Association of Sex with Survival and Adverse Events in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors: A Single-Center Experience in Türkiye

Introduction

Non-small cell lung cancer (NSCLC) accounts for 80–85% of all lung cancers. Despite surgical, chemotherapy, and radiotherapy options, survival rates in advanced lung cancer are still poor [1]. In recent years, immune checkpoint inhibitors (ICIs) have also been used in these patients because of the search for new targeted therapies. ICIs promote the autoimmune function of cancer cells by blocking the expression of immune checkpoint antibodies, programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways, which play an important role in the immune escape of tumor cells. The US Food and Drug Administration has approved nivolumab, pembrolizumab, durvalumab, and atezolizumab for patients with NSCLC [2]. Nivolumab, a PD-1 antibody, restores the function of existing anti-cancer T cells and strengthens anti-cancer immunity through immune system activation [3]. The PD-L1 monoclonal antibody atezolizumab resulted in significantly longer overall survival compared to platinum-based chemotherapy in patients with NSCLC with high PD-L1 expression, regardless of histological type [4]. While the common adverse effects of ICIs are anorexia, nausea, vomiting, fatigue, skin rashes, less frequent but important immune-related adverse effects such as pneumonitis, thyroiditis, hepatitis, vitiligo, and diarrhea also occur [5].

Although NSCLC is not a sex-specific cancer, there are sex differences in incidence, survival, and treatment response. For example, adenocarcinomas are more common in women, and small cell and squamous cell lung cancers (scc) are more common in men, even though they are associated with smoking [6]. Although overall survival is longer in women than in men, even when adjusted for age, smoking status, and stage, it remains to be seen how the global increase in the incidence of lung cancer in women will affect these results. In addition, among people who consumed the same amount of tobacco, women have a higher risk of developing lung cancer than men. Some risk factors vary according to sex, including biomass exposures, indoor cooking fumes, passive smoking, and hormone replacement therapy [7].

They are 2 times more likely to have CYP1A1 expression levels associated with lung cancer and 2 times more likely to have an S-transferase M1 mutation, which inactivates toxic products [8]. Overall mortality, tumor grade at diagnosis, and response to ICIs were higher in men [9]. Since there are differences in the adaptive and innate immune response between men and women, there are also differences in PD-1 and PDL-1 levels. One study revealed that female patients had higher levels of sPD-1 and PD-1 expression on CD4+T cells than male patients [10].

Another view is that sex is not an independent prognostic factor for ICI. However, several factors affect the ICI response, such as high PD-L1 expression, which is more common in men [11]. The relationship between the role of sex hormones and the immune system in facilitating this difference and the potential biological reason behind this difference remain unclear [9]. This study investigated the clinical characteristics, adverse effects, and overall survival (OS) status of 100 patients with NSCLC from a single center in Türkiye receiving ICI and their association with sex.

Material and Methods

STUDY DESIGN AND DATA COLLECTION:

This was a single-center, retrospective, observational study. All 100 NSCLC patients admitted to the Pulmonary and Medical Oncology Department of a training and research hospital between January 2018 and March 2024 were evaluated. All patients admitted between these dates were evaluated, and all patients had complete data.

ETHICS APPROVAL:

This study was conducted in accordance with the principles of the Declaration of Helsinki. Ethics committee approval was obtained from Dokuz Eylul University Faculty of Medicine Non-Interventional Clinical Research Ethics Committee (2024l19-20, 8756-GoA). Consent was obtained from all patients.

DEPENDENT AND INDEPENDENT VARIABLES:

The independent variables of the study were sociodemographic data (age, sex, occupation, comorbidities, smoking status), clinical and physical examination findings, lung carcinoma pathology, and treatment modalities such as conventional chemotherapy, ICI, and radiotherapy.

Patients had received nivolumab or atezolizumab treatments and there was no other ICI use. According to the reimbursement conditions in our country, atezolizumab is covered as the first-line treatment and nivolumab is covered as the second-line treatment. In ICI selection, the appropriate treatment modality within the scope of reimbursement is selected in consultation with the patient.

Serum albumin and lactate dehydrogenase levels were measured in whole blood. The neutrophil/leukocyte ratio (NLR) was determined based on the complete blood count. Physical activity status was determined using the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale [12]. The TNM clinical staging system score was NSCLC 8 [13]. PDL-1 levels were determined according to the tumor proportion score (TPS). Accordingly, TPS <1% was PDL-1-negative, TPS 1–49% was weakly positive, and TPS ≥50% was strongly positive [14]. Smoking status was based on the CDC definitions of smoking status [15]: current smokers are defined as having smoked at least 100 cigarettes during their lifetime and who currently smoke cigarettes; former smokers are defined as having smoked at least 100 cigarettes in their lifetime but had quit smoking by the time of the interview; and never smokers are defined as never smoked or smoked less than 100 cigarettes in their lifetime. Dependent variables were observed adverse effects and OS status. The most common adverse effects documented in patient files were also investigated and included tiredness, pneumonitis (including drug-related), pleural effusion, hypothyroidism, rash, and hyperthyroidism.

