
==== Front
Cancer Immunol Immunother
Cancer Immunol Immunother
Cancer Immunology, Immunotherapy : CII
0340-7004
1432-0851
Springer Berlin Heidelberg Berlin/Heidelberg

39237636
3797
10.1007/s00262-024-03797-0
Research
Triple therapy boosts survival in NSCLC patients with brain metastases: a retrospective cohort study of chemotherapy, ICIs, and antiangiogenic agents
Yang Dingyi 13
Munai Erha 2
Zeng Siwei 2
Tao Dan 3
Yuan Ze 3
Du Liang 3
Zhou Wei zhouwei998@cqu.edu.cn

3
Wu Yongzhong cqmdwyz@163.com

3
Zhu Xiao-Dong zhuxdonggxmu@126.com

14
1 https://ror.org/03dveyr97 grid.256607.0 0000 0004 1798 2653 Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, No. 71, He Di Road, Nanning, 530021 Guangxi China
2 https://ror.org/023rhb549 grid.190737.b 0000 0001 0154 0904 School of Medicine, Chongqing University, Chongqing, China
3 https://ror.org/023rhb549 grid.190737.b 0000 0001 0154 0904 Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China
4 https://ror.org/03m01yf64 grid.454828.7 0000 0004 0638 8050 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, China
6 9 2024
6 9 2024
11 2024
73 11 2261 5 2024
1 8 2024
© The Author(s) 2024
2024
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Background

Treatment of brain metastases (BMs) in non-small cell lung cancer (NSCLC) patients, especially those with non-sensitive genetic mutations, is hindered by limited drug delivery through the blood–brain barrier (BBB). This retrospective study explores the efficacy of systemic treatments during brain metastasis to radiotherapy evaluation window in improving patient survival.

Methods

In this retrospective cohort study, we evaluated 209 NSCLC patients with non-sensitive mutations and BMs, treated between 2016 and 2023 at two tertiary medical centers (Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital). The patients were divided into three groups, namely chemotherapy alone (C; n = 95), chemotherapy plus immune checkpoint inhibitors (ICIs) (C + I; n = 62), and chemotherapy with ICIs and antiangiogenic therapy (A) (C + I + A; n = 52). Statistical analyses were performed using R software, version 4.3.3. Categorical variables were compared using Fisher’s exact test, and survival curves were estimated with the Kaplan–Meier method and compared via the log-rank test. Univariate and multivariate Cox regression models were used to assess factors associated with overall survival (OS). Bayesian model averaging (BMA) was employed to address model uncertainty and improve result robustness. Subgroup analyses evaluated treatment-related mortality risk.

Results

From an initial cohort of 658 NSCLC patients with BMs, 209 were analyzed with a median age of 59; the majority were male (80.9%) and diagnosed with adenocarcinoma (78.9%). Univariate analysis identified significant variables influencing outcomes, including BMs radiotherapy EQD2, BMs count, local thoracic treatment, BMs radiotherapy field, intracranial response, and systemic treatment post-BMs diagnosis. The C + I + A regimen significantly improved median OS to 23.6 months compared to 11.4 months with C and 16.2 months with C + I, with a hazard ratio (HR) of 0.60 (95% CI: 0.43–0.82; P < 0.0001). The two-year OS rate was highest in the C + I + A group at 38.5%, versus 10.5% in C and 20.4% in C + I (P < 0.001). Cox regression and BMA analyses confirmed the stability of BMA in providing HR estimates, yielding area under the curve (AUC) values of 0.785 for BMA and 0.793 for the Cox model, with no significant difference in predictive performance. Subgroup analysis revealed a 71% mortality risk reduction with C + I + A (HR: 0.29; 95% CI: 0.18–0.47; P < 0.0001), showing consistent benefits regardless of patient sex, BMs count, extracranial metastases presence, and local thoracic treatments. Treatment sequence analysis indicated a median OS of 33.4 months for patients starting with A, though not statistically significant (HR: 0.59; P = 0.36). The overall incidence of radiation-induced brain injury was low at 3.3%, with rates in the C, C + I, and C + I + A groups being 3.2%, 4.8%, and 1.9%, respectively (P = 0.683).

Conclusion

Our study demonstrates the significant benefit of the C + I + A combination therapy in improving OS and reducing mortality risk in NSCLC patients with non-sensitive gene-mutated BMs. The sequential administration of A followed by ICIs shows a promising synergistic effect with cranial radiotherapy, highlighting the potential for optimized treatment sequencing. These findings emphasize the efficacy of tailored combination therapies in complex oncological care and suggest that our approach could lead to meaningful improvements in clinical outcomes for this challenging patient population.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00262-024-03797-0.

Keywords

Brain metastasis
Immune-related combination therapy
Non-small cell lung cancer
Non-sensitive genetic mutations
Peri-brain radiotherapy
National Natural Science Foundation ProjectNo. 82303673 No. 82073347 Chongqing Science and Health Joint Medical Research ProjectNo. 2023GGXM002 Chongqing Talent PlanNo. CQYC20210203119 Key Research and Development Program Project of Guangxi Zhuang Autonomous RegionNo. GuikeAB23026020 Independent Project of Key Laboratory of Early Prevention & Treatment for Regional HighIncidence TumorNo. GKEZZ202230 issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
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pmcIntroduction

Approximately 40%–50% of patients with non-small cell lung cancer (NSCLC) develop brain metastases (BMs), a complication that significantly affects prognosis and quality of life [1, 2]. Notably, around 25% of these patients exhibit BMs concurrently with their stage IV NSCLC diagnosis [3]. Despite advances in local interventions and systemic treatments, the blood–brain barrier (BBB) continues to pose a challenge in effectively treating intracranial lesions, particularly compared to extracranial ones [4–6].

Recent developments have highlighted the potential of molecular targeted therapies, as they demonstrate enhanced BBB penetration and thereby improved control of both intracranial and extracranial disease [7]. However, for NSCLC patients with non-sensitive gene mutations who develop BMs, effective systemic treatment options are limited. The evolving landscape of systemic treatments, including immune checkpoint inhibitors (ICIs) and antiangiogenic agents, has opened new avenues in the management of lung cancer BMs [8–12]. Studies such as Impower150 [13] have pioneered the integration of chemotherapy, antiangiogenic drugs, and ICIs, showing promising results in metastatic NSCLC. Yet, patients with BMs are often excluded from clinical trials, leading to a scarcity of data specifically addressing the efficacy of combination therapies in this subgroup [14–16].

