Clinical practice review of systemic treatment in large cell neuroendocrine carcinoma

Introduction

Neuroendocrine tumors (NETs) of the lung comprise a heterogeneous group of malignancies that arise from pulmonary neuroendocrine cells. These can be classified into four groups: typical carcinoid (TC), atypical carcinoid (AC), small-cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC). LCNEC of the lung was first described in 1991 as a pulmonary NET consisting of cells with large size, high mitotic rate, and with a neuroendocrine appearance both by light microscopy and either immunohistochemistry (IHC) or electron microscopy (EM) (1). The definition of LCNECs was further refined by the 2015 World Health Organization (WHO) Classification of Lung Tumors, and later by the 2021 classification (2,3). According to the 2021 WHO criteria, lung neuroendocrine neoplasms are divided into low-grade tumors (grades 1 and 2) and high-grade (grade 3) tumors. Low-grade tumors include TC and AC tumors, and high-grade tumors include SCLC, LCNEC, and carcinomas with mixed SCLC/LCNEC histology.

LCNEC, a rare and aggressive cancer, is most commonly seen in older patients and those with a smoking history, with earlier studies often showing a strong preponderance of male patients (4-7). Larger and more recent studies using the Surveillance, Epidemiology, and End Results (SEER) database have demonstrated a less unequal sex ratio, with sex ratios of 1.27 and 1.30 in LCNEC patients (8,9). LCNEC histology in tumors can also exist in combination with other lung cancer histologies, such as SCLC or non-small cell lung cancer (NSCLC) (10). Although primarily seen in the lung, extra-pulmonary neuroendocrine carcinoma (EP-NEC) can also be seen in the gastroenteropancreatic (GEP) tract, the genitourinary (GU) tract, and gynecological (GY) tract (11).

Patients with LCNEC generally show a poor prognosis with 5-year overall survival (OS) rates ranging from 15% to 57% (7,12). Similar to SCLC but contrasting to NSCLC, treatment for LCNEC has made minimal advancement and remains an area of need.

LCNEC of the lung is classified as a neuroendocrine carcinoma (NEC) which differs from NETs of the lung (13). The 2021 WHO criteria define LCNECs as a tumor with neuroendocrine morphology, high mitotic count (>10 mitoses/2 mm²), presence of necrosis, positive NET marker staining, large cell size and low nuclear to cytoplasmic ratio. This contrasts with SCLC, which typically presents with small cell size, high nuclear to cytoplasmic ratio, and typically less necrosis. Key characteristics of both pulmonary NETs and NECs are shown in Table 1. LCNEC as a formal pathologic diagnosis can only be determined in resected specimens. Smaller biopsies and fluid cytology results that are consistent with LCNEC are now described as non-small cell carcinomas not otherwise specified (NSCC NOS), as there is not sufficient structural detail in a small biopsy sample to definitively classify these as LCNEC. Pulmonary adenocarcinoma, pulmonary squamous cell carcinoma, or a metastasis from an unknown non-pulmonary primary site are other primary tumors that can yield an NSCC NOS pathologic diagnosis, for example, if the sample does not express thyroid transcription factor 1 (TTF-1) or p40 (2).

Previous studies have suggested that the subcategory of lung NETs accounts for 20% of all primary pulmonary neoplasms. The estimated incidence of LCNECs has varied between 0.58% to 3.1% of all lung cancers in several studies (8,14,15). The increased use of IHC staining for TTF-1 and p40 to characterize biopsy samples has allowed some tumors that would have previously been characterized as NSCLC NOS to instead be classified as adenocarcinomas or squamous cell carcinomas. Consequently, the decrease in more recent incidence rates may be due to stricter diagnostic criteria and more advanced pathology techniques post-2015 WHO guidelines.

Although there are pathologic similarities between NSCLC and LCNEC, the clinical course for LCNEC more closely mirrors that of SCLC. Genomic profiling can help further classify LCNEC (16). Similar to NSCLC, type I LCNEC exhibits serine/threonine kinase 11 (STK11) and Kelch-like ECH-associated protein 1 (KEAP1) alterations while additionally exhibiting NET markers such as delta-like ligand 3 (DLL3) and achaete-scute homolog 1 (ASCL1) that are seen in SCLC. Type II LCNEC, similarly to SCLC, is characterized by inactivation of tumor suppressor genes, tumor protein p53 (TP53) and retinoblastoma 1 (RB1). However, type II LCNEC expresses reduced levels of DLL3 and ASCL1 and high NOTCH signaling pathway activity. These subtypes are also seen in EP-NEC; however, two additional EP-NEC subtypes exist showing insulinoma-associated protein 1 (INSM1)-high and alternative ASCL1/DLL3 or neurogenic differentiation factor 1 (NEUROD1) high expression or MYCL proto-oncogene (MYCL1) and yes-associated protein 1 (YAP1) overexpression (17).

