Efficacy and safety of bronchial arterial chemoembolization in combination with tislelizumab for non-small cell lung cancer: a phase II study

doi:10.21203/rs.3.rs-5026061/v1

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Efficacy and safety of bronchial arterial chemoembolization in combination with tislelizumab for non-small cell lung cancer: a phase II study

https://doi.org/10.21203/rs.3.rs-5026061/v1

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This study was designed to assess the efficacy and safety of bronchial arterial chemoembolization (BACE) combined with tislelizumab for stage III-IV non-small cell lung cancer (NSCLC). In a single-arm, phase II study (NCT05058560), stage III-IV NSCLC patients who refused or were ineligible to receive standard treatments were enrolled. Patients received BACE followed by 200 mg tislelizumab every 3 weeks until disease progression, intolerable toxicities, or discontinuation determined by the investigators. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and quality of life (QoL). Thirty patients (median age, 67 years, 24 male) were enrolled in this study between December 2021 and August 2022. The median follow-up was 23 (95% confidence interval [CI], 21.5-24.5) months. At the data cutoff (March 1, 2024), the median PFS was 10.5 (95%CI, 7.8-13.2) months and the median OS was 15.0 (95%CI, 8.2-21.8) months. Of the 30 patients, 1 patient (3.3%) achieved complete response (CR).17 patients (56.7%) showed partial response (PR), 6 (20.0%) had stable disease (SD), and 6 patients (20.0%) had progressive disease (PD). The ORR was 60.0% (18 of 30 patients) and the DCR was 80.0% (24 of 30patients). The expression rate of PD-L1, tumor feeding arteries and previous treatment history were prognostic factors for PFS and OS. No grade 3 or higher treatment-related adverse events (TRAEs) occurred. Common grade 2 TRAEs were nausea, fever, and cough. QoL improved significantly after 1 cycle of treatment compared with baseline, including global quality of life, physical functioning, and emotional functioning. In conclusion, BACE with tislelizumab is a safe, feasible and efective palliative treatment option for stage III-IV NSCLC patients.

Biological sciences/Cancer

Biological sciences/Cancer/Lung cancer

Non-small cell lung cancer (NSCLC)

PD-1

tislelizumab

bronchial arterial chemoembolization (BACE)

Lung cancer is the leading cause of cancer-related deaths globally, with approximately half of deaths in China (1). Non-small cell lung cancer (NSCLC) accounts for 80%-85% (2); most patients are diagnosed with metastatic or advanced disease, making them ineligible for surgical resection, and had a poor prognosis with a 5-year overall survival (OS) of less than 10% (3, 4). Additionally, Some patients may not be able to tolerate standard treatment options such as chemotherapy and radiotherapy due to physical frailty, especially in Asia (5). Bronchial arterial chemoembolization (BACE) has been increasingly applied in patients with unresectable stage III-IV NSCLC, with reduced systemic toxicity and increased intertumoral drug concentration for the promising antitumor effects (6). While the short-term effects of BACE are significant, its long-term survival benefit are uncertain due to the easy occlusion of target vessels, the residual lung cancer cells survive through collateral circulation and then relapse and distant metastasis. On the other hand, PD-1/L1 monotherapy has become a standard therapeutic option for NSCLC due to its long-term survival benefits. The question remains whether the combination of PD-1/L1 inhibitors and BACE could provide both short-term and long-term benefits in the treatment of NSCLC.

As demonstrated in the preclinical settings, necrotic tumor tissue after BACE can significantly increase the tumor-associated antigens and improve the immune microenvironment, triggering an obvious tumor-specific immunological response and enhanced efficacy of BACE plus PD-1/L1 inhibitors (7, 8). Li et al. reported a median progression-free survival (PFS) of 11.0 months with BACE plus PD-1 blockade in 10 stage III-IV NSCLC patients in a retrospective preliminary study (9). Moreover, a retrospective study showed that immunotherapy plus BACE significantly prolonged PFS (7.0 vs. 4.0 months) compared with BACE alone for advanced NSCLC (10). Despite the importance and success of this combination regimen, the evidence guiding current management relates to retrospective studies and limited sample size. Thus, prospective studies with larger sample sizes are needed to confirm the efficacy of this combination regimen.