This gap is relevant considering the potential of cranial radiation therapy to disrupt the BBB, which could enhance the efficacy of systemic treatments [17]. Our retrospective analysis aimed to fill this gap by evaluating the impact of various systemic treatment protocols (C: chemotherapy; C + I: chemotherapy + ICIs; and C + I + A: chemotherapy + ICIs + antiangiogenic therapy) administered during brain metastasis to radiotherapy evaluation window on the survival of non-sensitive gene-mutated NSCLC patients with BMs. The present study contributes to the existing body of knowledge on NSCLC BMs treatment and addresses the critical need for effective therapeutic strategies in this high-risk patient population.

Materials and methods

Patient selection

This retrospective cohort study gathered clinical data from electronic medical records of patients with NSCLC who developed BMs and received systemic therapy between January 1, 2016, and January 31, 2023. The study was conducted at Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital. The study’s inclusion criteria were as follows: (1) histological or pathological confirmation of NSCLC; (2) radiological confirmation of BMs via cranial contrast-enhanced MRI, with at least one measurable brain lesion present; (3) no sensitive gene mutations identified or not tested; (4) at least one course of radiotherapy administered for BMs; (5) comprehensive imaging evaluations conducted before and after radiotherapy; and (6) complete records of treatment and follow-up available. The exclusion criteria encompassed the following: (1) presence of sensitive gene mutations (EGFR, ALK, ROSl) or unknown gene status but effective response to targeted therapies; (2) absence of either systemic treatment; (3) leptomeningeal metastasis; (4) primary malignancies in other systems; (5) incomplete imaging, treatment, or followup data.

Data collection

Data were extracted from electronic medical records, ensuring consistency in clinical data collection and patient follow-up. The following variables were included: age, sex, ECOG Performance Status, pathology (WHO classification), BMs count, perilesional edema of BMs, extracranial metastasis, BMs type and morphology of BMs, largest BMs diameter (D-max), local thoracic treatments, BMs radiotherapy EQD2(EQD2 of BMs-RT), BMs radiotherapy field(field of BMs-RT), pre- and post-radiotherapy neurological symptoms (NSB, NSA), neurological symptom improvement after radiotherapy (NSI), intracranial response, radiation-induced brain injury, and systemic treatment after BMs diagnosis. Systemic treatment regimens during brain metastasis to radiotherapy evaluation window were documented, which was from initial BMs diagnosis to six months after initial BMs-RT. Treatment choices were based on clinical guidelines, investigator discretion, or patient preference. The final follow-up date was August 15, 2023.

Research endpoints

The patients were categorized into the following three groups based on the systemic therapy received: C, C + I, and C + I + A. The primary end point was overall survival (OS), measured from the first BMs diagnosis to death or last follow-up. Therapeutic responses included complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Synchronous Brain Metastasis: metastases that are identified at the same time as the primary cancer diagnosis, or within a short period following the diagnosis, usually within 6 months. Metachronous Brain Metastasis: metastases that are diagnosed at a later time after the initial diagnosis of the primary cancer, typically more than 6 months later. Perilesional Edema: On contrast-enhanced MRI, with higher signal intensity compared with normal brain tissue, edema around the lesion often appears as an area of high signal on T2-weighted imaging (T2WI) and fluid-attenuated inversion recovery (FLAIR) sequences.

Statistical analysis

All statistical analyses were conducted using R software, version 4.3.3. Categorical variables were summarized by frequencies, percentages, or ratios, and continuous variables were expressed as mean ± standard deviation (SD). Differences in categorical variables between groups were evaluated using Fisher’s exact test, while survival curves were estimated using the Kaplan–Meier method and compared via the log-rank test. Univariate Cox regression was initially performed to identify factors significantly associated with OS. To address complexities in the dataset and potential confounders, an iterative optimization process was applied to a traditional Cox proportional hazards model (Cox model). This process involved adjusting variables based on statistical significance and clinical insights to refine the model’s accuracy and reduce overfitting. Due to challenges with variable stability and overfitting in the Cox model, Bayesian model averaging (BMA) was also utilized. By calculating the Area Under the Curve (AUC) values for the BMA and Cox models, and using the DeLong test to compare statistical differences. BMA was selected for its robust approach to integrating model uncertainty and enhancing the interpretability of results, proving advantageous in complex prognostic analyses. Detailed comparisons of model performance and the rationale for choosing BMA are discussed further in the results section.

Results

Baseline characteristics

From an initial cohort of 658 NSCLC patients with BMs receiving systemic therapy at Chongqing University Cancer Hospital and Guangxi Medical University Affiliated Cancer Hospital, 209 were included in the final analysis (Fig. 1).Fig. 1 Flowchart of patients’ selection

The median age of the final cohort was 59 years (range 30–80). The patients were predominantly male (80.9%), and the majority were diagnosed with adenocarcinoma (78.9%, P = 0.042). Notably, 57.7% of patients had metachronous BMs. A significant proportion of patients had fewer than five BM lesions (61.7%) and perilesional edema (81.3%). Furthermore, 137 patients (65.6%) did not receive any local thoracic treatment. As for BMs-RT, 53 patients (25.4%) underwent whole brain radiotherapy (WBRT), 86 patients (41.1%) received local radiotherapy, and 70 patients (33.5%) underwent WBRT + Boost (WBRT combined with an additional radiation ‘boost’ to intracranial metastases) (P < 0.001). The median D-max of BMs was 1.7 cm. Before BMs-RT, 56.9% of the patients reported neurological symptoms, which decreased to 29.7% after BMs-RT (P = 0.043). Post-initial BMs-RT efficacy assessment showed that 62.7% of the patients achieved either a complete response (CR) or partial response (PR). The baseline characteristics exhibited a good balance across the C, C + I, and C + I + A treatment groups. The overall incidence of radiation-induced brain injury was 3.3%, with the incidence rates in the C, C + I, and C + I + A groups being 3.2%, 4.8%, and 1.9%, respectively. The C + I + A group had a lower incidence of radiation-induced brain necrosis, but the difference was not statistically significant (P = 0.683). (Table 1).Table 1 Baseline features of patients

