ABSTRACT

Aim

The HALP score is a novel index based on easily accessible laboratory results, including albumin (ALB), platelet (PLT), lymphocyte (LYM), and hemoglobin (HGB), levels, and is used as a prognostic factor in various types of cancer. Our study aims to investigate the prognostic significance of the HALP score in patients with advanced non-small cell lung cancer (NSCLC) who progressed after platinum-based chemotherapy and subsequently received nivolumab treatment.

Materials and Methods

A retrospective evaluation of 142 patients diagnosed with advanced NSCLC between January 2019 and December 2023 at Trakya University Faculty of Medicine, Department of Medical Oncology, and Dr. İsmail Fehmi Cumalıoğlu City Hospital was conducted. Laboratory tests were performed within two weeks prior to the first nivolumab cycle, assessing LYM count, H level, PLT count, and ALB level. The HALP score was calculated using the formula: HGB level (g/L) × ALB level (g/L) × LYM count (/L) / PLT count (/L). The optimal cut-off point for the HALP score was determined by ROC curve analysis.

Results

Kaplan-Meier analysis demonstrated that the high-HALP score group had significantly better progression-free survival (PFS) compared to the low-HALP score group [median 5 months 95% confidence interval (CI): 4.1-5.9 versus 3.3 months 95% CI: 2.4-4.1, p=0.001]. In multivariate analysis, the HALP score (hazard ratio: 0.539, 95% CI: 0.331-0.876, p=0.013) was confirmed as the only independent risk factor associated with PFS.

Conclusion

A strong association was found between a low HALP score and shorter PFS in advanced NSCLC patients treated with nivolumab in the second line. Therefore, the HALP score may provide additional prognostic information in identifying the group of patients who will benefit the most from treatment.

Keywords:

HALP score, non-small cell lung cancer, progression-free survival, nivolumab, second-line treatment

INTRODUCTION

Lung cancer is the most common type of cancer in the world and ranks first in cancer-related deaths¹. According to GLOBOCAN cancer statistics, 41.264 people were diagnosed with lung cancer in Türkiye in 2020 and 37.070 people died from this disease². Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and 60% of patients are diagnosed at the metastatic stage³. First-line treatment in patients who do not carry targetable mutations is platinum-based chemotherapy. In patients who develop resistance to first-line treatment, second-line treatment options are limited and overall survival (OS) is below 12 months⁴.

The discovery of immunotherapy agents in recent years has led to an important paradigm shift in lung cancer second-line treatment approaches. The interaction between programmed cell death ligand 1 (PD-L1) in tumor cells and programmed cell death 1 (PD-1) in T-cells allows tumor cells to escape immune control⁵. Nivolumab, a human immunoglobulin G4 PD-1 antibody, potentiates antitumor immunity by disrupting signaling between T-cells and tumor cells⁶. In 2015, two large randomized phase 3 trials found that second-line nivolumab treatment in NSCLC patients showed superiority in OS, progression-free survival (PFS) and overall response rate compared with standard docetaxel chemotherapy^{7, 8}.

However, nivolumab has limited efficacy due to its high cost and development of resistance to treatment in 60-80% of patients⁹. This necessitates the identification of patient groups that will respond the most to treatment, improving quality of life and effective management of treatment costs¹⁰. Despite limitations such as low test sensitivity, tissue failure, tumor heterogeneity and expression variability, PD-L1 is the most important biomarker for second-line treatment selection in advanced NSCLC patients without targetable mutations. In addition, other biomarkers such as tumor mutation burden, tumor infiltrating lymphocytes (L) and DNA mismatch repair are still under investigation^{11, 12}. The limitations of existing biomarkers increase the need for new predictive tools that are more accessible, cost-effective and practical.

Studies had revealed that hematologic indicators such as albumin (ALB), hemoglobin (HGB) and L were associated with NSCLC prognosis, reflecting inflammation or nutritional status^{13, 14}. However, these single indicators are limited as they only reflect certain aspects. Previous research has shown that combinations of these indicators provide more accurate prognosis prediction than single indicators. For example, parameters such as platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio have been demonstrated as prognostic factors in various cancer types^15-17. In recent years, the HALP score, which combines HGB, ALB, L and platelet (PLT) levels, has shown a strong association with prognosis in various cancers. However, there is insufficient research on the prognostic role of the HALP score in advanced NSCLC patients¹⁸.
This study evaluates the efficacy of nivolumab used as second-line therapy in patients with advanced NSCLC and the potential prognostic significance of HALP score in predicting treatment response, and investigates its role in clinical practice as a biomarker in determining the right patient selection and treatment strategies.