Tislelizumab is an anti-PD-1 monoclonal antibody engineered with a nullified Fc portion to minimize binding to FcγR on macrophages, thereby abrogating antibody-dependent phagocytosis and partly overcoming resistance to anti-PD-1 therapy (11, 12). In pretreated patients with advanced NSCLC, tislelizumab was found to significantly improve and provide long-term clinical benefits in OS compared with docetaxel, regardless of PD-L1 expression (RATIONALE 303). As for the first-line treatment of NSCLC, the addition of tislelizumab to chemotherapy resulted in significantly improved progression-free survival (PFS) compared with chemotherapy alone in patients with stage IIIB or IV squamous NSCLC in phase III studies (RATIONALE 307, RATIONALE 304) (13–15). Therefore, BACE plus tislelizumab may have better efficacy for stage III-IV NSCLC patients. Taken together, based on the activity profile of tislelizumab and aforementioned rationale, a prospective phase Ⅱ clinical study was designed to assess the efficacy and safety of this combination regimen, which may provide a feasible treatment option for this population.

Study design

This single-center, single-arm, open-label, phase II clinical study was approved by the Institutional Review Board of Zhengzhou university committee on human investigation. The primary goal of this study was to evaluate the efficacy and safety of BACE plus tislelizumab for patients with stage III-IV NSCLC who refused or were ineligible to receive standard treatments. The study was conducted in accordance with the International Conference on Harmonization of Good Clinical Practice guidelines (GCP), the Declaration of Helsinki, and applicable local laws and regulations. Patients were informed of the investigational nature of the study and provided written informed consent before registration. Written informed consent was obtained from all patients. All methods were performed in accordance with the relevant guidelines and regulations. The study adhered to the CONSORT guidelines and was registered with clinicalTrial.gov (clinicaltrials.gov ID: NCT05058560, 31/08/2021).

Patient population

Patients aged 18–75 years with histologically or cytologically confirmed TNM stage Ⅲ (not amenable to curative surgery or radiotherapy) or stage Ⅳ NSCLC (who have failed, refused or ineligible to chemotherapy.) according to the International Association for the Study of Lung Cancer and the American Joint Committee on Classification of Cancer 8th Edition were enrolled in this study. Eligible patients had at least one measurable lesion, adequate organ functions, and predicted life expectancy of at least 3 months. Patients were required to provide fresh or archival tumor tissues for PD-L1 expression in tumor cells.

Patients who had received interventional therapy within 3 months before first administration or previous treatment with immune checkpoint inhibitors (ICIs) were ineligible for this study. Patients with symptomatic central nervous system metastasis, EGFR sensitizing mutation, or ALK gene translocation were excluded from the study. Pregnant or lactating patients, as well as patients with childbearing potential who did not use contraception if sexually active, were also excluded. Detailed eligibility criteria were listed in Supplementary Table S1.

Procedures

BACE

The patient was placed in the supine position, and the modified Seldinger puncture technique was performed under local anesthesia. A 5-F Cobra catheter was then introduced through a 5-F vascular sheath, and then angiography of the bronchial arteries were performed to find how many bronchial arteries were involved in supplying blood to lung cancer. If the bronchial arteries were not involved or partially involved in the cancer’ arterial blood-supply, special angiography of intercostal artery, internal thoracic artery, phrenic artery, internal mammary artery, proper esophageal artery, and thyrocervical trunk artery was performed to determine the blood supply to the tumors. Meanwhile, the interventional doctors assess whether the tumor-feeding arteries supply esophagus or spinal cord. If there was no branch, the feeding artery to the tumor was superselected and perfused successively with cisplatin 75 mg/m² plus gemcitabine 1000 mg/m² for 1 hour (squamous carcinoma) or cisplatin 75 mg/m² plus pemetrexed 500 mg/m² for an hour (adenocarcinoma). After perfusion chemotherapy, the feeding artery of the tumor was embolized with 350–560 µm PVA particles. Embolization endpoint was the absence of tumor staining and near complete blood flow stasis. All the procedures were finished by two interventional doctors with ten years of work experience.

