Efficacy and safety of ICI‑based triple combination therapy for gene‑negative advanced lung adenocarcinoma

Introduction

Lung cancer is among the most common cancers worldwide (1). Lung adenocarcinoma, a major subtype of non-small cell lung cancer (NSCLC), accounts for 40–55% of all lung cancer cases (2). Owing to the insidious nature of its early clinical symptoms, most patients are diagnosed at an advanced stage, which limits treatment efficacy and can markedly reduce the 5-year survival rate (3). Currently, for patients with advanced-stage NSCLC, treatment strategies primarily depend on driver gene status. For patients without definite driver gene alterations, clinical practice typically involves the use of chemotherapy combined with immunotherapy and/or antiangiogenic targeted therapy.

Immune escape mechanisms in the tumor microenvironment are key factors contributing to lung adenocarcinoma progression and treatment resistance. Tumor cells utilize multiple immunosuppressive pathways, especially the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways, to effectively suppress immune surveillance and cytotoxic. The PD-1/PD-L1 interaction induces functional exhaustion of cytotoxic T lymphocytes (CTLs), thereby promoting immune escape by tumor cells (2). Angiogenesis is a critical biological hallmark of tumor growth and metastasis. As a key angiogenic regulator, vascular endothelial growth factor (VEGF) supports tumor cell survival by promoting endothelial cell proliferation, migration and lumen formation.

Despite the remarkable progress achieved in immune checkpoint inhibitors ICIs and antiangiogenic therapy in recent years, the optimal treatment regimen for advanced driver gene-negative NSCLC remains controversial. In lung cancer clinical practice guidelines (4), atezolizumab in combination with bevacizumab, carboplatin and paclitaxel has been approved as a standard first-line treatment for advanced NSCLC, demonstrating substantial clinical advantages. However, the efficacy of other chemotherapy agents combined with ICIs and antiangiogenic agents still lacks sufficient evidence-based support. Thus, there is an urgent clinical need for more alternative ICI-based triple combination regimens for driver gene-negative NSCLC. In recent years, clinical studies have shown that ICI-based triple combination regimens can confer survival benefits to patients with advanced lung adenocarcinoma (5,6).

The present study aimed to investigate the clinical efficacy and safety of the ICI-based triple combination regimen in the first-line treatment of advanced lung adenocarcinoma in a real-world, single-arm retrospective study, thereby providing a reference basis for clinicians to optimize treatment strategies and improve patient prognosis.

Materials and methods

Study subjects

The present study was a single-center, retrospective study. Patients with driver gene-negative advanced lung adenocarcinoma who received ICIs combined with antiangiogenic agents and chemotherapy as first-line treatment at The Sixth Affiliated Hospital (School of Medicine, South China University of Technology, Foshan, China) between January 1, 2022 and December 31, 2024, were enrolled. The present study was a retrospective observational study and its protocol was approved by the Medical Ethics Committee of The Sixth Affiliated Hospital, School of Medicine, South China University of Technology (approval no. 2023080).

Inclusion criteria were i) Age: ≥18 years; ii) disease stage and treatment history: Patients with stage IIIb or IV lung adenocarcinoma as defined by the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) 8th edition TNM staging system (https://ajccstaging.org/en) with no prior systemic treatment for advanced disease; iii) driver gene-negative; iv) Physical status: Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2 (ecog-acrin.org/scale); v) complete imaging data and laboratory test indicators and vi) treatment contraindication exclusion: No pneumonia induced by systemic treatment.

Exclusion criteria were i) severe organ dysfunction or cachexia: Patients who were definitively diagnosed with severe hepatic or renal insufficiency before treatment or those with terminal cancer cachexia (characterized by severe weight loss, muscle wasting, and inability to tolerate antitumor treatment), ii) insufficient treatment duration: Patients who received <3 cycles of combination therapy; iii) prolonged treatment interruption: Patients whose treatment was interrupted for >1 month during the course of combination therapy course; iv) missing key data: Patients with missing imaging data or laboratory test data; v) chronic use of immunosuppressive drugs: Patients with long-term continuous use of glucocorticoids or other immunosuppressants before or during treatment.

Patient baseline characteristics are given in Table I.

Table I. Patient baseline characteristics.

Table I.

