Efficacy and safety of albumin-bound paclitaxel combined with anlotinib and immunotherapy in advanced non-small cell lung cancer with liver metastases: a retrospective study

Abstract

Objective

To investigate the efficacy and safety of albumin-bound paclitaxel (nab-paclitaxel) combined with anlotinib and immunotherapy as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC) and liver metastases.

Methods

This single-center, retrospective study enrolled patients with advanced NSCLC and liver metastases who experienced disease progression after first-line first‑line chemoimmunotherapy and subsequently received second-line treatment with nab-paclitaxel plus anlotinib and a PD-1/PD-L1 inhibitor between January 2021 and April 2024. The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and adverse events (AEs).

Results

A total of 32 patients were included in the analysis. The combination regimen demonstrated notable antitumor activity, with an ORR of 25.00% (8/32) and a DCR of 53.13% (17/32). The median PFS was 4.0 months (95% CI: 4.05–4.64), and the median OS was 9.0 months (95% CI: 8.38–9.49). Subgroup analysis indicated that patients who experienced treatment-related AEs such as hypertension, proteinuria, or hand-foot syndrome achieved better therapeutic outcomes than those who did not. Exploratory biomarker analysis suggested that the regimen may exert synergistic antitumor effects by modulating immune cell profiles and alleviating immunosuppression. The safety profile was generally manageable, with most AEs being mild to moderate in severity, indicating favorable tolerability.

Conclusion

The combination of nab-paclitaxel, anlotinib, and immunotherapy appears to be a feasible and effective second-line treatment option for advanced NSCLC patients with liver metastases, offering comparable efficacy with acceptable toxicity. These findings warrant validation in prospective, randomized controlled trials.

Background

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide, with a significant proportion of patients presenting with advanced disease at diagnosis [1]. Among the various complications associated with advanced NSCLC, liver metastasis represents a critical challenge, as it is linked to poor prognosis and limited treatment options [2, 3].

Despite the fact that drug treatments, whether chemotherapy, immunotherapy, or anti-tumor angiogenesis therapy, have certain efficacy, single treatment modalities not only have limited effects but are also prone to resistance. Furthermore, previous treatments have mostly focused on the general population, leaving a lack of evidence-based medical support for certain special groups, such as those with liver metastases or brain metastases [4]. This underscores the urgent need to find effective treatment modalities for patients with advanced NSCLC and liver metastases [5].

Considering the above, it is likely that the treatment modalities that can improve outcomes for this patient group are still combination therapies [6]. This may be one of the main reasons why multi-drug combinations are becoming the trend in current cancer treatment. In selecting specific drug combinations, it is essential to consider not only the mechanisms of action of the drugs but also factors such as efficacy, side effects, and cost-effectiveness [7]. From a clinical application perspective, the combination of albumin-bound paclitaxel, anlotinib, and immunotherapy may be a promising drug combination. Our previous studies have shown that this three-drug combination can significantly enhance the efficacy of second-line treatment for advanced NSCLC, and it has a high safety profile [8]. We also observed that this combination is effective for patients with liver metastases. Although the number of liver metastasis patients included in the study was less than 20%, these preliminary results indicate that the three-drug combination may also improve outcomes for patients with liver metastases [9].

Although immunotherapy rechallenge-defined as the continued use of immunotherapy following disease progression on first-line chemoimmunotherapy is generally considered unfavorable in principle [10], it is undeniable that a subset of patients may still derive clinical benefit from such an approach, particularly when multidrug combination strategies are employed [11, 12]. The underlying mechanism may involve the incorporation of immunomodulatory chemotherapeutic agents (e.g., nab-paclitaxel [13]) and anti-angiogenic drugs (e.g., anlotinib [14]), which could remodel the tumor microenvironment and reverse immunosuppression, thereby restoring or enhancing the sensitivity to subsequent immunotherapy. This provides a theoretical rationale for continuing PD-1/L1 inhibitor‑based combinations even after first‑line treatment failure [15, 16]. Grounded in the concepts of immunotherapy rechallenge and synergistic potentiation, this study aims to evaluate the value of such a regimen in a specific hard‑to‑treat population — patients with liver‑metastatic NSCLC who have progressed on first‑line chemoimmunotherapy — thereby refining the research objective and offering a more effective therapeutic option for this patient population.

