Efficacy and safety of immune checkpoint inhibitors in lung large-cell neuroendocrine carcinoma

Introduction

Lung large-cell neuroendocrine carcinoma (L-LCNEC) is a rare and highly aggressive malignancy, representing approximately 2.0–3.5% of all primary lung cancers (1). In the 2021 World Health Organization (WHO) histological classification of lung tumors, L-LCNEC is classified as a neuroendocrine tumor with the following pathological criteria: non-small cell cytological features, neuroendocrine morphology, high mitotic rate, and positive expression of at least one marker including chromogranin-A, synaptophysin, or neural-cell adhesion molecule-1 (2). Additionally, about 10–25% of patients with LCNEC are diagnosed with combined LCNEC (c-LCNEC), characterized by the coexistence of LCNEC with adenocarcinoma (AC), squamous cell carcinoma (SCC), or other components (2-6). c-LCNEC typically indicates poorer prognosis compared to pure LCNEC (p-LCNEC), as associated with a higher incidence of lymph nodes and distant metastasis (1,7).

For L-LCNEC patients, even after early surgical resection, the postoperative recurrence is still high, with 63.9–82.0% of patient experiencing recurrence in 1 year (8-10). Currently, no standard therapeutic regimen exists for locally advanced or metastatic unresectable L-LCNEC. Due to its distinct biological characteristics, L-LCNEC is known to be more aggressive than non-small cell lung cancer (NSCLC) such as AC, and demonstrates a lower response rate to standard chemotherapy regimens used for small-cell lung cancer (SCLC). There is considerable debate regarding whether L-LCNEC should be approached and treated similarly to SCLC or NSCLC (11-13). In previous studies, the overall survival (OS) of advanced L-LCNEC patients receiving chemotherapy was approximately 7.0–12.6 months (14-18). Systemic chemotherapy appears to be of limited value to L-LCNEC patients. Therefore, it is necessary to develop more effective therapeutic regimens to treat L-LCNEC.

Immune checkpoint inhibitors (ICIs) have provided a major paradigm shift in the management of various cancers (19). For example, ICIs have been approved as a first-line treatment for NSCLC and SCLC, leading to significant improvements in prognoses (20,21). Despite the lack of prospective data correlating ICIs and L-LCNEC, several retrospective studies and case reports have been reported, providing insight into the effectiveness of ICIs for L-LCNEC (22-30). However, due to the rarity of L-LCNEC, the efficacy and safety of ICIs application remain unclear, and different pathological types may exhibit diverse treatment responses and prognoses.

This study therefore aimed to evaluate the efficacy and safety of ICIs on the treatment of advanced L-LCNEC. Moreover, we investigated the differences in the efficacy of ICIs application between pure and combined pathological types. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-348/rc).

Methods

Study design

The medical records of ICI-treated L-LCNEC patients at Zhejiang Cancer Hospital (Hangzhou, Zhejiang) from February 6, 2018 to February 6, 2023 were retrospectively analyzed. All patients met 2021 WHO LCNEC pathological diagnostic criteria using pathological and immunohistochemical (IHC) analyses. Cases with diagnostic uncertainties or controversies were excluded from the analysis. In non-surgical cases, additional tissue sampling was often performed after the initial biopsy to ensure accurate pathological assessment. The final diagnosis was established by two experienced pathologists. According to pathological diagnoses and IHC analyses, LCNEC with AC, SCC, or other components were defined as c-LCNEC, while LCNEC without other components was defined as p-LCNEC (2). The 22C3 pharmDx companion diagnostic assay (Agilent Technologies, Santa Clara, CA, USA) was utilized for IHC analysis of programmed cell death 1 ligand 1 (PD-L1) in formalin-fixed paraffin-embedded tissues. A tumor proportion score (TPS) of ≥1% was considered positive. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Ethics Committee at Zhejiang Cancer Hospital (No. IRB-2023-136) and individual consent for this retrospective analysis was waived.

Assessment of treatment responses

Data collection for this study involved comprehensive reviews of patients’ medical and follow-up records. Therapeutic regimens consisted of monotherapy or combination therapy clinical efficacy was assessed via regular computed tomography scans, typically taking place every two cycles or in the event of significant disease progression.

