Chemotherapy-free regimen: Real-world efficacy and safety of anlotinib plus PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer

Abstract

Objective

Chemotherapy-based regimens remain the standard first- and second-line treatment options for patients with driver gene-negative non-small cell lung cancer (NSCLC). However, in real-world settings, certain patients cannot tolerate chemotherapy or opt to decline it. Immune checkpoint inhibitors (ICIs) constitute the preferred chemotherapy-free alternative. To enhance patient prognosis, this study aimed to examine the efficacy of ICIs combined with anlotinib in real-world scenarios.

Methods

This prospective, multicenter, real-world study evaluated the efficacy and safety of ICIs combined with anlotinib in patients with advanced NSCLC. Patients undergoing first- or second-line treatment were enrolled. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.

Results

In total, 242 patients were enrolled from 28 centers. The median PFS for the entire cohort was 7.8 [95% confidence interval (95% CI), 7.0−9.5] months, OS events occurred in 112 (46.3%) patients, with a current median OS of 17.0 (95% CI, 15.1−19.4) months. The ORR and DCR were 36.0% (95% CI, 30.2%−42.2%) and 97.9% (95% CI, 95.3%−99.1%), respectively. The median PFS was 9.8 (95% CI, 7.4−12.5) months for first-line therapy and 6.9 (95% CI, 6.0−8.3) months for second-line therapy. Treatment-related adverse events (AEs) occurred in 198 (81.8%) patients, with grade 3−4 AEs reported in 22 (9.1%) patients.

Conclusions

This multicenter, real-world study demonstrates that the anlotinib-ICI combination regimen exhibits clinically meaningful efficacy and tolerability as a chemotherapy-free alternative for advanced NSCLC, offering viable evidence to guide treatment for patients who are unsuitable for conventional chemotherapy.

Introduction

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases (1,2). Platinum-based chemotherapy has long served as the cornerstone of NSCLC treatment, however, its efficacy is limited by systemic toxicity, acquired resistance, and limited survival benefits (3). The advent of immunotherapy has advanced the treatment paradigm of NSCLC. Monotherapy with immune checkpoint inhibitors (ICIs), such as pembrolizumab and atezolizumab, has demonstrated improved survival compared to chemotherapy for programmed cell death ligand 1 (PD-L1) positive NSCLC, whether first- or second-line treatment (4-6). Furthermore, several studies including ORIENT-11, CHOICE-01, GEMSTONE-302, and RATIONALE-304 have revealed that the progression-free survival (PFS) of certain immunotherapy-chemotherapy combinations ranges from 7.6 to 11.3 months, with overall survival (OS) varying between 17.5 and 27.1 months. Nevertheless, intolerance to or unwillingness to undergo chemotherapy among some patients may undermine the potential therapeutic benefits of combined therapy (7-10). Consequently, developing effective chemotherapy-free immunotherapy combinations holds substantial clinical value for patients with NSCLC who are ineligible for platinum-based chemotherapy (11).

Angiogenesis plays a pivotal role in tumor progression and immunosuppression within the tumor microenvironment (TME) (12). Anlotinib, a novel multi-target tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptors, has exhibited considerable efficacy in combating tumor angiogenesis (13). The ALTER series of trials have demonstrated that anlotinib confers survival benefit to patients with NSCLC and functions as a potential therapy for treatment-refractory patients (14-17). Preclinical evidence suggests that anlotinib potentially synergizes with ICIs by normalizing aberrant tumor vasculature, enhancing T-cell infiltration, and reversing immunosuppression (18,19). The open-label phase III IMpower150 trial provided compelling evidence that atezolizumab, in conjunction with bevacizumab and chemotherapy, is effective for metastatic non-squamous NSCLC (20). In addition, sintilimab [a programmed cell death protein 1 (PD-1) inhibitor] combined with anlotinib as a first-line therapy achieved a objective response rate (ORR) of 72.7% and a disease control rate (DCR) of 100%, with a median PFS of 15.0 months in advanced NSCLC (21). The randomized, multicenter phase III CAMPASS study demonstrated that benmelstobart (TQB2450, a PD-L1 inhibitor) in combination with anlotinib exhibited superior PFS compared to pembrolizumab [11.0 months vs. 7.1 months, hazard ratio (HR): 0.7, P=0.057] as a first-line treatment for advanced NSCLC, further validating the potential of “chemotherapy-free” regimens (22). The HARMONi-2 study indicated that ivonescimab significantly improved PFS compared with pembrolizumab in previously untreated patients with advanced PD-L1 positive NSCLC. In the second-line setting for patients with advanced NSCLC lacking driver gene mutations, benmelstobart, either alone or in conjunction with anlotinib, yielded an ORR of 30.9% and a median PFS of 8.7 months (23).

