Efficacy of immune checkpoint inhibitors in advanced large cell neuroendocrine carcinoma of the lung: A single‑institution experience
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- Published online on: January 31, 2024 https://doi.org/10.3892/ol.2024.14268
- Article Number: 135
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Copyright: © Yan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare disease, accounting for ~3% of all lung cancer cases (1,2). The cancer is highly invasive, with rapid development and hidden symptoms, and is difficult to diagnose early (3). In total, ~40% of patients with LCNEC are initially diagnosed at stage IV, with no opportunity for surgery. Hence, the overall prognosis is poor, with a median overall survival (mOS) time of only 8–12 months (4). In 2015, the World Health Organization defined LCNEC as a unique subtype of lung neuroendocrine neoplasms and one of the subtypes of non-small cell lung cancer (NSCLC) (5). However, its biological and clinical characteristics, and prognostic factors, are similar to those of SCLC (6). Next-generation sequencing has revealed molecular heterogeneity among patients with LCNEC that could be roughly divided into two subtypes: The SCLC-like subtype that mainly co-occurs with TP53 and RB1 mutations, and the NSCLC-like subtype that is mainly associated with KRAS, STK11/KEAP1 and/or TP53 mutations (7,8). Studies have shown that the NSCLC-like and SCLC-like subsets have no differences in terms of mOS and median progression-free survival (mPFS) (7). However, Zhuo et al (9) demonstrated that genomic subtype analysis plays a role in the prognostic and therapeutic decisions for patients with LCNEC.
The clinical management of LCNEC is controversial due of its low incidence rate and unusual pathological features. Radical surgical resection is primarily recommended for early stage LCNEC (10), with reported OS benefits for patients with resectable LCNEC (11–13). Postoperative platinum-based single-agent or multi-agent adjuvant chemotherapy can prolong survival time (14,15); however, utilizing preoperative neoadjuvant chemotherapy remains controversial due to uncertain efficacy (3). Currently, no standardized treatment strategy exists for the multi-disciplinary and comprehensive treatment of advanced LCNEC, with most regimens relying on chemotherapy. Existing evidence supports the efficacy of drugs commonly used in the treatment of SCLC, such as platinum-etoposide (SCLC-like regimen), and advanced LCNEC (16–18). The selection of a first-line treatment for metastatic LCNEC poses challenges due to the predominantly small scale and retrospective nature of available studies, with some yielding conflicting results, as some choose SCLC-like regimens, while other select NSCLC-like regimens (4).
Immune checkpoint inhibitors (ICIs) targeting programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have transformed treatment planning for patients with driver mutation-negative advanced NSCLC (19,20). Due to the lack of prospective evidence, the efficacy of immunotherapy in LCNEC remains unestablished. Data from existing case reports and small retrospective studies are promising, indicating that the mPFS time of patients with advanced LCNEC using ICIs was 4.2–14.2 months, while the mOS time was 11.8 months (21–24). However, the efficacy and safety of ICIs in patients with LCNEC remain controversial. Therefore, further assessment is necessary to validate the effect of LCNEC on ICI efficacy in a more homogeneous patient subgroup, especially given that the treatment regimen may considerably affect outcomes. The present study aimed to evaluate the effect of ICIs on treatment response and survival outcomes in patients with advanced LCNEC.
Materials and methods
Patient selection and clinical data
The present retrospective study included patients with pathologically confirmed advanced LCNEC (stage IV; poorly differentiated, large cell, abundant cytoplasm and multiple necrosis) who visited The First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between January 1, 2019, and September 9, 2021. The main inclusion criteria were as follows: i) Pathologically confirmed LCNEC, mixed LCNEC and SCLC, and mixed LCNEC and NSCLC with a predominant LCNEC component; and ii) the presence of at least one observable or measurable lesion. The exclusion criteria were as follows: i) The presence of non-primary lung cancer; ii) previous or current malignant tumors of other types; and iii) uncontrolled dysfunction of any major organ. After obtaining approval from the Institutional Ethical Review Board of the First Affiliated Hospital of Zhengzhou University (approval no. 2022-KY-0592-002), baseline demographic [including age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS score) (25), and smoking history], clinical, pathological and treatment characteristics, were retrospectively collected, in addition to toxicity and outcome data.