Materials and methods

This study is a retrospective cohort study aimed at evaluating the efficacy and safety of nab-paclitaxel (nab-PTX) combined with anlotinib and immunotherapy in second-line treatment of advanced non-small cell lung cancer (NSCLC) with liver metastasis. The study population consisted of patients diagnosed with advanced NSCLC with liver metastasis who were treated at our hospital between January 2021 and April 2024. All patients were second-line treatment candidates, meaning they had failed to respond adequately to first-line PD-1/L1 plus chemotherapy or targeted therapy and had no contraindications to immunotherapy. The study was approved by the Ethics Committee of Hubei Cancer Hospital Affiliated with Tongji Medical College, which waived the requirement for informed consent due to the retrospective nature of the study. Patient confidentiality was maintained throughout the research process, adhering to established ethical guidelines.

Inclusion and exclusion criteria

Inclusion criteria: ① Diagnosis of advanced NSCLC with liver metastasis, and previous treatment with at least one line of standard first-line therapy; ② Presence of measurable lesions that could be evaluated by imaging; ③ Expected survival ≥ 12 weeks; ④ Normal organ function and able to tolerate chemotherapy, targeted therapy, and immunotherapy. Exclusion criteria: ① Presence of other malignancies or immunodeficiency disorders; ② Recent receipt of other experimental treatments; ③ Severe comorbidities or known allergies to any study drug.

Gene or biomarker detection

Most of the patients had undergone CT-guided needle aspiration for diagnosis. Once the diagnosis was confirmed pathologically, part of the sample was used for multiple gene detection, such as EGFR, ALK, C-Met, and K-RAS, the detection was performed using standard assay. The detection of PD-L1 was conducted according to the standard assay (Dako 22 C-3 antibody), and the cutoff value for PD-L1 was set as 1%.

Lymph cell subpopulation analysis by FCAM

Samples of ethylenediamine tetra acetic acid (EDTA) anticoagulated peripheral blood (2 mL) were collected from patients with advanced NSCLC before initial treatment and a second sample was collected after subsequent treatment cycles. All samples were tested within 6 h of being obtained. Briefly, CD3⁺/CD4⁺/CD8⁺ T-cell, CD19⁺ B-cell, and CD16⁺CD56⁺ natural killer (NK)-cell counts (cells/µL) were measured by multiple-color flow cytometry with human monoclonal anti-CD3-fluorescein isothiocyanate (FITC), anti-CD4-phycoerythrin (PE), anti-CD8-allophycocyanin (APC), anti-CD19-PE, anti-CD16-APC, and anti-CD56-PE antibodies [BD Multitest; Becton, Dickinson, and Co. (BD) Biosciences, Franklin Lakes, NJ, USA] according to the manufacturer’s instructions. The cells were analyzed on a BD FACS Canto II flow cytometry system (BD Biosciences).

Treatment protocol

All participants had received one or more lines of treatment. Upon disease progression or development of drug resistance confirmed by clinical assessment, a modified regimen comprising a triple-drug combination of PD-1/L1 inhibitors, nab- paclitaxel, and anlotinib was administered, with adjustments made to the dosage. The dosage of nab-paclitaxel ranged from 100 to 200 mg/m² every 3 weeks. The dosage for PD-1/L1 inhibitors (such as pembrolizumab, nivolumab, atezolizumab, camrelizumab, tislelizumab, sintilimab, among others) was administered as per the instructions. Anlotinib was orally administered (12 mg) for two consecutive weeks, followed by a one-week break, with each cycle lasting 3 weeks, The dose can be adjusted to 10 mg or even 8 mg based on the patient’s tolerance during treatment. Treatment was continued until disease progression or the onset of intolerable toxicities. In the treatment sequence, PD-1/L1 inhibitors were administered intravenously first, followed by nab-paclitaxel.

Efficacy and safety assessment

Efficacy outcomes were measured based on overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, with imaging performed at baseline and every two cycles thereafter. PFS was defined as the time from the initiation of treatment to disease progression or death, while OS was calculated from the start of treatment to the date of death from any cause. Adverse events (AEs) were recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The severity and type of AEs were systematically noted throughout the treatment period. Laboratory tests, including complete blood counts and liver function tests, were routinely conducted to monitor for potential toxicities related to the treatment regimen.