Patient baseline characteristics.

Clinical feature	Cases (n=12)	Percentage (%)
Sex
Male	11	91.7
Female	1	8.3
Age
<60	2	16.7
≥60	10	83.3
Smoker
Yes	2	16.7
No	10	83.3
Underlying diseases
Yes	8	66.7
No	4	33.3
Tumor location
LUL	2	16.7
LLL	1	8.3
RUL	5	41.7
RML	2	16.7
RLL	2	16.7
TNM staging
Stage IV	9	75.0
Stage IIIb	3	25.0
PD-1 expression
Positive	3	25.0
Negative	9	75.0
ECOG
1	9	75.0
2	3	25.0
Chemotherapeutic agents
Pemetrexed	12	100.0
Carboplatin	10	83.3
Nedaplatin	3	25
Cisplatin	1	8.3
ICIs
Tislelizumab	10	83.3
Sintilimab	1	8.3
Toripalimab	1	8.3
Anti-angiogenic agents
Bevacizumab	11	91.7
Endostatin	1	8.3
Anlotinib	1	8.3

[i] LUL, Left upper lobe of the lung; LLL, Left lower lobe of the lung; RUL, Right upper lobe of the lung; RML, Right middle lobe of the lung; RLL, Right lower lobe of the lung; PD-1, programmed cell death protein 1; ECOG, Eastern Cooperative Oncology Group; ICIs, immune checkpoint inhibitors.

Treatment regimen

All enrolled patients were definitively diagnosed with NSCLC via integrated multimodal assessment, including imaging (CT/MRI), pathological biopsy, and clinical symptom evaluation. Lung cancer staging was performed according to the AJCC/UICC 8th TNM staging system, with all patients categorized as stage IIIb or IV. PD-L1 expression was detected using the Dako 22C3 assay, and a tumor proportion score ≥1% was defined as positive.

All patients received first-line combination therapy consisting of ICIs, antiangiogenic agents, and platinum-based chemotherapy, which was administered in a synchronous manner unless contraindicated. The specific regimens were as follows:

ICIs: Tislelizumab, 200 mg every 3 weeks; toripalimab, 240 mg every 3 weeks; sintilimab, 200 mg every 3 weeks; camrelizumab, 200 mg every 3 weeks.

Antiangiogenic agents: bevacizumab, 15 mg/kg every 3 weeks; recombinant human endostatin, 15 mg/m2 on Days 1–3 of each 21-day cycle; anlotinib, 12 mg orally once daily for 2 weeks, followed by a 1-week break (21-day cycle).

Chemotherapy: Pemetrexed 500 mg/m2; paclitaxel 175 mg/m2; cisplatin 75 mg/m2; carboplatin AUC 5–6.

Efficacy and safety evaluation

Efficacy was assessed on the basis of imaging findings (such as contrast-enhanced CT or MRI) and the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (7).

The primary outcome measures of the present study included the disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The definitions of each indicator were consistent with international oncology research standards and the RECIST 1.1 criteria, as detailed below: PFS was defined as the time interval from the date of the first dose of the ICI-based triple combination regimen to the earliest occurrence of radiologically confirmed tumor progression, mortality from any cause, or the present study cutoff date. OS was defined as the time interval from the date of the first dose of the ICI-based triple combination regimen to the earliest occurrence of death from any cause or The present study cutoff date. The ORR was defined as the percentage of patients who achieved the best overall complete response (CR) or partial response (PR) after the initiation of the ICI-based triple combination regimen. DCR was defined as the percentage of patients who achieved the best overall response [CR, PR, or stable disease (SD)] after treatment initiation.

Safety assessment

In the present retrospective study, the monitoring of adverse events (AEs), such as blood pressure, proteinuria and hepatic function during treatment was performed using routine clinical tests based on archived medical records (blood pressure was measured with a standard electronic sphygmomanometer, proteinuria was quantified by dry chemistry-based urinalysis and overall hepatic function was evaluated by routine serum liver biochemical tests). All AEs were graded according to the Common Terminology Criteria for Adverse Events, version 5.0 (8).