Next-generation sequencing (NGS) of LCNEC has identified three distinct molecular subtypes: SCLC-like, NSCLC-like, and carcinoid-like (18). NSCLC-like carries mutations in Kirsten rat sarcoma viral oncogene (KRAS), STK11, and KEAP1. SCLC-like shows concurrent TP53 and RB1 loss. Lastly, carcinoid-like is characterized by multiple endocrine neoplasia type 1 (MEN1) mutations. These classifications further solidify LCNEC as a unique subtype of lung cancer needing to be distinguished from other subtypes and have been shown to have prognostic and predictive implications. Zhuo et al. have shown that despite a higher response rate to chemotherapy, SCLC-LCNEC has a lower OS when compared to NSCLC-LCNEC (19). Additionally, platinum-etoposide chemotherapy was associated with increased response in survival in SCLC-LCNEC when compared to platinum-pemetrexed or platinum-gemcitabine/taxane chemotherapy, while platinum-etoposide and platinum-pemetrexed led to increased survival in NSCLC-LCNEC when compared to platinum-gemcitabine/taxane chemotherapy (19). As we further understand the heterogeneous nature of LCNEC, these classifications may help guide treatment choice in the future.

Modern-day clinical trials in NSCLC exclude patients with LCNEC histology, confirming the need for prospective clinical trials in LCNEC. Additionally, despite LCNEC being included in the NSCLC classification, LCNEC treatment approaches have been extrapolated from the treatment of SCLC due to its aggressive nature. We aim to review and summarize the current literature on systemic treatment in LCNEC.

Systemic treatment of LCNEC

Treatment of localized disease

Surgical resection is the preferred treatment for patients with LCNEC who have localized disease. Reported survival rates vary significantly among studies, even among patient populations with the same clinical stage. This variability is likely due to a combination of relatively low sample size (typically less than 100 patients) in most of these single-center retrospective studies, variation in surgical techniques, and the administration or absence of neoadjuvant and adjuvant chemotherapy administered from one center to another. Reported 5-year OS rates in single-center studies for stage I LCNEC have ranged from 27–67%, for stage II LCNEC 17–75%, and for stage III LCNEC 0–45% (6,7,15).

Large-scale analyses using SEER data have demonstrated that patients with stage I–III disease benefit from both surgery and adjuvant chemotherapy (8,9). These retrospective studies also suggest that chemoradiation may be superior to chemotherapy alone for patients with stage I–III disease not amenable to surgical resection, although the inclusion of radiation has not been tested in a randomized controlled trial.

In one retrospective study, OS was shown to be higher after lobectomy compared to sublobar resection (wedge or segmentectomy) after propensity score matching to control for other variables, yielding a 5-year OS of 60.3% for lobectomy versus 41.5% for sublobar resection with 185 patients per group (20).

Multiple retrospective studies at different sites have indicated a benefit to platinum-based adjuvant chemotherapy when compared to historical controls with surgery alone (4,7,21). Due to the lack of equipoise, no prospective randomized trials have been done to test the benefit of adjuvant therapy versus observation.

Neoadjuvant therapy has also demonstrated an independent prognostic benefit in retrospective studies, using multivariate analysis to control for other variables (22,23).

The choice of chemotherapy regimen for LCNEC has historically been largely based on regimens that are used for SCLC, due to the pathologic similarities between these two types of NETs. A single-arm prospective study of adjuvant cisplatin and etoposide, compared to historical controls without adjuvant therapy, showed significant benefit of adjuvant cisplatin and etoposide with a 5-year disease-free survival (DFS) of 86.7% in the experimental group, compared to 34.8% in historical control and a 5-year OS of 88.9% in the experimental group and 47.4% in the historical control (24).

A phase II single-arm study suggested that adjuvant cisplatin and irinotecan might be efficacious in LCNEC, with a 3-year OS of 81% in a cohort consisting mostly of stage I patients (25). However, the subsequent multicenter randomized phase III trial comparing cisplatin and etoposide to cisplatin and irinotecan in high grade pulmonary neuroendocrine carcinomas did not show significant difference in 3-year recurrence free survival between the treatment arms in either the SCLC [65.2% vs. 66.5%; hazard ratio (HR) 1.029, 95% confidence interval (CI): 0.544–1.944] or LCNEC (66.5% vs. 72%; HR 1.072, 95% CI: 0.517–2.222) groups (26). The trial was stopped early due to futility.

