Abstract
Background
Anlotinib is established as a standard later-line treatment for advanced non-small cell lung cancer (NSCLC). However, the real-world efficacy of anlotinib-based chemotherapy-free combinations—particularly in earlier lines of therapy—remains insufficiently characterized. This study aimed to evaluate the survival outcomes of anlotinib monotherapy versus combination regimens and assess the impact of treatment line on efficacy.
Methods
In this single-center, real-world retrospective cohort study, we analyzed 170 patients with advanced NSCLC. Patients were stratified into three cohorts: anlotinib monotherapy (Group A, n=62), anlotinib plus immunotherapy (Group A+I, n=57), and anlotinib plus targeted therapy (Group A+T, n=51). The primary endpoints were progression-free survival (PFS) and overall survival (OS), analyzed using Kaplan-Meier methods and Cox proportional hazards models.
Results
The median PFS and OS for the entire cohort were 10 and 18.5 months, respectively. The objective response rate (ORR) and disease control rate (DCR) for the entire population were 17.6% and 84.8%, respectively. In the subgroups, the ORR was 18.8% (A+I) and 23.1% (A+T) vs. 10.5% (monotherapy), while the DCR was 93.8% (A+I) and 82.1% (A+T) vs. 76.3% (monotherapy). Compared with monotherapy, combination regimens demonstrated superior survival benefits. Specifically, the A+I group showed significantly reduced risks of progression [hazard ratio (HR): 0.461, P=0.001] and mortality (HR: 0.576, P=0.03). Similarly, the A+T group exhibited marked improvements in PFS (median 13.5 vs. 4.0 months; HR: 0.360, P<0.001) and OS (median 26.5 vs. 10.0 months; HR: 0.332, P<0.001). Subgroup analyses revealed that administering anlotinib in the first- or second-line setting yielded significantly longer PFS (22.5 vs. 8.5 months) and OS (37.0 vs. 14.0 months) compared to third-line use. Notably, among patients with driver mutations, the A+T regimen extended median OS to 26.5 months compared to 10.0 months in the monotherapy group. Lack of prior anti-angiogenic therapy was identified as an independent predictor for improved PFS.
Conclusions
Anlotinib-based, chemotherapy-free regimens demonstrate significantly greater efficacy than anlotinib monotherapy in advanced NSCLC. Furthermore, the upstream application of these regimens in earlier treatment lines is associated with markedly prolonged survival. These findings support anlotinib-based combinations as a promising chemotherapy-sparing strategy, particularly for patients unsuitable for or refusing chemotherapy.
Keywords: Anlotinib, non-small cell lung cancer (NSCLC), combination therapy, chemotherapy-free
Highlight box.
Key findings
• In this single-center, retrospective cohort study of 170 patients with advanced non-small cell lung cancer (NSCLC), anlotinib-based chemotherapy-free combinations showed better efficacy than anlotinib monotherapy.
• Earlier-line use of anlotinib-based regimens was associated with longer survival, particularly in combination strategies.
What is known and what is new?
• Anlotinib is mainly recommended as a later-line treatment for advanced NSCLC, while chemotherapy-free strategies are clinically needed for patients who are unable or unwilling to receive chemotherapy.
• This study provides real-world evidence comparing anlotinib monotherapy, anlotinib plus immunotherapy, and anlotinib plus targeted therapy, and supports the potential value of anlotinib as a backbone drug in chemotherapy-free combinations.
What is the implication, and what should change now?
• Anlotinib-based combinations may represent a practical chemotherapy-sparing option for selected patients with advanced NSCLC.
• Larger prospective multicenter studies are needed to confirm patient selection, treatment sequencing, and safety.
Introduction
According to global cancer statistics, lung cancer remained the leading cause of cancer incidence and mortality in 2022, with nearly 2.5 million new cases and more than 1.8 million deaths worldwide, accounting for 12.4% of all newly diagnosed cancers and 18.7% of cancer-related deaths, respectively (1). In China, approximately 75% of patients present with advanced disease at diagnosis, posing considerable treatment challenges (2). Meanwhile, targeted and immunotherapeutic approaches have substantially improved survival in patients with advanced non-small cell lung cancer (NSCLC) (3). For patients harboring driver mutations, targeted therapy is the first-line treatment of choice, offering a marked increase in progression-free survival (PFS) (4), whereas patients without driver mutations are typically managed with chemotherapy plus programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors as the standard regimen (5). Moreover, immunotherapy monotherapy with immune checkpoint inhibitors (ICIs)—or dual-antibody immunotherapy without chemotherapy—has been approved for advanced NSCLC patients with a tumor proportion score (TPS) of ≥50% or ≥1% (6,7). Nonetheless, therapeutic resistance and the complex tumor microenvironment (TME) still limit the degree of improvement achievable. In real-world clinical practice, a significant subset of patients—due to advanced age, poor Eastern Cooperative Oncology Group performance status (ECOG PS), or significant comorbidities—are intolerant to or refuse chemotherapy (8). Consequently, there is a growing clinical demand for “chemotherapy-free” strategies that balance efficacy with quality of life, particularly for patients who are intolerant to or refuse cytotoxic chemotherapy. Therefore, identifying therapeutic approaches that are both well-tolerated and highly effective holds substantial clinical value.