Statistical analysis

Statistical analysis of the baseline data was performed using IBM SPSS Statistics 27 (version 27.0.1). Patients' baseline characteristics were summarized using frequency (n) and the constituent ratio (%) for descriptive statistics. Continuous variables that conformed to a normal distribution were analyzed using the independent samples t test, and nonnormally distributed variables were analyzed using the Mann-Whitney test. In the influencing factor analysis, univariate analysis was performed using the log-rank test to explore the associations of variables (including sex, tumor location, comorbid underlying diseases, smoking history and treatment drugs) with PFS and OS. Progression-free survival and overall survival curves were plotted using the Kaplan-Meier method, ensuring consistency with the survival endpoint definitions in the present study. A two-tailed P<0.05 was considered to indicate a statistically significant difference.

Results

Patient characteristics

All patients were identified from the hospital medical records system, diagnosed with advanced lung adenocarcinoma and received first-line treatment at The Sixth Affiliated Hospital (School of Medicine, South China University of Technology) between January 1, 2022 and December 31, 2024. Follow-up was initiated from the date of the first combined regimen administration and ended at the time of censoring, the present study cutoff date (March 31, 2025), or the occurrence of the primary endpoint (patient mortality). The median follow-up duration was 26.6 months (95% CI: 21.3–31.8 months). During the follow-up period, seven patients were censored and six patients succumbed. The median age of the patients was 71 years (range: 45–76 years), including two patients (16.7%) aged <60 years and ten patients (83.3%) aged ≥60 years. There were eleven male patients (91.7%) and one female patient (8.3%). Among them, ten patients (83.3%) had no smoking history, and eight patients (66.7%) had comorbid underlying diseases such as diabetes mellitus, hypertension, and coronary heart disease. The patients were staged according to the tumor TNM staging system, with nine patients (75.0%) at stage IV and three patients (25.0%) at stage IIIb. (Fig. 1; Table I).

Figure 1. Patient flow diagram.

Efficacy evaluation

All patients received ≥3 cycles of ICI-based triple combination therapy comprising ICIs, antiangiogenic agents, and chemotherapy. After treatment, therapeutic efficacy was assessed by integrating imaging examinations and other relevant tests: the primary pulmonary lesions were defined as target lesions, and the sizes of the baseline lesions and posttreatment lesions were compared. The evaluation was conducted in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (9). The results were as follows: a PR of 58.3%, an SD of 33.3%, a PD of 8.3%, an ORR of 58.3%, and a DCR of 83.3% (Tables II and III).

Table II. Therapeutic efficacy.

Table II.

Therapeutic efficacy.

Efficacy	Cases (n=12)	Percentage (%)
CR	0	0.0
PR	7	58.3
SD	4	33.3
PD	1	8.3
ORR	7	58.3
DCR	11	83.3

[i] CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.

Table III. Treatment conditions.

Table III.

Treatment conditions.

Patient	Sex	Age	Treatment	Pre-Treatmenta (mm)	Post-Treatmenta (mm)	Tumor Reduction Rate (%)	Efficacy
1	Male	71	Pemetrexed + Carboplatin/Nedaplatin/Cisplatin + Bevacizumab/Endostatin + Tislelizumabb	13.0	7.0	46.2	PR
2	Male	71	Pemetrexed + Nedaplatin + Anlotinib + Tislelizumab	69.0	48.0	30.4	PR
3	Male	45	Pemetrexed + Nedaplatin + Bevacizumab + Tislelizumab	44.0	19.0	56.8	PR
4	Male	66	Pemetrexed + Carboplatin + Bevacizumab + Tislelizumab	38.0	47.0	−23.7	PD
5	Female	75	Pemetrexed + Carboplatin + Bevacizumab + Tislelizumab	86.0	53.0	38.4	PR
6	Male	75	Pemetrexed + Carboplatin + Bevacizumab + Tislelizumab	79.0	44.0	44.3	PR
7	Male	70	Pemetrexed + Carboplatin + Bevacizumab + Sintilimab	56.0	35.0	37.5	PR
8	Male	72	Pemetrexed + Carboplatin + Bevacizumab + Toripalimab	51.0	37.0	27.5	SD
9	Male	62	Pemetrexed + Carboplatin + Bevacizumab + Sintilimab	26.0	19.0	26.9	SD
10	Male	46	Pemetrexed + Carboplatin + Bevacizumab + Sintilimab	14.0	14.0	0.0	SD
11	Male	76	Pemetrexed + Carboplatin + Bevacizumab + Sintilimab	43.0	35.0	18.6	SD
12	Male	73	Pemetrexed + Carboplatin + Bevacizumab + Sintilimab	58.0	38.0	34.5	PR

a Maximum tumor diameter;

b changed multiple times during the treatment period. PR, partial response; PD, progressive disease; SD, stable disease.