Study design and treatment methods
Patients were divided into group A (patients who received ICIs as any treatment line; n=73) and group B (patients who did not receive ICIs; n=75). Group A was further divided into group C (patients who received chemotherapy combined with ICIs; n=34) and group D (patients who received anti-angiogenic agents combined with ICIs; n=32) for analysis. Additionally, patients were divided into pure LCNEC and mixed LCNEC (squamous cell carcinoma, adenocarcinoma and small-cell carcinoma) based on the pathological type.
Chemotherapy consisted of etoposide (80–100 mg/m2, administered on days 1–3 of each 21-day cycle), pemetrexed (500 mg/m2), docetaxel (75 mg/m2) or paclitaxel (175 mg/m2) (administered on day 1 of each cycle), with or without carboplatin (area under the curve, 4–6), cisplatin (75–80 mg/m2) or nedaplatin (80–100 mg/m2) (administered on day 1 of each 21-day cycle), based on the investigator's judgment. Patients in groups A and C received 4–6 cycles of chemotherapy plus ICIs, followed by maintenance ICIs every 3 weeks. Anti-angiogenic therapy consisted of anlotinib (8–12 mg, taken orally once a day for 2 weeks with a 1-week break), apatinib (250 mg, taken continuously) and bevacizumab (15 mg/kg, administered on day 1 of each 21-day cycle). ICIs consisted of pembrolizumab (200 mg), camrelizumab (200 mg), sintilimab (200 mg), toripalimab (240 mg), tislelizumab (200 mg), atezolizumab (1,200 mg) or durvalumab (1,500 mg, administered on day 1 of each 21-day cycle). Patients continued treatment until disease progression based on investigator assessment, unacceptable toxicity or other discontinuation criteria. Continuation of the study's treatment regimen following disease progression was permitted if clinical benefit was proven. Group C was comprised of 34 patients as follows: Patients with NSCLC who received pemetrexed-platinum (n=1), paclitaxel-platinum (n=5), docetaxel-platinum (n=2) and gemcitabine-platinum (n=2), and patients with SCLC who received etoposide-platinum (n=20) (4 patients received thoracic radiotherapy and 1 patient received palliative radiotherapy for brain metastasis) and irinotecan-platinum (n=4). In total, 32 patients were included in group D, and the following anti-angiogenesis drugs were used: Anlotinib, apatinib and bevacizumab. A single patient with brain metastasis received palliative radiotherapy.
Evaluation of efficacy
The revised Response Evaluation Criteria in Solid Tumors, version 1.1 (26), was used to evaluate the treatment efficacy, including complete response, partial response (PR), stable disease (SD) and progressive disease (PD) statuses. PFS was defined as the time from the start of ICI treatment to the date of disease progression or death due to any cause. Overall survival (OS) was defined as the time from advanced disease diagnosis until death or censored at the last follow-up visit. Immune-related adverse events (irAEs) were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5.0 (27). Duration of follow-up was calculated from the time of advanced disease diagnosis until the last follow-up visit or censored at death. The cut-off date for data collection was June 14, 2022.
Statistical analysis
Categorical variables are presented as numbers and percentiles. Medians and ranges are reported for continuous variables. Fisher's exact and χ2 tests were used to compare the baseline demographic, clinical and pathological characteristics (except for age, tumor size and Ki-67 values, which are continuous variables that were tested using an independent sample t-test). The Kaplan-Meier method was used to estimate survival rates and the log-rank test was used to analyze between-group survival differences. Case characteristics were regarded as independent prognostic factors if they showed a significant association (P<0.05) in the multivariable regression with a Cox proportional hazards model. Statistical analyses were conducted using SPSS 26.0 (IBM Corp). P<0.05 was used to indicate a statistically significant difference.