Anlotinib hydrochloride is a novel multi-target tyrosine kinase inhibitor that exerts multifaceted antitumor activity by inhibiting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) (9). While currently recommended as a third-line treatment for advanced NSCLC in China (10), attention has shifted toward chemotherapy-free combinations. For instance, anlotinib combined with TQB2450 has shown significant efficacy and manageable toxicity in patients without gene mutations (11). Mechanistically, emerging evidence indicates that anlotinib can reprogram the TME—specifically by inducing C-C motif chemokine ligand 5 (CCL5) to promote CD8+ T-cell infiltration and downregulating CCL2—thereby creating a synergistic effect with ICIs (9,12,13). This biological rationale is supported by clinical data in treatment-resistant, EGFR-mutant patients, where anlotinib plus programmed cell death PD-1/PD-L1 inhibitors yielded favorable survival outcomes (14).
While current guidelines primarily recommend anlotinib as a later-line therapy, its potential in earlier treatment lines is increasingly recognized. Clinical trials have demonstrated that adding anlotinib to immunotherapy (e.g., sintilimab) or targeted agents (e.g., icotinib, gefitinib) in the first-line setting yields promising survival benefits (15-17). However, most existing evidence derives from trials with strict inclusion criteria, leaving a significant gap in understanding how these “chemo-free” regimens perform in a broader, real-world population. Consequently, data regarding the comparative efficacy of combination strategies (A+I or A+T) and their optimal positioning—specifically whether they confer greater benefit in first- or second-line settings compared to standard third-line use—remain insufficient.
Based on the synergistic mechanisms described above, we hypothesized that combining anlotinib with immunotherapy or targeted therapy would elicit superior survival outcomes compared to anlotinib monotherapy. Furthermore, we postulated that the application of these chemotherapy-free regimens in earlier treatment lines (first- or second-line) would yield greater clinical benefit than their standard third-line use. To test these hypotheses, we conducted this real-world retrospective study to systematically compare the efficacy of monotherapy versus combination regimens. Specifically, the study aimed to quantify the survival benefits of adding anlotinib to ICIs or targeted agents and to identify independent prognostic factors, thereby providing evidence to optimize treatment sequencing for patients who decline or are unsuitable for chemotherapy. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2307/rc).
Methods
Patients and study design
This was a single-center, retrospective, real-world observational cohort study conducted at Lianyungang Clinical College of Nanjing Medical University. We retrospectively analyzed electronic medical records (EMR) of patients with advanced NSCLC who received anlotinib-based therapy at the Lianyungang Clinical College of Nanjing Medical University between April 2019 and August 2024. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Lianyungang First People’s Hospital (No. KY-20241018002-01) and individual consent for this retrospective analysis was waived.
Patients were enrolled based on the following criteria: (I) pathologically confirmed stage IIIB–IV NSCLC according to the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual; (II) receipt of at least one cycle of anlotinib (8, 10, or 12 mg once daily, administered for two weeks followed by one week off, forming a 21-day cycle); and (III) an ECOG PS of 0–2. Exclusion criteria included: (I) incomplete medical records or follow-up information that precluded accurate assessment of therapeutic efficacy. (II) concurrent other primary malignancies; or (III) severe uncontrolled comorbidities that significantly impacted survival independent of cancer progression. The source population comprised all consecutive NSCLC patients treated at our center during the study period. The exposure period was defined as the duration from the first dose of anlotinib-based therapy until treatment discontinuation or death. Follow-up was conducted via regular clinic visits and telephone interviews every 6–8 weeks. The data cutoff date for survival analysis was September 15, 2024, ensuring a minimum potential follow-up of three months for all surviving patients. According to the treatment regimens, patients were assigned to one of three groups: anlotinib monotherapy (Group A), anlotinib plus immunotherapy (Group A+I), or anlotinib combined with other targeted agents (Group A+T). Specifically, the immunotherapy agents used in Group A+I varied based on clinical availability and physician choice, including sintilimab, camrelizumab, tislelizumab, and pembrolizumab. Given that these agents share a common mechanism targeting the PD-1/PD-L1 axis, they were analyzed as a collective class. To reflect real-world clinical practice and minimize selection bias, consecutive sampling was employed rather than probability sampling. Data for all variables were retrospectively extracted from the Hospital Information System (HIS) and the Picture Archiving and Communication System (PACS). Demographic data, including age, sex, smoking status, and ECOG PS, were ascertained from initial admission nursing records and physician progress notes. Pathological subtypes and genetic mutations, including EGFR, ALK, and ROS1, were retrieved from pathology reports and molecular diagnostic logs. Detailed treatment information, including dosage, dates of administration, and cycle numbers for anlotinib, immunotherapy, and targeted agents, was obtained from electronic pharmacy prescription records and nurse administration logs. Tumor measurements were performed on contrast-enhanced computed tomography (CECT) scans stored in the PACS. To minimize measurement bias, all radiographic images were independently reviewed by two senior radiologists who were blinded to treatment group assignments and clinical outcomes; in cases of disagreement, a third expert adjudicator provided the final consensus. To ensure comparability across the three cohorts, all patients were treated at the same institution, data were obtained from the same EMR and PACS systems, and the follow-up protocol was standardized across groups. CT scans were performed every two cycles, approximately every 6–8 weeks, during treatment and every 3 months thereafter, thereby reducing detection bias caused by unequal imaging frequency. This uniform assessment interval prevents detection bias (ensuring that earlier detection of progression in one arm is not driven solely by more frequent imaging assessments).