Analysis of factors influencing short-term efficacy

To investigate the effect of baseline data (such as age, sex, tumor location and comorbid underlying diseases) on the ORR of short-term efficacy, univariate analysis was performed. Patients whose efficacy was evaluated as CR or PR were classified into the high-sensitivity group, while those whose efficacy was evaluated as SD or PD were classified into the low-sensitivity group. The analysis revealed that there was no statistically significant difference in the effect on short-term efficacy among factors such as age, sex, tumor location, smoking status, chemotherapeutic agents, ICIs and targeted agents (P>0.05). By contrast, comorbid underlying diseases had a statistically significant effect on short-term treatment efficacy (P<0.05; Table IV).

Table IV. Analysis of factors affecting recent therapeutic efficacy.

Table IV.

Analysis of factors affecting recent therapeutic efficacy.

Clinical features	High-sensitivity group (%)	Low-sensitivity group (%)	Total	F	P-value
Sex
Male	6 (85.7)	5 (100.0)	11 (91.7)	0.694	0.624
Female	1 (14.3)	0 (0.0)	1 (8.3)
Age
<60	1 (14.3)	1 (20.0)	2 (16.7)	0.057	0.815
≥60	6 (85.7)	4 (80.0)	10 (83.3)
Tumor location
Left lung	1 (14.3)	2 (40.0)	3 (25.0)	0.938	0.356
Right lung	6 (85.7)	3 (60.0)	9 (75.0)
Underlying diseases
Yes	3 (42.9)	5 (100.0)	8 (66.7)	5.556	0.04a
No	4 (57.1)	0 (0.0)	4 (33.3)
Smoker
Yes	0 (0.0)	2 (40.0)	2 (16.7)	3.889	0.077
No	7 (100.0)	3 (60.0)	10 (83.3)
Chemotherapeutic agentsb
Pemetrexed + carboplatin	4 (66.7)	5 (100.0)	9 (81.8)	2.045	0.186
Pemetrexed + nedaplatin	2 (33.3)	0 (0.0)	2 (18.2)
ICIs
Tislelizumab	6 (85.7)	4 (80.0)	10 (83.3)	0.969	0.416
Sintilimab	1 (14.3)	0 (0.0)	1 (8.3)
Toripalimab	0 (0.0)	1 (20.0)	1 (8.3)
Anti-Angiogenic Agentsb
Bevacizumab	5 (83.3)	5 (100.0)	10 (90.9)	0.818	0.389
Anlotinib	1 (16.6)	0 (0.0)	1 (9.1)

a P≤0.05, indicating a statistically significant difference.

b Patients with multiple medication changes during treatment were excluded.

Safety

All patients developed various adverse reactions. The specific manifestations and incidence were as follows: Seven patients (58.3%) experienced toxicity and six patients (50.0%) experienced nausea and vomiting. All adverse reactions were alleviated after symptomatic treatment, and no severe adverse events (SAEs) occurred (Table V).

Table V. Occurrence of adverse reactions.

Table V.

Occurrence of adverse reactions.

Adverse reaction	Case (n=12)	Incidence rate (%)	Proportion of grade 1–2 (%)	Proportion of grade 3 (%)	Proportion of grade 4–5 (%)
Hematological toxicity	7	58.3	5 (71.4)	2 (28.6)	0 (0.0)
Nausea and vomiting	6	50.0	6 (100.0)	0 (0.0)	0 (0.0)
Fatigue and anorexia	4	33.3	4 (100.0)	0 (0.0)	0 (0.0)
Myalgia	4	33.3	3 (75.0)	1 (25.0)	0 (0.0)
Chest tightness and shortness of breath	4	33.3	4 (100.0)	0 (0.0)	0 (0.0)
Liver dysfunction	2	16.6	2 (100.0)	0 (0.0)	0 (0.0)
Hypothyroidism	2	16.6	2 (100.0)	0 (0.0)	0 (0.0)
Fever	1	8.3	1 (100.0)	0 (0.0)	0 (0.0)
Rash	1	8.3	1 (100.0)	0 (0.0)	0 (0.0)
Abnormal blood glucose	1	8.3	1 (100.0)	0 (0.0)	0 (0.0)
Dizziness and palpitations	1	8.3	1 (100.0)	0 (0.0)	0 (0.0)