Postoperative antiemetic, analgesia, hydration, and other symptomatic and supportive treatments were given. The BACE was repeated on demand every 6 weeks for patients who were assessed stable disease (SD), up to a total of 3 times.

Tislelizumab

Patients received intravenous tislelizumab at 200 mg 3–5 days following the first BACE in a 21-day cycle. Treatment continued until completion of 1-year tislelizumab, disease progression, unacceptable toxicity, withdrawal of consent, death, or other events requiring discontinuation of treatment, whichever occurred first.

Assessments

Tumor assessment was performed using enhanced computed tomography (CT) by investigators at baseline and every 6 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (16) criteria until disease progression, withdrawal of consent, or death. The imaging technique should be the same for the same patient. Clinical safety was assessed by adverse events (AEs), which were monitored by the laboratory, hematological, and biochemical assessments, vital signs, laboratory abnormalities, and physical examination. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

Quality of life (QoL) was assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire after 1-cycle treatment (6 weeks after the first BACE). The QLQ-C30 showed self-rated health and social, physical, and emotional functioning based on 30 items. The items were divided into five functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), three symptom scales (fatigue, nausea and vomiting, and pain), and six single-item questions (assessing the severity of dyspnea, insomnia, loss of appetite, constipation, diarrhea, and financial difficulties).

Endpoints

The primary endpoint was PFS (defined as the time from the start of the BACE treatment to disease progression or death from any reason, whichever occurred first) and OS (defined as the time from the start of the BACE treatment to any-cause death). The secondary endpoints were objective response rate (ORR, calculated as the proportion of patients achieving CR [complete response] and PR [partial response]), disease control rate (DCR, referred to as the proportion of patients with CR, PR, and SD), safety, and QoL.

Statistical analysis

The sample size of 30 patients was determined based on the exploratory nature of this study. Efficacy was analyzed in the full analysis set (FAS), which included all participants who received at least one dose of the study treatment. Safety analysis was performed in the safety analysis set (SS), which comprised the FAS population with available safety records.

Patient characteristics, safety outcomes, and tumor responses were summarized descriptively. Descriptive measures for continuous variables were interquartile range (IQR) or range, and for categorical variables were frequencies (percentage [%]). Continuous data were compared by T-test, and categorical data were compared by chi-square or Fisher's exact test. QoL scores were standardized transformed, and the results were analyzed by treatment group with descriptive statistics and Wilcoxon test. PFS, ORR, DCR were estimated using the Kaplan-Meier method. HR and associated 95% confidence intervals [CI] were assessed using a stratified Cox proportional hazards model. P < 0.05 was considered statistically significant. All data were analyzed using SPSS 26.0 statistical software (IBM Corporation, Armonk, NY, USA).

Patient characteristics

A total of 36 patients from the first affiliated hospital of zhengzhou university were screened between November 2021 and August 2022. Six patients were excluded from study due to screening failure; thus 30 were enrolled and received the treatment and were included in the FAS and SS (Fig. 1). At the data cutoff (March 1, 2024), 13 patients had discontinued treatment because of death and 6 patients had discontinued treatment because of lose to follow-up.

The baseline characteristics of the 30 patients are presented in Table 1. The median age for all patients was 67.0 years (range, 47–80 years); the majority were male (80%), and 21 (70%) patients had squamous cell carcinoma. Five (16.6%) patients had an ECOG performance status of 2. Half of the patients had TNM stage Ⅲ disease, and PD-L1 expression in tumor cells ≥ 50% was observed in 12 (40%) cases. Twelve (40%) patients had multiple arterial supplies for their tumors. Detailed embolized vessels were listed in Supplementary Table S2. Fifteen (50%) patients had metastases, with 7 (23.3%) had intrapulmonary metastases, 4 (13.3%) patients had liver metastases, and 4 (13.3%) had bone metastases. Most patients (76.7%) had complicated disease at baseline, with pneumonia being common (8/30, 26.7%). Thirteen (43.3%) patients had a history of previous treatment.