Nonetheless, these findings, which were derived from controlled trial populations with strict eligibility criteria, may have limited generalizability to real-world cohorts characterized by greater heterogeneity in performance status, comorbidities, and prior therapies. Real-world evidence is critical for validating the efficacy and safety of this combination in broader clinical contexts, particularly as a first- or second-line therapy.

Consequently, this real-world study aimed to evaluate the efficacy of anlotinib combined with ICIs for patients with advanced NSCLC treated in routine clinical settings. By excluding chemotherapy, this study aligns with the growing emphasis on personalized, patient-centric care in oncology. Ultimately, this study endeavors to provide clinicians with actionable insights into the feasibility of integrating anlotinib with immunotherapy, potentially expanding treatment options for patients who are ineligible or resistant to conventional regimens.

Materials and methods

Study design and patients

This study was registered in the Chinese Clinical Trial Registry (ChiCTR) website (No. ChiCTR2100049975). It was a prospective, single-arm, multicenter real-world study involving patients with advanced NSCLC. Between August 1, 2021, and August 7, 2024, a total of 320 patients were screened, and 263 patients were enrolled from 28 centers. Finally, 242 patients who received more than two treatment cycles constituted the entire full analysis set (Figure 1). They were assigned to various study regimens based on patient preference, multidisciplinary team, or physician discretion, and they all provided written informed consent for clinical research. The study was approved by the Institutional Review Board of each participating hospital.

Figure 1.

Schematic diagram of case screening process. PS, performance status; ICI, immune checkpoint inhibitor.

Patients who satisfied the following criteria were included: 1) Male or female aged ≥18 years; 2) pathologically confirmed stage IIIB−IV NSCLC; 3) at least one measurable lesion; 4) treatment with ICIs combined with anlotinib as a first- or second-line therapy; and 5) an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0−2. Patients were excluded, if they had small-cell lung cancer (SCLC) alongside other pathological malignancies or if they had previously received anlotinib.

Treatment

Patients received anlotinib orally daily from d 1 to d 14 of each cycle, while PD-1/PD-L1 inhibitors were administered once on d 1 every 3 weeks. The initial anlotinib dose was determined by the investigator on a case-by-case basis. Treatment continued until progressive disease (PD), treatment intolerance, death, and withdrawal or the initiation of a new antitumor therapy. Patients experiencing intolerable adverse events (AEs) that caused delays or the discontinuation of one drug continued receiving treatment with the other study drug.

Assessment

Patients were followed up once a month by the team of investigators, who evaluated patient responses, classified as complete response (CR), partial response (PR), stable disease (SD), or PD, according to Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1) guidelines using computed tomography or magnetic resonance imaging every 6 weeks during treatment. All imaging was independently reviewed by two qualified and experienced radiologists to ensure accuracy and consistency.

The primary endpoint was PFS, defined as the time from treatment initiation until disease progression or death from any cause before disease progression. Secondary endpoints encompassed OS (time from treatment initiation to death), ORR (the proportion of patients who achieved CR or PR), and DCR (the proportion of patients who achieved CR, PR or SD). AEs were recorded from d 1 of treatment and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (Version 5.0).