Characteristics, n (%)	Total(n = 209)	C (n = 95)	C + I (n = 62)	C + I + A (n = 52)	P Value	
Age (years), median (range)	59.0 (30.0–80.0)	60.0 (30.0–75.0)	62.0 (44.0–80.0)	57.5(33–78)	0.060	
Age					0.260	
   < 65	148 (70.8%)	70 (73.7%)	39 (62.9%)	39 (75.0%)		
   ≥ 65	61 (29.2%)	25 (26.3%)	23 (37.1%)	13 (25.0%)		
Sex					0.316	
  Male	169 (80.9%)	75 (78.9%)	54 (87.1%)	40 (76.9%)		
  Female	40 (19.1%)	20 (21.1%)	8 (12.9%)	12 (23.1%)		
Pathology					0.042	
  Adenocarcinoma	165 (78.9%)	76 (80.0%)	43 (69.4%)	46 (88.5%)		
  Squamous	44 (21.1%)	19 (20.0%)	19 (30.6%)	6 (11.5%)		
ECOG Performance Status					0.181	
  0–1	118 (56.5%)	49 (51.6%)	41 (66.1%)	28 (53.8%)		
   ≥ 2	91 (43.5%)	46 (48.4%)	21 (33.9%)	24 (46.2%)		
BMs count					0.064	
  1	61 (29.2%)	19 (20.0%)	22 (35.5%)	20 (38.5%)		
  2–4	68 (32.5%)	38 (40.0%)	15 (24.2%)	15 (28.8%)		
   ≥ 5	80 (38.3%)	38 (40.0%)	25 (40.3%)	17 (32.7%)		
Perilesional edema of BMs					0.635	
  Absent	39 (18.7%)	16 (16.8%)	11 (17.7%)	12 (23.1%)		
  Present	170 (81.3%)	79 (83.2%)	51 (82.3%)	40 (76.9%)		
Extracranial metastases					0.930	
  Absent	84 (40.2%)	38 (40.0%)	26 (41.9%)	20 (38.5%)		
  Present	125 (59.8%)	57 (60.0%)	36 (58.1%)	32 (61.5%)		
BMs type					0.091	
  Synchronous	113 (54.1%)	58 (61.1%)	33 (53.2%)	22 (42.3%)		
  Metachronous	96 (45.9%)	37 (38.9%)	29 (46.8%)	30 (57.7%)		
Morphology of BMs					0.812	
  Cystica	125 (59.8%)	58 (61.1%)	35 (56.5%)	32 (61.5%)		
  Solid	84 (40.2%)	37 (38.9%)	27 (43.5%)	20 (38.5%)		
D-max(cm), median (range)	1.7(0.3–6.4)	1.9(0.4–5.5)	1.7(0.3–6.4)	1.7(0.3–6.4)	0.138	
D-max					0.228	
   < 1.8 cm	106 (50.7%)	42 (44.2%)	35 (56.5%)	29 (55.8%)		
   ≥ 1.8 cm	103 (49.3%)	53 (55.8%)	27 (43.5%)	23 (44.2%)		
Local thoracic treatment					0.875	
  No	137 (65.6%)	65 (68.4%)	40 (64.5%)	32 (61.5%)		
  Surgery	39 (18.7%)	16 (16.8%)	11 (17.7%)	12 (23.1%)		
  RT	33 (15.8%)	14 (14.7%)	11 (17.7%)	8 (15.4%)		
EQD2 of BMs-RT (Gy),

median (range)

	48.0 (12.0–72.0)	48.8 (12.0–62.5)	42.8 (16.0–72.0)	48.8 (32.5–68.0)	0.095	
EQD2 of BMs-RT					0.016	
   < 40 Gy	65 (31.1%)	36 (37.9%)	21 (33.9%)	8 (15.4%)		
   ≥ 40 Gy	144 (68.9%)	59 (62.1%)	41 (66.1%)	44 (84.6%)		
Field of BMs-RT					 < 0.001	
  WBRT	53 (25.4%)	32 (33.7%)	14 (22.6%)	6 (11.5%)		
  Local	86 (41.1%)	21 (22.1%)	34 (54.8%)	26 (50.0%)		
  WBRT + Boost	70 (33.5%)	42 (44.2%)	14 (22.6%)	20 (38.5%)		
NSB					0.579	
  Absent	90 (43.1%)	38 (40.0%)	30 (48.4%)	22 (42.3%)		
  Present	119 (56.9%)	57 (60.0%)	32 (51.6%)	30 (57.7%)		
NSA					0.043	
  Absent	147 (70.3%)	68 (71.6%)	49 (79.0%)	30 (57.7%)		
  Present	62 (29.7%)	27 (28.4%)	13 (21.0%)	22 (42.3%)		
NSI					0.268	
  Absent	121 (57.9%)	51 (53.7%)	35 (56.5%)	35 (67.3%)		
  Present	88 (42.1%)	44 (46.3%)	27 (43.5%)	17 (32.7%)		
Intracranial response					0.200	
  CR	15 (7.2%)	8 (8.4%)	4 (6.5%)	3 (5.8%)		
  PR	116 (55.5%)	43 (45.3%)	41 (66.1%)	32 (61.5%)		
  SD	52 (24.9%)	31 (32.6%)	11 (17.7%)	10 (19.2%)		
  PD	26 (12.4%)	13 (13.7%)	6 (9.7%)	7 (13.5%)		
Radiation-induced brain injury					0.683	
  Absent	202 (96.7%)	92 (96.8%)	59 (95.2%)	51 (98.1%)		
  Present	7 (3.3%)	3 (3.2%)	3 (4.8%)	1 (1.9%)		
Data are n (%)

C = chemotherapy, I = Immune checkpoint inhibitors therapy, A = Antiangiogenic therapy. RT = radiotherapy, ECOG = Eastern Cooperative Oncology Group performance status

WBRT = whole brain radiotherapy, Local = PGTV radiotherapy only, include Stereotactic Radiosurgery (SRS), Stereotactic Radiotherapy (SRT), Intensity-Modulated Radiation Therapy (IMRT) and Conventional Radiation Therapy (CRT)

IMRT and CRT: The median total dose for BMs was 40 Gy (ranging from 30 to 54 Gy), delivered in 10 to 25 fractions (median of 14 fractions). SRT: The median total dose for BMs was 27 Gy (ranging from 24 to 32 Gy), delivered in 3 to 8 fractions (median of 4 fractions). SRS: The median total dose for BMs was 22 Gy (ranging from 20 to 24 Gy), delivered in 1 fractions (median of 1 fractions)