A panel of at least two independent medical professionals assessed treatment efficacy using the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). Disagreements among professionals were collaboratively resolved through information re-reviews and dialogues, and ultimately confirming both the objective response rate (ORR) and disease control rate (DCR). OS was defined as the time from advanced L-LCNEC diagnosis to death or the last follow-up. Progression-free survival (PFS) was defined as the time from the initial day of ICI treatment to disease progression or death, or to the last follow-up for surviving patients without disease progression.

Assessment of adverse events (AEs)

AEs and safety were evaluated based on the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE V5.0). Immune-related adverse events (irAEs) were AEs associated with the activation of the immune system and had an immunological basis. All irAEs were diagnosed and graded from 1 to 5 by a panel of at least two independent medical professionals.

Statistical analysis

Statistical analysis was conducted using SPSS Statistics for Windows, Version 25.0 (IBM, Armonk, NY, USA) and Prism, Version 9.0 (GraphPad, San Diego, CA, USA). Categorical variables were compared using Fisher’s exact test, and statistical significance was set at a two-sided probability (P) value <0.05. To estimate the PFS and OS, the Kaplan-Meier method was used, and the log-rank test was used to compare groups. Cox regression was used for multivariate analysis, and corresponding forest plots were generated. As of February 6, 2023, the last follow-up data were recorded.

Results

Patient characteristics

From February 6, 2018 to February 6, 2023, 34 ICI-treated L-LCNEC patients were included in this study. Table 1 provides an overview of the patients’ baseline characteristics. The median age of patients receiving ICI treatment was 64.5 years (range, 46–79 years), and the majority of patients were male (31/34, 91.2%) and former or current smokers (28/34, 82.4%). The Eastern Cooperative Oncology Group performance status was 2 in two patients (5.9%) and 0/1 in 32 (94.1%). Tumor-node, metastasis staging showed that most patients (29/34, 85.3%) were stage IV, and extrathoracic metastases were observed in 23 patients (23/34, 67.6%). Fifteen patients (15/34, 44.1%) had undergone early surgical resection with the median time to recurrence being 7.6 months (range, 1.3–68.9 months). Excluding these 15 patients, 15 of the remaining patients (44.1%) underwent percutaneous lung biopsy, and four underwent bronchial biopsy to confirm pathological diagnoses. Pathological examination revealed seven patients (7/34, 20.6%) were c-LCNEC, while 27 patients (27/34, 79.4%) were p-LCNEC. The median expression level of neuron-specific enolase (NSE) was 18.53 µg/L (range, 11.00–370.00 µg/L).

Table 2 summarizes the ICI treatment characteristics, where more than half of the patients (19/34, 55.9%) received second- or higher-line ICI treatments. Only two patients (5.9%) received ICI monotherapy, while 32 (94.1%) received ICIs in combination with chemotherapy. The most frequent ICI types were Tislelizumab (7/34, 20.6%), Sintilimab (7/34, 20.6%), and Camrelizumab (5/34, 14.7%). Of the 34 patients, 9 (26.5%) were tested for PD-L1 expression, and five patients (5/34, 14.7%) were PD-L1 positive. As of the last follow-up, the ICI treatments were ongoing in two patients (5.9%).

Treatment response and survival analysis

Among the 34 ICIs-treated L-LCNEC patients, 10 (29.4%) achieved partial response (PR), and 18 (52.9%) achieved stable disease (SD). The ORR of ICI treatment was 29.4% and the DCR was 82.4%. The median PFS was 6.30 months [95% confidence interval (CI): 4.33–8.27], the 1-year PFS was 17.6% (6/34), and the median OS was 14.77 months (95% CI: 10.07–19.46), with a 1-year OS of 64.7% (22/34). Figure 1 provides specifics on the ICI treatments.

Figure 1 Swimmer plot of immune checkpoint inhibitors-treated lung LCNEC patients. LCNEC, large-cell neuroendocrine carcinoma; PR, partial response; SD, stable disease; PD, progressive disease.