Statistical analysis

Descriptive statistics were employed to summarize patient demographics and clinical characteristics. Continuous variables were expressed as median and range, while categorical variables were presented as frequencies and percentages. Survival analyses were conducted using the Kaplan-Meier method, and PFS and OS were compared using the log-rank test. A p-value of < 0.05 was considered statistically significant. All statistical analyses were conducted using [specify software, SPSS, 13.0].

Results

Patients’ characters

In this retrospective study, we analyzed the clinical outcomes of patients with advanced NSCLC and liver metastases who received a combination therapy of nab-ptx, anlotinib, and immunotherapy. A total of 32 patients were included, with a median age of 62 years, and 20 (62.50%) were male. Most patients 26(81.25%) had a performance status of 0–1 according to the Eastern Cooperative Oncology Group (ECOG) criteria. From the perspective of pathological types, the proportions of patients with adenocarcinoma and squamous carcinoma were 23(71.88%) and 9(28.13%), respectively. Regarding metastatic sites, the proportions of patients with brain metastasis, bone metastasis, and malignant pleural effusion were 10(31.25%), 11(34.38%), and 8(25.00%), respectively. In terms of liver metastasis, the proportions of patients with single and multiple metastases were 7(21.88%) and 25(78.13%), respectively. In terms of systemic therapy, the majority of patients were diagnosed as negative for driver genes and initially received PD-1/L1 plus platinum-based doublet chemotherapy (The proportions of patients receiving the PD-1/L1 plus PC regimen, PD-1/L1 plus TC regimen, and PD-1/L1 plus GC regimen were 21 (65.63%), 3 (9.38%), and 6 (18.74%), respectively. Regarding previous treatment efficacy, the proportions of patients with CR/PR, SD/PD, and those with unassessable efficacy were 15 (46.88%), 16 (49.99%), and 1 (3.13%), respectively. Additionally, when categorized by the time from the last treatment to the start of the next treatment (interval since last IO), the proportions of patients who received treatment for more than 6 months, 3–6 months, and within 3 months were 20 (62.50%), 9 (28.12%), and 3 (9.38%), respectively. Based on genetic testing results, only two patients were positive for driver genes, both with EGFR sensitive mutations (one with EGFR Del19 and one with EGFR L858R). Both patients experienced disease progression after receiving first-line EGFR-TKI treatment.For the expression levels of PD-L1, the proportions of patients with PD-L1 < 1%, 1% ≤ PD-L1 < 49%, and PD-L1 ≥ 50% were 18(56.25%), 10(31.25%), and 4(12.50%), respectively. In terms of staging, the proportions of patients in stages IVA, IVB, and IVC were 9(28.13%), 12(37.50%), and 11(34.38%), respectively (See Table 1).

Table 1.

Baseline clinical characteristics of the study cohort

Characteristics	No. of patients (%)
Age
Years	62
Range	47–75
Gender
Male	20(62.50%)
Female	12(37.50%)
Smoking history
Never smoker	10(31.25%)
Former smoker	22(68.75%)
Histology
Adenocarcinoma	23(71.88%)
Squamous carcinoma	9(28.13%)
ECOG score
0–1	26(81.25%)
≥ 2	6(18.75%)
Previous Radiotherapy
Yes	11(34.38%)
No	21(65.63%)
Brain metastasis
Yes	10(31.25%)
No	22(68.75%)
Liver metastasis
Single	7(21.88%)
Multiple	25(78.13%)
Plural effusion
Yes	8(25.00%)
No	24(75.00%)
Bone metastasis
Yes	11(34.38%)
No	21(65.63%)
PD-L1 expression
< 1%	18(56.25%)
1 < < 49%	10(31.25%)
>>50%	4(12.50%)
Prior IO status
IO-naïve	3(9.38%)
IO-pretreated	29(90.62%)
PD-1/L1 inhibitors
Pembrolizumab	6(18.75%)
Atezolizumab	3(9.38%)
Camrelizumab	10(31.25%)
Tislelizumab	8(25.00%)
Sintilimab	5(15.62%)
IO treatment mode
Single PD-1/L1	2(6.25%)
PD-1/L1 plus PC regimen	21(65.63%)
PD-1/L1 plus TC regimen	3(9.38%)
PD-1/L1 plus GC regimen	6(18.74%)
Best response to last antiPD-(L)1–containing regimen, f No. (%)
Responder (CR/PR)	15(46.88%)
Nonresponder (SD/PD)	16(49.99%)
Not available	1(3.13%)
Interval since last IO
>>6 m	20(62.50%)
3 < < 6 m	9(28.12%)
< 3 m	3(9.38%)
Previous therapy for AGA, No. (%)
Yes	2(6.25%)
EGFR alteration	2(6.25%)
ALK alteration	0(0.00%)
No	30(93.75%)
Stage
IVA	9(28.13%)
IVB	12(37.50%)
IVC	11(34.38%)