NSA and NSI = The recorded time window are within 3 months after BMs-RT. BMs-RT response = The best efficacy of intracranial lesions within 6 months after BMs-RT was recorded according to RECIST1.1 standard

Overall survival (OS)

By the last follow-up (August 15, 2023), 77.0% of patients had died, with a median follow-up of 36.5 months (95% CI: 29.6–43.3). The median OS was 14.4 months (95% CI: 12.0–16.8) overall, with the C + I + A group showing a significantly longer OS of 23.6 months (95% CI: 12.9–34.3), compared with 11.4 months in the C group and 16.2 months in the C + I group (HR: 0.60, 95% CI: 0.43–0.82, P < 0.001) (Fig. 2). The two-year OS rate was also the highest in the C + I + A group (38.5%) compared with the C (10.5%) and C + I (20.4%) groups (P < 0.001).Fig. 2 Comparison of OS between C group, C + I group and C + I + A group

Univariate and multivariate analysis of prognostic factors for OS

Univariate Cox Analysis: The preliminary univariate Cox regression analysis assessed the association of various factors with OS. This initial analysis revealed significant variables including EQD2 of BMs-RT, BMs count, local thoracic treatment, field of BMs-RT, intracranial response, and systemic treatment after BMs diagnosis (Table 2). Notably, certain variables like sex, NSA, and BMs type did not show significant associations at this stage.Table 2 Univariable Analyses of Overall Survival

Characteristics	Univariate analysis	
HR (95%CI)	P value	
Age			
   < 65	1(reference)		
   ≥ 65	1.23(0.89–1.10)	0.205	
Sex			
  Male	1(reference)		
  Female	0.78(0.52–1.16)	0.219	
Pathology			
  Adenocarcinoma	1(reference)		
  Squamous	1.27(0.87–1.85)	0.214	
ECOG performance status			
  0–1	1(reference)		
   ≥ 2	0.90(0.66–1.24)	0.522	
BMs count		0.013	
  1	1(reference)		
  2–4	1.45(0.97–2.22)	0.071	
   ≥ 5	1.82 (1.22–2.72)	0.003	
Perilesional edema of BMs			
  Absent	1(reference)		
  Present	1.06(0.71–1.58)	0.791	
Extracranial metastases			
  Absent	1(reference)		
  Present	1.28(0.93–1.76)	0.125	
BMs type			
  Synchronous	1(reference)		
  Metachronous	1.14(0.84–1.56)	0.403	
Morphology of BMs			
  Solid	1(reference)		
  Cystica	1.04(0.76–1.43)	0.810	
D-max			
   < 1.8cm	1(reference)		
   ≥ 1.8cm	1.02(0.75–1.39)	0.909	
Local thoracic treatment		0.012	
  No	1(reference)		
  Surgery	0.52(0.33–0.81)	0.004	
  RT	0.76(0.49–1.19)	0.228	
EQD2 of BMs-RT			
   < 40 Gy	1(reference)		
   ≥ 40 Gy	0.64(0.46–0.89)	0.007	
Field of BMs-RT		0.004	
  WBRT	1(reference)		
  Local	0.52(0.35–0.77)	0.001	
  WBRT + Boost	0.78(0.54–1.17)	0.247	
NSB			
  Absent	1(reference)		
  Present	0.96(0.70–1.32)	0.811	
NSA			
  Absent	1(reference)		
  Present	1.27(0.91–1.78)	0.160	
NSI			
  Absent	1(reference)		
  Present	0.86(0.62–1.17)	0.330	
Intracranial response		 < 0.001	
  CR	1(reference)		
  PR	1.36 (0.72–2.70)	0.322	
  SD	2.04(1.03–4.06)	0.042	
  PD	4.91(2.33–10.35)	 < 0.001	
Radiation-induced brain injury			
  Absent	1(reference)		
  Present	0.70(0.26–1.92)	0.489	
Systemic treatment after BMs diagnosis		 < 0.001	
  C	1(reference)		
  C + I	0.63(0.44–0.91)	0.015	
  C + I + A	0.35(0.23–0.53)	 < 0.001	

Cox Model Refinement and Iterative Optimization: Following the univariate analysis, both statistically significant variables and those deemed clinically important were carried forward to multivariate Cox regression analysis. The process involved iterative refinement to identify the most impactful factors, eventually selecting nine key variables as detailed in Supplemental Table 1. This optimized model highlighted systemic treatment modes as highly influential. However, during the construction of the comprehensive Cox model, certain variables such as sex, BMs type, and NSA, initially non-significant, emerged as significant (Supplemantary Table 2). This shift raised concerns about potential overfitting or the influence of unaccounted interactions within the traditional Cox framework.Table 3 Multivariate BMA analysis of Overall Survival

Characteristics	Multivariate analysis	
Coefficients	HR	
Sex			
  Male		1(reference)	
  Female	 −0.0870	0.916	
BMs count			
  1		1(reference)	
  2–4	0.0007	0.999	
   ≥ 5	0.0112	1.011	
Extracranial metastases			
  Absent		1(reference)	
  Present	0.0280	1.028	
BMs type			
  Synchronous		1(reference)	
  Metachronous	0.5630	1.755	
Local thoracic treatment			
  No		1(reference)	
  Surgery	 −0.7550	0.470	
  RT	 −0.0740	0.928	
EQD2 of BMs-RT			
   < 40 Gy		1(reference)	
   ≥ 40 Gy	 −0.0032	0.996	
Field of BMs-RT			
  WBRT		1(reference)	
  Local RT	 −0.0390	0.962	
  WBRT + Boost	0.0017	1.002	
NSA			
  Absent		1(reference)	
  Present	0.3700	1.447	
Intracranial response			
  CR		1(reference)	
  PR	0.0340	1.035	
  SD	0.4240	1.528	
  PD	1.3260	3.768	
Systemic treatment after BMs diagnosis			
  C		1(reference)	
  C + I	 −0.0710	0.931	
  C + I + A	 −1.020	0.361	

Decision to Employ Bayesian Model Averaging (BMA): Given the inconsistencies observed in the Cox model—specifically, the shifting significance of variables like sex, NSA, and BMs type from non-significant in univariate analysis to significant in multivariate Cox analysis—we turned to BMA for a more robust analytical approach. BMA was selected to better manage model uncertainty and provide a more reliable estimation of effects, particularly for variables exhibiting unstable significance in the Cox model.