Table 1

Baseline Characteristics of study patients.
Characteristics	Patients (n = 30)
Sex
Male	24 (80.0%)
Female	6 (20.0%)
Age, median (range)-years	67.0 (47–80)
≤ 60	10 (33.3%)
>60	20 (66.7%)
ECOG PS
0	8 (26.7%)
1	17 (56.7%)
2	5 (16.7%)
Histology
Adenocarcinomas	9 (30.0%)
Squamous	21 (70.0%)
TNM stage
III	15 (50.0%)
Ⅳ	15 (50.0%)
PD-L1 expression in tumor cells
< 1%	6 (20.0%)
1%-49%	12 (40.0%)
≥ 50%	12 (40.0%)
Tumor blood supply
Multi	12 (40.0%)
Single	18 (60.0%)
Metastatic sites
Intrapulmonary	7 (23.3%)
Liver	4 (13.3%)
Bone	4 (13.3%)
Complication
Bronchial stenosis	5 (16.7%)
Superior vena cava syndrome	2 (6.7%)
Pneumonia	8 (26.7%)
Pulmonary heart disease	4 (13.3%)
Hemoptysis	4 (13.3%)
Previous treatment history
Yes (chemotherapy;radiotherapy)	13 (43.3%)
No	17 (56.7%)
Note: Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; TNM, Tumor Node Metastasis; PD-L1, programmed cell death ligand-1.

Treatment

Twenty (66.7%) patients had received 1–2 sessions of BACE, and 10 (33.3%) had received 3. Twelve (40%) patients received ≤ 10 cycles of tislelizumab and 18 (60%) patients received > 10 cycles.

Efficacy

At the cutoff date, the median follow-up time was 23 (95%CI, 21.5–24.5) months. The median PFS was 10.5 (95%CI, 7.8–13.2, Fig. 2) months, with 6-, 12- and 18-month PFS rates of 76.7% (95%CI, 57.7%-90.1%), 36.7% (95%CI, 19.9%-56.1%), 33.3% (95%CI, 17.3%-52.8%)respectively. The median OS was 15.0 (95%CI, 8.2–21.8, Fig. 3) months, with 6-, 12- and 18-month OS rates of 80.0% (95%CI, 61.4%-92.3%), 56.7% (95%CI, 37.4%-74.5%), 43.3% (95%CI, 25.5%-62.6%) respectively.

1 patient (3.3%) achieved CR. 17 patients (56.7%) showed a PR, 6 (20.0%) had SD, and 6 patients (20.0%) had PD. The ORR was 60.0% (18 of 30 patients) and the DCR was 80.0% (24 of 30patients) (Table 2 and Fig. 4). An example of the best response of CR observed in a patient with advanced lung squamous carcinoma is shown in Fig. 5.

Table 2

Confirmed best overall responses
Response	No.(%)
CR	1 (3.3%)
PR	17(56.7%)
SD	6 (20.0%)
PD	6 (20.0%)
ORR	18 (60.0%, 40.6%-77.3%)
DCR	24 (80.0%, 61.4%-92.3%)
Note: Data are expressed as n (%), n (%; 95%CI), or median (95%CI).
Objective response rate was defined as complete response and partial response.
Disease control rate was defined as complete response, partial response, or stable disease.

Statistically significant longer PFS was found in patients with PD-L1 expression ≥ 50% (12 months, HR = 0.29, P = 0.039), single tumor blood supply (12 months, HR = 0.35, P = 0.028) and no history of previous treatment (12 months, HR = 0.31, P = 0.014). There was no statistical difference in PFS across other subgroups. (Table 3).