Statistical analysis

We anticipated that PFS will improve from 6 months (ICIs monotherapy) to 8 months in the first-line group receiving ICIs plus anlotinib. Similarly, we expected an increase of PFS from 3 months (ICI monotherapy) to 4 months in the second-line group receiving ICIs plus anlotinib. Based on these estimates, we determined that 124 patients would be needed for the first-line therapy group and 107 patients for the second-line therapy group. This assessment was conducted using a two-sided α of 0.05 and 80% power to demonstrate statistical significance. Considering a potential dropout rate of 10%, a total of 257 patients will be required for the study. Efficacy analysis and safety evaluation will be perform on the full analysis set.

Statistical analyses were conducted using with R software (Version 4.5.1; R Foundation for Statistical Computing, Vienna, Austria) and IBM SPSS Statistics (Version 25.0; IBM Corp., New York, USA). The PFS, OS and associated 95% confidence interval (95% CI) were estimated using the Kaplan-Meier method. The log-rank test was employed to compare differences between subgroups, as well as hazard ratio (HR) were estimated using a Cox regression model. A two-tailed t test with a significance level of P<0.05 was considered statistically significant.

Results

Patient characteristics

In total, 263 patients were enrolled from 28 centers and 242 patients with NSCLC who underwent treatment with ICIs and anlotinib for more than two cycles between August 2021 and August 2024 were included in the full analysis set. The baseline characteristics of these 242 NSCLC are summarized in Table 1. The median age of the patients was 66 (range: 32−89) years, with 44 (18.2%) patients aged over 75 years. In the entire cohort, 182 (75.2%) patients were males, while 60 (24.8%) were females. Non-squamous NSCLC comprised 149 (61.6%) cases, primarily adenocarcinoma, which included 4 cases of neuroendocrine carcinoma and 2 cases of sarcomatoid carcinoma. Squamous NSCLC comprised 93 (38.4%) cases. The ECOG PS scores of 0−1 were observed in 214 (88.4%) cases. Additionally, 199 (82.2%) patients presented with stage IV, while the remaining 43 (17.8%) cases were classified as IIIB−IIIC. PD-1 inhibitors were administered as follows: sintilimab in 98 cases, tislelizumab in 49 cases, camrelizumab in 44 cases, penpulimab in 36 cases, pembrolizumab in 10 cases, and toripalimab and cadonilimab in 1 case each. Furthermore, 3 cases received PD-L1 inhibitors, namely durvalumab, sugemalimab and envafolimab. Among the 242 patients, 132 had received first-line treatment, while 110 had undergone second-line therapy. Different initial doses of anlotinib were administrated: 12 mg (114 cases, 47.1%), 10 mg (106 cases, 43.8%), and 8 mg (22 cases, 9.1%).

Table 1. Basic characteristics of all participants (N=242).

Characteristic	n (%)
PD-L1, programmed cell death ligand 1; NA, not available; TNM, tumor node metastasis; ECOG, Eastern Cooperative Oncology Group; PS, performance status; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; BRAF, B-Raf rapidly accelerated fibrosarcoma; KRAS, kirsten rat sarcoma viral oncogene homolog; HER2, human epidermal growth factor receptor 2.
Age (year) [median (range)]	66 (32−89)
Sex
Male	182 (75.2)
Female	60 (24.8)
Smoking history
Never	120 (49.6)
Current/former	122 (50.4)
Metastasis
Liver	13 (5.4)
Bone	34 (14.1)
Brain	19 (7.9)
PD-L1
Positive	47 (19.4)
Negative	28 (11.6)
NA	167 (69.0)
Initial dose of anlotinib (mg)
12	114 (47.1)
10	106 (43.8)
8	22 (9.1)
Histology
Non-squamous	149 (61.6)
Squamous	93 (38.4)
TNM stage
IIIB−IIIC	43 (17.8)
IV	199 (82.2)
Treatment
First-line	132 (54.5)
Second-line	110 (45.5)
ECOG PS
0	35 (14.5)
1	179 (74.0)
2	28 (11.6)
Gene mutation
Negative	222 (91.7)
EGFR	9 (3.7)
ALK	1 (0.4)
BRAF_V600E	3 (1.2)
KRAS	5 (2.1)
HER2	2 (0.8)