According to the number of treatment lines, 34 patients were divided into first-line and second- or higher-line groups. Among the 15 patients (44.1%) in the first-line group, 8 (53.3%) achieved PR and 5 (33.3%) achieved SD. Of the 19 patients (55.9%) in the second- or higher-line group, 2 (10.5%) achieved PR, and 13 (68.4%) achieved SD. The ORR of ICIs as first-line treatment (53.3%, 8/15) was higher than that of the second- or higher-line (10.5%, 2/19), with a statistically significant difference (P=0.007). There was no significant difference in DCR between the first- and second- or higher-line groups (86.7%, 13/15 vs. 78.9%, 15/19, P=0.558). The median PFS and OS of the 15 patients receiving first-line treatment were 6.53 months (95% CI: 3.54–9.52) and 12.13 months (95% CI: 7.43–16.83), respectively. The median PFS and OS of the 19 patients receiving second- or higher-line treatment were 5.87 months (95% CI: 3.26–8.47) and 19.47 months (95% CI: 14.28–24.66), respectively. There was no significant difference in PFS between the two groups (P=0.949, Figure 2A), but the difference in OS was statistically significant (P=0.031, Figure 2B).

Figure 2 Kaplan-Meier curves of PFS and OS according to treatments and pathological types. (A) PFS of first-line vs. second- and higher-line treatments. (B) OS of first-line vs. second- and higher-line treatments. (C) PFS of combined LCNEC vs. pure LCNEC patients. (D) OS of combined LCNEC vs. pure LCNEC patients. PFS, progression-free survival; OS, overall survival; LCNEC, large-cell neuroendocrine carcinoma.

All L-LCNEC patients were further grouped into the c-LCNEC (7/34, 20.6%) and p-LCNEC (27/34, 79.4%) groups according to pathological types. Comparison of the characteristics between the two groups is listed in Table S1. The ORRs of the c-LCNEC and p-LCNEC groups were 14.3% (1/7) and 33.3% (9/37), respectively, with no significant difference (P=0.261). The DCRs of the two groups were 100% (7/7) and 77.8% (21/27), respectively, with no statistical difference (P=0.261). The median PFS and OS in the c-LCNEC group were 12.47 months (95% CI: 6.82–18.12) and 21.27 months (95% CI: 3.37–39.17), respectively. The median PFS and OS in the p-LCNEC group were 5.60 months (95% CI: 3.12–8.08) and 14.73 months (95% CI: 12.71–16.76), respectively. The PFS and OS survival curves (Figure 2C,2D) were separated between the two groups, and the difference in PFS was statistically significant (P=0.032, Figure 2C), but the difference in OS was not statistically significant (P=0.233, Figure 2D).

Safety and toxicity evaluations

The 34 L-LCNEC patients included in the study were evaluated for treatment toxicity, and the irAEs of any grade are recorded in Table 3. Among the 34 patients, irAEs occurred in 21 patients (61.8%), mainly grades 1 (38.2%, 13/34) and 2 (20.6%, 7/34). The incidence of grade 3 irAE patients was 5.9% (2/34), and no irAE patients above grade 3 occurred. Elevated transaminases (14.7%, 5/34), pneumonia (8.8%, 3/34), and fatigue (8.8%, 3/34) were the most common irAEs. Two (5.9%) patients had grade 3 pneumonia, and 1 (2.9%) patient discontinued ICI treatment.

Discussion

Due to the rarity of L-LCNEC and the lack of relevant prospective studies, there is currently no consensus on an effective therapeutic regimen for advanced L-LCNEC (20). However, our results indicated that ICIs treatment showed efficacy in L-LCNEC patients, especially in c-LCNEC patients. Moreover, the toxicity of treatment was manageable. To the best of our knowledge, our study presents the first comparative analysis between c-LCNEC and p-LCNEC patients, and is the largest record of irAEs patients.

In our retrospective study, the ORRs and DCRs of 34 ICIs-treated L-LCNEC patients were 29.4% and 82.4%, respectively, and the median PFS and OS were 6.30 and 14.77 months, respectively. These results were consistent with comparable retrospective studies (Table S2). In two studies with sample sizes greater than 20, Dudnik et al. (28) reported a median OS of 12.4 months (95% CI: 10.7–23.4) in a cohort of 41 ICIs-treated L-LCNEC patients. Sherman et al. (27) reported an ORR of 33%, median PFS of 4.2 months, and median OS of 11.8 months in a cohort of 21 ICIs-treated L-LCNEC patients. Compared with their results, our results showed a longer PFS and OS, which may be attributed to the fact that we included more patients with PS 0/1 (32/34, 94.1%) and a higher proportion of ICIs combined with chemotherapy (32/34, 94.1%). In several other small sample studies (8–13 patients), the ORR was 9.1–75.0%, the PFS was 2.70–6.85 months, and the OS was 4.6–25.2 months (24-26). When comparing the first-line and later-line treatments, we observed a shorter OS in the first-line (12.13 months) compared to the latter (19.47 months, P=0.031), despite achieving a higher ORR in the first-line (53.3% vs. 10.5%, P=0.007). We speculate that these results may be attributed to the inclusion of relatively small sample size and the potential biases introduced by baseline characteristics, such as adjuvant chemotherapy after surgery, PD-L1 expression, and subsequent treatment regimens, which could have influenced the OS outcome. Although we could not directly compare our results with historical control studies, the above studies and our study still showed efficacy of ICIs for the treatment of L-LCNEC. Consequently, ICIs are a potential therapeutic regimen for L-LCNEC patients.