Table 3

Univariate analysis of prognostic factors associated with progression-free survival.
Characteristics	No. of patients	Median PFS (m, 95%CI)	HR (95%CI)	P value
Sex
Male	24 (80.0%)	12.0 (9.2–14.8)	1.00 (Ref.)
Female	6 (20.0%)	9.0 (5.4–12.6)	1.15 (0.38–3.48)	0.808
Age(years)
≤ 60	10 (33.3%)	9.0 (2.0–16.0)	1.00 (Ref.)
>60	20 (66.7%)	10.5 (7.9–13.1)	0.99 (0.38–2.62)	0.989
ECOG PS
0	8 (26.7%)	12.0 (NE-NE)	1.00 (Ref.)
1	17 (56.7%)	10.5 (7.5–13.5)	1.66 (0.53–5.24)	0.387
2	5 (16.7%)	9.0 (5.8–12.2)	2.06 (0.51–8.30)	0.308
Histology
Adenocarcinomas	9 (30.0%)	10.5 (6.1–14.9)	1.00 (Ref.)
Squamous	21 (70.0%)	12.0 (8.7–15.3)	0.91 (0.35–2.40)	0.849
TNM stage
Ⅲ	15 (50.0%)	12.0 (8.3–15.7)	1.00 (Ref.)
Ⅳ	15 (50.0%)	10.5 (6.2–14.8)	1.26 (0.51–3.11)	0.614
PD-L1% expression in tumor cells
< 1%	6 (20.0%)	3.0 (0-7.8)	1.00 (Ref.)
1–49%	12 (40.0%)	9.0 (6.5–11.5)	0.44 (0.14–1.40)	0.165
≥50%	12 (40.0%)	12.0 (10.7–13.3)	0.29 (0.09–0.94)	0.039
Tumor blood supply
Multi	12 (40.0%)	3.0 (0-10.6)	1.00 (Ref.)
Single	18 (60.0%)	12.0 (10.5–13.6)	0.35 (0.14–0.89)	0.028
Presence of complications
Yes	23 (76.7%)	9.0 (5.5–12.5)	1.00 (Ref.)
No	7 (23.3%)	12.0 (10.1–13.9)	0.66 (0.22–1.99)	0.659
Previous treatment history
Yes (chemotherapy;radiotherapy)	13 (43.3%)	6.0 (1.8–10.2)	1.00 (Ref.)
No	17 (56.7%)	12.0 (NE-NE)	0.31 (0.12–0.79)	0.014
Abbreviations: PFS, progression-free survival; HR, hazard ratio; ECOG PS, Eastern Cooperative Oncology Group performance status; TNM, Tumor Node Metastasis; PD-L1, programmed cell death ligand-1; NE, not evaluable.

Statistically significant longer OS was found in patients with PD-L1 expression ≥ 50% (20 months, HR = 0.33, P = 0.064), single tumor blood supply (20 months, HR = 0.39, P = 0.044) and no history of previous treatment (20 months, HR = 0.36, P = 0.028).. There was no statistical difference in OS across other subgroups. (Table 4).

Table 4

Univariate analysis of prognostic factors associated with overall survival .
Characteristics	No. of patients	Median OS (m, 95%CI)	HR (95%CI)	P value
Sex
Male	24 (80.0%)	18.0 (10.7–25.3)	1.00 (Ref.)
Female	6 (20.0%)	12.0 (4.8–19.2)	1.09 (0.36–3.30)	0.875
Age(years)
≤ 60	10 (33.3%)	12.0 (0.0-24.4)	1.00 (Ref.)
>60	20 (66.7%)	15.0 (8.4–21.6)	0.99 (0.37–2.59)	0.976
ECOG PS
0	8 (26.7%)	20.0 (NE-NE)	1.00 (Ref.)
1	17 (56.7%)	15.0 (10.2–19.8)	1.83 (0.58–5.81)	0.304
2	5 (16.7%)	12.0 (5.6–18.4)	2.06 (0.51–8.28)	0.309
Histology
Adenocarcinomas	9 (30.0%)	15.0 (6.2–23.8)	1.00 (Ref.)
Squamous	21 (70.0%)	18.0 (9.6–26.4)	0.96 (0.37–2.53)	0.937
TNM stage
Ⅲ	15 (50.0%)	18.0 (8.6–27.4)	1.00 (Ref.)
Ⅳ	15 (50.0%)	15.0 (6.7–23.3)	1.24 (0.50–3.06)	0.639
PD-L1% expression in tumor cells
< 1%	6 (20.0%)	6.0 (0.6–11.4)	1.00 (Ref.)
1–49%	12 (40.0%)	12.0 (8.7–15.3)	0.51 (0.16–1.60)	0.246
≥50%	12 (40.0%)	20.0 (17.8–22.2)	0.33 (0.10–1.07)	0.064
Tumor blood supply
Multi	12 (40.0%)	6.0 (1.9–10.1)	1.00 (Ref.)
Single	18 (60.0%)	20.0 (17.4–22.6)	0.39 (0.16–0.97)	0.044
Presence of complications
Yes	23 (76.7%)	12.0 (6.0–18.0)	1.00 (Ref.)
No	7 (23.3%)	20.0 (13.6–26.4)	0.64 (0.21–1.95)	0.437
Previous treatment history
Yes (chemotherapy;radiotherapy)	13 (43.3%)	9.0 (5.0–13.0)	1.00 (Ref.)
No	17 (56.7%)	20.0 (17.5–22.5)	0.36 (0.14–0.90)	0.028
Abbreviations: OS, overall survival; HR, hazard ratio; ECOG PS, Eastern Cooperative Oncology Group performance status; TNM, Tumor Node Metastasis; PD-L1, programmed cell death ligand-1.

