Introduction
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide [1], with locally advanced (LA)-NSCLC accounting for a significant portion of diagnoses [2]. Concurrent chemoradiation therapy (CCRT) has long been the standard of care for these patients, offering locoregional control and improved survival [3]. However, the emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape. The original PACIFIC trial [4] published in 2017, established durvalumab – a monoclonal antibody targeting the PD-L1 receptor – as a new standard of care by demonstrating a significant improvement in overall survival (OS) compared to placebo in patients with unresectable stage III NSCLC receiving concurrent platinum-based chemotherapy and radiation therapy [5]. This landmark study paved the way for the widespread adoption of durvalumab consolidation therapy in clinical practice.
Investigations into biomarkers associated with a response to durvalumab are ongoing. Tumor PD-L1 expression has been shown to be a predictive factor in some studies, although its role remains controversial due to variations in testing methods and interpretation [5]. Other biomarkers, such as tumor mutational burden [6] and immune gene signatures [7], are also being investigated and may provide valuable insights into patient selection and treatment response. Additionally, emerging research suggests that genetic alterations, such as KRAS mutations, may hold promise for identifying patients who are less likely to benefit from durvalumab therapy [8].
Recent studies have explored the potential of various clinical and biological factors to predict survival in durvalumab-treated NSCLC patients. For instance, a study by Liu et al. identified the baseline neutrophils-to-lymphocytes ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as promising predictors of OS, highlighting the potential role of systemic immune status in treatment response [9]. Similarly, another study published in 2021 found that patients with low infiltration of CD8+ PD-L1+ T-cells and M2 macrophages achieved better progression-free survival (PFS) following durvalumab consolidation, suggesting the importance of pre-existing antitumor immunity [10]. In patients diagnosed with squamous cell carcinoma the higher percentage of basophils in tumor microenvironment (TME) was associated with longer OS [11]. The higher basophil counts were also demonstrated as significant predictors for a higher probability of tumor size reduction within three months, with an increased risk of immune-related adverse events [12]. In a study by Wang et al. the basophil-to-lymphocyte ratio was associated with a shorter OS [13]. Durvalumab has been available to the general patient population in Poland since 2021 via a government-controlled program.
In this single-center study, we aimed to contribute to the growing body of knowledge on predictive factors for OS in LA-NSCLC patients treated with CCRT and adjuvant durvalumab.
Material and methods
Population
In this retrospective cohort analysis, we examined cases of inoperable NSCLC that were treated with CCRT and with adjuvant durvalumab during the years 2021–2022 at our institution (Copernicus Memorial Hospital, Lodz, Poland). Since 2021, the cost of adjuvant durvalumab has been covered by the public healthcare system in Poland, thereby making it accessible to all patients in this cohort. The patients were followed up until December 31, 2023. Our group consisted of 16 (35.6%) women and the median age of participants was 70 years old (65–75). The majority of patients received cisplatin as a chemotherapeutic agent (62.2%), and the median radiation dose was 60 Gy.
All the participants who received durvalumab were enrolled in a strictly government-regulated program for the adjuvant treatment of histopathologically diagnosed NSCLC in Poland. To qualify for the durvalumab consolidation therapy, patients must be diagnosed with stage III NSCLC and demonstrate no disease progression following concurrent chemoradiotherapy. The absence of disease progression must be confirmed through a computed tomography (CT) scan, conducted within a six-week window following the completion of the radiotherapy. Moreover, the patients must have completed a course of CCRT involving platinum derivatives. The patient’s overall health and wellness are also considered, with only those having a good performance status (Eastern Cooperative Oncology Group Performance Status, ECOG PS, 0 or 1) being deemed fit for the treatment. Furthermore, patients must not have any uncontrolled coexisting diseases or active autoimmune diseases, with the exception of diabetes, hypothyroidism, psoriasis, or vitiligo (which are manageable and do not interfere with the durvalumab treatment).
Additionally, before the treatment, the patients’ bone marrow, kidney, and liver functions must be also assessed to ensure they are within the normal range and suitable for treatment. Pregnant women were not enrolled to study, and women of a maternal age were obliged to use appropriate contraception methods. Any contraindications to durvalumab or the presence of other uncontrolled malignancies disqualify a patient from the program. However, patients who have previously undergone durvalumab therapy may be considered for continued treatment, provided they met all the aforementioned criteria and showed no signs of disease progression.