Efficacy evaluation and survival analysis

Among the 242 patients, CR was achieved in 3 (1.2%) patients, PR in 84 (34.7%) patients, SD in 150 (62.0%) patients, and PD in 5 (2.1%) patients. The overall ORR and DCR were 36.0% (95% CI, 30.2%−42.2%) and 97.9% (95% CI, 95.3%−99.1%), respectively. Specifically, the ORR and DCR for first-line treatment patients were 37.9% (95% CI, 30.0%−46.4%) and 98.5% (95% CI, 94.6%−99.6%), while those for second-line patients were 33.6% (95% CI, 25.5%−42.9%) and 97.3% (95% CI, 92.3%−99.1%), respectively (Table 2). In addition, the tumor response data between different anlotinib doses indicated that ORR for the 12 mg group was 41.2%, while ORR of the 10 mg group and the 8 mg group were 32.1% and 27.3%, respectively (Supplementary Table S1). At the data cutoff on March 15, 2025, 153 (63.2%) cases had either progressed or died. The median follow-up duration was 12.4 (range: 8.6−16.3) months, with a median PFS was 7.8 (95% CI, 7.0−9.5) months (Figure 2A). The OS events occurred in 112 (46.3%) patients, with a median OS of 17.0 (95% CI, 15.1−19.4) months (Figure 2B).

Table 2. Best therapeutic response evaluation.

Best response	n (%)
	Total (N=242)	First-line (N=132)	Second-line (N=110)
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate; 95% CI, 95% confidence interval.
CR	3 (1.2)	2 (1.5)	1 (0.9)
PR	84 (34.7)	48 (36.4)	36 (32.7)
SD	150 (62.0)	80 (60.6)	70 (63.6)
PD	5 (2.1)	2 (1.5)	3 (2.7)
ORR [% (95% CI)]	36.0 (30.2−42.2)	37.9 (30.0−46.4)	33.6 (25.5−42.9)
DCR [% (95% CI)]	97.9 (95.3−99.1)	98.5 (94.6−99.6)	97.3 (92.3−99.1)

Figure 2.

Kaplan-Meier curves illustrating PFS (A) and OS (B) associated with ICIs and anlotinib combination treatment. PFS, progression-free survival; OS, overall survival; ICI, immune checkpoint inhibitor; 95% CI, 95% confidence interval.

Analysis of factors influencing PFS and OS during treatment with ICIs and anlotinib

We utilized a causality-driven variable selection approach using directed acyclic graphs (DAGs), incorporating the following variables into our models: sex, age, histological type, smoking status, tumor node metastasis (TNM) stage, and ECOG PS. Additionally, variables directly influencing PFS or OS, such as treatment line and anlotinib dosage, were also incorporated into the models.

We conducted univariate Cox regression analyses to identify the factors potentially impacting PFS during combination treatment with ICIs and anlotinib. Moreover, we executed multivariate analyses on factors with a P value less than 0.2 in the univariate analyses, classifying these as candidate prognostic factors. The univariate Cox regression analysis revealed that treatment line (P=0.012) significantly influenced survival outcomes, while gender (P=0.070), initial anlotinib dose (P=0.184), and ECOG PS (P=0.148) exhibited nonsignificant trends (Supplementary Table S2). The subsequent multivariate analysis confirmed treatment line (HR=0.608, 95% CI: 0.439−0.841, P=0.003) and gender (HR=0.653, 95% CI: 0.438−0.973, P=0.036) as independent prognostic factors.

Regarding survival benefits, the PFS for first-line (n=132) and second-line (n=110) treatment were 9.8 (95% CI, 7.4−12.5) months and 6.9 (95% CI, 6.0−8.3) months, respectively (HR: 0.664, 95% CI, 0.482−0.914, P=0.011) (Figure 3A). Moreover, the PFS for male (n=182) and female (n=60) patients were 7.5 (95% CI, 6.7−8.9) months and 9.5 (95% CI, 7.0−16.8) months, respectively (P=0.068, Figure 3B).

Figure 3.