Results
Demographic and clinical characteristics
In total, 174 patients with histologically confirmed LCNEC were diagnosed at The First Affiliated Hospital of Zhengzhou University between January 1, 2019, and September 9, 2021. A total of 26 patients with early stage disease were excluded. Thus, 148 patients were clinically evaluated (Fig. 1). The baseline demographic, clinical and pathological characteristics of the 148 patients are summarized in Table I, and the detailed treatment regimens and outcomes for all patients are presented in Table II. All patients in the clinical analysis underwent follow-up from the time of pathological diagnosis to June 14, 2022, or until death.
 | Table I.Baseline clinical, pathological and treatment characteristics of patients with advanced large cell neuroendocrine carcinoma of divided according to exposure to ICI. |
The patients had a median age of 67 years (age range, 32–86 years), were mostly men (88.5%) and had a history of smoking (58.8%). Patients with an ECOG PS score ≥2 at diagnosis accounted for 20.3% of the population. LCNEC occurred in the lung lobe, and no significant differences were observed in the distribution of LCNEC between the left and right lungs. All the patients had stage IV LCNEC at diagnosis, while 20.3% had brain metastases, 13.5% had liver metastases and 14.9% had bone metastases. Moreover, 104 patients (70.3%) had pure LCNEC and 44 had combined LCNEC (mixed LCNEC and SCLC, 22.3%; mixed LCNEC and NSCLC, 7.4%). The positive rate of serum tumor marker cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) was the highest (65.5%), followed by neuron-specific enolase (NSE) (61.5%), and the positivity rates for carcinoembryonic antigen (CEA) and cancer antigen (CA)-125 were low. The levels of peripheral blood markers such as the neutrophil/lymphocyte ratio (NLR), cholesterol and triglyceride were low, while the lactate dehydrogenase (LDH) level was higher than normal in ~66.2% of patients. The median Ki-67 level was 80.0% [inter-quartile range (IQR), 66.2–80.0%]. Group B had more patients with increased NSE and CA125 levels (P=0.033 and P=0.020, respectively) than group A. All patients received chemotherapy, anti-angiogenic therapy or immunotherapy according to their condition, and some patients received radiotherapy. Of these, 73 patients received ICIs (group A) and 75 patients did not receive ICIs (group B). In group A, 7 patients (9.6%) received immunotherapy alone, 34 patients (46.6%) received chemotherapy combined with immunotherapy and 32 patients (43.8%) received anti-angiogenic combined immunotherapy (Tables I, II, and Fig. 2).
Patient outcomes
Efficacy of ICI based on LCNECThe primary endpoint of this study was OS. The mean follow-up duration was 18.18 months (IQR, 1.8–56.13 months) in group A and 12.56 months (IQR, 0.43–40.37 months) in group B. By the end of follow-up, 34 patients (46.6%) in group A and 50 patients (66.7%) in group B had died. The mOS time of group A was 23.500 months [95% confidence interval (CI), 18.524–28.476] and that of group B was 11.230 months (95% CI, 4.530–18.930). The survival time of group A was significantly longer than that of group B (P=0.001) (Fig. 3A). In the univariate analysis, ICI administration (P<0.001), histological type (P=0.043), lymph node metastases (P=0.032) and number of metastatic organs (P=0.009) demonstrated a significant association with OS (Fig. 3A-D; Table III). However, sex, smoking status, ECOG PS score, presence of brain, liver and bone metastases, and levels of NLR, CEA, CA125, CYFRA21-1, LDH, cholesterol and triglycerides did not demonstrate any significant associations with OS (all P>0.05) (Table III). In the multivariate Cox regression analysis model, which incorporated all factors significantly associated with OS from the univariate analysis, ICI administration (P<0.001), pathological type (P=0.005), lymph node metastases (P=0.030) and number of metastatic organs (P=0.011) were significantly associated with OS (Table III).