L-LCNEC can be classified as a combined or pure type according to its components (2). Our cohort included 7 c-LCNEC patients, with an occurrence rate of 20.6% falling within the range of 10–25% reported in previous studies (2-6). Most patients were diagnosed by surgery (85.7%) and c-LCNEC with AC (57.1%). Previous research consistently associates c-LCNEC with poorer prognosis and the occurrence of multiple metastases (1,7,12,31,32). In Zhang’s study (12), in which we participated previously, a total of 220 p-LCNEC and 30 c-LCNEC patients were analyzed. The median OS was found to be significantly longer in p-LCNEC compared to c-LCNEC. However, Tsutsumi et al. (29) reported that a 73-year-old c-LCNEC patient with brain metastases achieved PR after receiving atezolizumab combined with carboplatin and nab-paclitaxel, which was maintained for 12 months. Xu et al. (30) reported a 54-year-old locally advanced c-LCNEC patient who was maintained with durvalumab after concurrent radiotherapy and chemotherapy, who achieved complete remission. The above cases suggested that c-LCNEC patients may exhibit favorable treatment response to ICIs. We therefore further analyzed the efficacy of different pathological types of ICI-treated L-LCNEC patients. Survival analysis revealed that c-LCNEC patients receiving ICI treatment had longer PFS compared to p-LCNEC patients (12.47 vs. 5.60 months, P=0.032), while OS showed a longer duration but did not reach statistical significance (21.27 vs. 14.73 months, P=0.233), possibly due to the small sample size. In subsequent multivariate analysis (Figure S1), pathological type (HR =0.281, 95% CI: 0.091–0.865, P=0.027) remained a significant factor affecting PFS, but not for OS. Additionally, in three cases mixed with AC, with an evaluable composition ratio, AC accounted for 80%, 30%, and 15%. The corresponding PFS times were 9.47, 6.00, and 3.73 months. Therefore, we propose the potential for greater benefit of ICIs to c-LCNEC, which may be related to the high tumor mutational burden (33) and the distinct biological characteristics of combined components, but more clinical evidence is still needed.

In addition, we recorded all observed irAEs. Overall, the toxicity profile of ICI treatment in L-LCNEC patients was manageable, with grade 3 irAEs detected in only 5.9% of patients (2/34), and most irAEs were grade 1/2 (55.9%, 19/34). Elevated aminotransferases (14.7%, 5/34), pneumonia (8.8%, 3/34), and fatigue (8.8%, 3/34) were the most common irAEs. Specifically, pneumonia occurred in three patients, and one had to discontinue treatment accordingly. No patients died from ICI treatment.

Our study had several limitations. First, the rarity of L-LCNEC led to a small sample size, potentially limiting the generalizability of our findings. Second, as a retrospective study, our analysis depended on medical records, which might have introduced biases in data collection. Third, the absence of a centralized pathological revision could have resulted in the inclusion of certain c-LCNEC cases within the p-LCNEC group. Additionally, a considerable number of cases lacked PD-L1 assessment, which could introduce bias when evaluating the impact of treatment outcomes.

Conclusions

ICIs showed therapeutic efficacy in treating L-LCNEC patients, with the potential for greater benefits in the c-LCNEC subtype. However, larger cohort studies, especially prospective studies, are needed to further investigate their effectiveness.

Acknowledgments

We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

Funding: This study was funded by the Medical Scientific Research Foundation of Zhejiang Province (No. 2022KY653).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-348/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-348/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-348/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-348/coif). ZS reports that this study was funded by the Medical Scientific Research Foundation of Zhejiang Province (No. 2022KY653). ZS was sponsored by Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Ethics Committee at Zhejiang Cancer Hospital (No. IRB-2023-136) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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