MATERIALS AND METHODS

This retrospective study included 142 patients diagnosed with advanced NSCLC at the, Trakya University Faculty of Medicine, Department of Medical Oncology and Dr. İsmail Fehmi Cumalıoğlu City Hospital between January 2019 and December 2023. The inclusion criteria are: 1) pathologically confirmed NSCLC, 2) Stage IIIB-IIIC or IV disease with at least one measurable lesion, 3) Completed at least two cycles of second-line treatment with 240 mg intravenous nivolumab every 14 days. The exclusion criteria are as follows: 1) Concurrent other malignancies, 2) Presence of active infection, 3) Presence of a targetable driver gene mutation, 4) Inadequate treatment or laboratory data. In total, 142 patients met the study criteria.
Clinical characteristics such as gender, age, Eastern Collaborative Oncology Group (ECOG) performance status, smoking history, type of pathologic diagnosis, stage of diagnosis and metastasis sites were recorded. Laboratory tests were performed no more than two weeks before the first cycle of nivolumab treatment and included L count, HGB level, PLT count and ALB level. The HALP score was calculated by the formula HGB level (g/L) × ALB level (g/L) × L count (/L) / PLT count (/L). Treatment response was classified as progressive disease, stable disease, partial response or complete response according to RECIST 1.1 criteria. PFS time was defined as the time from the start of nivolumab treatment to the time of the first signs of disease progression or death.
This study was conducted in accordance with national regulations, institutional policies and the principles of the Declaration of Helsinki and was approved by the Non-Interventional Scientific Research Ethics Committee of the Dean’s Office of the Trakya University Faculty of Medicine (decision no: 2024/74, date: 04.03.2024).

Statistical Analysis

Statistical Package for Social Sciences for Windows (SPSS 20.0, SPSS Inc., Chicago, IL, USA) was used in the analyses. PFS represents the time from nivolumab treatment start date to the time of disease progression or death. Frequency, percentage, mean and standard deviation values were calculated for descriptive statistics. Independent samples t-test and chi-square (χ²) test were used to compare categorical variables. The optimal cut-off point of the HALP score was determined by ROC curve analysis, at which point sensitivity, specificity, positive and negative predictive values were calculated.
The impact of prognostic factors and clinico-pathologic features on PFS was evaluated by Kaplan-Meier analyses and log-rank test. Cox proportional hazard regression model was used to identify independent prognostic variables. Parameters with a significant effect on PFS were selected among variables that did not show multiple linear relationships. The statistical significance criterion was set as p<0.05.

RESULTS

Patient Characteristics

The study cohort consisted of 142 patients with a median age of 65.1 years (range: 40-83). 52.8% (n=75) of the patients were 65 years and older. 89.4% (n=127) of the cohort were male. 62% (n=88) of patients had an ECOG performance score of 0, 1 or 2. 90.8% (n=129) of the cohort were current smokers or had a long-term smoking history. Of the 96 patients (67.6%) with PD-L1 test results, 53.1% (n=51) had PD-L1 expression ≥1. EGFR and ALK mutations were not detected in any patient included in the study. However, Kirsten Rat Sarcoma Virus (KRAS) mutations were detected in 20.4% (n=29) and 24.1% (n=7) of this group had KRAS G12C mutation. Brain metastases were seen in 13.4% (n=19), visceral metastases in 35.9% (n=51) and metastases to two or more sites in 33.1% (n=47). Clinical and demographic data are summarized in Table 1.

Evaluation of HALP Score as a Prognostic Factor for PFS

ROC curve analysis was performed to determine the optimal cut-off point for the HALP score to predict disease progression. The analysis showed that the optimal cut-off point for the HALP score predicting disease progression was ≥27.24 [area under the curve: 0.623; 95% confidence interval (CI): 0.531-0.715; p=0.014] (Figure 1). The results of Cox analysis revealed that the ROC cut-off for the HALP score showed a better risk ratio (RR) compared to the median cut-off (ROC cut-off: RR: 0.470; p=0.001, median cut-off: RR: 0.594; p=0.023). In this analysis, using the ROC curve cut-off, patients were divided into two groups: low HALP score (<27.24, n=77) and high HALP score (≥27.24, n=69). Kaplan-Meier analysis revealed that the high HALP score group showed significantly longer PFS than the low HALP score group (median: 5.0 months; 95% CI: 4.1-5.9 vs. 3.3 months; 95% CI: 2.4-4.1; p=0.001) (Figure 2). In our study, the median PFS for the whole group was 4.1 months (95% CI: 95% 3.6-4.6). Clinical and demographic data of the patients classified according to HALP score are presented in Table 1. In order to evaluate the effects on prognosis, factors that may affect PFS were analyzed by univariate analysis. In this analysis, significant differences were found in relation to gender (p=0.031), smoking habit (p=0.014), number of metastatic sites (p=0.053) and HALP score (p=0.001). In multivariate analysis, HALP score (p=0.013) was the only independent prognostic factor associated with PFS. The median PFS values determined by Kaplan-Meier and the results of univariate and multivariate analysis are summarized in Table 2.