*Notes: The following are abbreviations for the chemotherapy regimens in the table. PC reprents pemetrexed + platinum, TC represents docetaxel + platinum, GC represents gemcitabine + platinum, AGA represents actionable genomic alteration

Efficacy

Our preliminary results exhibited that the overall response rate (ORR) for the cohort was 25%, with 0 patients achieving a complete response (CR) and 8 achieving a partial response (PR). Stable disease (SD) was observed in 28.13% of patients, while disease progression (PD) occurred in 46.87% during the treatment period. The median progression-free survival (PFS) was 4 months(95% CI = 4.05–4.64), and the median overall survival (OS) was 9 months 95% CI = 8.38–9.49 (See Fig. 1), indicating a favorable outcome compared to historical controls (See Table 2). The further analysis exhibited that The efficacy of this regimen is not affected by PD-L1 expression levels (PD-L1 (+) vs. PD-L1 (-), mPFS 4.5 months vs. 4.0 months, P = 0.9508, HR: 1.035, 95% CI = 0.3312–3.237; mOS 9.0 months vs. 9.0 months, P = 0.8302, HR: 1.222, 95% CI = 0.4816–3.102) (See Fig. 1), prior immune therapy efficacy (CR/PR vs. SD/PD, mPFS 5.0 months vs. 4.0 months, P = 0.3281, HR: 0.5645, 95% CI = 0.1795–1.776; mOS 9.0 months vs. 9.0 months, P = 0.9169, HR: 1.051, 95% CI = 0.4121–2.681), and the interval since last IO (≥ 6 months vs. < 6 months, mPFS 5.0 months vs. 4.0 months, P = 0.0575, HR: 3.143, 95% CI = 0.09521-1.037; mOS 9.5 months vs. 9.0 months, P = 0.4218, HR: 0.6628, 95% CI = 0.2430–1.808) (See Fig. 2). However, compared to those who did not experience these adverse effects, patients who experienced hypertension, proteinuria, or hand-foot syndrome during treatment had better efficacy (with AEs vs. without AEs, mPFS 5.0 months vs. 4.0 months, P = 0.0002, HR: 0.1079, 95% CI = 0.03388–0.3436; mOS 10.0 months vs. 8.5 months, P = 0.0204, HR: 0.4125, 95% CI = 0.1618–1.052) (See Fig. 1), indicating that the identification of adverse effects during treatment could serve as a potential indicator for screening priority population.

Fig. 1.

Median PFS and OS in patients with advanced NSCLC with liver metastasis receiving second-line treatment with a combination of nab-ptx, anlotinib, and immunotherapy. Figures A and B represent the median PFS and OS for the general population, respectively; Figures C and D show comparisons of PFS and OS between patients with PD-L1 (+) and patients with PD-L1 (-) (PD-L1 (+) vs. PD-L1 (-)). Figures E and F show comparisons of PFS and OS between patients with and without adverse events (AEs) during the entire treatment (with AEs vs. without AEs). PD-L1 (+) is defined as a PD-L1 expression level ≥ 1%, and PD-L1 (-) is defined as a PD-L1 expression level < 1%. mPFS, median progression-free survival; mOS, median overall survival; sAE specifically refers to any adverse event, including hypertension, proteinuria, and hand-foot syndrome. Censored data points are marked on the Kaplan-Meier curves. The number of patients at risk at each time point is shown below the graph

Table 2.