Survival status

The results of the analysis revealed that there was no statistically significant difference in survival status between the high-sensitivity group (CR, PR) and the low-sensitivity group (SD, PD) (P>0.05). In accordance with AJCC/UICC 8th TNM staging system (10), staging was performed on the basis of the maximum tumor diameter: two patients (16.7%) were in the T1 stage, four patients (33.3%) were in the T2 stage, four patients (33.3%) were in the T3 stage, and two patients (16.7%) were in the T4 stage. Of the patients, eight (66.67%) were in the N2 stage and four (33.33%) were in the N3 stage. The data revealed no statistically significant difference in the effect of tumor size or lymphatic metastasis on survival status (Table VI).

Table VI. Analysis of the effect of therapeutic efficacy and tumor size on survival status.

Table VI.

Analysis of the effect of therapeutic efficacy and tumor size on survival status.

	Survival status (%)
Category	Survived	Died	Total (%)	F	P-value
Efficacy				0.008	0.930
High-sensitivity group	4 (57.1)	3 (60.0)	7 (58.3)
Low-sensitivity group	3 (42.9)	2 (40.0)	5 (41.7)
T Staging				0.444	0.728
T1	2 (28.6)	0 (0.0)	2 (16.7)
T2	2 (28.6)	2 (40.0)	4 (33.3)
T3	2 (28.6)	2 (40.0)	4 (33.3)
T4	1 (14.3)	1 (20.0)	2 (16.7)
N Staging				0.145	0.711
N2	5 (71.43)	3 (60)	8 (66.67)	N2
N3	2 (28.57)	2 (40)	4 (33.33)	N3

Survival time

PFS and OS curves of patients were plotted using the Kaplan-Meier method. The median PFS of patients reached 25.4 months (95% CI: 12.7–38.0 months), as shown in Fig. 2. The median OS of patients reached 26.6 months (95% CI: 21.3–31.8 months), as shown in Fig. 3.

Figure 2. Kaplan-Meier analysis of PFS among patients enrolled in the present study. The median PFS of patients reached 25.4 months (95% CI: 12.7–38.0 months). PFS. progression-free survival; CI, confidence interval.

Figure 3. Kaplan-Meier analysis of OS among patients enrolled in the present study. The median OS of patients reached 26.6 months (95% CI: 21.3–31.8 months). OS, overall survival; CI, confidence interval.

As shown in the figures, the median PFS and median OS were not reached in either the high-sensitivity group or the low-sensitivity group. The log-rank test was used to compare intergroup survival differences, and the results revealed that, compared with the low-sensitivity group, the high-sensitivity group had a longer PFS; however, there was no statistically significant difference in PFS between the two groups (P=0.332). Additionally, there was no statistically significant difference in OS between the two groups (P=0.691; Figs. 4 and 5). This was primarily due to the limited sample size (n=12) and the relatively small number of events (five deaths) in the present study, which resulted in insufficient endpoint events occurring in some subgroups during the observation period, making accurate estimation of the median survival times challenging.

Figure 4. The Log-rank test of PFS among high-sensitivity and low-sensitivity patients. Compared with the low-sensitivity group, the high-sensitivity group had a higher PFS. Low-sensitivity group: Patients evaluated as SD or PD. High-sensitivity group: Patients evaluated as CR or PR. PFS, progression-free survival; CI, confidence interval; SD, stable disease; PD, progressive disease; CR, complete response; PR, partial response.

Figure 5. Log-rank test of OS among high-sensitivity and low-sensitivity patients. Two groups have no statistically significant difference. OS, overall survival.

Discussion

The present study investigated the efficacy and safety of a first-line ICI-based triple combination for advanced lung adenocarcinoma. The results demonstrated clinical benefits of this regimen. Although the present study has several limitations, including a small sample size, a lack of a control group and other confounding factors, these findings still possess certain heuristic value. Its underlying mechanism is closely associated with the synergistic effects of immune modulation and angiogenesis inhibition.