BMA allowed for the integration of uncertainty across multiple models, each weighted according to its posterior probability based on the data. This method effectively addressed the overfitting issues observed with the Cox model and enhanced the robustness of the findings. The BMA analysis, incorporating the same 10 factors used in the refined Cox model, resulted in 56 potential models(Supplemental Document S1). The composite outcome of these models produced an AUC value of 0.785 (Fig. 3A), indicating good predictive performance without the inconsistencies noted in the Cox analysis.Fig. 3 The Area Under the Curve (AUC) of two models. A BMA model; B Cox proportional hazards model

Comparative Evaluation and Final Decision: Simultaneously, the refined Cox model, also documented in Supplemental Table 1, was critically evaluated. Despite achieving a comparable AUC value of 0.793 (Fig. 3B), the decision favored BMA due to its advantages in handling the complexities and uncertainties inherent in the data. The DeLong test confirmed no statistically significant(Z =  −0.29228, P = 0.7701, 95% CI: −0.059–0.044) difference between the AUC values of the two methodologies, yet the more stable and consistent hazard ratios provided by BMA, especially for variables with previously inconsistent significance, substantiated its selection for the final analysis.

Summary of Multivariate BMA Analysis: The BMA analysis highlighted several significant factors influencing the outcomes of patients with BMs. Notably, metachronous BMs were associated with a substantially higher risk compared to synchronous BMs, with a HR of 1.755, indicating increased vulnerability in these patients. Surgical interventions in local thoracic treatments demonstrated a significant protective effect, reducing the risk (HR = 0.470). Additionally, the occurrence of post-RT neurological symptoms (NSA) may suggest irreversible neurological damage due to destruction of neural cells by metastatic lesions rather than mere compression, significantly worsening patient outcomes and increasing the hazard (HR = 1.447). Among intracranial responses, SD (HR = 1.528) and PD (HR = 3.768) significantly increased mortality risk compared to CR, highlighting the importance of effective cranial radiotherapy in improving patient survival outcomes. Furthermore, the C + I + A group significantly lowered the risk (HR = 0.361), showing a substantial benefit in treatment efficacy. (Table 3).

Subgroup and treatment sequence analyses

Subgroup analyses were conducted to evaluate the efficacy of the C + I + A treatment compared to the C group. A Cox model was used for these analyses due to the limited sample size in each subgroup, which provided clear insights without overcomplicating the interpretations (Supplemantary Table 3).

Key findings

Overall Efficacy: The C + I + A treatment significantly reduced mortality risk by 71% compared to the C regimen, demonstrating its superior efficacy across diverse patient groups.

Treatment Sequence Analysis: The C + I + A group showed variability in treatment initiation, with notable differences in OS. Analysis of 23 patients (44.2%) starting with ICIs, 21 patients (40.4%) with antiangiogenic therapy (A), and 8 patients (15.4%) with both I and A concurrently showed differences in OS. Namely, the patients beginning with A had a median OS of 33.4 months, longer than those starting with ICIs (19.1 months) or I and A concurrently (18.6 months). Though the P value of 0.36 was not statistically significant, this trend suggests a potential clinical advantage of starting with A, which warrants further investigation (Fig. 4).Fig. 4 Survival analysis based on drug administration order differences in patients treated with C + I + A therapy

Detailed subgroup impacts

Sex: Both genders benefited from the C + I + A regimen, with females showing a particularly pronounced risk reduction.

BMs Count and Type: The treatment was effective across all BM counts and types, especially for patients with a higher count of BMs (≥ 5).

Extracranial Metastases: The efficacy of C + I + A was consistent regardless of the presence of extracranial metastases.

Local Thoracic Treatments and Radiotherapy Parameters: Patients receiving any local thoracic treatments (including surgery and radiotherapy) showed improved outcomes (all the P for interactions > 0.05).

These analyses highlight the broad applicability and potential of the C + I + A regimen across diverse clinical scenarios. The data suggest the regimen’s effectiveness is not confined to specific subgroups, supporting its use as a versatile treatment option. Further investigation into optimal treatment sequences could refine these findings and enhance treatment protocols.

Discussion

Our study offers critical insights into the efficacy of immune-related combination therapies for NSCLC patients with BMs, specifically targeting those without sensitive gene mutations. The study period between 2016 and 2023 marks a pivotal shift in oncological treatments in China, highlighted by the widespread acceptance of ICIs following regulatory endorsements by China’s Drug Administration (CDA) and National Medical Products Administration (NMPA) [18].

A cornerstone of our research is the remarkable OS achieved with the C + I + A regimen during brain metastasis to radiotherapy evaluation window, an innovative amalgamation of chemotherapy, ICIs, and antiangiogenic agents. This regimen clearly surpasses the outcomes of chemotherapy alone and chemotherapy combined with ICIs, showcasing the significant benefits of a comprehensive treatment strategy in NSCLC patients with BMs.

The KEYNOTE-189 study confirmed that C + I is superior to C, showing a significant increase in overall survival with pembrolizumab combined with chemotherapy (19.2 months) compared to chemotherapy alone (7.5 months) [19], but it did not involve the use of antiangiogenic agents. The combined results of KEYNOTE-021, −189, and −407 further confirmed this, demonstrating a higher response rate in the combination therapy group[8]. The C + I + A regimen, which combines antiangiogenic therapy, is a less explored but very promising approach. As shown in the retrospective analyses by Shubin Chen et al. [20] and Haowei Wang et al. [21], Chen et al. reported an impressive median OS of 37.3 months for the group receiving PD-1/PD-L1 inhibitors + antiangiogenic agents + chemotherapy. However, both studies included a small number of patients with BMs and did not focus on a specific population (driver gene-negative NSCLC with BMs), and details on intracranial radiotherapy were not provided. In contrast, our study, by specifying a well-defined population and providing detailed information on the first intracranial radiotherapy, analyzed the impact of three treatment modalities on patient OS. It affirmed the survival efficacy of the C + I + A regimen in driver gene-negative NSCLC patients with BMs.

While sex differences significantly influence the efficacy of immune-related combination therapies, this effect should be interpreted cautiously in our study. A trial of atezolizumab in NSCLC patients showed enhanced benefits for women [22]. Similarly, KEYNOTE-189 and KEYNOTE-407 reported a more pronounced overall survival advantage for women compared to men [19, 23]. In our study, the Cox model analysis indicated a significant benefit for female patients (HR, 0.61; 95% CI, 0.40–0.93; P = 0.021). However, BMA model suggested that the difference was less pronounced (HR = 0.916). These findings suggest a potential trend that female patients might derive greater benefits from immune-related therapies, highlighting the need for further research to better understand sex-based differences in response to these therapies [24].