Statistical analysis
Statistical analyses were performed using R software v4.2.2 (R Foundation for Statistical Computing, Vienna, Austria).
P values < 0.05 were considered significant. Nominal variables are shown as numbers with percentages and continuous variables are shown as medians with the interquartile range. We used the Cox proportional hazards model to evaluate the prognostic value of clinical and laboratory results in univariable and multivariable analysis after adjusting for patient sex, age, T-characteristics, and nodal status. OS curves were analyzed using the Kaplan–Meier method; to calculate differences between groups a log-rank test was used.
Results
In the period spanning 2021–2022, CCRT and adjuvant durvalumab were administered to a cohort of 45 patients. The clinical characteristics of the study group are presented in table I. During the follow-up period, which extended to 42 months (with a median follow-up time of 14 months), 10 patients experienced fatal events (fig. 1A).
|
Parameter |
n (% or median – IQR) |
|
Parameter |
n (% or median – IQR) |
|
female |
16 (35.56%) |
|
male |
29 (64.44%) |
|
age – years |
70.0 (65.0–75.0) |
|
smoking during RCHT – yes |
12 (29.27%) |
|
pack years |
50 (40.0–70.0) |
|
T characteristic |
|
|
1 |
9 (20.0%) |
|
2 |
10 (22.22%) |
|
3 |
20 (44.44%) |
|
4 |
5 (11.11%) |
|
x |
1 (2.22%) |
|
N characteristic |
|
|
1 |
6 (13.33%) |
|
2 |
35 (77.78%) |
|
3 |
4 (8.89%) |
|
PTV volume – cm3 |
321.1 (231.1–480.8 ) |
|
treatment time – days |
44.0 (41.0–46.0) |
|
cisplatin vs. carboplatin |
28 (62.22%) |
|
histology |
|
|
adenocarcinoma |
18 (40.0%) |
|
squamous-cell carcinoma |
20 (44.44%) |
|
large cell neuroendocrine carcinoma |
3 (6.67%) |
|
not otherwise specified |
4 (8.89%) |
|
second agent |
|
|
etoposide |
11 (24.44%) |
|
paclitaxel |
9 (20.0%) |
|
vinorelibine |
25 (55.56%) |
|
time from end of RT to durvalumab administration – days |
71.0 (60.5–79.0) |
|
time from lab test to RT start |
1.0 (0.0–3.0) |
|
laboratory parameters |
|
|
white blood cell count – 103/µl |
7.18 (6.20–8.72) |
|
red blood cell count – 106/µl |
4.26 (3.79–4.57) |
|
hemoglobin – g/dl |
12.60 (11.60–13.80) |
|
hematocrit – % |
37.60 (34.50–41.00) |
|
PLT – 103/µl |
254.0 (204.00–301.00) |
|
PCT – % |
0.27 (0.21–0.31) |
|
neutrophils – % |
60.10 (51.10–66.30) |
|
lymphocytes – % |
26.10 (20.60–34.30) |
|
monocytes – % |
9.40 (8.20–11.90) |
|
eosinophils – % |
1.60 (0.70–3.20) |
|
basophils – % |
0.70 (0.40–0.90) |
|
neutrophil count – 103/µl |
4.14 (3.30–5.09) |
|
lymphocyte count – 103/µl |
1.88 (1.55–2.40) |
|
monocyte count – 103/µl |
0.72 (0.56–0.93) |
|
eosinophil count – 103/µl |
0.12 (0.06–0.22) |
|
basophil count – 103/µl |
0.04 (0.03–0.06) |
|
glucose – mg/dl |
106.00 (96.00–130.00) |
|
sodium – mmol/l |
139.00 (137.00–142.00) |
|
potassium – mmol/l |
4.50 (4.20–4.90) |
|
urea – mg/dl |
38.30 (30.10–49.10) |
|
creatinine – mg/dl |
0.84 (0.72–1.10) |
|
eGFR – ml/min/1,73 m2 |
60.00 (60.00–60.00) |
|
CRP – mg/l |
4.65 (1.84–11.90) |
|
D dimers |
0.74 (0.55–1.29) |
|
prothrombin time – seconds |
12.20 (11.35–13.50) |
|
INR |
1.05 (0.97–1.17) |
|
APTT – seconds |
25.60 (25.25–28.60) |
|
fibrinogen – mg/dl |
401.00 (344.00–565.25) |
|
procalcitonine – ng/ml |
0.12 (0.06–0.25) |
|
NLR |
2.31 (1.51–3.08) |
|
LMR |
2.82 (1.98–3.34) |
|
PLR |
132.45 (103.64–184.71) |
|
SII |
571.67 (368.81–962.29) |
As shown in table II, the univariable analysis revealed that nodal status (p = 0.015), (fig. 1C), a higher initial percentage of basophils (p = 0.020), though not their absolute number (p = 0.109), and d-dimers (p = 0.048) were significant predictors of OS in this group of patients. The smoking pack years did not demonstrate statistical significance in predicting overall survival (p = 0.731). In a multivariable analysis adjusted for patient age and sex, T characteristic, and nodal status, the percentage of basophils was a significant predictor of OS (p = 0.037) (tab. IV). After adjusting for the same clinical prognostic factors, d-dimers were not associated significantly with OS (p = 0.115).