Kaplan-Meier curves depicting PFS for patients with advanced NSCLC undergoing combination with ICIs and anlotinib. The analyses are categorized by treatment line (first and second) (P=0.011) (A), sex (male and female) (P=0.068) (B), varying initial anlotinib dose (P=0.180) (C), histological type (non-squamous and squamous) (P=0.571) (D), PD-L1 expression level (P<0.001) (E), and TNM staging (P=0.436) (F). PFS, progression-free survival; NSCLC, non-small cell lung cancer; ICI, immune checkpoint inhibitor; 95% CI, 95% confidence interval; PD-L1, programmed cell death ligand 1.

To evaluate the impact of the initial anlotinib dosage on PFS, patients were categorized into two groups based on dosage: 12 mg and 8/10 mg. The median PFS for the 12 mg group (n=114) was 8.9 (95% CI, 7.9−11.5) months, while that for the 8/10 mg group (n=128) was 6.5 (95% CI, 5.9−8.2) months, respectively (HR: 0.806, 95% CI, 0.586−1.108, P=0.180, Figure 3C). Furthermore, we analyzed PFS according to histological type, demonstrating that the median PFS for non-squamous and squamous were 8.1 (95% CI, 7.0−10.1) months and 7.2 (95% CI, 6.6−11.1) months, respectively (HR: 0.909, 95% CI, 0.656−1.260, P=0.571, Figure 3D). Moreover, we examined PFS in relation to PD-L1 test result, which indicated PFS for patients with a tumor proportion score ≥50% (n=26) was 19.6 (95% CI, 8.2−NR) months. Meanwhile, those with PD-L1 expression values of 1%−49% (n=21) and <1% (n=28) were 7.4 (95% CI, 4.6−11.1) months and 5.8 (95% CI, 4.3−7.9) months, respectively (P<0.001, Figure 3E). The PFS for patients at stage III (n=43) and IV (n=199) patients were 8.6 (95% CI, 7.4−13.1) months and 7.4 (95% CI, 6.6−9.0) months, respectively (P=0.436, Figure 3F).

In addition, we conducted univariate and multivariate Cox regression analyses of OS during combination treatment with ICIs and anlotinib (Supplementary Table S3). However, none of the prognostic factors (gender, age, histology, TNM stage, ECOG PS, treatment line and initial anlotinib dose) were found to be statistically significant. We further analyzed OS for treatment line and dose of anlotinib. The first-line (n=132) and second-line (n=110) treatment yielded median values of 18.8 (95% CI, 15.3−22.3) months and 15.7 (95% CI, 12.7−19.3) months, respectively (P=0.141, Figure 4 A), and the initial dose of anlotinib was associated with an OS of 17.0 (95% CI, 15.2−22.1) months for the 12 mg group (n=114), and 16.5 (95% CI, 14.4−21.6) months for the 8/10 mg (n=128), respectively (P=0.879, Figure 4B).

Figure 4.

Kaplan-Meier curves demonstrating OS following combination treatment with ICIs and anlotinib in advanced NSCLC. The analyses include treatment line (first and second) (P=0.141) (A) and varying initial doses of anlotinib (P=0.879) (B). OS, overall survival; ICI, immune checkpoint inhibitor; NSCLC, non-small cell lung cancer; 95% CI, 95% confidence interval.

Safety analysis

The safety presented in this present study are consistent with findings from previous clinical studies involving anlotinib and immunotherapy, without newly occurred AEs (Table 3). Treatment-related AEs occurred in 198 (81.8%) patients. The most common AEs (all grades, more than 20.0%) included fatigue (56.2%), hypertension (36.4%), hypothyroidism (32.6%), hand-foot syndrome (28.1%), and lymphocytopenia (23.1%). The incidence rates of immune pneumonitis and immune myocarditis were 5.8% and 2.5%, respectively. A total of 22 (9.1%) patients experienced grade 3−4 AEs, with the most common being hypertension (2.5%), fatigue (2.1%), proteinuria (1.7%), and immune pneumonitis (1.2%). Twelve (5.0%) patients led to dose reduction of anlotinib owing to fatigue, proteinuria, hemoptysis or elevated aminotransferase. Notably, 3 cases developed grade 3 immune-related pneumonia, and 1 case experienced grade 3 immune-related myocarditis, necessitating the discontinuation of ICIs. Immune-related AEs are shown in Supplementary Table S4.