| Table III.Univariate and multivariate Cox regression analyses of overall survival since the diagnosis of advanced disease in patients with advanced large cell neuroendocrine carcinoma. |
Efficacy analysis of combination therapy based on immunotherapy
Comparison of the survival rateSince different treatment regimens were used in group A (patients who received ICIs), it was subdivided into group C (patients who received chemotherapy combined with ICIs; n=34) and group D (patients who received anti-angiogenic agents combined with ICIs; n=32). A total of 7 patients who received monotherapy with an anti-PD-1/PD-L1 agent were not included in the analysis. No differences were found in baseline characteristics between the two groups, except for age (P=0.026), and the clinical and pathological characteristics of the patients are summarized in Table IV.
| Table IV.Baseline clinical, pathological and treatment characteristics of patients with advanced large cell neuroendocrine carcinoma of the lung by treatment regimen. |
Among the 66 response evaluable patients, 22 (33.3%) patients achieved a confirmed PR, 35 (53.0%) patients achieved SD and 9 (13.6%) patients experienced PD. The disease control rate (DCR) was 86.4% (n=57/66) (Tables II and V). No significant differences were found in the DCR between the two groups (χ2=0.730, P=0.460) (Table V).
The median follow-up period was 13.7 months in group C (IQR, 9.25–18.95 months) and 18.97 months in group D (IQR, 12.38–35.33 months). At the end of the study period, 16 patients (47.1%) in group C and 15 patients (46.9%) in group D had died. The median OS times were 20.70 months (95% CI, 12.065–29.335) and 25.97 months (95% CI, 19.095–32.839) in groups C and D, respectively (P=0.181; Fig. 4). The PFS times were 9.77 months (95% CI, 4.991–14.542) and 9.37 months (95% CI, 2.015–16.718) in groups C and D, respectively (P=0.82; Fig. 4). Immuno-based combination therapy (group C vs. group D) exhibited no significant association with regard to mPFS and mOS. Univariate analysis showed that the ECOG PS score (P=0.045), number of metastatic organs (P=0.02), and CA125 level (P=0.01) exhibited a significant association with regard to mOS but not mPFS (Fig. 4; Table VI). In addition, age, sex, smoking status, pathological type (pure LCNEC vs. mixed LCNEC), presence of brain, liver and bone metastases, and levels of NLR, CEA, CYFRA21-1, LDH, cholesterol and triglycerides were also not associated with OS (all P>0.05). However, in the multivariate Cox regression analysis, no statistical significance was observed between the CA125 level and OS (P=0.070) (Table VI).
| Table VI.Univariate and multivariate Cox regression analyses of overall survival in patients with advanced LCNEC by treatment regimen. |
irAEs
No statistically significant differences were observed between the development of irAEs and the use of combined immunotherapy regimen (group C vs. group D, P=0.48). The frequency of corticosteroid use was significantly higher in group C than that in group D (P=0.001). The most common irAEs were hypothyroidism (n=5) and immune-associated pneumonitis (n=3). No statistically significant differences were observed with regard to irAE grade (P=0.49) and permanent treatment discontinuation due to irAEs (P=0.65) between the two groups (Table VII).