Our study contributes to this field by examining a substantial cohort, including both synchronous and metachronous BMs, focusing on patients with non-sensitive gene mutations, all within the context of cranial radiotherapy. This comprehensive approach offers a more accurate picture of clinical practice, enhancing the relevance of our findings to real-world settings.

The observed potential synergistic effect between ICIs and antiangiogenic drugs in our study reflects their combined impact on tumor angiogenesis and immune response. Antiangiogenic agents potentially enhance the effects of ICIs by facilitating CD8 + T-cell infiltration and optimizing drug delivery [25]. Concurrently, ICIs disrupt the tumor’s immunosuppressive microenvironment, which could amplify the impact of antiangiogenic therapy [26, 27]. The interplay between antiangiogenic therapy and immune modulation presents a promising avenue for NSCLC treatments, particularly for patients with BMs, suggesting a nuanced approach to therapy that leverages the strengths of both drug classes.

A notable finding in our research is the tendency for enhanced survival outcomes when antiangiogenic therapy precedes the use of ICIs in the C + I + A treatment group. This observation is in line with current research suggesting advantages of such a sequential approach [25, 28]. It highlights the critical role of strategic sequencing in treatment regimens, emphasizing that the order of therapeutic administration can be key to maximizing treatment efficacy.

Additionally, our study indicates that combining cranial radiotherapy with chemotherapy, ICIs, and antiangiogenic therapy can result in significant clinical benefits with good patient tolerance. From another perspective, cranial radiotherapy may alter the tumor microenvironment, enhancing the systemic effects of ICIs[29–31]. This synergistic effect appears to be further amplified when antiangiogenic drugs are included, suggesting an intricate interaction between these therapies that merits further exploration. Our findings highlight the necessity for more research into the interactions between cranial radiotherapy, ICIs, and antiangiogenic therapy to maximize therapeutic efficacy. Understanding these interactions could lead to optimized treatment protocols that leverage the full potential of these combined modalities.

However, our study is not without limitations. Its retrospective nature and reliance on data from only two centers may have introduced selection bias, potentially affecting the generalizability of the results. The modest sample size might have also limited the statistical robustness of our analyses, indicating a need for larger, multicenter, or prospective studies for more conclusive validation. In our retrospective study, we focused on treatment regimens initiated within six months after the initial diagnosis of BMs and subsequent cranial radiotherapy. This research design allowed us to focus on assessing short-term treatment outcomes but limited our ability to examine long-term toxic effects, particularly those that may manifest later post-treatment. We observed the incidence rates of radiation-induced brain necrosis in three treatment groups (C, C + I, and C + I + A), which were 3.2%, 4.8%, and 1.9%, respectively. These differences were not statistically significant (P = 0.683). This outcome indicates that, in our study, adding I and A did not significantly increase the risk of radiation-induced brain necrosis. However, we did not assess other potential toxic effects, which is a major limitation of our study. Recent meta-analyses supporting our observations show that radiotherapy combined with I significantly improves OS in patients with BMs (hazard ratio: 0.55; P < 0.001), without increasing major toxicities such as radiation necrosis or brain failure (all P > 0.05) [32]. These results highlight the potential efficacy and feasibility of our treatment strategies, although further research is necessary to comprehensively evaluate their long-term benefits and risks.

In conclusion, our research makes a clear contribution to the evolving narrative of NSCLC treatment, particularly for patients with BMs and non-sensitive gene mutations. It suggests that a personalized C + I + A therapy during brain metastasis to radiotherapy evaluation window, initiated with antiangiogenic agents, could be both viable and effective, potentially refining patient management and outcomes. This study advocates for more individualized and integrated treatment approaches in this complex patient group, paving the way for future advancements in oncological care.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 18 KB)

Supplementary file2 (DOCX 18 KB)

Supplementary file3 (DOCX 20 KB)

Supplementary file4 (DOCX 25 KB)

Author contributions

All authors contributed to the article and approved the submitted version. Dingyi Yang and Xiao-Dong Zhu conceived the project and designed the experiments. Siwei Zeng, Dan Tao, Ze Yuan, and Liang Du were involved in patient inclusion and sample acquisition. Erha Munai wrote the manuscript with advice and feedback from all authors. Wei Zhou and Yongzhong Wu discussed the results and revised them critically for important intellectual content. All authors contributed to the article and approved the submitted version.

Funding

The current study was supported by grants from the Chongqing Science and Health Joint Medical Research Project (No. 2023GGXM002 to YZ Wu), National Natural Science Foundation Project (No. 82073347 to YZ Wu) and Chongqing Talent Plan (No. CQYC20210203119 to YZ Wu), the Key Research and Development Program Project of Guangxi Zhuang Autonomous Region (Grant No. GuikeAB23026020), the Independent Project of Key Laboratory of Early Prevention & Treatment for Regional HighIncidence Tumor (Grant No. GKEZZ202230), and the National Natural Science Foundation Project (No. 82303673 to LD).

Data availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

The research involving human participants was reviewed and approved by the ethics committees of Chongqing University Cancer Hospital and Guangxi Medical University Cancer Hospital. Patients/participants provided written informed consent to participate in this study.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Dingyi Yang and Erha Munai contributed equally as first authors. Wei Zhou, Yongzhong Wu, and Xiao-Dong Zhu contributed equally as senior authors.
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References