Table 3. Treatment-related AEs (N=242).

AEs	n (%)
	Any grade	Grade 1−2	Grade 3−4
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase.
Fatigue	136 (56.2)	131 (54.1)	5 (2.1)
Hypertension	88 (36.4)	82 (33.9)	6 (2.5)
Hypothyroidism	79 (32.6)	79 (32.6)	0 (0)
Hand-foot syndrome	68 (28.1)	68 (28.1)	0 (0)
Lymphocytopenia	56 (23.1)	56 (23.1)	0 (0)
Anemia	41 (16.9)	41 (16.9)	0 (0)
Proteinuria	37 (15.3)	33 (13.6)	4 (1.7)
Hoarseness	36 (14.9)	36 (14.9)	0 (0)
ALT elevation	32 (13.2)	31 (12.8)	1 (0.4)
AST elevation	27 (11.2)	26 (10.7)	1 (0.4)
Neutropenia	26 (10.7)	26 (10.7)	0 (0)
Rash	26 (10.7)	26 (10.7)	0 (0)
Hemoptysis	18 (7.4)	17 (7.0)	1 (0.4)
Immune pneumonitis	14 (5.8)	11 (4.5)	3 (1.2)
Thrombocytopenia	15 (6.2)	15 (6.2)	0 (0)
Immune myocarditis	6 (2.5)	5 (2.1)	1 (0.4)

Discussion

This real-world study provides compelling evidence for the efficacy and safety of a chemotherapy-free regimen — ICIs combined with anlotinib, in patients with advanced NSCLC, applicable as first- or second-line therapy. With a relatively large sample size (n=242), our findings indicate a median PFS of 7.8 months and a median OS of 17.0 months, accompanied by a manageable safety profile. These results validate the feasibility of chemotherapy-free strategies in routine clinical practice, and support therapeutic options for patients who are intolerant or resistant to conventional chemotherapy-based regimens (3,24).

Driver mutation-negative patients with NSCLC account for approximately 40%−50% of the total lung cancer population (25,26). Currently, ICIs, either in combination with chemotherapy or as monotherapy, have become the preferred first-line treatment option for advanced NSCLC without driver gene mutations (27,28). Several approvals have been granted for chemoimmunotherapy both in squamous and non-squamous NSCLC. Pembrolizumab in combination with platinum-based chemotherapy, has received approval for both histological types based on KEYNOTE-407 and KEYNOTE-189 studies, which indicated OS benefits (29,30). Similarly, studies involving camrelizumab, tislelizumab, sugemalimab, toripalimab, and atezolizumab have revealed that combination treatment with ICIs and chemotherapy yields significant outcome benefits compared with monotherapy chemotherapy (29,31-33).

However, in real-world settings, a substantial proportion of patients cannot tolerate or refuse platinum-based chemotherapy. This challenge particularly affects older adults, patients with poor ECOG PS, and individuals with significant comorbidities, such as cardiovascular or metabolic diseases (34). For these patients, ICI monotherapy has emerged as the preferred treatment regimen. Studies such as IMpower110 and KEYNOTE-024 have demonstrated that ICI monotherapy significantly mitigates mortality risk compared with chemotherapy in patients with high PD-L1 expression (4,5). Nevertheless, for patients with PD-L1-unselected advanced NSCLC, the 5-year survival rate following immunotherapy monotherapy remains low, at only 10%−20% (35). Additionally, elderly patients and those with poor PS scores experience limited survival benefits from immunotherapy monotherapy (36). Therefore, developing chemotherapy-free combination regimens that incorporate immunotherapy may better address the clinical treatment demands of patients with NSCLC in real-world settings.