Quality of Life

QoL with QLQ-C30 questionnaire was administered in the treatment population (Table 5). According to the QLQ-C30 questionnaire, global quality of life, physical functioning, and emotional functioning after one-cycle treatment were significantly improved compared with baseline. Besides, fatigue, nausea and vomiting, dyspnea, and insomnia were reduced after 1 cycle of treatment (P < 0.05).

Table 5

Quality of life assessment with QLQ-C30.
	Baseline	one-cycle treatment	P-value
Functional
Global quality of life	58.3 (50.0-66.7)	66.7 (66.7–83.3)	< 0.001
Physical functioning	73.3 (58.3–81.7)	80.0 (66.7–88.4)	0.046
Role functioning	83.3 (79.2–100.0)	83.3 (83.3–100.0)	0.213
Emotional functioning	83.3 (75.0-91.7)	91.7 (83.3–100.0)	0.045
Cognitive functioning	83.3 (66.7–100.0)	83.3 (83.3–100.0)	0.168
Social functioning	83.3 (66.7–100.0)	83.3 (79.2–100.0)	0.209
Symptom
Fatigue	33.3 (22.2–55.5)	22.2 (11.1–33.3)	0.003
Nausea and vomiting	0 (0-16.7)	0 (0–0)	0.005
Pain	16.7 (0-16.7)	0 (0-16.7)	0.306
Dyspnea	66.7 (33.3–66.7)	0 (0-33.3)	< 0.001
Insomnia	33.3 (33.3–66.7)	0 (0-33.3)	< 0.001
Appetite loss	0 (0-33.3)	0 (0–0)	0.375
Constipation	0 (0-33.3)	0 (0–0)	0.545
Diarrhea	0 (0-33.3)	0 (0–0)	0.545
Financial difficulties	0 (0-33.3)	0 (0–0)	0.247
Note: Values given as median (IQR).

Safety and tolerability

TRAEs in the safety population are summarized in Table 6. All patients experienced at least one AE of any grade, with no grade 3 or worse events being reported. Common grade 1–2 events were nausea (6/30, 20%), fever (5/30, 16.7%), leukopenia (3/30, 10%), rash (3/30, 10%), cough (3/30, 10%), hemoglobin decreased (2/30, 6.7%), thrombocytopenia (2/30, 6.7%), fatigue (2/30, 6.7%). No serious TRAEs or treatment-related deaths were observed.

Table 6

Treatment-related adverse events (TRAEs).
Adverse reactions n (%)	Grade 1 n(%)	Grade 2 n(%)	Grade 3 and above n(%)
BACE
nausea	4 (13.3%)	2 (6.7%)	0
fever	3 (10.0%)	2 (6.7%)	0
hemoglobin decrease	2 (6.7%)	0	0
leukopenia	2 (6.7%)	1 (3.3%)	0
thrombocytopenia	2 (6.7%)	0	0
Tislelizumab
fatigue	2 (6.7%)	0	0
rash	2 (6.7%)	1 (3.3%)	0
cough	1 (3.3%)	2 (6.7%)	0

BACE plus tislelizumab demonstrated a favorable PFS of 10.5 months, improved quality of life, and acceptable safety profiles, potentially representing a novel promising treatment option for stage III-IV NSCLC. Our findings may provide new clinical insights regarding the feasibility of BACE plus tislelizumab in stage III-IV NSCLC.