Efficacy evaluation
The primary exposure of interest was the treatment regimen. Treatment response was monitored by computed tomography (CT) at each assessment. Objective tumor response was categorized according to the RECIST 1.1 criteria. The primary endpoints were PFS and overall survival (OS). PFS was defined as the time from the start of anlotinib treatment until the first documented tumor progression or death from any cause, whichever occurred first. Patients without these events were censored at the last follow-up. OS was defined as the time from the start of anlotinib treatment until death from any cause. Surviving patients were censored at the last contact date. Secondary endpoints included objective response rate (ORR) [percentage of patients achieving complete response (CR) or partial response (PR)] and disease control rate (DCR) [percentage of patients achieving CR, PR, or stable disease (SD)].
Statistical analysis
Sample size was determined by the number of eligible patients available in our database during the defined study period (April 2019 to August 2024). No formal a priori power calculation was performed due to the retrospective nature of the study. However, based on the general rule of thumb for Cox regression analysis (requiring at least 10 outcome events per covariate), our sample size of 170 patients with 92 events was considered sufficient to support the inclusion of 12 covariates in the multivariate models without risk of overfitting. In the final survival analysis and baseline comparison, continuous variables were categorized to facilitate clinical interpretation and applicability. Patients were dichotomized into <65 and ≥65 years. This cutoff was chosen based on standard geriatric oncology definitions and previous clinical trials in NSCLC, allowing for the assessment of treatment efficacy in the elderly population. Continuous variables such as age were converted into categorical variables based on clinical relevance (e.g., age <65 vs. ≥65 years). Ordinal variables like ECOG PS were grouped (0–1 vs. 2) for survival analysis. Descriptive statistics were used to summarize patient clinical and demographic characteristics. Kaplan-Meier analysis was performed to estimate survival curves, and the log-rank test was applied to compare differences across subgroups. Univariate Cox proportional hazards regression was conducted to identify prognostic factors, including age, sex, smoking history, ECOG PS, histological subtype, tumor stage, metastatic sites, baseline gene mutation status, PD-L1 expression, treatment regimen, line of treatment, and prior anti-angiogenic therapy. Statistical significance was set at two-sided P<0.05, with Benjamini-Hochberg (BH) correction applied for multiple comparisons. All statistical analyses and data visualization were carried out using R software (version 4.3.1). Subgroup analyses were performed based on baseline characteristics, including age (<65 vs. ≥65 years), gender, smoking history, and metastatic sites, as presented in the forest plot. Missing data were addressed by complete-case analysis. Patients with missing key clinical data or incomplete medical records were excluded from the study during the initial screening phase. Patients were followed up until death or the data cutoff date. Individuals lost to follow-up were censored at the date of their last confirmed contact or clinical visit.
Results
Patient characteristics
Between April 2019 and August 2024, a total of 1,854 patients diagnosed with advanced NSCLC were initially screened from the hospital database. Of these, 1,684 patients were excluded for the following reasons: (I) incomplete medical records or lack of follow-up data (N=479); (II) no measurable lesions at baseline (n=601); (III) concurrent other malignancies (N=298); and (IV) failure to complete at least one cycle of anlotinib treatment (N=476). The patient selection process is illustrated in Figure 1. A total of 170 patients with advanced NSCLC met the inclusion criteria and were enrolled in this study. Based on the treatment regimens received, patients were categorized into three cohorts: the anlotinib monotherapy group (Group A, N=62), the anlotinib plus immunotherapy group (A+I, N=57), and the anlotinib plus targeted therapy group (A+T, N=51). No patients were excluded from the analysis after the final enrollment. A total of 170 patients comprise 116 males (68.2%) and 54 females (31.8%). The mean age was 65.8 years, with a median age of 67.5 years (range, 35–83 years); among them, 59.4% were older than 65 years, and 25.2% had a smoking history. In terms of histological subtype, 124 patients (72.9%) had adenocarcinoma and 46 patients (27.1%) had squamous cell carcinoma. Most patients (151, 88.8%) were stage IV according to the 8th edition of the AJCC staging system. ECOG PS indicated that 141 patients (82.9%) had a PS of 0–1, suggesting relatively good physical condition. The most common baseline metastatic site was the pleura (61 patients, 35.8%), followed by bone (57 patients, 33.5%) and the contralateral lung (41 patients, 24.1%). Additionally, 57 patients (33.5%) had malignant pleural effusion, and 65 patients (38.2%) had previously received other anti-angiogenic agents. Of the total 170 patients, 41 (24.1%) received anlotinib as first-line treatment, 59 (34.7%) as second-line treatment, and 70 (41.2%) as third-line or beyond. Based on the treatment regimen, they were divided into three groups: anlotinib monotherapy (Group A, n=62), anlotinib plus immunotherapy (Group A+I, n=57), and anlotinib plus other targeted agents (Group A+T, n=51). Table 1 summarizes the demographic and clinicopathological characteristics of the three patient groups.