Several studies have previously demonstrated the efficacy of ICIs combined with anti-angiogenic therapy for selected patients with NSCLC. The phase II SUNRISE study, which investigated first-line treatment with sintilimab combined with anlotinib, documented a median PFS of 14.4 months in a selected patient population (37). At the 2025 ASCO meeting, the phase III CAMPASS study involving 531 participants indicated that benmelstobart combined with anlotinib resulted in a median PFS of 11.0 months, compared to 7.1 months for pembrolizumab in the first-line treatment of PD-L1 positive advanced NSCLC (22). Additionally, benmelstobart combined with anlotinib achieved a median PFS of 8.7 months at second-line treatment (23). Nonetheless, the aforementioned studies are clinical trials characterized by stringent inclusion criteria, which impose limitations regarding patient age, performance status, comorbidities, and other factors. Consequently, these criteria may not adequately reflect the actual conditions of patients in real-world settings. Our real-world analysis of first-line treatment in 132 patients revealed a median PFS of 9.8 months, which is comparable to the PFS yielded by pembrolizumab combined with chemotherapy in first-line patients with NSCLC, and longer than the PFS reported for pembrolizumab monotherapy in PD-L1 positive patients (5,38,39). Likewise, our second-line subgroup (n=110) achieved a median PFS of 6.9 months, surpassing previous monotherapy ICI trials that reported PFS ranging from 2.8 to 4.0 months in the second-line setting (40,41). Consequently, although the data presented in this study are slightly inferior to those from the SUNRISE and COMPASS studies, they similarly demonstrate that immunotherapy combined with anlotinib exhibits clear efficacy in real-world settings. These findings consistently underscore the benefits of the chemotherapy-free regimen — anlotinib combined with ICIs across diverse clinical populations.

In our study, the primary influencing factors of PFS were the line of treatments, underscoring the importance of early intervention with immunotherapy. Several factors may explain this trend: firstly, first-line patients likely retain better immune function and tumor immunogenicity, enhancing ICI responsiveness (42). Second, prior therapies in second-line settings, such as chemotherapy and TKIs, may induce immunosuppressive phenotypes or clonal selection of resistant tumor cells (43). Third, a higher tumor mutational burden (TMB) in treatment-naïve tumors could potentiate neoantigen-driven immune activation (44). These observations align with findings from the CheckMate 227 trial, where first-line nivolumab plus ipilimumab resulted in superior survival outcomes compared with later-line applications (45). These findings suggest a clinical benefit of employing chemotherapy-free combination regimens earlier in the disease course. In contrast, the absence of significant PFS differences between squamous and non-squamous histology, TNM stages III and IV, as well as between anlotinib initial doses (12 mg vs. 10/8 mg), suggests the broad applicability of this regimen. Although no significant difference in PFS was observed across different starting doses of anlotinib, the ORR among the various dosage groups indicates that patients in the 12 mg group exhibited a greater response than these in the 10 mg and 8 mg groups. Additionally, multivariate analysis revealed a trend favoring PFS benefit in the 12 mg group. Therefore, to circumvent insufficient initial dosing, we recommend initiating treatment with 12 mg, and adjusting the dose as necessary. Our findings are consistent with those of previous studies, indicating that PD-L1 expression influences the efficacy of combination treatment with ICIs and anlotinib, despite some patients not being assessed for PD-L1 status. Multiple investigations in the KEYNOTE series have discovered that patients with NSCLC exhibiting high PD-L1 expression benefit more from pembrolizumab, as elevated PD-L1 levels correlate with enhanced responses to PD-1/PD-L1 treatments. PD-L1 stratification should consider the histological differences between squamous and non-squamous carcinoma types to avoid obscuring efficacy differences. Anlotinib, as an anti-angiogenic drug, also affects immune microenvironment by normalizing blood vessels and improving tumor blood perfusion, which facilitates immune cell infiltration. It regulates the composition of immune cells within tumor tissues, thereby alleviating the immunosuppressive state in the TME and enhancing the release of anti-tumor cytokines to boost the anti-tumor response. Moreover, although the current OS maturity is 46.3%, we have also sought to analyze factors affecting OS in patients treated with ICIs in combination with anlotinib, however, no significant differences have been observed thus far.

