions due to TRAEs in this cohort.

Discussion

This study demonstrated that in the specific cohort of patients with EGFR-mutant advanced non-squamous NSCLC who experienced gradual progression after first-line osimertinib treatment, continued use of osimertinib combined with anlotinib showed encouraging efficacy and safety. The DCR of the patients in this study reached 86.5%, and the mPFS of the patients could reach 9.35 months, providing a reference for the treatment of this specific progression pattern population. Compared with previous similar retrospective studies, this study established an independent cohort focusing on the specific pattern of gradual progression. It conducted a longer follow-up, with a median follow-up time of 34.8 months, and included more patients with ECOG PS 2 and brain metastases, thereby improving the accuracy of the efficacy and survival data for patients with this progression pattern and verifying the external consistency.

The FLAURA trial established osimertinib as the standard first-line treatment for NSCLC harboring EGFR-sensitizing mutations (6). With significantly superior efficacy compared to first-generation EGFR-TKIs, osimertinib has become the preferred first-line targeted agent in clinical practice. However, as treatment duration extends, acquired resistance has emerged as an inevitable challenge (7). Currently, resistance mechanisms to osimertinib are broadly classified into four categories: target-dependent resistance, among which the C797S mutation is the most prevalent, alongside other secondary mutations such as L718Q and G796D (5,25,26); non-target-dependent resistance, involving bypass track activation such as MET amplification, HER2 amplification, and RET fusions (27-29); histological transformation, including the transition from adenocarcinoma to small cell lung cancer or squamous cell carcinoma (30,31); and non-classical mechanisms, such as epithelial-mesenchymal transition and aberrant remodeling of the tumor microenvironment (32,33). At present, various therapeutic options are available following disease progression on osimertinib, primarily including: targeted therapies guided by repeat molecular testing, standard platinum-pemetrexed doublet chemotherapy, single-agent immunotherapy or chemoimmunotherapy, local radiotherapy combined with systemic therapy, and the continuation of the original EGFR-TKI combined with anti-angiogenic agents. Among these strategies, combining an EGFR-TKI with anti-angiogenic therapy offers distinct advantages, including the convenience of oral administration and favorable patient compliance, while demonstrating definitive efficacy. Several clinical studies have validated the efficacy of EGFR-TKIs combined with anti-angiogenic agents in the EGFR-TKI-resistant population. Long et al. reported that in patients with advanced lung adenocarcinoma who developed resistance to EGFR-TKIs, the combination of the original EGFR-TKI and bevacizumab achieved a DCR of 93.94% and an mPFS of 8 months (34). A multicenter retrospective study demonstrated that in 39 patients with osimertinib resistance, treatment with osimertinib plus apatinib resulted in a DCR of 79.5% and an mPFS of 4 months (35). Furthermore, Zhang et al. found that following resistance to almonertinib, combining almonertinib with anlotinib yielded a DCR of 93.75%, with 6- and 12-month PFS rates of 92.9% and 84.4%, respectively (36).

Anlotinib is an oral, small-molecule, multi-targeted TKI independently developed in China. Compared with chemotherapy or large-molecule anti-angiogenic agents, anlotinib is convenient for oral administration, well-tolerated, and suitable for long-term maintenance. The hypothesized mechanism underlying the synergistic antitumor effect of EGFR-TKI combined with anlotinib may be that sustained EGFR inhibition suppresses residual sensitive clones, whereas anti-angiogenic therapy targets tumor vasculature and alternative signaling pathways. Multiple preclinical studies have investigated this hypothesis. Lei et al. demonstrated that the combination of anlotinib and osimertinib reverses acquired resistance to osimertinib in NSCLC by inactivating the c-MET/MYC/AXL pathway (37). Hua et al. showed that combining osimertinib with anlotinib synergistically arrests the cell cycle, promotes apoptosis, inhibits invasion and metastasis, and partially reverses osimertinib resistance (38). Yang et al. confirmed that almonertinib plus anlotinib synergistically suppresses proliferation and induces apoptosis in PC-9/HCC827 cells by inhibiting the PI3K/AKT pathway (39).