Figure 1.
Flow diagram of patient screening, exclusion, cohort allocation, and survival analysis. NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival.
Table 1. Clinical and pathological characteristics of the patients.
| Variable | Group A (N=62) | Group A+I (N=57) | Group A+T (N=51) | P value |
|---|---|---|---|---|
| Gender | ||||
| Male | 46 (74.2) | 45 (78.9) | 25 (49.0) | 0.002 |
| Female | 16 (25.8) | 12 (21.1) | 26 (51.0) | |
| Smoking history | ||||
| Yes | 16 (25.8) | 20 (35.1) | 7 (13.7) | 0.04 |
| No | 46 (74.2) | 37 (64.9) | 44 (86.3) | |
| Age, years | ||||
| <65 | 29 (46.8) | 17 (29.8) | 23 (45.1) | 0.13 |
| ≥65 | 33 (53.2) | 40 (70.2) | 28 (54.9) | |
| ECOG PS | ||||
| 0–1 | 49 (79.0) | 50 (87.7) | 42 (82.4) | 0.45 |
| 2 | 13 (21.0) | 7 (12.3) | 9 (17.6) | |
| Histological subtype | ||||
| Adenocarcinoma | 42 (67.7) | 34 (59.6) | 48 (94.1) | <0.001 |
| Squamous | 20 (32.3) | 23 (40.4) | 3 (5.9) | |
| Site of metastasis | ||||
| Contralateral lung | ||||
| Yes | 20 (32.3) | 6 (10.5) | 15 (29.4) | 0.01 |
| No | 42 (67.7) | 51 (89.5) | 36 (70.6) | |
| Bone | ||||
| Yes | 17 (27.4) | 19 (33.3) | 21 (41.2) | 0.31 |
| No | 45 (72.6) | 38 (66.7) | 30 (58.8) | |
| Liver | ||||
| Yes | 8 (12.9) | 2 (3.5) | 3 (5.9) | 0.13 |
| No | 54 (87.1) | 55 (96.5) | 48 (94.1) | |
| Brain | ||||
| Yes | 12 (19.4) | 19 (33.3) | 15 (29.4) | 0.21 |
| No | 50 (80.6) | 38 (66.7) | 36 (70.6) | |
| Pleura | ||||
| Yes | 19 (30.6) | 16 (28.1) | 26 (51.0) | 0.03 |
| No | 43 (69.4) | 41 (71.9) | 25 (49) | |
| Other metastatic | ||||
| Yes | 13 (21.0) | 6 (10.5) | 8 (15.7) | 0.30 |
| No | 49 (79.0) | 51 (89.5) | 43 (84.3) | |
| Line of therapy | ||||
| 1 | 17 (27.4) | 10 (17.5) | 14 (27.5) | 0.57 |
| 2 | 18 (29.0) | 23 (40.4) | 18 (35.2) | |
| ≥3 | 27 (43.5) | 24 (42.1) | 19 (37.3) | |
| Use of other anti-angiogenic therapies | ||||
| Yes | 26 (41.9) | 21 (36.8) | 18 (35.3) | 0.57 |
| No | 36 (58.1) | 36 (63.2) | 33 (64.7) | |
| Gene mutation | ||||
| Yes | 22 (35.5) | 13 (22.8) | 49 (96.1) | <0.001 |
| No | 40 (64.5) | 44 (77.2) | 2 (3.9) | |
| PD-L1 expression | ||||
| Yes | 8 (12.9) | 3 (5.3) | 2 (3.9) | 0.14 |
| No | 54 (87.1) | 54 (94.7) | 49 (96.1) | |
| Tumor stage | ||||
| IIIB, IIIC | 11 (17.7) | 7 (12.3) | 1 (2.0) | 0.03 |
| IV | 51 (82.3) | 50 (87.7) | 50 (98.0) | |
Data are presented as n (%). Group A: anlotinib monotherapy; Group A+I: anlotinib plus immunotherapy; Group A+T: anlotinib plus targeted therapy. ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed death-ligand 1.