Notably, our safety data further strengthens the rationale for this combination therapy. The incidence of grade ≥3 treatment-related AEs was found to be 9.1%, predominantly comprising hypertension (2.5%), fatigue (2.1%), and proteinuria (1.7%). This toxicity profile is favorable when compared to platinum-based chemoimmunotherapy regimens (46,47). Such tolerability is particularly significant for vulnerable populations, including older adults, individuals with compromised organ function, and patients who decline chemotherapy (48). Specifically, elderly patients frequently present with age-related organ dysfunction and comorbidities that increase their susceptibility to conventional chemotherapy toxicities (49). The reduced hematologic toxicity associated with our regimen aligns with the safety requirements of this demographic. Similarly, patients with renal or hepatic impairment can benefit from the favorable toxicity profile, as non-platinum regimens mitigate additional nephro- and hepatotoxicity while maintaining efficacy. The manageable safety profile further corroborates its use in outpatient settings, potentially reducing hospitalizations and enhancing quality of life.

Despite the promising results observed with the ICI-anlotinib combination, several points should be acknowledged in our study. First, the absence of a control group (for example, chemotherapy or ICIs) may preclude definitive interpretations of efficacy. Second, imbalances in certain baseline characteristics (for example, ECOG PS, TNM stage) might have either overestimated or underestimated the actual efficacy of the regimens. The lack of formal multiple testing necessitates the cautious interpretation of some results, and these exploratory findings require validation in larger, prospective cohorts. Third, our study did not include biomarker analyses, such as PD-L1 expression, TMB, or circulating tumor DNA, which limits the potential for precision stratification. Finally, the brief overall follow-up duration renders the OS data remain immature, and the corresponding survival estimates should be interpreted with caution. Despite these limitations, this study provides valuable medical evidence for selecting chemotherapy-free strategies in NSCLC for first- or second- line treatment. Future research should involve larger-scale, multicenter, and prospective clinical trials to improve data quality and the reliability of results, ultimately guiding clinical practice more effectively.

Conclusions

In this sizable real-world cohort, combination treatment with anlotinib and ICIs demonstrated clinically meaningful efficacy with acceptable tolerability as a chemotherapy-free option for advanced NSCLC. This validation in an unselected, heterogeneous patient population within real-world clinical practice offers robust actionable evidence to inform treatment decisions for patients who are ineligible for conventional chemotherapy.

SUPPLEMENTARY DATA

Supplementary data to this article can be found online.

Funding Statement

This study was supported by Key Research and Development Projects of Henan Province in 2023-Key Technologies of Novel Precision Immunotherapy for Refractory Malignant Tumors (No. 231111313300), Zhongyuan Qianren Jihua (No. ZYQR201912118), Key Research and Development Projects of Henan Province (No. 251111310100), Henan Province Medical Science and Technology Talent Overseas Training Program (HNMOT2024062), and The Excellent Young Talent Cultivation Project of Henan Health Science and Technology Innovation Talents (No. YXKC2020046).

Author contributions

Conceptualization: HY Chen, GH Yang and QM Wang; Data curation, writing − review & editing: HY Chen, GH Yang, T Wang, GB Chen, AG Xu, CZ Ma, K Shang, PJ Liu, HL Zhou, ZW Wang, XJ Xu, X Sun, FY Zhai, YY Ji, J Huangpu, XL Jia, CQ Li, JZ Mei, MY Jia, SH Niu, GG Zhang, YQ Liu, L Lu, JT Zhang, LJ Wang, TJ Ma, LW Gao, CL Jin and QM Wang; Formal analysis: HY Chen and GH Yang; Funding acquisition: HY Chen, GB Chen and QM Wang; Project administration: HY Chen, GB Chen and QM Wang; Visualization: AG Xu and QM Wang; Software, writing − original draft: HY Chen; Investigation and validation: T Wang; Resources: AG Xu; Methodology supervision: QM Wang.

Data sharing statement

A data sharing statement provided by the authors is available with this article at https://doi.org/10.21147/j.issn.1000-9604.2026.01.03.