The present study demonstrated an ORR of 7.7%, a DCR of 86.5%, and an mPFS of 9.9 months in the enrolled cohort. CTONG-1803/ALTER-L001 was a nationwide multicenter phase II prospective trial that enrolled 120 patients, 90.8% of whom had gradual progression. Among them, 32 patients with gradual progression following first-line osimertinib achieved an mPFS of 10.3 months, however, ORR and DCR were not reported for this subgroup (23). Another single-center retrospective study included 28 patients with gradual progression after first-line osimertinib who received osimertinib plus anlotinib, reporting an mPFS of 10.0 months and a DCR of 85.7% (40). Nevertheless, that study was limited by its small sample size and relatively short follow-up duration. ALTER-L058 enrolled 150 patients with gradual progression or local progression after first-line treatment with various third-generation TKIs and contained a non-randomized comparative cohort. In the osimertinib-plus-anlotinib arm (n=100), the ORR was 7.0%, DCR was 91.0%, and mPFS was 9.23 months. By contrast, the anlotinib-monotherapy arm (n=50) demonstrated an ORR of 0%, DCR of 34.0%, and mPFS of 5.42 months (24). The outcomes observed in our study appear comparable to those reported for corresponding cohorts in the above-mentioned studies. Furthermore, subgroup analyses in the present study revealed longer PFS with this combination regimen in patients with ECOG PS <2, absence of brain metastasis, and a prior PR to first-line osimertinib. Exploratory multivariable Cox regression analysis suggested that ECOG PS and brain metastasis status were associated with PFS.

The combined strategy adopted in this study cohort was based on the clinical progression patterns and cannot replace molecular testing for guiding treatment. Repeating tissue or plasma molecular testing after the progression of osimertinib has significant clinical significance, as the modifiable resistance mechanisms such as MET amplification, EGFR C797S, acquired fusion, and histological transformation may alter the treatment options. The study protocol did not mandate that patients repeat molecular testing after the gradual progression on osimertinib. Due to the majority of patients refusing another invasive biopsy or for economic reasons, only 12 out of 52 patients underwent repeated molecular testing after the gradual progression. The limited molecular testing data post-progression constrained the classification and further exploration of resistance mechanisms.

Regarding safety, the incidence of TRAEs of any grade in this study was 78.8%, while the incidence of grade 3 or 4 TRAEs was only 9.6%. The most common TRAEs were diarrhea (42.3%), hypertension (34.6%), proteinuria (30.8%), decreased appetite (28.8%), and weight loss (28.8%). No treatment-related deaths occurred. The spectrum and incidence of TRAEs across all grades in our study were consistent with those reported in the literature (23,40,41).

This study has several limitations. Firstly, it is a single-center retrospective study with a relatively small sample size of 52 patients, which inherently restricts the generalizability of the conclusions. Despite a relatively high number of PFS events, the limited sample size could produce unstable multivariable estimates; the identified prognostic factors should be considered exploratory findings. Secondly, this study lacks a control group, and patients with gradual progression may be a subgroup of relatively indolent diseases, possibly inherently having better survival rates independent of the treatment itself. Thirdly, the follow-up duration is insufficient, and the OS data are not yet mature, precluding a comprehensive evaluation of the impact of this combination regimen on long-term survival. Finally, retrospective designs are subject to information bias, mild AEs are prone to underreporting in medical records, which may lead to an overall incidence of AEs that is slightly lower than the actual clinical reality. Therefore, the conclusions of this study should be interpreted with caution.

Conclusions

In conclusion, for this specific cohort of patients with EGFR-mutant non-squamous NSCLC who developed gradual progression following first-line osimertinib therapy, favorable DCR and PFS were observed in our study. Whether this strategy is superior to chemotherapy or other therapeutic approaches warrants further validation by multicenter, large-sample prospective comparative studies in the future.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0785/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0785/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0785/prf

Funding: This work was supported by the Fundamental Research Funds for the Central Universities (No. YD9115202678).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0785/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. This study was approved by the Ethics Committee of The First Affiliated Hospital of the University of Science and Technology of China (No. 2026-RE-396). Due to its retrospective design, 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/.