Overall efficacy
As of September 15, 2024, 92 (54.1%) of the 170 patients had died and 78 (45.9%) were still alive. The median PFS (mPFS) for the entire population was 10 months [95% confidence interval (CI): 8.177–11.823], and the median OS (mOS) was 18.5 months (95% CI: 12.991–24.009) (Figure 2). In terms of tumor response within the evaluable population, the overall ORR and DCR were 17.6% and 84.8%, respectively. When stratified by treatment regimen, the ORR was 10.5% in Group A, 18.8% in Group A+I, and 23.1% in Group A+T. The DCR was 76.3% in Group A, 93.8% in Group A+I, and 82.1% in Group A+T. These results indicate that combination regimens (A+I and A+T) tended to yield higher response rates compared to anlotinib monotherapy. When stratified by treatment cohort, the summary measures were as follows (Figure 3): Group A: mPFS 5.5 months (95% CI: 3.49–7.51); mOS 12.0 months (95% CI: 8.99–15.01). Group A+I: mPFS 14.0 months (95% CI: 9.60–18.40); mOS 19.0 months (95% CI: 9.24–28.76). Group A+T: mPFS 15.0 months (95% CI: 7.99–22.01); mOS 26.5 months (95% CI: 12.25–40.75). Both Group A+I and Group A+T showed a significantly longer mPFS than the monotherapy group (P<0.001), whereas there was no significant difference between A+I and A+T (P=0.31) (Figure 4A). In terms of mOS, Group A+I and Group A+T were both superior to Group A (P=0.02 and P<0.001, respectively), with no statistically significant difference between A+I and A+T (P=0.055) (Figure 4B).
Figure 2.
Survival analysis for all patients. PFS (A) and OS (B) for the overall cohort. CI, confidence interval; mOS, median OS; mPFS, median PFS; OS, overall survival; PFS, progression-free survival.
Figure 3.
Univariate Cox regression analysis showing the impact of each variable on patient survival. A, anlotinib monotherapy; A+I, anlotinib plus immunotherapy; A+T, anlotinib plus targeted therapy; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; PD-L1, programmed death-ligand 1.
Figure 4.
Efficacy outcomes of the three treatment regimens. PFS (A) and OS (B) across the three regimens. A, anlotinib monotherapy; A+I, anlotinib plus immunotherapy; A+T, anlotinib plus targeted therapy; CI, confidence interval; mOS, median OS; mPFS, median PFS; OS, overall survival; PFS, progression-free survival.
Prognostic factors
Univariate analysis indicated that age [hazard ratio (HR): 0.68, 95% CI: 0.474–0.976, P=0.04], ECOG PS (HR: 1.737, 95% CI: 1.083–2.786, P=0.02), prior anti-angiogenic therapy (HR: 1.533, 95% CI: 1.058–2.221, P=0.02), treatment regimen, and treatment line significantly influenced PFS. Relative to Group A, patients in Group A+I (HR: 0.461, 95% CI: 0.295–0.719, P=0.001) and Group A+T (HR: 0.36, 95% CI: 0.223–0.582, P<0.001) had a reduced risk of progression. Similarly, compared with third-line therapy, first-line (HR: 0.299, 95% CI: 0.183–0.491, P<0.001) and second-line (HR: 0.455, 95% CI: 0.301–0.688, P<0.001) treatment significantly decreased the risk of progression. For OS, ECOG PS (HR: 2.273, 95% CI: 1.409–3.666, P=0.001), liver metastasis (HR: 2.117, 95% CI: 1.092–4.103, P=0.03), treatment regimen (A+I: HR: 0.576, 95% CI: 0.351–0.945, P=0.03; A+T: HR: 0.332, 95% CI: 0.189–0.583, P<0.001), and treatment line (first-line: HR: 0.418, 95% CI: 0.244–0.715, P=0.001; second-line: HR: 0.560, 95% CI: 0.348–0.901, P=0.02) were identified as prognostic factors. The results of the univariate analysis are depicted in the forest plot (Figure 3).
Efficacy comparisons at different treatment lines within the same regimen
To further investigate the effect of different treatment lines, we compared PFS and OS for each regimen across first-, second-, and third-line (or beyond) therapy.
Group A
Among these 62 patients, 17 were treated in the first-line, 18 in the second-line, and 27 in the third-line or beyond. The mPFS values were 10 months (95% CI: 4.659–15.341), 7.5 months (95% CI: 5.059–9.941), and 3 months (95% CI: 1.728–4.272), respectively. First- and second-line treatment achieved significantly longer PFS than third-line or later therapy (P<0.001), with no significant difference between first- and second-line (P=0.32) (Figure 5A). The corresponding mOS values were 15 months (95% CI: 10.814–19.186), 12 months (95% CI: 4.645–19.355), and 10 months (95% CI: 7.877–12.123), with no statistically significant difference among the three lines (Figure 5B).
Figure 5.
Comparison of first-line, second-line, and third-line (or beyond) treatment efficacy among the three regimens. (A,B) PFS and OS for anlotinib monotherapy used as first-line, second-line, and third-line or beyond. (C,D) PFS and OS for anlotinib plus immunotherapy across different treatment lines. (E,F) PFS and OS for anlotinib plus targeted therapy as first-line, second-line, and third-line or beyond. CI, confidence interval; mOS, median OS; mPFS, median PFS; OS, overall survival; PFS, progression-free survival.