| Table VII.Safety analysis of the total study population based on advanced large cell neuroendocrine carcinoma of the lung. |
Discussion
The prognosis of patients with LCNEC is generally poor, and the 5-year survival rate of those with advanced stage disease is as low as 8% (28). Currently, the first-line treatment of metastatic LCNEC is still controversial, and the chemotherapy regimen for advanced LCNEC tends to be the same regimen as that for SCLC. Based on the results of the present study and those of current small-scale and retrospective studies, the prognosis remains poor, with an mOS time of 8–12 months (17,29). The combination of immunotherapy with etoposide-platinum chemotherapy has been identified as the standard first-line treatment for advanced SCLC (30,31). However, due to the rarity of LNCEC and the lack of prospective evidence, the efficacy of immunotherapy in LCNEC has not been determined. According to the present findings, the mOS of the ICI group was 23.500 months, which was double that of the non-ICI group (11.230 months). The results of univariate and multivariate analyses further supported the positive effect of ICI on the OS time of patients with advanced LCNEC. The present results are in line with the previously reported data on LCNEC (21), suggesting that immunotherapy is a superior treatment and providing valuable insight regarding possible therapeutic options for advanced LCNEC. For instance, a recent retrospective study (24) assessed the efficacy and safety of ICIs in 37 patients with advanced LCNEC and concluded that patients receiving mono-immunotherapy or a combination of different ICIs exhibited a favorable prognosis with an objective response rate of 33%, an mPFS time of 4.2 months and a mOS time of 11.8 months. In addition, a real-world study (21) showed that ICIs had a positive impact on OS, with mOS time of 12.4 months in patients who received ICIs and 6.0 months in patients who did not. Agar et al (22) reported that the mOS time of patients administered nivolumab treatment was 12.1 months (95% CI, 7.10–14.20), indicating that nivolumab as a second-line treatment or beyond showed a high level of tumor response and prolonged OS time in patients with advanced LCNEC. This result is consistent with the present finding that ICI administration is associated with prolonged OS time in patients with LCNEC.
In population-based studies, age, sex, primary tumor size, lymph node metastasis and tumor stage have been identified as prognostic factors for lung cancer survival (32,33). Previous studies have shown that LCNEC is highly prevalent in elderly men with a history of smoking (3). In the present study, the median age of patients was 67 years, with a predominance of men. Among them, 58.8% had a history of smoking and 100% had stage IV LCNEC at the time of diagnosis, with distant metastases mainly in the brain, liver and bones. Serum tumor markers such as CEA, NSE, CA125 and CYFRA21-1 are important indicators of an auxiliary diagnosis of lung cancer (34). In the present study, CYFRA21-1 had the highest positivity rate, followed by NSE, while the positivity rates of CEA and CA125 were low. Studies have shown that peripheral blood markers such as NLR and LDH are high-risk factors for a poor prognosis in patients with NSCLC (35). In the present study, 61.5 and 66.2% of the patients had elevated NLR and LDH levels, respectively, but univariate and multivariate analyses showed no statistical association between these markers and OS. Considering the presence of differences in baseline and treatment characteristics favoring patients treated with ICIs in the present cohort, further analysis after elimination of confounding factors is required. A recent retrospective study of 251 patients with LCNEC after surgical resection (36) showed that only lymphatic infiltration was an independent prognostic factor. The present study showed a significant association between OS and lymph node metastasis and the number of metastatic organs. Patients with lymph node metastasis and >2 metastatic organs had a poor prognosis. Thus, lymphatic invasion affects surgical efficacy in the early stage and functions as an independent risk factor of poor prognosis in patients with advanced LCNEC. In addition, distant metastasis is an indicator of prognosis.
In clinical practice, the incidence of LCNEC with other lung cancer subtypes (e.g., SCLC, adenocarcinoma and squamous cell carcinoma) is ~10% (37,38). However, the differences in clinical characteristics, prognosis and treatment between pure LCNEC and mixed LCNEC remain unclear. Zhang et al (16) showed that the mOS time of patients with pure LCNEC was significantly greater than that of patients with combined LCNEC (P=0.083). The present study explored the difference in prognosis between pure and combined LCNEC. The results of the univariate and multivariate analyses showed that the histological type of LCNEC was significantly associated with the mOS time, and the difference in the mOS time between patients with pure LCNEC and combined LCNEC was statistically significant. Therefore, the prognosis of mixed LCNEC was worse than that of pure LCNEC. However, the retrospective nature and limited sample size of the present study may impact the ability to draw a definite conclusion. Nevertheless, the data indicate that the heterogeneity of pathological components may be related to prognosis.