The clinical efficacy of nab-ptx combined with anlotinib and immunotherapy in second-line treatment of advanced NSCLC with liver metastasis

	Patient No.	Ratio
Complete response	0	0
Partial response	8	25.00% (8/32)
Stable response	9	28.13% (9/32)
Progressive disease	15	46.87% (15/32)
Objective response		25.00%
Median PFS		4.0 m
Disease control Rate		53.13%
Median OS		9.0 m

Fig. 2.

Subgroup analyses of PFS and OS. A, B By prior immunotherapy response (CR/PR vs. SD/PD); C, D By interval since last immunotherapy (≥ 6 months vs. < 6 months). Censored data points are marked on the Kaplan-Meier curves. The number of patients at risk at each time point is shown below the graph

Exploratory biomarker analysis

Considering that the efficacy of this regimen may be related to immune regulation, we also examined the changes in the proportions of immune cells in peripheral blood before and after treatment. Preliminary results indicate that the proportion of Treg cells in the peripheral blood of patients is generally elevated relative to the normal range, after six weeks of treatment with a multi-drug combination regimen, the proportion of Treg cells in the peripheral blood of patients significantly decreased (P < 0.01). Further observation revealed that patients with Treg depletion had better objective response rates (ORR) and disease control rates (DCR) compared to those patients without Treg depletion. Survival analysis also showed that compared to patients without Treg depletion, those with Treg depletion had significant improvements in progression-free survival (PFS) and overall survival (OS) (with Treg depletion vs. without Treg depletion, mPFS 5.0 months vs. 4.0 months, P = 0.0215, HR: 0.2970, 95% CI = 0.08618-1.024; mOS 10.0 months vs. 7.5 months, P = 0.0012, HR: 0.1773, 95% CI = 0.05934–0.5299) (See Fig. 3). These data suggest that while liver metastasis is associated with a negative immune microenvironment, the mechanism of action of this regimen is likely based on depleting immune cells to activate immunity, demonstrating a synergistic anti-tumor effect of the multi-drug combination. It also indicates that changes in the proportion of Treg cells in peripheral blood may serve as a potential molecular biomarker for efficacy prediction.

Fig. 3.

Changes in the proportion of Treg cells in peripheral blood before and after the three-drug combination treatment in Advanced NSCLC with liver metastasis and their association with treatment efficacy. Figure A shows the changes in Treg proportions before and after treatment; Figure B represents the ORR and DCR in different populations after treatment based on Treg depletion status (with Treg depletion vs. without Treg depletion); Figures C and D illustrate the PFS and OS comparisons among different populations after treatment based on Treg depletion status (with Treg depletion vs. without Treg depletion). Censored data points are marked on the Kaplan-Meier curves. The number of patients at risk at each time point is shown below the graph

Safety

Regarding safety, the most common adverse events (AEs) included decreased appetite (50.00%), fatigue (37.50%), leukopenia (34.38%), neutropenia (37.50%), thrombocytopenia (28.13%), anemia (18.75%), hypertension (31.25%), hand-foot syndrome (34.38%), proteinuria (28.13%), peripheral neuropathy (28.13%), elevated transaminases (25.00%), hypothyroidism (34.38%), hyperthyroidism (31.25%), and rash (28.13%), indicating that there was no cumulative effect of toxic side reactions. Fortunately, most AEs were manageable with dose adjustments and supportive care. The incidence rates of grade 3 or higher hematologic, non-hematologic, and immune-related adverse reactions were 15.63%, 25.00%, and 15.63%, respectively. Serious AEs leading to treatment discontinuation occurred in 15% of patients. No treatment-related deaths were recorded (See Table 3). These data demonstrate the safety of the multi-drug combination therapy.

Table 3.