DISCUSSION

International studies have shown that immunotherapy improves survival in patients with advanced NSCLC¹⁹. These findings are also supported by real world data²⁰. In our study, only PFS was evaluated in advanced NSCLC patients receiving second-line nivolumab treatment and the median duration was 4.3 months. Since OS data were not yet mature during the statistical analysis process of our study, statistical evaluation could not be performed. The PFS durations obtained in our real-life cohort were found to be longer than those in the CheckMate 017 and 057 studies^{7, 8}. This indicates that treatment efficacy continues in real-world conditions. Similar limitations have been observed in other real-world studies due to short follow-up periods and immature data^{19, 21, 22}.
Although nivolumab is superior to standard chemotherapy in second-line treatment, only less than 20% of treated patients show PFS after two years⁹. This highlights the importance of correctly identifying the patient group that will benefit the most from treatment. The development of simple and effective predictive models that can predict prognosis and treatment response in advanced NSCLC patients is critical to improve treatment efficacy. Thus, it will be possible to establish individualized treatment strategies¹⁰.
Nutritional status and inflammatory response play a critical role in cancer disease progression²³. Cancer-associated anemia, which occurs in approximately one third of cancer patients at diagnosis, is associated with advanced stages of the disease²⁴. HGB level in the diagnosis of anemia and ALB level in the evaluation of nutritional status are the basic parameters; in addition, ALB is an important marker in the prognosis of advanced NSCLC as a negative acute phase reactant²⁵. Low L count is associated with poor immune response and indicates poor prognosis²⁶, while PLT count promotes metastasis of tumor cells by increasing endothelial permeability through VEGF. Furthermore, P form a protective barrier around tumor cells by blocking natural killer cell attacks and trigger metastasis. ALB decrease in PLT levels provides a stronger inhibition of metastasis compared to a decrease in granulocyte levels²⁷. In recent years, the HALP score (HGB, ALB, L and PLT) created by the combination of these four parameters has been defined as a parameter with high clinical predictive power in various cancer types by reflecting nutritional and inflammatory status¹⁸.
In a study conducted for the first time in 2015 in gastric cancer patients, Chen et al.²⁸ showed that the HALP score calculated preoperatively was an independent prognostic factor and was closely associated with the course of the disease and clinicopathologic features (p<0.001). The study revealed that an increase in ALB, L and HGB levels was associated with a good prognosis, while an increase in PLT levels was associated with a poor prognosis. Following these initial findings, Jiang et al.²⁹ examined the HALP score in locally advanced colorectal cancer patients and found that a low HALP score was associated with a high risk of death (p<0.001). Subsequent studies have confirmed that the HALP score shows similar positive associations in different cancer types, such as pancreatic, esophageal, bladder and small cell lung cancer, and has clinical value as a prognostic marker³⁰.
The HALP score was previously evaluated in early-stage resectable NSCLC and it was shown that OS was significantly longer in the HALP-High group than in the HALP-Low group (p<0.001)³¹. In a study of 362 NSCLC patients receiving adjuvant chemotherapy, lower HALP score was associated with shorter disease-free survival (DFS) (p<0.01) and OS (p=0.02). Furthermore, subgroup analyses revealed that lower HALP score was a strong predictor of OS (p=0.01) and DFS (p=0.04) in patients with locally advanced or metastatic NSCLC³².
In the recent study by Gao et al.³³ evaluating HALP score before first-line treatment in advanced NSCLC patients, PFS (13 months vs. 9 months) and survival times (36 months vs. 16 months) were significantly longer in the HALP-High group in 203 patients. These findings support the HALP score as a strong prognostic marker.
In our study, ROC analysis determined the optimal cut-off point for HALP score to predict disease progression as ≥27.24, and Kaplan-Meier analysis showed that the high HALP score group showed better DFS than the low HALP score group (5 months vs. 3.3 months, p=0.001). In univariate analysis, HALP score as well as gender, smoking habit and number of metastatic sites were found to be associated with prognosis; in multivariate analysis, HALP score was confirmed as the only independent prognostic factor associated with DFS (p=0.013). These findings demonstrate for the first time that the HALP score is an important prognostic marker not only for early-stage or chemotherapy-treated patients but also for advanced-stage patients receiving immunotherapy.

Study Limitations

Our study has some limitations. The retrospective design and the limited number of patients with only two centers makes the generalizability of the results difficult and limits the applicability of the findings to a wider population. Another point is that the HALP score does not have an ideal cut-off value that prevents routine use.

CONCLUSION

This study demonstrated the efficacy of nivolumab treatment and the prognostic value of HALP score in patients with advanced NSCLC. Higher HALP score was associated with longer PFS. HALP score can be used as a potential biomarker to predict immunotherapy response, but larger studies are needed to confirm the findings.

Ethics

Ethics Committee Approval: This study was conducted in accordance with all relevant national regulations, institutional policies and the principles of the Declaration of Helsinki and was approved by the Non-Interventional Scientific Research Ethics Committee of the Dean’s Office of the Trakya University Faculty of Medicine (decision no: 2024/74, date: 04.03.2024).

Informed Consent: Retrospective study.

Footnotes

Authorship Contributions

Concept: İ.G., B.G., Design: F.A., Data Collection or Processing: F.A., B.G., İ.B., A.F.A., T.İ.A., Analysis or Interpretation: B.H., B.E., S.T., Literature Search: F.A., B.G., D.D., G.B.K., Writing: F.A., İ.B.

Conflict of Interest: The authors have no conflicts of interest to declare.

Financial Support: No financial support was received for this study.

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Prognostic Significance of HALP Score in Second-Line Nivolumab Treatment of Advanced Non-Small Cell Lung Cancer