|
Characteristic |
HR (95% CI) |
p value |
|
Characteristic |
HR (95% CI) |
p value |
|
female |
– |
– |
|
male |
1.447 (0.374–5.602) |
0.592 |
|
age – years |
1.094 (0.985–1.210) |
0.092 |
|
smoking during RCHT – yes |
0.749 (0.144–3.90) |
0.731 |
|
pack years |
0.995 (0.970–1.020) |
0.731 |
|
T characteristic |
||
|
1 |
– |
– |
|
2 |
4.126 (0.459–37.060) |
|
|
3 |
2.307 (0.269–19.750) |
0.206 |
|
4 |
– |
– |
|
x |
– |
– |
|
N characteristic |
||
|
1–2 |
– |
– |
|
3 |
5.653 (1.407–22.720) |
0.015 |
|
PTV volume |
2.718 (2.716–2.718) |
0.195 |
|
treatment time |
2.858 (2.557–3.287) |
0.369 |
|
platin |
||
|
carboplatin |
– |
– |
|
cisplatin |
0.306 (0.086–1.088) |
0.067 |
|
second agent |
||
|
etoposide |
– |
– |
|
paclitaxel |
0.989 (0.1650–5.927) |
>0.9 |
|
vinorelibine |
1.033 (0.242–4.417) |
>0.9 |
|
durvalumab to RT time |
1.020 (0.965–1.080) |
0.485 |
|
time from lab test to RT start |
||
|
white blood cell count – 103/µl |
0.973 (0.843–1.120) |
0.704 |
|
red blood cell count – 106/µl |
0.555 (0.156–1.980) |
0.365 |
|
hemoglobin – g/dl |
0.850 (0.562–1.290) |
0.443 |
|
hematocrit – % |
0.974 (0.848–1.120) |
0.707 |
|
PLT – 103/µl |
0.993 (0.982–1.000) |
0.194 |
|
PCT – % |
0.000 (3.04 x 10-9–10.1) |
0.122 |
|
neutrophils – % |
1.020 (0.973–1.060) |
0.453 |
|
lymphocytes – % |
0.983 (0.926–1.040) |
0.575 |
|
monocytes – % |
0.982 (0.849–1.140) |
0.812 |
|
eosinophils – % |
0.905 (0.67–1.220) |
0.516 |
|
basophils – % |
0.063 (0.006–0.642) |
0.020 |
|
Characteristic |
HR (95% CI) |
p value |
|
female |
– |
– |
|
male |
0.800 (0.078–8.162) |
0.851 |
|
age – years |
1.316 (1.066–1.618) |
0.010 |
|
T characteristic |
0.820 (0.150–4.495) |
0.819 |
|
nodal status |
10.026 (1.017–98.846) |
0.048 |
|
pack years |
1.003 (0.969–1.039) |
0.845 |
|
Characteristic |
HR (95% CI) |
p value |
|
female |
– |
– |
|
male |
2.728 (0.476–15.620) |
0.257 |
|
age – years |
1.080 (0.987–1.182) |
0.093 |
|
T characteristic |
0.996 (0.265–3.741) |
0.995 |
|
nodal status |
11.20 (1.746–71.827) |
0.011 |
|
basophils – % |
0.077 (0.007–0.853) |
0.037 |
The best cutoff value for the percentage of basophils was 0.7% (fig. 1B). In the univariable Cox model, the group with a percentage of basophils below this value demonstrated a trend toward significantly shorter OS (HR = 3.917, CI: 0.991–15.480, p = 0.052).