Group A+I
Of these 57 patients, 10 received first-line, 23 received second-line, and 24 received third-line or beyond. The mPFS was 18 months (95% CI: 6.069–29.931), 16 months (95% CI: 12.643–19.357), and 9.5 months (95% CI: 1.835–17.165), respectively. Second-line treatment showed a significantly longer mPFS than third-line (P=0.041); however, there were no significant differences between first- and second-line (P=0.86) or between first- and third-line (P=0.08) (Figure 5C). The respective mOS values were 27 months (95% CI: 22.366–31.634), 23 months (95% CI: 9.525–36.475), and 15.5 months (95% CI: 7.794–23.206), with no statistically significant differences among the three lines (Figure 5D).
Group A+T
In this group, 14 patients received first-line, 18 received second-line, and 19 received third-line or beyond. Regarding mutational status, 49 patients harbored actionable driver mutations, while 2 wild-type patients in the second-line setting received this combination empirically due to poor performance status and refusal of chemotherapy. The mPFS values were 22.5 months (95% CI: 21.712–23.288), 13.5 months (95% CI: 3.002–23.998), and 8.5 months (95% CI: 3.348–13.652), respectively. First-line therapy was associated with significantly longer mPFS compared with both second-line (P=0.044) and third-line (P=0.044) (Figure 5E). The corresponding mOS values were 37 months (95% CI: 31.361–42.639), 22 months (95% CI: 10.374–33.626), and 14 months (95% CI: 9.459–18.541). First-line therapy yielded a significantly longer mOS than third-line (P=0.044), whereas there were no significant differences between first- and second-line (P=0.33) or between second- and third-line (P=0.33) (Figure 5F).
The impact of gene mutations and other anti-angiogenic therapy on efficacy
Among patients with confirmed gene mutations (Group A: n=22; Group A+I: n=13; Group A+T: n=49), the mPFS was 4 months (95% CI: 2.247–5.753) in Group A, 5.5 months [95% CI: not estimable (NE)–11.372] in Group A+I, and 13.5 months (95% CI: 7.258–19.742) in Group A+T. Notably, Group A+T demonstrated a significantly longer mPFS than Group A (P<0.001) (Figure 6A). The mOS in Group A was 10 months (95% CI: 6.470–13.530), whereas it reached 19 months (95% CI: NE) in Group A+I and 26.5 months (95% CI: 12.364–40.636) in Group A+T. Again, Group A+T achieved a significantly longer mOS compared with Group A (P<0.001) (Figure 6B). Regarding the anlotinib plus immunotherapy (A+I) group, we observed a notable numerical trend toward prolonged survival. Although this survival advantage did not reach statistical significance in the current cohort (P>0.05)—likely a reflection of the limited sample size—the substantial extension in median survival represents a clinically meaningful signal that warrants further verification in larger studies.
Figure 6.
Impact of gene mutations and prior anti-angiogenic therapy on treatment efficacy. (A,B) PFS and OS among patients with gene mutations receiving the three different regimens. (C,D) Comparison of the PFS and OS in patients who had or had not received other anti-angiogenic agents. A, anlotinib monotherapy; A+I, anlotinib plus immunotherapy; A+T, anlotinib plus targeted therapy; CI, confidence interval; mOS, median OS; mPFS, median PFS; NA, not available; OS, overall survival; PFS, progression-free survival.
Further analysis of patients who had or had not received prior anti-angiogenic therapy (such as bevacizumab, apatinib, or endostar) showed that patients who had not received other anti-angiogenic agents had a mPFS of 11 months (95% CI: 7.017–14.983), while patients who had developed resistance after prior anti-angiogenic therapy and subsequently received anlotinib treatment had a mPFS of 7 months (95% CI: 2.925–11.075) (Figure 6B). This difference was statistically significant (P=0.02). The mOS for the two groups was 19 months (95% CI: 12.996–25.004) and 18.5 months (95% CI: 10.839–26.161), respectively (Figure 6D), with no statistically significant difference between the groups.