PD-1 is an inhibitory receptor expressed on the surface of T cells (2), whereas its ligand, PD-L1, is expressed primarily on antigen-presenting cells (APCs) and tumor cells. The binding of PD-1 to PD-L1 accelerates the apoptosis of activated lymphocytes and suppresses the activation and proliferation of T cells. By blocking this PD-1/PD-L1 interaction, PD-1 inhibitors increase the number and functional activity of antitumor CTLs, thereby achieving tumor control (11,12).

VEGF plays a critical role in tumor initiation and progression by mediating angiogenesis and vascular regulation. Specifically, the binding of VEGF-A to VEGF receptor 2 (VEGFR-2) activates the Raf/MEK/ERK signaling pathway (13,14). This pathway promotes endothelial cell proliferation and increases vascular permeability by activating endothelial nitric oxide synthase, thereby facilitating angiogenesis. Antiangiogenic agents exert antitumor effects by blocking VEGF-induced signal transduction, ultimately inhibiting tumor growth (15).

VEGF is not only a key angiogenic factor but also an immunomodulator in the tumor microenvironment (TME). It exerts immunosuppressive effects by inhibiting antigen presentation, stimulating regulatory T cells and inducing an immunosuppressive TME (14). Studies have shown that continuous VEGF infusion reduces the number and proportion of T cells in patients and decreases thymus volume, suggesting that VEGF inhibitors can abrogate such immunosuppression (16,17). Additionally, tumor cells achieve immune escape by killing immune cells via high expression of Fas ligand (FasL). VEGF further contributes to immunosuppression by upregulating FasL levels, which impair T-cell function and modulate T-cell recruitment in the TME, thereby enhancing immunosuppressive activity (14). Thus, VEGF antagonism can prevent excessive FasL expression and increase the efficacy of immunotherapy.

Moreover, dendritic cells (DCs), a critical subset of APCs, are responsible for antigen presentation. VEGF suppresses the activation of DC transcription factors, thereby inhibiting DC differentiation and maturation; notably, high PD-L1 expression also impairs DC function (18). Collectively, these findings suggest that tumor vascular normalization promotes the infiltration of effector T cells and enhances immunotherapeutic efficacy. Conversely, activated immune cells further facilitate tumor vascular normalization, resulting in the formation of a positive feedback loop. This bidirectional interaction highlights the robust synergistic effects between VEGF inhibitors and PD-1 inhibitors.

Efficacy

In recent years, clinical trials investigating the combination of ICIs, antiangiogenic agents, and chemotherapy for advanced driver gene-negative lung cancer have yielded promising results. The IMpower150 study (19) demonstrated significant improvements in survival outcomes among driver gene-negative patients, the ICI-containing arm achieved a median progression-free survival (mPFS) of 8.3 months and a median overall survival (mOS) of 19.2 months, both of which were markedly longer than those in the control arm. Lee et al (20) reported that the addition of bevacizumab to ICIs further improved mPFS and mOS, supporting the value of salvage therapy with this combination. In a multicenter, phase II prospective cohort study (21), revealed that the combination of Rh-endostatin with PD-1 inhibitors and chemotherapy could yield favorable clinical outcomes and tolerable toxicity profile, the ORR was 57.7 vs. 34.2%, DCR was 88.5 vs. 84.2%, and the mPFS was 16.7 months vs. 16.4 months.

In studies exploring small-molecule multitarget tyrosine kinase inhibitors combined with ICIs, anlotinib plus ICIs conferred survival benefits in terms of PFS and OS (22). Specifically, first-line treatment with this combination in advanced driver gene-negative NSCLC achieved a high mPFS of 15 months; however, the incidence of grade ≥3 adverse events was 54.5% (23), highlighting a trade-off between efficacy and toxicity. By contrast, the TISAL-FE-01 study (24) reported exceptional efficacy with anlotinib plus ICIs, with an ORR of 75% and a DCR of 100%.