Discussion
In this study, we conducted a comprehensive single-center analysis of lung cancer patients who were treated with concurrent radiochemotherapy and adjuvant durvalumab. We sought associations between pre-treatment clinical and laboratory variables with overall survival in a real-world setting. Ongoing studies are currently focused on exploring various factors associated with the benefits of durvalumab [14–17]. While the neutrophil-to-lymphocyte ratio (NLR) has previously been identified as a predictor of OS in lung cancer patients [18], in our cohort, NLR did not show any significance in predicting OS in both univariate and multivariable models. However, in the multivariable model adjusted for age, sex, T characteristic, and nodal status, the percentage of basophils was significantly associated with OS; while the mechanism behind this association is presently unclear, it may be validated in bigger cohorts. In a study by Krizova et al., higher baseline basophils were demonstrated as a significant predictor of longer PFS in NSCLC patients treated with ICIs [19]. The absolute count of basophils was also demonstrated as a potential biomarker of ICI in advanced gastric cancer patients [20]. Another report by Liu et al. associated lower baseline basophil count with shorter disease-free survival [21].
In NSCLC patients, the main clinical predictors of survival are staging, ECOG status, weight loss, and serum albumin levels [22]. With the emergence of ICIs in the treatment of NSCLC, the PD-L1 expression was analyzed as a predictive factor. In a report by Bryant et al. [15], the group treated with durvalumab and with higher expression of PD-L1 had a longer PFS compared to the group that was not treated with ICI. Unfortunately, due to missing PD-L1 expression status in our cohort, we were not able to analyze its predictive value.
The tumor microenvironment is composed of various immune cells, and alterations in the composition of this infiltration have garnered significant interest in recent years [11, 25–27]. A study by Lavin et al. utilizing single-cell analysis to inspect the TME found fewer basophils in the TME of stage I adenocarcinoma compared to normal lung tissue [28]. Interestingly, a small proportion of basophils found in TME and non-involved lung parenchyma expressed PD-L1. The basophil levels in tumor-draining lymph nodes has been shown to be a useful predictor in pancreatic ductal adenocarcinoma, where, contrary to our results, higher levels were associated with poorer survival [29]. Additionally, a low percentage of basophils was found by Stankovic et al. in the immune infiltrate of NSCLC patients [30]. Future studies should explore the exact molecular alterations in basophils found in the TME.
One major limitation of our study is the small sample size. Additionally, our observation period was limited to two years, which may be considered relatively short. Furthermore, patients in our study received various chemotherapy regimens (carboplatin vs. cisplatin) (fig. 1D). To fully evaluate the significance of survival predictors in LA-NSCLC patients, more extensive studies with larger cohorts are needed.
Conclusions
In our univariate analysis significant predictors of OS in this group of patients were: nodal status, higher percentage of basophils, and D-dimer levels prior to the CCRT. In the multivariable Cox model, the percentage of basophils was associated with OS. The findings from this study could potentially contribute to the existing body of knowledge, influencing future studies search for predictors of OS, and illustrating the benefits of treatment with durvalumab in NSCLC.
Article information and declarations
Author contributions
Barbara A. Łochowska – conceptualization, investigation.
Konrad Stawiski – formal analysis, methodology, writing – review and editing.
Kasper Kuna – project administration, validation, writing – original draft preparation.
Zuzanna Nowicka – visualization, data curation, writing – review and editing.
Mariusz Łochowski – resources.
Jacek Fijuth – supervision.
Data availability
Datasets used for analysis for this study are available from the corresponding author upon reasonable request.
Ethics statement
The study was conducted in accordance with the Declaration of Helsinki.
Acknowledgments
The authors thank Jacek Fijuth for his supervision.
Conflict of interest
None declared
Barbara A. Łochowska
Copernicus Memorial Hospital in Lodz
Department of Radiotherapy and General Oncology
ul. Pabianicka 62
93-513 Łódź, Poland
e-mail: blochowska@op.pl
Received: 30 Jan 2024
Accepted: 5 Mar 2024