Discussion
Anlotinib, a multi-targeted agent, exerts its antitumor effects by blocking phosphorylation of VEGFR 2/3 and inhibiting its downstream signaling pathways, while simultaneously exerting strong inhibitory activity against PDGFR and FGFR. Through these mechanisms, anlotinib suppresses angiogenesis and tumor progression. In addition, anlotinib further impedes tumor growth via inhibition of the stem cell factor receptor c-Kit. Compared with single-target inhibitors, anlotinib achieves tumor suppression through multiple pathways, thereby reducing the risk of treatment failure arising from resistance to a single target (18,19). This approach aligns with recent conceptual syntheses that highlight the biological rationale for combining anlotinib with immune or targeted agents. Evidence suggests that such chemotherapy-free regimens can effectively modulate the TME, thereby overcoming resistance mechanisms associated with monotherapy (20). In recent years, progress in immunotherapy and targeted therapy has substantially reshaped the management of advanced NSCLC. Anlotinib’s effects on the immune microenvironment have drawn particular attention, basic research indicates that anlotinib can induce CCL5 to enhance CD8+ T cell infiltration, thereby potentiating the efficacy of PD-1/PD-L1 blockade and providing a theoretical basis for immunotherapy combinations (12). Additionally, it promotes vascular normalization through CD4+ T cells and reprograms the immunosuppressive TME (21,22). Studies have demonstrated that combining anlotinib with PD-1 checkpoint inhibitors effectively prolongs vascular normalization and mitigates the immunosuppressive effects brought about by upregulated PD-L1 following monotherapy, ultimately leading to tumor regression (23). Furthermore, combining anlotinib with osimertinib can reverse osimertinib resistance by inactivating the c-MET/MYC/AXL axis, providing additional support for its role in combination therapy (13). Therefore, for patients with advanced NSCLC who cannot tolerate or refuse chemotherapy, chemotherapy-free regimens incorporating anlotinib present a novel therapeutic option. Nevertheless, current guidelines predominantly recommend anlotinib for third-line or later treatment in advanced NSCLC (10). In light of anlotinib’s ability to induce vascular normalization, enhance the immune microenvironment, and reverse drug resistance, we sought to explore its use beyond the third-line setting and thereby offer patients an improved range of therapeutic strategies. In this retrospective analysis of 170 patients with advanced NSCLC, the mPFS for the entire cohort was 10 months, with a mOS of 18.5 months. Cox regression analysis revealed that ECOG PS, anlotinib treatment regimen, and treatment line were independent prognostic factors. Subgroup analyses further demonstrated that both immunotherapy- and targeted therapy-based combinations significantly improved mPFS and mOS relative to monotherapy, in alignment with previous reports (24,25).
We also examined the influence of different treatment lines on anlotinib efficacy. Whether administered as monotherapy or combination therapy, earlier use of anlotinib significantly prolonged PFS. In the monotherapy subgroup, mPFS values of 10 months and 7.5 months were observed in first- and second-line therapy, respectively, both significantly exceeding the 3-month mPFS in third-line or beyond (P<0.001). Although the difference in mOS was not statistically significant (15 vs. 12 vs. 10 months), earlier anlotinib use still showed a trend toward improved survival. This may be attributable to timely vascular normalization, which facilitates greater therapeutic efficacy and slows tumor progression (26). In the combination subgroups, group A+I showed significantly longer mPFS in second-line therapy than in third-line (16 vs. 9.5 months, P=0.041). Meanwhile, group A+T yielded significantly longer mPFS in both first- and second-line treatment compared to third-line (22.5 vs. 13.5 vs. 8.5 months, P=0.044). Notably, first-line therapy in the A+T subgroup achieved a significantly prolonged mOS of 37 months compared to 14 months in the third-line setting (P=0.044), suggesting substantial survival benefit from earlier use of anlotinib. Consistent with these observations, growing evidence indicates the potential value of anlotinib in first- or second-line therapy. In the NCT04028778 trial, gefitinib combined with anlotinib as a first-line regimen for EGFR-mutant patients demonstrated significantly enhanced PFS and favorable tolerability (27). The Phase III prospective study NCT03628521 further evaluated anlotinib plus erlotinib as first-line therapy in EGFR-mutant advanced NSCLC, as well as anlotinib combined with immunotherapy in first-line treatment for patients without common driver mutations. Results showed a median PFS of 21.6 months (95% CI: 15.6–24.9) in the anlotinib plus targeted therapy group, with a 24-month OS rate of 87.1%; for anlotinib plus immunotherapy, the median PFS was 15.6 months (95% CI: 12.9–NE), and the 24-month OS rate was 83.9% (28). These findings underscore that earlier use of anlotinib can achieve greater survival benefits while maintaining an acceptable safety profile. Rather than serving solely as a primary antitumor drug, anlotinib may optimize outcomes by potentiating the efficacy of other agents and delaying resistance. Additionally, patients who develop resistance may respond better to subsequent therapies. Hence, introducing anlotinib earlier could be a key strategy for achieving prolonged survival. Future research should further refine the optimal line of therapy for anlotinib, particularly in chemotherapy-free regimens, to provide additional safe and effective options for those unwilling to receive chemotherapy.