1. Peters S The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer Cancer Treat Rev 2016 45 139 162 10.1016/j.ctrv.2016.03.009 27019457
Peters S et al (2016) The impact of brain metastasis on quality of life, resource utilization and survival in patients with non-small-cell lung cancer. Cancer Treat Rev 45:139–162. 10.1016/j.ctrv.2016.03.00927019457 10.1016/j.ctrv.2016.03.009
2. Ricciardi S de Marinis F Multimodality management of non-small cell lung cancer patients with brain metastases Curr Opin Oncol 2010 22 2 86 93 10.1097/CCO.0b013e3283350106 20009927
Ricciardi S, de Marinis F (2010) Multimodality management of non-small cell lung cancer patients with brain metastases. Curr Opin Oncol 22(2):86–93. 10.1097/CCO.0b013e328335010620009927 10.1097/CCO.0b013e3283350106
3. Waqar SN Non-small-cell Lung Cancer With Brain Metastasis at Presentation Clin Lung Cancer 2018 19 4 e373 e379 10.1016/j.cllc.2018.01.007 29526531
Waqar SN et al (2018) Non-small-cell Lung Cancer With Brain Metastasis at Presentation. Clin Lung Cancer 19(4):e373–e379. 10.1016/j.cllc.2018.01.00729526531 10.1016/j.cllc.2018.01.007
4. Vogelbaum MA Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline J Clin Oncol 2022 40 5 492 516 10.1200/jco.21.02314 34932393
Vogelbaum MA et al (2022) Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline. J Clin Oncol 40(5):492–516. 10.1200/jco.21.0231434932393 10.1200/jco.21.02314
5. Eichler AF The biology of brain metastases-translation to new therapies Nat Rev Clin Oncol 2011 8 6 344 356 10.1038/nrclinonc.2011.58 21487419
Eichler AF et al (2011) The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol 8(6):344–356. 10.1038/nrclinonc.2011.5821487419 10.1038/nrclinonc.2011.58
6. Fortin D The blood-brain barrier: its influence in the treatment of brain tumors metastases Curr Cancer Drug Targets 2012 12 3 247 259 10.2174/156800912799277511 22229251
Fortin D (2012) The blood-brain barrier: its influence in the treatment of brain tumors metastases. Curr Cancer Drug Targets 12(3):247–259. 10.2174/15680091279927751122229251 10.2174/156800912799277511
7. Nishino M Soejima K Mitsudomi T Brain metastases in oncogene-driven non-small cell lung cancer Transl Lung Cancer Res 2019 8 Suppl 3 S298 S307 10.21037/tlcr.2019.05.15 31857953
Nishino M, Soejima K, Mitsudomi T (2019) Brain metastases in oncogene-driven non-small cell lung cancer. Transl Lung Cancer Res 8(Suppl 3):S298–S307. 10.21037/tlcr.2019.05.1531857953 10.21037/tlcr.2019.05.15
8. Powell SF Outcomes With Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With NSCLC and Stable Brain Metastases: Pooled Analysis of KEYNOTE-021, -189, and -407 J Thorac Oncol 2021 16 11 1883 1892 10.1016/j.jtho.2021.06.020 34265431
Powell SF et al (2021) Outcomes With Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With NSCLC and Stable Brain Metastases: Pooled Analysis of KEYNOTE-021, -189, and -407. J Thorac Oncol 16(11):1883–1892. 10.1016/j.jtho.2021.06.02034265431 10.1016/j.jtho.2021.06.020
9. Gandhi L Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer N Engl J Med 2018 378 22 2078 2092 10.1056/NEJMoa1801005 29658856
Gandhi L et al (2018) Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 378(22):2078–2092. 10.1056/NEJMoa180100529658856 10.1056/NEJMoa1801005
10. Sperduto PW Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases J Clin Oncol 2012 30 4 419 425 10.1200/jco.2011.38.0527 22203767
Sperduto PW et al (2012) Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol 30(4):419–425. 10.1200/jco.2011.38.052722203767 10.1200/jco.2011.38.0527
11. Besse B Bevacizumab in Patients with Nonsquamous Non-Small Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): A Nonrandomized Phase II Study Clin Cancer Res 2015 21 8 1896 1903 10.1158/1078-0432.Ccr-14-2082 25614446
Besse B et al (2015) Bevacizumab in Patients with Nonsquamous Non-Small Cell Lung Cancer and Asymptomatic, Untreated Brain Metastases (BRAIN): A Nonrandomized. Phase II Study Clin Cancer Res 21(8):1896–1903. 10.1158/1078-0432.Ccr-14-208225614446 10.1158/1078-0432.Ccr-14-2082
12. Han B Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial JAMA Oncol 2018 4 11 1569 1575 10.1001/jamaoncol.2018.3039 30098152
Han B et al (2018) Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non-Small Cell Lung Cancer: The ALTER 0303 Phase 3 Randomized Clinical Trial. JAMA Oncol 4(11):1569–1575. 10.1001/jamaoncol.2018.303930098152 10.1001/jamaoncol.2018.3039
13. Socinski MA IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC J Thorac Oncol 2021 16 11 1909 1924 10.1016/j.jtho.2021.07.009 34311108
Socinski MA et al (2021) IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J Thorac Oncol 16(11):1909–1924. 10.1016/j.jtho.2021.07.00934311108 10.1016/j.jtho.2021.07.009
14. Herbst RS Previously treated advanced NSCLC cohort from a multi-disease phase 1 study of ramucirumab (R) plus pembrolizumab (P): Efficacy and safety data Ann Oncol 2017 28 2 10.1093/annonc/mdx091.010
Herbst RS et al (2017) Previously treated advanced NSCLC cohort from a multi-disease phase 1 study of ramucirumab (R) plus pembrolizumab (P): Efficacy and safety data. Ann Oncol 28:210.1093/annonc/mdx091.010
15. Rizvi NA Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) Maintenance as Monotherapy or in Combination With Bevacizumab (BEV) for Non-Small Cell Lung Cancer (NSCLC) Previously Treated With Chemotherapy Int J Radiat Oncol Biol Phys 2014 90 S32 S32 10.1016/j.ijrobp.2014.08.206
Rizvi NA et al (2014) Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) Maintenance as Monotherapy or in Combination With Bevacizumab (BEV) for Non-Small Cell Lung Cancer (NSCLC) Previously Treated With Chemotherapy. Int J Radiat Oncol Biol Phys 90:S32–S32. 10.1016/j.ijrobp.2014.08.20610.1016/j.ijrobp.2014.08.206
16. Gadgeel SM Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non-small-cell lung cancer: Phase 1 cohorts from the KEYNOTE-021 study Lung Cancer 2018 125 273 281 10.1016/j.lungcan.2018.08.019 30429032
Gadgeel SM et al (2018) Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non-small-cell lung cancer: Phase 1 cohorts from the KEYNOTE-021 study. Lung Cancer 125:273–281. 10.1016/j.lungcan.2018.08.01930429032 10.1016/j.lungcan.2018.08.019