Notably, some studies investigating other antiangiogenic agents combined with ICIs, such as lenvatinib plus ICIs and cabozantinib plus ICIs (25,26), failed to meet their primary endpoints. This discrepancy may be attributed to excessive modification of the tumor vasculature by antiangiogenic agents, which induces intratumoral hypoxia and subsequently exacerbates immunosuppression in the TME.

In this real-world, single-center, retrospective study, the ICI-based triple combination therapy showed promising preliminary antitumor activity in patients with advanced driver gene-negative lung adenocarcinoma, with an ORR of 58.3%, a DCR of 83.3%, a mPFS of 25.4 months, and a median OS of 26.6 months. Numerically, the median PFS and OS in the cohort were longer than those reported in previously published trials of similar combination regimens, and the ORR and DCR suggested clinically relevant antitumor effects. For historical reference, the NCT02039674 study (27) (evaluating pembrolizumab plus bevacizumab, paclitaxel, and carboplatin) reported an ORR of 56%, mPFS of 7.1 months, and median OS of 16.7 months; the present study revealed a numerically prolonged median PFS and OS compared with these historical data. Notably, 75% of patients in the present cohort were PD-L1-negative, which may suggest that the ICI-based triple combination could help overcome immunotherapy resistance in patients with negative PD-L1, although this hypothesis requires validation in larger, well-controlled studies.

The clinical benefits observed in the present study may be attributed to two factors: Strategic drug selection and unique patient population characteristics. First, all the patients received pemetrexed. High tissue specificity for lung adenocarcinoma is well documented for pemetrexed. Some studies have shown that pemetrexed enhances the efficacy of immunotherapy by reducing the infiltration of myeloid-derived suppressor cells (MDSCs) in the TME (28,29). MDSCs are a major component of the immunosuppressive TME, and their depletion by pemetrexed creates a more favorable environment for ICI-mediated antitumor immune responses, thereby synergizing with ICIs and antiangiogenic agents. Second, the majority of patients were treated with tislelizumab, an anti-PD-1 antibody with proprietary Fc region engineering. This modification reduces the phagocytosis of T cells by macrophages (30), which prevents the loss of effector T cells and may further amplify the synergistic antitumor effect, contributing to its enhanced efficacy in this cohort. Univariate analysis revealed that comorbid underlying diseases (such as diabetes mellitus and hypertension) were critical factors affecting short-term treatment efficacy (P<0.05). The potential mechanism underlying this association involves chronic inflammatory states induced by comorbidities: Persistent elevation of proinflammatory cytokines (such as IL-6 and TNF-α) can alter TME homeostasis (31). These changes ultimately reduce the responsiveness to the ICI-based triple combination, highlighting the need for optimized comorbidity management in clinical practice. By contrast, age, sex, and PD-L1 expression status did not markedly affect treatment efficacy (all P>0.05). Notably, the effect of smoking history on efficacy also did not reach statistical significance (P>0.05), which may be attributed to insufficient statistical power due to the small sample size. Larger-scale studies are therefore needed to further validate the association between smoking history and the efficacy of this ICI-based triple combination.

Safety

In terms of safety, the majority of adverse reactions were grade 1 or 2 in the present study and patients exhibited good tolerance to the ICI-based triple combination. The most frequently reported AEs were hematological toxicity (58.3%), followed by nausea and vomiting (50.0%), fatigue and anorexia (33.3%), myalgia (33.3%) and chest tightness with dyspnea (33.3%). Of the patients. three developed grade 3 adverse events, including hematological toxicity and myalgia, all of which improved after symptomatic treatment. Myalgia was mainly transient. Prophylactic interventions for myelosuppression were actively administered during subsequent antitumor therapy, and the patients successfully completed the remaining treatment cycles. As a limitation, retrospective data failed to clarify the monitoring frequency of adverse reactions, so the present study was unable to calculate their median onset time.

Hematological toxicity and gastrointestinal reactions were the primary treatment-related adverse events, which is consistent with the common toxicity profile of platinum-based chemotherapy (32). Notably, hypertension and proteinuria, two typical adverse events associated with antiangiogenic agents, were not observed in the present cohort, further supporting the favorable safety of the regimen. Compared with the IMpower150 study (19), which reported a grade 3–4 AEs incidence of 67% in the ICI-containing arm, the severity of AEs in the present study was substantially lower. This discrepancy may be attributed to differences in drug doses, specific drug types, or patient baseline characteristics. The low incidence of severe hypertension and proteinuria in the present study may also be associated with the long-term use of antihypertensive drugs in some patients with preexisting hypertension, which masked the onset of such adverse reactions. Regardless, the milder toxicity profile observed here reinforces the good tolerability of the ICI-based triple combination (22), particularly providing a safe basis for elderly patients with advanced lung adenocarcinoma. Importantly, all AEs were alleviated after intervention and no treatment discontinuation or dose reduction was attributed to SAE.