Post-surgical recurrence is very common. One single-site study found a 5-year disease-free survival post resection of only 42.7%. The vast majority of patients with recurrent disease (91.7%) experienced recurrence within 3 years of initial surgery (27). Distant metastases are present in the majority (57%) of cases of recurrent disease (15). To date, there are no prospective trials demonstrating benefit of the addition of immunotherapy to adjuvant chemotherapy in LCNEC.

Treatment of unresectable or metastatic disease

Similarly to adjuvant therapy in early-stage LCNEC, the treatment for metastatic disease is extrapolated from the treatment of SCLC due to histologic similarities with LCNEC. Additionally, most available data are retrospective studies with low sample sizes. The first chemotherapy regimens studied in LCNEC were cisplatin-based regimens. Cisplatin in combination with either etoposide, vindesine, or mitomycin was tested in 20 unresectable LCNEC patients, showing a response rate of 50% (28).

Trials comparing NSCLC and SCLC treatment regimens in LCNEC patients have generally—though not uniformly—shown improved results with SCLC-derived regimens. One retrospective study of different chemotherapy regimens for the treatment of stage IV LCNEC patients found a median OS of 5.9 months with platinum plus pemetrexed, 6.7 months with platinum and etoposide, and 8.5 months with platinum and investigator’s choice chemotherapy, which included gemcitabine, docetaxel, paclitaxel or vinorelbine (29).

However, most other studies have shown improved results using SCLC regimens. Another study of 45 patients with advanced LCNEC received palliative chemotherapy following either SCLC or NSCLC regimens, with clear benefit being shown by SCLC regimens over NSCLC regimens (median OS 16.5 vs. 9.2 months) (30).

Another retrospective study showed a median OS of 51 months in stage IV LCNEC patients treated with SCLC-based regimens that included a platinum plus either etoposide or irinotecan, compared to only 21 months in patients treated with NSCLC-based regimens that included a platinum plus gemcitabine or paclitaxel (31).

Similar results were seen in a study of 14 unresectable LCNEC patients and 77 extensive stage SCLC patients, which showed that response and prognosis were roughly similar in the two groups when treated with SCLC-directed chemotherapy regimens (median OS of 10 months for LCNEC and 12.3 months for SCLC) (32).

Retrospective database studies have shown that chemoradiation provided greater benefit than chemotherapy alone in patients with stage I–III disease. However, there was no difference in OS of stage IV patients who were treated with either chemotherapy or chemoradiation (9,33).

Although retrospective studies have supported the use of SCLC chemotherapy regimens in LCNEC, there have been few prospective studies to date. One phase II trial looking at cisplatin and etoposide in 42 advanced LCNEC patients showed a median progression-free survival (PFS) of 5.2 months (95% CI: 3.1–6.6) and a median OS of 7.7 months (95% CI: 6.0–9.6) (34).

Another phase II trial looked at the use of cisplatin and irinotecan in 44 patients with LCNEC which showed median PFS of 5.9 months (95% CI: 5.5–6.3), and an OS of 15.1 months (95% CI: 11.2–19.0) (35). However, after central pathologist review, 30 patients were found to have confirmed LCNEC, 10 patients had confirmed SCLC, and 1 patient had confirmed NSCLC. The median PFS was similar in the LCNEC group (5.8 months) and in the SCLC group (6.2 months) (P=0.382) (35). However, a difference in OS was seen between the LCNEC and SCLC groups with a median OS of 12.6 and 17.3 months (P=0.047), respectively (35). This study highlights the importance of correct pathologic diagnosis for patients.

Lastly, a phase II trial looked at the combination of carboplatin, paclitaxel, and everolimus in 49 patients which showed a median PFS of 4.4 months and median OS of 9.9 months (36). However, grade 3 and 4 adverse effects were seen in 51% of patients and this regimen is not routinely used in practice. A summary of prospective data of chemotherapy use in LCNEC is shown in Table 2.

Ongoing trials and future treatment directions

Although nothing has yet replaced platinum-based chemotherapy for unresectable or metastatic LCNEC, there are novel treatment strategies on the horizon which may offer some additional benefit either in the first-line setting or as salvage treatment for patients who progress on platinum therapy.

In patients with SCLC, platinum doublet chemotherapy in combination with an immune checkpoint inhibitor (ICI) has become the standard of care in the first-line setting after improving OS in two randomized, controlled trials when compared to a platinum doublet alone (37,38). Although there are ongoing trials looking at this combination in patients with LCNEC, the data we currently have with ICIs in this population come from retrospective, small case series or case reports. A case series of 10 patients with advanced LCNEC treated with single-agent ICIs after progression on platinum-based therapy showed a median PFS of 14 months and response rate of 60% (39). There are multiple ongoing studies looking at the use of ICIs in patients with LCNEC, both in combination with other agents such as chemotherapy or as monotherapy.