Moreover, among patients harboring driver mutations, we compared the efficacy of different regimens. Anlotinib combined with targeted therapy was significantly superior to monotherapy (mPFS: 13.5 vs. 4 months; mOS: 26.5 vs. 10 months), whereas anlotinib combined with immunotherapy (mPFS: 5.5 months; mOS: 19 months) yielded intermediate outcomes, though intergroup differences did not reach statistical significance. Other studies lend support to these results. A retrospective analysis by Han et al. showed that osimertinib plus anlotinib improved prognosis in TKI-resistant NSCLC patients, prolonging both PFS and OS compared with osimertinib alone (29). In patients with uncommon mutations, the NCT04790409 trial demonstrated a median PFS of 7.0 months (95% CI: 5.4–8.6) and a median OS of 20.0 months (95% CI: 15.6–24.4) for sintilimab combined with anlotinib, indicating durable efficacy (30). In addition, a study by Yu et al. showed that for patients with lung adenocarcinoma that had progressed on TKI therapy, immunotherapy plus anlotinib provided greater efficacy than chemotherapy, further confirming the promise of combination therapy (31). Notably, a recent meta-analysis of anlotinib plus docetaxel has established a substantial survival benchmark for chemotherapy-containing regimens (32). In this context, our study contributes novel real-world evidence demonstrating that anlotinib-based chemotherapy-free strategies can achieve comparable survival benefits to such chemotherapy-intensified combinations. This reinforces the clinical rationale for sparing patients from cytotoxic toxicity without compromising efficacy, providing robust external validation for our approach. These data collectively suggest that anlotinib-based regimens offer favorable outcomes for patients with driver mutations, regardless of prior targeted therapy. In particular, for those who have developed TKI resistance, anlotinib-based combinations represent a safe and effective option. Crucially, while our data indicate that the efficacy of anlotinib monotherapy is relatively limited (mPFS 5.5 months; mOS 12.0 months), combination approaches show highly promising outcomes (e.g., mPFS 15.0 months and mOS 26.5 months in the A+T cohort). This clear pattern suggests that in routine clinical practice, anlotinib functions optimally as a robust therapeutic backbone rather than as an effective stand-alone option. Given the relatively high prevalence of EGFR mutations in East Asian patients with NSCLC, the observed efficacy of anlotinib plus EGFR-TKIs may have particular clinical relevance for East Asian real-world practice. Furthermore, considering that these “chemo-free” strategies are frequently chosen for patients with limited physiologic reserve who are unfit for intensive cytotoxic chemotherapy, tolerability is a paramount concern. In our cohort, the safety profiles across all anlotinib-based regimens were generally manageable. The most common adverse events (e.g., hypertension, hand-foot syndrome, and fatigue) were predominantly mild to moderate (Grade 1–2) and could be effectively controlled through dose adjustments, confirming the safety margin of these combination strategies.
We also investigated whether prior anti-angiogenic therapy influenced the efficacy of anlotinib. The results showed that patients who had not previously received anti-angiogenic therapy had a longer PFS than those who had (P=0.022). This finding is consistent with a retrospective study by Sun et al., which suggested that the absence of prior anti-angiogenic therapy is an independent risk factor for anlotinib PFS (24). However, the subgroup analysis of the ALTER0303 trial indicated that prior anti-angiogenic therapy had a limited impact on the efficacy of anlotinib (HR: 1.588, 95% CI: 0.802–3.145, P=0.185) (33). Mechanistically, overlapping targets and modes of action among different anti-angiogenic agents may influence subsequent response to anlotinib, an aspect that warrants further investigation in larger, more targeted studies.
In parallel with investigating these mechanistic interactions, expanding the clinical scope to special populations remains a priority. Emerging evidence, including a recent systematic review, highlights that combining anlotinib with radiotherapy—such as whole-brain radiotherapy (WBRT)—can significantly improve intracranial control and survival outcomes in patients with brain metastases compared to radiotherapy alone (34). Although our current study focused on systemic efficacy, incorporating such multidisciplinary modalities represents a critical direction for future research aimed at optimizing outcomes in patients with high disease burden.
This study has several limitations. First, as a single-center retrospective real-world study, it is susceptible to selection, reporting, and information biases, and treatment allocation was not randomized. Regimen selection was based on comprehensive clinical assessment, drug accessibility, patient condition, and patient preference; therefore, physician-guided selection may have influenced survival outcomes. Second, the A+T cohort predominantly included patients with actionable driver mutations, especially EGFR-mutant adenocarcinoma, which may limit the generalizability of the findings to patients without driver mutations. Third, the sample size was relatively small, especially in subgroup analyses, resulting in statistical imprecision and wide confidence intervals. Finally, data completeness depended on the accuracy of medical records, and treatment or follow-up schedules may have been affected by the coronavirus disease 2019 (COVID-19) pandemic. Therefore, the findings should be interpreted cautiously and validated in larger prospective multicenter studies.
Conclusions
In this real-world study conducted in China, we compared anlotinib monotherapy with chemotherapy-free regimens that included anlotinib in patients with advanced NSCLC. We conclude that while anlotinib monotherapy provides relatively limited benefit as a stand-alone treatment, it serves as a highly effective therapeutic backbone. The addition of anlotinib to combination therapy significantly improved both PFS and OS relative to monotherapy. Moreover, earlier introduction of anlotinib (i.e., in first- or second-line settings) was associated with markedly enhanced survival benefits, underscoring its potential for use beyond third-line therapy. Moving forward, further research is warranted to broaden its indications and offer more treatment options for patients who are unable—or unwilling—to undergo chemotherapy.
Supplementary
The article’s supplementary files as
Acknowledgments
During the preparation of this work, the authors used ChatGPT in order to improve the readability and language of the manuscript. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.
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 Ethics Committee of Lianyungang First People’s Hospital (No. KY-20241018002-01) and individual consent for this retrospective analysis was waived.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2307/rc
Funding: This work was supported by the Beijing Medical and Health Public Welfare Foundation (grant numbers LD- LC037).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2307/coif). All authors report that this work was supported by the Beijing Medical and Health Public Welfare Foundation (grant numbers LD- LC037). The authors have no other conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2307/dss
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