References

1. Zhou C, Wang Z, Fu C, et al. The efficacy and safety of PD-1 inhibitors for EGFR-mutant non-small cell lung cancer after tyrosine kinase inhibitor failure: a retrospective real-world cohort study. Ann Transl Med 2023;11:157. [Crossref] [PubMed]
2. Wang C, Yu Q, Song T, et al. The heterogeneous immune landscape between lung adenocarcinoma and squamous carcinoma revealed by single-cell RNA sequencing. Signal Transduct Target Ther 2022;7:289. [Crossref] [PubMed]
3. Zhang C, Lu X, Liu X, et al. Carbonic Anhydrase IX Controls Vulnerability to Ferroptosis in Gefitinib-Resistant Lung Cancer. Oxid Med Cell Longev 2023;2023:1367938. [Crossref] [PubMed]
4. Lin EH, Hsu JW, Lee TF, et al. Targeting cancer stemness mediated by BMI1 and MCL1 for non-small cell lung cancer treatment. J Cell Mol Med 2022;26:4305-21. [Crossref] [PubMed]
5. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 2017;376:629-40. [Crossref] [PubMed]
6. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25. [Crossref] [PubMed]
7. Ding D, Xu C, Zhang J, et al. Revealing underlying regulatory mechanisms of LINC00313 in Osimertinib-resistant LUAD cells by ceRNA network analysis. Transl Oncol 2024;43:101895. [Crossref] [PubMed]
8. Araki T, Kanda S, Komatsu M, et al. Rechallenge of afatinib for EGFR-mutated non-small cell lung cancer previously treated with osimertinib: a multicenter phase II trial protocol (REAL study). Transl Lung Cancer Res 2023;12:1320-7. [Crossref] [PubMed]
9. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol 2024;35:77-90. [Crossref] [PubMed]
10. Peled N, Tufman A, Sequist LV, et al. COMPEL: osimertinib plus platinum-based chemotherapy in patients with EGFR-mutated advanced NSCLC and progression on first-line osimertinib. ESMO Open 2025;10:105807. [Crossref] [PubMed]
11. Chen CL, Wang ST, Liao WC, et al. When to add anti-angiogenesis drugs to EGFR-mutated metastatic non-small cell lung cancer patients: a real-world study from Taiwan. BMC Cancer 2022;22:571. [Crossref] [PubMed]
12. Yang JJ, Chen HJ, Yan HH, et al. Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer. Lung Cancer 2013;79:33-9. [Crossref] [PubMed]
13. Xue L, Gong Z, Vlantis AC, et al. Autophagy regulates anti-angiogenic property of lenvatinib in thyroid cancer. Am J Cancer Res 2023;13:1457-70. [PubMed]
14. Kuo CS, Su PL, Wei YF, et al. T790M detection rate after first-line combination therapy with bevacizumab and EGFR-TKIs in advanced NSCLC (TERRA Study). Am J Cancer Res 2023;13:3100-12. [PubMed]
15. Saito H, Fukuhara T, Furuya N, et al. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol 2019;20:625-35. [Crossref] [PubMed]
16. Zhao H, Yao W, Min X, et al. Apatinib Plus Gefitinib as First-Line Treatment in Advanced EGFR-Mutant NSCLC: The Phase III ACTIVE Study (CTONG1706). J Thorac Oncol 2021;16:1533-46. [Crossref] [PubMed]
17. Soo RA, Han JY, Dafni U, et al. A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial. Ann Oncol 2022;33:181-92. [Crossref] [PubMed]
18. Kenmotsu H, Wakuda K, Mori K, et al. Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: WJOG9717L Study. J Thorac Oncol 2022;17:1098-108. [Crossref] [PubMed]
19. Akamatsu H, Toi Y, Hayashi H, et al. Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial. JAMA Oncol 2021;7:386-94. [Crossref] [PubMed]
20. Yu L, Xu J, Qiao R, et al. Comparative efficacy and safety of multitarget angiogenesis inhibitor combined with immune checkpoint inhibitor and nivolumab monotherapy as second-line or beyond for advanced lung adenocarcinoma in driver-negative patients: a retrospective comparative cohort study. Transl Lung Cancer Res 2023;12:1108-21. [Crossref] [PubMed]
21. Guan Y, Gu X, Si J, et al. The efficacy of small molecule anti-angiogenic drugs in previously treated Thymic carcinoma. BMC Cancer 2023;23:16. [Crossref] [PubMed]
22. Han B, Li K, Wang Q, et al. Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial. JAMA Oncol 2018;4:1569-75. [Crossref] [PubMed]