Adverse events of the three-drug combination therapy consisting of nab-ptx, anlotinib, and immunotherapy in second-line treatment of advanced NSCLC with liver metastasis

Adverse Event	anlotinib, nab-ptx and PD-1/L1 [n (%)]
	Any Grade	Grade 3 or 4
Hematological
Leukopenia	11(34.38%)	2(6.25%)
Neutropenia	12(37.50%)	2(6.25%)
Thrombocytopenia	9(28.13%)	1(3.13%)
Anemia	6(18.75%)	0%
Nonhematologic
Decreased appetite	16(50.00%)	0%
Fatigue	12(37.50%)	0%
Hypertension	10(31.25%)	2(6.25%)
Hand-foot syndrome	11(34.38%)	2(6.25%)
Proteinuria	9(28.13%)	2(6.25%)
Peripheral neuropathy	9(28.13%)	1(3.13%)
Elevated transaminase	8(25.00%)	1(3.13%)
Oral ulcer	5(15.63%)	0%
Stomatitis	5(15.63%)	0%
Abdominal pain	4(12.50%)	0%
Diarrhea	5(15.63%)	0%
Hyperbilirubinemia	4(12.50%)	0%
Elevated LDH	3(9.38%)	0%
ALP increased	3(9.38%)	0%
Elevated GGT	3(9.38%)	0%
Hypoproteinemia	2(6.25%)	0%
Dysphagia	2(6.25%)	0%
Dysphonia	2(6.25%)	0%
Bleeding	0%	0%
Immunological
Hypothyroidism	11(34.38%)	0%
Hyperthyroidism	10(31.25%)	0%
Rash	9(28.13%)	2(6.25%)
Hepatitis	6(18.75%)	1(3.13%)
Itching	6(18.75%)	1(3.13%)
Pneumonia	3(9.38%)	1(3.13%)
Infusion reaction	2(6.25%)	0%
Nephritis	1(3.13%)	0%

Discussion

The management of advanced NSCLC with liver metastases remains a significant clinical challenge due to its association with a poor prognosis and limited therapeutic options [2, 4]. This retrospective study evaluated the novel combination of nab-paclitaxel, anlotinib, and immunotherapy in this setting. Our findings indicate comparable efficacy and a manageable safety profile, suggesting this regimen could offer a meaningful survival benefit for this difficult-to-treat population.

Immunotherapy has revolutionized the treatment landscape for advanced lung cancer [17]. However, for NSCLC patients with liver metastases, its clinical outcomes remain unfavorable, and evidence specific to this population is notably lacking. In early studies [3, 18], When immunotherapy is used as monotherapy in non-small cell lung cancer (NSCLC) patients with liver metastases, the median PFS is only 1.8 months, whereas it reaches 4.0 months in patients without liver metastases [19]. Moreover, in the liver metastasis subgroup treated with first-line camrelizumab monotherapy, the objective response rate (ORR) was only 17.5% [20]. In contrast to monotherapy, the combination of docetaxel and ramucirumab has demonstrated significantly improved efficacy in NSCLC patients with liver metastases, achieving an objective response rate (ORR) of 48.6% and a median progression-free survival (mPFS) of 3.5 months (95% CI 1.89–5.11) [12], underscoring the potential of combination strategies in this challenging population. Although the efficacy observed in our study (ORR, 25%; disease control rate [DCR], 53.13%; mPFS, 4.0 months; median overall survival [mOS], 9.0 months) was modest compared to this reported regimen, our combination offers distinct advantages in terms of a favorable safety profile, superior drug accessibility, and enhanced cost-effectiveness [21]. These attributes may render it a more practical and sustainable option that aligns closely with real-world clinical needs [22, 23].the regimen leverages complementary mechanisms: nab-paclitaxel enhances tumor-specific drug delivery, anlotinib provides broad anti-angiogenic activity, and immunotherapy reactivates anti-tumor immunity. This multi-targeted approach likely underpins the observed synergistic effect and may help overcome the immunosuppressive microenvironment often associated with liver metastases [24, 25].

A key finding was that clinical efficacy appeared independent of traditional biomarkers such as PD-L1 expression, prior response to immunotherapy (CR/PR vs. SD/PD), or the interval since last immunotherapy [26, 27]. This suggests a potentially broader applicability of the regimen beyond populations selected by these factors. Interestingly, the development of specific treatment-emergent adverse events (hypertension, proteinuria, or hand-foot syndrome) was strongly associated with improved PFS and OS [28, 29]. This correlation implies that these AEs might serve as early clinical biomarkers for identifying patients most likely to benefit, supporting a more personalized treatment approach [30, 31].