STATISTICAL ANALYSIS:

The data obtained were evaluated using the software package SPSS (IBM SPSS Statistics for Mac OS, Version 27.0. Armonk, NY). The conformity of continuous variables to a normal distribution was examined visually (through histograms and probability plots) and statistically (through Kolmogorov-Smirnov/Shapiro-Wilk tests). Descriptive statistics are presented as numbers and percentages for categorical variables and medians (IQR) for continuous variables. The t test was used to compare 2 independent groups with normally distributed continuous data, and the Mann-Whitney U test was used to compare 2 independent groups with non-normally distributed continuous data. The chi-squared test was used to compare categorical data. Kaplan-Meier survival curves were prepared, and survival times were compared using the log-rank test. Analyses and visualizations were performed using GraphPad Prism 10. Statistical significance was defined as a two-way P value of <0.05.

Results

BASELINE DATA OF PATIENTS:

This study included 100 patients, with 88 (88%) men and 12 (%12) women. The average age of the patients was 64.3±8.5 years. The patients had been smoking for a mean of 41.1±22.8 package years. Ten percent of patients were never smokers, 55% were former smokers, and 35% were current smokers. The demographic data of the patients are shown in Table 1.

CANCER-RELATED DATA OF PATIENTS:

NSLC subtypes were 63% adenocarcinoma, 33% scc and 4% other. The other group consisted of large-cell carcinoma and those for which the exact subtype could not be determined. The stages of the patients were stage 4, stage 3c, stage 3b, stage 3a and stage 2b (80.6%, 9.2%, 7.1%, 2%, and 1%, respectively). The ECOG scores of 0, 1, and 2 were 43.4%, 34.3%, and 21.2%, respectively. Nivolumab was by far the most frequently used ICI agent (99%). PDL-1 levels were reached in 54% of the patients. Of these patients, 34% were negative, 8% were weakly positive, and 12% were strongly positive. First-line chemotherapy was administered to 98% of patients, radiotherapy was administered to 83%, and 99% received nivolumab as ICI. The histology, cancer stage, ECOG, ICI agents and PDL-1 levels of patients are shown in Table 2.

EVALUATION OF ICI-RELATED ADVERSE EFFECTS AND LABORATORY VALUES ACCORDING TO SEX:

Adverse effects were observed in 91% of the patients. Pleural effusion (P=0.040), hypothyroidism (P=0.003), and rash (P<0.001) were more common in women, whereas tiredness (P=0.804), pneumonitis (P=0.097), and hyperthyroidism (P=0.507) were not significantly different according to sex. Albumin, LDH, and PDL-1 levels did not differ significantly according to sex (P=0.098, P=0.663, P=0.552). Tumor histology was not significantly associated with sex (P=0.557) (Table 3).

UNIVARIATE SURVIVAL ANALYSIS OF PATIENTS ACCORDING TO SEX:

The average follow-up period was 33.8±22.6 months, and 25% of patients died. OS was significantly lower in women than in women (P=0.047) (Figure 1). OS did not differ according to sex in stage 4 patients (P=0.087) (Table 4). Among men, survival was significantly lower in the radiotherapy group (P=0.004). OS could not be determined based on NLR. There was no distinct predictive value for men (AUC: 0.628, P=0.088) or women (AUC: 0.583, P=0.631). The NLR levels in women (P=0.800) and men (P=0.226) were not significantly different in terms of OS. NLR levels were not significantly different according to sex between living (P=0.777) and dead (P=0.877) patients. The lowest OS was observed in the M1c group (P=0.035). OS was lowest among those with an ECOG performance score of 2 (P=0.030). OS was higher in those who received RT (P=0.024). No significant difference was found in OS among the other compared variables (P>0.05).

MULTIVARIATE COX REGRESSION ANALYSIS TO PREDICT MORTALITY BY CREATING A MODEL ACCORDING TO ALL VARIABLES:

Cox regression analysis was performed to predict mortality. Multivariate analyses showed that sex was not a predictor of mortality (P=0.168). According to the multivariate analysis, the risk of death increased 3.3-fold in those who did not receive RT (OR, 3.311; 95% CI: 1.291–8.492, P=0.013). A 1-unit increase in the ECOG score increased the risk of death by 1.7-fold (OR, 1.744; 95% CI: 3.311–1.291, P=0.036). A 1-unit increase in albumin level reduced the risk of death by 10% (OR, 0.907; 95% CI: 0.841–0.977, P=0.010) (Table 5).

Discussion

STUDY LIMITATIONS:

The main limitations of this study were its retrospective design, the different follow-up periods of the patients, and the relatively small number of women. In addition, the disease-free survival and PFS rates could not be analyzed. Familial history, socioeconomic status, education level, and working status were not included in our data; therefore, it was not possible to analyze the effects of these factors on the prognosis of lung cancer according to sex. Nevertheless, the results of our study are still important because sex can be an important factor in individualized treatments for NSCLC patients.

Conclusions

Sex was not shown to significantly predict mortality in women with NSCL receiving ICI, but there are differences between female and male in some adverse effects of ICI treatment. Our results may be useful for future individualized treatment based on sex. Prospective randomized controlled trials are needed to better understand these relationships.