BACE has been reported as an attractive alternative for the management of NSCLC, as it allows for the direct delivery of high amounts of chemotherapy drug to the tumor site with a lower risk of systemic toxicity, and induce ischemic necrosis in the tumor to improve clinical efficacy, especially for chemotherapy-ineligible/rejected patients (17–19). The short-term effect of BACE is significant, with an ORR of 50% at 2 months (compared to an ORR of about 20% for chemotherapy)(20, 21). However, the long-term survival benefit of BACE/DEB-BACE is uncertain, with a median PFS of 6.5-8 months (20, 35–36), due to the easy occlusion of target vessels, residual lung cancer cells surviving through collateral circulation and subsequent relapse and distant metastasis. On the other hand, It has been confirmed that PD-1/L1 monotherapy offers a long-term survival advantage as a promising therapeutic option for advanced NSCLC, with a 5-year OS rate of 20–30% (22). Our study sought to determine whether the combination of PD-1 inhibitors and BACE could provide both short-term and long-term benefits in the treatment of NSCLC.

In conclusion, numerically more favorable ORR, PFS and OS were observed in our study. Median PFS (10.5 > 8.0 months) was significantly higher than that of BACE/DEB-BACE alone as reported in previous studies (20, 35–36). The median OS of BACE/DEB-BACE alone in the treatment of NSCLC reported in previous major studies were 11,11.5, and 16.5 months, respectively. Our study showed that the median OS of BACE combined with tislelizumab in the treatment of NSCLC was 15.0 months, which was slightly lower than the 16.5 months in one of the studies (20), which retrospectively analyzed only six patients, five of whom had no prior treatment. In our study, 43% (13/30) of the patients had a previous treatment history, and stratified analysis showed that the mOS of patients without previous treatment history was 20.0 months. Therefore, our study showed that BACE combined with tislelizumab improved the long-term survival of NSCLC patients compared with BACE/DEB-BACE, including PFS and OS. This means that BACE combined with tislelizumab retains the advantage of good short-term tumor shrinkage effect of BACE/DEB-BACE in the treatment of NSCLC, and the issue of rapid recurrence is improved. In patients with previously treated locally advanced or metastatic NSCLC, combination of BACE with tislelizumab showed improved ORR (60% vs 22.6%), median PFS (6.0 > 4.2 months) and comparable median OS (15.0 vs 16.9 months) comparing with tislelizumab(14). As first-line treatment for locally advanced or metastatic NSCLC, the combination of BACE with tislelizumab showed improved median PFS in both nonsquamous NSCLC (12 > 9.8months) and squamous NSCLC(12 > 9.6/7.7 months), and comparable median OS in both nonsquamous NSCLC (20 vs 21.9months) and squamous NSCLC༈20 vs 23.3/26.1 months) (13, 15). The above data are encouraging given that more patients with a PS score of 2 and with complication were included in our study. This is possibly reflects the better tolerability of BACE compared to systemic chemotherapy and that the addition of tislelizumab does not negatively impact tolerability (7, 8).

In addition, quality of life (QoL) is considered as important as survival in patients with advanced NSCLC (25). In our study, QoL questionnaires showed significant improvements (P < 0.01, Table 5) in overall quality of life, physical function and emotional function after treatment. Furthermore, we observed that patients receiving the combined treatment had decreased scores on symptom scales (fatigue, nausea and vomiting, dyspnea, and insomnia). The possible reasons might be that BACE increased therapeutic efficacy, resulting in better clinical presentation for patients receiving BACE, which was reflected in the improvement of functioning in advanced NSCLC patients. (20, 21) Certainly, further studies with a larger sample size are necessary to make a definitive conclusion regarding the efficacy of the combination regimen in this population.

Previous studies have shown that a PD-L1 expression proportion score of at least 50% was associated with a higher response rate and longer PFS and OS compared to a proportion score of less than 50% in both previously untreated and treated patients (26). The greatest relative benefit was observed in the subgroup with a PD-L1 expression of 50% or greater in our study, a finding that was consistent with the results of previous studies of PD-L1 inhibition in advanced NSCLC (26–28).