Exploratory biomarker analysis provided insights into a potential mode of action. We observed a significant decrease in peripheral blood Treg cell proportions following treatment, and this Treg depletion was correlated with superior ORR, DCR, PFS, and OS [28, 32]. This aligns with the hypothesis that the combination can modulate the immunosuppressive landscape [33], possibly reversing one of the hallmarks of metastatic progression. Monitoring peripheral Treg dynamics could emerge as a useful predictive tool [34].

The safety profile was consistent with the known toxicities of each component drug. Although the overall incidence of AEs was high, most were low-grade and manageable [9, 32]. The incidence of Grade ≥ 3 events was relatively low (hematologic: 15.63%, non-hematologic: 25.00%, immune-related: 15.63%), and no treatment-related deaths occurred. This tolerability is crucial, as it allows patients to maintain treatment duration and quality of life [8]. The “platinum-free” chemotherapy backbone and the use of optimized, lower doses of nab-paclitaxel may have contributed to the manageable toxicity [35, 36].

This study addresses the clinically pertinent question of immunotherapy continuation or rechallenge after disease progression [26, 27]. Our data suggest that combining a PD-1/L1 inhibitor with anlotinib and nab-paclitaxel can yield clinical benefit even in patients who have progressed on prior first-line chemoimmunotherapy, offering a viable strategy in the post-resistance setting. Compared to other emerging post-immunotherapy options like ADCs(Sacituzumab Govitecan is used for second-line treatment of advanced non-small cell lung cancer (NSCLC), with an ORR of 13.7%, mPFS of 4.1 months, and mOS of 11.1 months) [37] Anti-angiogenesis therapy combined with immunotherapy (ramucirumab combined with pembrolizumab) is used for second-line treatment of advanced NSCLC with first-line chemotherapy and immunotherapy. The ORR is 22%, mPFS is 4.5 months, and mOS is 14.5 months [38], this regimen presents advantages in terms of accessibility and cost-effectiveness, which are important practical considerations [39, 40].

Nevertheless, this study has several limitations. Its retrospective design introduces inherent biases and precludes definitive causal conclusions. The single-center experience and relatively small sample size limit the generalizability of the findings [8]. The heterogeneity in the specific PD-1/L1 inhibitors used, while reflecting real-world practice, may also influence outcomes [41]. These limitations preclude any definitive conclusions regarding its superiority at this stage. Accordingly, the principal contribution of this study is to propose a novel combination regimen for NSCLC patients with liver metastases following failure of first-line chemoimmunotherapy [42–44]. This regimen demonstrates a manageable safety profile and preliminary evidence of clinical activity, meriting further validation in prospective clinical trials.

In conclusion, the combination of nab-paclitaxel, anlotinib, and immunotherapy demonstrates observed efficacy and a tolerable safety profile in the second-line treatment of advanced NSCLC with liver metastases. Its efficacy appears broad and may be predicted by on-treatment AEs [30]and Treg dynamics [45, 46]. These findings warrant validation in larger, prospective, multicenter randomized controlled trials to establish the role of this combination in the therapeutic landscape and to further refine patient selection strategies [5, 14, 47].

Authors’ contributions

Hui Teng &Ni Qin: drafting manuscripts. Kaiyan Liu&Cheng Gong: analyzing and collecting data. Jing Tang: sampling and testing. Xiaobing Li: supervising the implementation of clinical research.

Funding

The study was supported by The Beijing Integrative Medicine Association Research Project (No. ZHKY-2025-5193).

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Declarations

Ethics approval and consent to participate

The authors bear full responsibility for ensuring the accuracy and integrity of all aspects of the study. Any queries regarding the precision or honesty of any part of the work were duly investigated and addressed. The study adhered to the principles outlined in the Declaration of Helsinki (revised in 2013). Approval for this retrospective trial was obtained from the Ethics Committee of Hubei Cancer Hospital Affiliated with Tongji Medical College (Wuhan, China) (Approval No. HBCHEC2021099). informed consent was waived due to the retrospective nature of the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.