Tarlatamab is a bispecific T cell engager (BiTE) which binds to DLL3 and CD3 and thus directs endogenous T cell activity to cells expressing DLL3. In 2024, the Food and Drug Administration (FDA) granted accelerated approval for tarlatamab in patients with extensive stage SCLC who had progressed on platinum-based chemotherapy, based on the results of the DeLLphi-301 trial. This trial of 220 patients showed objective response in 32–40% of treated patients and OS of 66–68% of patients at the 9-month time point after beginning treatment (40).

In one IHC analysis, DLL3 was overexpressed in SCLC and LCNEC compared with NSCLC, and showed higher expression levels in male patients and former smokers compared to female patients and nonsmokers (41).

One case report of tarlatamab for a 20-year-old male with metastatic LCNEC which had progressed on prior platinum and etoposide therapy described a partial response to tarlatamab (42). The patient did have grade 2 cytokine release syndrome (CRS) which required tocilizumab and dexamethasone administration.

Obrixtamig is another DLL3-targeted BiTE that has shown promising results. In a phase I dose escalation study, obrixtamig showed an overall response rate (ORR) of 54% and a PFS of 3.6 months in 14 LCNEC patients (43). Further trials are ongoing.

Rovalpituzumab tesirine (Rova-T) is a DLL3 targeting antibody-drug conjugate that was studied in advanced DLL3-expressing tumors, including NEC and SCLC. Although Rova-T initially showed promising results, its development was stopped due to negative results and significant toxicity seen in phase III trials in SCLC (44).

DLL3 continues to be evaluated as a therapeutic target through other novel therapies. An autologous CAR-T therapy, LB2102, that targets DLL3 has been shown to be safe at multiple dose levels in patients with SCLC and LCNEC and continues to be studied (45).

Oncolytic viruses (OVs) and cancer vaccines remain an area of interest and research in patients with malignancies. In patients with LCNEC, Seneca Valley Virus (SVV-001) is a promising OV in pre-clinical development showing encouraging anti-cancer properties, particularly when combined with ICIs (46). The tumor endothelial marker 8 (TEM-8) appears to be a useful biomarker for identifying patients who may benefit from treatment with SVV-001, and human studies are currently in development (47).

Unlike NSCLC, targetable driver mutations in LCNEC are rare but have been reported in patients with LCNEC, including epidermal growth factor receptor (EGFR), B-Raf proto-oncogene (BRAF), and KRAS mutations (48). Given the continued approval of therapies targeting these mutations in addition to the approval of tumor agnostic targeted therapies, performing molecular testing with NGS is imperative to ensure personalized treatment selection for patients.

A summary of ongoing, recruiting clinical trials in LCNEC of the lung is listed in Table 3.

Given the rarity of LCNEC, recruitment for prospective clinical trials can be challenging, which reinforces the need for preclinical models to evaluate new and novel therapeutics for LCNEC. To date, there have been a limited number of preclinical models developed; however, novel mouse xenografts and patient-derived tumoroid models have shown success with both molecular characterization and evaluating therapeutic efficacy in LCNEC (49,50).

Conclusions

LCNEC is a rare and aggressive form of primary lung neoplasms with limited treatment options and a poor prognosis. Patients should be referred to academic centers with LCNEC experience to confirm their diagnosis due to its rarity, unique pathology, and treatment challenges. There is currently a lack of prospective, randomized, clinical trial data in patients with LCNEC but treatment with chemotherapy regimens used in SCLC produces similar outcomes and prognosis. Further research is needed in the molecular characterization of LCNEC and using these results to tailor patient treatment. There has been promising data with immunotherapy and novel agents in LCNEC, but continued research and enrollment in clinical trials are imperative to not only better understand LCNEC but to improve treatment outcomes for these patients.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1394/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1394/coif). R.A.R. serves as an unpaid editorial board member of Translational Lung Cancer Research from January 2026 to December 2027. A.S.C. reports participation in advisory boards for Regeneron, Exelixis, BMS, Takeda, and Daiichi Sankyo. R.A.R. has been a consultant for ITM Radiopharma, Regeneron, Exelixis, Novartis, Lantheus, Sanofi, and Ter Sera Therapeutics, and has served on the speaker bureau for AstraZeneca. R.A.R. is also on the North American Neuroendocrine Tumor Society Board of Directors. 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.

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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