Anti-angiogenic agents can regulate the tumor immune microenvironment and exert synergistic action when combined with ICIs (38,39), highlighting the potential of the combined application of antitumor therapy as a new treatment strategy for advanced LCNEC. In a multicenter, open-label, single-arm, phase II clinical study of surufatinib in combination with toripalimab in patients with advanced neuroendocrine carcinoma (NCT04169672) (40), 21 patients received combination therapy. Among 20 tumor evaluable patients, the objective response rate (4 patients achieved confirmed PR and 10 patients achieved SD) and DCR were 20 and 70%, respectively. The median PFS time was 3.94 months (95% CI, 1.31 to unknown). Based on these findings, the present study further analyzed the efficacy and influencing factors of combined chemotherapy and anti-angiogenesis therapy on the basis of immunotherapy. In the present study, the difference in the DCR between the two groups was not statistically significant. Moreover, immuno-based combination therapy (chemotherapy vs. anti-vascular endothelial growth factor therapy) was not significantly associated with the mPFS or mOS time. Further analysis showed that the ECOG PS score, number of metastatic organs and CA125 level were significantly associated with a poor prognosis, but not with PFS time. In the multivariate Cox regression analysis, CA125 level was still significantly associated with the mOS time. No statistically significant differences were found with regard to the effects of ICI combination therapy on mOS time among patients with elevated levels of NLR, CEA, CYFRA21-1, LDH, cholesterol and triglycerides. Furthermore, patients with advanced LCNEC in the enrolled cohort with a better ECOG PS score, fewer metastatic organs and lower CA125 levels had better outcomes after ICI-based systemic therapy than their counterparts. Considering that 34 and 32 patients were included in groups C and D, respectively, in this retrospective study, the influence of the small sample size and selection bias, and other related factors, could not be excluded. Therefore, expanding the sample size to conduct a multi-cohort study is necessary to verify the findings.
This single-center retrospective study had several limitations. First, no centralized histological review of the enrolled patients was present. LCNEC may be difficult to diagnose, and a small biopsy is usually insufficient; thus, a surgical lung biopsy is usually required (3,4). In the present study, the diagnosis of patients depended on findings from histological examinations, and only some patients underwent next-generation sequencing to determine the pathological type. Second, comprehensive molecular tumor characteristic data that could be applied to most patients were lacking, and the PD-L1 status of some patients was unknown. Therefore, the study did not analyze the prognostic correlation between PD-L1 expression levels and ICI treatment, which needs to be analyzed in future studies. Lastly, other limitations to the present study included its retrospective design, lack of a central pathology assessment and a small sample size of patients receiving ICIs. Overall, the results of the present study suggest that ICIs are a reasonable choice for the treatment of advanced LCNEC in the absence of other treatment options, but prospective clinical studies are needed to confirm the value of ICIs in the treatment of LCNEC.
Acknowledgements
Not applicable.
Funding
This study was funded by the Joint Construction Project of Henan Province and Ministry (grant no. LHGJ20190013).
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
NY, SG, SS and XL conceived and designed the study. Administrative support was provided by NY and XL. SG, ZZ and SS provided study materials or patients. Collection and assembly of data was performed by NY and SG. Data analysis and interpretation was performed by NY, SG, ZZ and SS. NY, SG, SS and XL confirm the authenticity of all the raw data. All authors helped to write the manuscript. All authors have read and approved the manuscript.
Ethics approval and consent to participate
The Ethics Committee of the First Affiliated Hospital of Zhengzhou University approved this study (approval no. 2022-KY-0592-002). The requirement for informed consent was waived by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University due to the retrospective design and use of anonymized patient information. All procedures have been performed in accordance with the Declaration of Helsinki.
Patient consent for publication
The requirement for informed consent was waived by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (approval no. 2022-KY-0592-002).
Competing interests
The authors declare that they have no competing interests.
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