Limitations

The present study has several limitations that should be acknowledged. First, owing to its single-center retrospective nature and relatively small sample volume, the present investigation may be subject to inherent selection bias. Furthermore, non-typical baseline demographic and clinical characteristics could impair the generalizability of the research outcomes across diverse patient populations. Additionally, the small sample size limited the statistical power of the subgroup analyses, leading to insufficient statistical stability and making it difficult to draw reliable conclusions about these subgroups. Although the drug types included in the patient treatment regimens were the same, there were differences in specific drugs for some patients. Additionally, some patients changed their treatment regimens during the treatment process. Since no subgroup analysis was performed on the drugs, there may be potential effects of specific drug combinations on efficacy. This could affect the accuracy of the experimental results. In the future, it is planned to increase the number of included patients and perform subgroup analysis of patient medications to exclude the effects produced by specific drug combinations. The limited sample size and number of events resulted in reduced statistical power, which not only made it difficult to detect statistically significant differences in survival between groups but also restricted the application of multivariable Cox proportional hazards regression models (as the model failed to converge when multiple covariates were included). Therefore, The present study primarily employed the Kaplan-Meier method for survival analysis. Second, the present study lacked a control group, which precluded direct comparison of the ICI-based triple combination with other commonly used combination regimens. Without such a comparison, it is not possible to definitively determine whether the survival benefits observed in the present study were unique to the ICI-based triple combination or comparable to those of alternative therapies. Third, one patient was administered anlotinib. Although anlotinib exerts targeted inhibitory effects on VEGFR, it also suppresses multiple receptor tyrosine kinases including PDGFR, FGFR and c-Kit. Due to the limited sample size, sensitivity or subgroup analyses to eliminate the influence of anlotinib-related drug heterogeneity on the outcomes could not be performed, which may partially affect the results. Finally, radiotherapy-related factors were not included in the analysis. A subset of patients may have received local radiotherapy during treatment, which could have confounded survival outcomes. Subsequent studies should explicitly account for radiotherapy use and adjust for this variable to exclude potential confounding effects on efficacy assessments.

In summary, as a first-line therapy for patients with advanced driver-gene-negative lung adenocarcinoma, ICI-based triple combination therapy results in relatively high response rates and a manageable safety profile to a certain extent. To further validate the efficacy of the regimens and identify factors influencing their therapeutic outcomes, multicenter, large-sample randomized controlled trials are needed in the future to support the integration of this ICI-based triple combination into personalized treatment strategies for advanced lung adenocarcinoma, ultimately improving clinical outcomes for patients with this disease. In addition, it is planned to perform basic research for direct verification of the underlying mechanism and detection of critical biomarkers in subsequent investigations.

Acknowledgements

Not applicable.

Funding

The present study was funded by Wu Jieping Medical Foundation (grant no. 320.6750.2023–6-27).

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

DM and XP conceived and designed the present study. ZZ, KW and XY collected and organized data. HC, ZZ and GX performed data analysis. DM, HC and ZZ wrote the original draft. JY, LL and YL reviewed and verified the clinical data, reviewed and interpreted the experimental data and provided supervision. XP and LL reviewed and revised the manuscript and approved the final version. DM, JY and XP confirm the authenticity of all the raw data. All authors read and approved the final version of the manuscript.

Ethics approval and consent to participate

The present study was a retrospective observational study and its protocol was approved by the Medical Ethics Committee of The Sixth Affiliated Hospital, School of Medicine, South China University of Technology (approval no. 2023080). The present study registration number is MR-44-25-045421 (available at http://www.medicalresearch.org.cn/). Written informed consent was obtained from all participants at admission for routine clinical treatment, which included authorization for the use of their anonymized clinical data in this retrospective research.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References