The combination of BACE plus tislelizumab was clinically safe for patients with advanced NSCLC. All of the TRAEs were grade 1–2 and no serious TRAEs or treatment-related deaths were observed. Common events, including nausea, fever, leukopenia, rash, and cough, were usually manageable and disappeared rapidly after supportive treatment. In our study, BACE-related AEs were mainly chemoembolization-related syndromes and myelosuppression, which was consistent with previous studies (29). The tislelizumab-related AEs in our study were similar to those observed with tislelizumab alone (23), indicating that combining tislelizumab with BACE did not increase the toxic effects. Furthermore, no new safety signals were identified.

Certain limitations should be acknowledged. First, this was a single-arm, non-randomized, phase II study with a relatively limited sample size from only one institution, lacking comparison with other existing regimens. Based on the results of this pilot study a multicenter randomized controlled trial to determine the efficacy and safety of PD-1 antibody in addition to BACE in stage III-IV NSCLC patients is ongoing (NCT05605613). Additionally, by the end of the study duration, only one patient achieved CR; 12 patients (40%) could not complete embolization due to multiple arterial supplies, including bronchial arteries and collateral circulation arteries (intercostal artery, spinal artery and proper esophageal artery adjacent to the tumor) involved in the vascularization of NSCLC tumors (30, 31). This is attributed to the potential occurrence of severe complications such as intercostal nerve injury, esophageal injury, and spinal artery embolism following collateral circulation embolization (20, 32–34).

In conclusion, the combination of BACE and tislelizumab demonstrated feasible survival outcomes and acceptable safety profiles for stage III-IV NSCLC, potentially representing a novel treatment option for this patient population in the clinical setting. A multicenter randomized controlled trial to determine the efficacy and safety of PD-1 antibody in addition to BACE in stage III-IV NSCLC patients is ongoing (NCT05605613)

BACE: Bronchial arterial chemoembolization; NSCLC: non-small cell lung cancer; PFS: progression-free survival; OS: overall survival; ORR: objective response rate; DCR: disease control rate; QoL: quality of life; CI: confidence interval; TRAEs: treatment-related adverse events; GCP: Good Clinical Practice guidelines; ICIs: immune checkpoint inhibitors; SD: stable disease; CT: computed tomography

RECIST: Response Evaluation Criteria in Solid Tumors; AEs: adverse events; CTCAE: Common Terminology Criteria for Adverse Events; CR: complete response; PR: partial response; DCR: disease control rate; FAS: full analysis set; SS: safety analysis set; IQR: interquartile range

Competing interests

The authors declare no competing interests.

Funding

This work was supported by the National Natural Science Foundation of China (U2004119); The Co-operation Research Plan of Medical Science and Technology in Henan Province (SBGJ202102100) and the Natural Science Foundation of Henan Province (202300410361).

Author Contribution

Chao Liang，Daqian Han：Writing - original draft，Conceptualization; Hao Li：Data curation; Manzhou Wang：Formal analysis; Donglin Kuang：Investigation; Pengfei Chen：Resources; Huibin Lu：Supervision; Pengfei Jiao：Validation; Jianzhuang Ren：Visualization; Xinwei Han：Funding acquisition; Fang li：Writing - review & editing; Xuhua Duan：Writing - review & editing，Conceptualization

Acknowledgement

The authors would like to thank physicians and nurses at the First Affiliated Hospital of Zhengzhou University for their assistance and support for this project. We thank Minmin Song from Medical Affairs, BeiGene, Ltd for her academic assistance in this study.

Data Availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

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Efficacy and safety of bronchial arterial chemoembolization in combination with tislelizumab for non-small cell lung cancer: a phase II study

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Introduction

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Patient population

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BACE

Tislelizumab

Assessments

Endpoints

Statistical analysis

Results

Patient characteristics

Treatment

Efficacy

Quality of Life

Safety and tolerability

Discussion

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Competing interests

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Author Contribution

Acknowledgement

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