23. Chen HJ, Tu HY, Hu Y, et al. A phase II trial of anlotinib plus EGFR-TKIs in advanced non-small cell lung cancer with gradual, oligo, or potential progression after EGFR-TKIs treatment (CTONG-1803/ALTER-L001). J Hematol Oncol 2025;18:3. [Crossref] [PubMed]
24. Zhou F, Zhuo M, Wang H, et al. Anlotinib added to third generation EGFR tyrosine kinase inhibitor therapy for advanced NSCLC patients with oligo-progression: a retrospective study (ALTER-L058). Front Pharmacol 2025;16:1686364. [Crossref] [PubMed]
25. Yang Z, Yang N, Ou Q, et al. Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients. Clin Cancer Res 2018;24:3097-107. [Crossref] [PubMed]
26. Zheng D, Hu M, Bai Y, et al. EGFR G796D mutation mediates resistance to osimertinib. Oncotarget 2017;8:49671-9. [Crossref] [PubMed]
27. Chabon JJ, Simmons AD, Lovejoy AF, et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun 2016;7:11815. [Crossref] [PubMed]
28. Chmielecki J, Mok T, Wu YL, et al. Analysis of acquired resistance mechanisms to osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer from the AURA3 trial. Nat Commun 2023;14:1071. [Crossref] [PubMed]
29. Le X, Puri S, Negrao MV, et al. Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC. Clin Cancer Res 2018;24:6195-203. [Crossref] [PubMed]
30. Minari R, Bordi P, Del Re M, et al. Primary resistance to osimertinib due to SCLC transformation: Issue of T790M determination on liquid re-biopsy. Lung Cancer 2018;115:21-7. [Crossref] [PubMed]
31. Lau LYE, Skanderup AJ, Tan AC. Lineage Plasticity and Histologic Transformation in EGFR-TKI Resistant Lung Cancer. Int J Mol Sci 2025;27:445. [Crossref] [PubMed]
32. Weng CH, Chen LY, Lin YC, et al. Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI. Oncogene 2019;38:455-68. [Crossref] [PubMed]
33. Wang C, Fei K, Liu L, et al. Abnormal activation of NF-κB and MAPK signaling pathways affect osimertinib resistance and influence the recruitment of myeloid-derived suppressor cells to shape the immunosuppressive tumor immune microenvironment. Thorac Cancer 2023;14:1843-56. [Crossref] [PubMed]
34. Long J, Lei S, Wu Z, et al. Efficacy and safety of original EGFR-TKI combined with bevacizumab in advanced lung adenocarcinoma patients harboring EGFR-mutation experiencing gradual progression after EGFR-TKI treatment: a single-arm study. Ann Transl Med 2022;10:1334. [Crossref] [PubMed]
35. Yang X, Xia Y, Xu L, et al. Efficacy and Safety of Combination Treatment With Apatinib and Osimertinib After Osimertinib Resistance in Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Carcinoma-A Retrospective Analysis of a Multicenter Clinical Study. Front Mol Biosci 2021;8:639892. [Crossref] [PubMed]
36. Zhang Y, Wang C, Zhao J, et al. The efficacy of almonertinib and anlotinib combination therapy for advanced non-small-cell lung cancer patients who continued to experience cancer progression during third-generation EGFR-TKI treatment: a retrospective study. Thorac Cancer 2024;15:1757-63. [Crossref] [PubMed]
37. Lei T, Xu T, Zhang N, et al. Anlotinib combined with osimertinib reverses acquired osimertinib resistance in NSCLC by targeting the c-MET/MYC/AXL axis. Pharmacol Res 2023;188:106668. [Crossref] [PubMed]
38. Hua X, Wu X, Lv L, et al. Anlotinib enhances the anti-tumor activity of osimertinib in patients with non-small cell lung cancer by reversing drug resistance. Transl Lung Cancer Res 2025;14:40-57. [Crossref] [PubMed]
39. Yang Y, Liu X, Liu W, et al. Aumolertinib combined with anlotinib inhibits proliferation of non-small cell lung cancer cells by down-regulating the PI3K/AKT pathway. Nan Fang Yi Ke Da Xue Xue Bao 2024;44:1965-75. [Article in Chinese]. [Crossref] [PubMed]
40. Hua Y, Liu M, Li B, et al. Anlotinib Plus Osimertinib in Osimertinib-Resistant Nonsquamous Nonsmall Cell Lung Cancer With Gradual Progression: A Retrospective Study. Thorac Cancer 2025;16:e70071. [Crossref] [PubMed]
41. Wang M, Zhao J, Chen T, et al. Efficacy and safety of osimertinib plus anlotinib in advanced non-small-cell lung cancer patients after drug resistance. Thorac Cancer 2023;14:873-80. [Crossref] [PubMed]