17. Hart E Blood-brain barrier permeability following conventional photon radiotherapy - A systematic review and meta-analysis of clinical and preclinical studies Clin Transl Radiat Oncol 2022 35 44 55 10.1016/j.ctro.2022.04.013 35601799
Hart E et al (2022) Blood-brain barrier permeability following conventional photon radiotherapy - A systematic review and meta-analysis of clinical and preclinical studies. Clin Transl Radiat Oncol 35:44–55. 10.1016/j.ctro.2022.04.01335601799 10.1016/j.ctro.2022.04.013
18. Jin Y The regulatory approvals of immune checkpoint inhibitors in China and the United States: A cross-national comparison study Int J Cancer 2023 152 11 2351 2361 10.1002/ijc.34427 36632000
Jin Y et al (2023) The regulatory approvals of immune checkpoint inhibitors in China and the United States: A cross-national comparison study. Int J Cancer 152(11):2351–2361. 10.1002/ijc.3442736632000 10.1002/ijc.34427
19. Gadgeel S Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer J Clin Oncol 2020 38 14 1505 1517 10.1200/jco.19.03136 32150489
Gadgeel S et al (2020) Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 38(14):1505–1517. 10.1200/jco.19.0313632150489 10.1200/jco.19.03136
20. Chen S PD-1/PD-L1 inhibitors plus anti-angiogenic agents with or without chemotherapy versus PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment for patients with advanced non-small cell lung cancer: A real-world retrospective cohort study Front Immunol 2022 13 1059995 10.3389/fimmu.2022.1059995 36569915
Chen S et al (2022) PD-1/PD-L1 inhibitors plus anti-angiogenic agents with or without chemotherapy versus PD-1/PD-L1 inhibitors plus chemotherapy as second or later-line treatment for patients with advanced non-small cell lung cancer: A real-world retrospective cohort study. Front Immunol 13:1059995. 10.3389/fimmu.2022.105999536569915 10.3389/fimmu.2022.1059995
21. Wang H Outcome differences between PD-1/PD-L1 inhibitors-based monotherapy and combination treatments in NSCLC with brain metastases Exp Hematol Oncol 2023 12 1 56 10.1186/s40164-023-00412-3 37353805
Wang H et al (2023) Outcome differences between PD-1/PD-L1 inhibitors-based monotherapy and combination treatments in NSCLC with brain metastases. Exp Hematol Oncol 12(1):56. 10.1186/s40164-023-00412-337353805 10.1186/s40164-023-00412-3
22. Rittmeyer A Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial Lancet 2017 389 10066 255 265 10.1016/s0140-6736(16)32517-x 27979383
Rittmeyer A et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389(10066):255–265. 10.1016/s0140-6736(16)32517-x27979383 10.1016/s0140-6736(16)32517-x
23. Paz-Ares L Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer N Engl J Med 2018 379 21 2040 2051 10.1056/NEJMoa1810865 30280635
Paz-Ares L et al (2018) Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 379(21):2040–2051. 10.1056/NEJMoa181086530280635 10.1056/NEJMoa1810865
24. Ye Y Sex-associated molecular differences for cancer immunotherapy Nat Commun 2020 11 1 1779 10.1038/s41467-020-15679-x 32286310
Ye Y et al (2020) Sex-associated molecular differences for cancer immunotherapy. Nat Commun 11(1):1779. 10.1038/s41467-020-15679-x32286310 10.1038/s41467-020-15679-x
25. Sato M Angiogenic inhibitor pre-administration improves the therapeutic effects of immunotherapy Cancer Med 2023 12 8 9760 9773 10.1002/cam4.5696 36808261
Sato M et al (2023) Angiogenic inhibitor pre-administration improves the therapeutic effects of immunotherapy. Cancer Med 12(8):9760–9773. 10.1002/cam4.569636808261 10.1002/cam4.5696
26. Fang L Combination of Immune Checkpoint Inhibitors and Anti-Angiogenic Agents in Brain Metastases From Non-Small Cell Lung Cancer Front Oncol 2021 11 670313 10.3389/fonc.2021.670313 34017689
Fang L et al (2021) Combination of Immune Checkpoint Inhibitors and Anti-Angiogenic Agents in Brain Metastases From Non-Small Cell Lung Cancer. Front Oncol 11:670313. 10.3389/fonc.2021.67031334017689 10.3389/fonc.2021.670313
27. Yi M Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment Mol Cancer 2019 18 1 60 10.1186/s12943-019-0974-6 30925919
Yi M et al (2019) Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer 18(1):60. 10.1186/s12943-019-0974-630925919 10.1186/s12943-019-0974-6
28. Yang Y Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of PD-1 blockade in lung cancer Cancer Immunol Immunother 2020 69 12 2523 2532 10.1007/s00262-020-02641-5 32577817
Yang Y et al (2020) Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of PD-1 blockade in lung cancer. Cancer Immunol Immunother 69(12):2523–2532. 10.1007/s00262-020-02641-532577817 10.1007/s00262-020-02641-5
29. Strickland MR Tumor Immune Microenvironment of Brain Metastases: Toward Unlocking Antitumor Immunity Cancer Discov 2022 12 5 1199 1216 10.1158/2159-8290.Cd-21-0976 35394521
Strickland MR et al (2022) Tumor Immune Microenvironment of Brain Metastases: Toward Unlocking Antitumor Immunity. Cancer Discov 12(5):1199–1216. 10.1158/2159-8290.Cd-21-097635394521 10.1158/2159-8290.Cd-21-0976
30. Zhang Z Radiotherapy combined with immunotherapy: the dawn of cancer treatment Signal Transduct Target Ther 2022 7 1 258 10.1038/s41392-022-01102-y 35906199
Zhang Z et al (2022) Radiotherapy combined with immunotherapy: the dawn of cancer treatment. Signal Transduct Target Ther 7(1):258. 10.1038/s41392-022-01102-y35906199 10.1038/s41392-022-01102-y
31. Shafqat A Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy Front Immunol 2023 14 1200941 10.3389/fimmu.2023.1200941 37520562
Shafqat A et al (2023) Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy. Front Immunol 14:1200941. 10.3389/fimmu.2023.120094137520562 10.3389/fimmu.2023.1200941
32. He Q Zhang C Tang S Li J Ren Q Intracranial radiotherapy with or without immune checkpoint inhibition for brain metastases: a systematic review and meta-analysis Transl Cancer Res. 2020 9 10 5909 5924 10.21037/tcr-20-902 35117204
He Q, Zhang C, Tang S, Li J, Ren Q (2020) Intracranial radiotherapy with or without immune checkpoint inhibition for brain metastases: a systematic review and meta-analysis. Transl Cancer Res. 9(10):5909–5924. 10.21037/tcr-20-90235117204 10.21037/tcr-20-902
