Large-cell neuroendocrine lung carcinomas (LCNEC) include approximately 3% of pulmonary malignancies and combine characteristics of the neuroendocrine and non-small-cell (NSCLC) histotypes (1). Their cells typically have a size larger than three times the diameter of resting lymphocyte, abundant cytoplasm, prominent nucleoli, and display organoid nesting, trabecular growth, rosette-like structures and/or nuclear palisading, along with positivity for at least 1 of the neuroendocrine markers synaptophysin, chromogranin A, and CD56 (2). Up to 20% of cases show a mixed histology with an additional squamous, adenocarcinoma or not-otherwise-specified NSCLC component, but this cannot be reliably assessed based on the small biopsies routinely used in the metastatic setting (3). The typically high proliferation rate (>11 mitoses/10 high-power fields or Ki67 >50%) is associated with an aggressive clinical course and poor prognosis (4–6).

Therapeutic progress is particularly difficult for LCNEC. Routinely treatable genetic alterations, such as EGFR mutations or ALK translocations, are exceedingly rare, so that tyrosine kinase inhibitors (TKI) and other targeted drugs have a very limited role (7, 8). In addition, due to the rarity of these patients, there are no clinical trials that define the optimal therapy for either localized or advanced disease (9). Treatment decisions are based on a few small retrospective series and rely on the recommendations for other NSCLC or SCLC. In case of chemotherapy doublets, the choice of the platinum partner between etoposide and NSCLC cytostatics (mainly paclitaxel, gemcitabine, and pemetrexed) has been controversial in the literature (10–12). Interestingly, more recent studies have suggested differential sensitivity according to presence of an SCLC or NSCLC-typical molecular profile (i.e. TP53 and RB1 vs. KRAS and STK11/KEAP1 alterations), however, efficacy remains limited with a median overall survival (OS) invariably shorter than 10-12 months (8, 13, 14). Administration of immune checkpoint inhibitors appears to prolong survival in some retrospective series (15–18), however, the overall impact in the real-world setting is challenging to assess, due to the considerable clinical heterogeneity of this rare disease. Aim of the current study was to thoroughly dissect of LCNEC management across the entire clinical spectrum of the disease.

LCNEC is a rare pulmonary malignancy with poor prognosis and scarce evidence to guide management. These patients are underrepresented in clinical trials of unselected NSCLC, while published LCNEC series are either small, with generally fewer than 50-70 cases (27), or rely on the basic information available in national registers (28–32). Detailed capturing of heterogeneity across the entire clinical spectrum of LCNEC requires deep annotation of large patient numbers in order to provide insights useful for management of this challenging entity.

The single most important factor for longer patient survival in the vast majority of LCNEC patients without routinely treatable genetic alterations according to the results of the current study is highly active systemic treatment with administration of platinum-based chemotherapy and/or immunotherapy ( Table 2 and Figure 2 ). The type of systemic treatment had a stronger effect on OS and PFS than clinical disease parameters and laboratory results, like the metastatic pattern and serum levels of various tumor markers. In addition, the type of treatment emerged as more important for patient survival than patient-related characteristics, like age and ECOG PS, whose relationship with OS did not persist in multivariable testing ( Table 2 ) and therefore likely results from their association with administration or not of platinum-based chemotherapy ( Figure 3 ). The observed association between administration of local treatments and longer OS ( Figure 7 ) is probably also secondary, due to the longer duration of treatment, which permits more ablative interventions across the entire disease trajectory, since this relationship did not persist in multivariable testing either ( Table 2 ). On the other hand, the type of platinum drug (cisplatin or carboplatin) and the cytotoxic partner in the platinum doublet (etoposide vs. other NSCLC drugs) did not matter ( Table 2 ). However, it should be noted here that our “NSCLC-drug” group included mainly patients with platinum/paclitaxel (n=54/64, footnote 3 of Table 1 ), so that putative equivalence with etoposide cannot be safely concluded for other chemotherapeutics, inasmuch a previous study has demonstrated inferiority of pemetrexed in this setting (33). The median PFS and OS of 4.6 and 9.0 months, respectively, observed for patients receiving platinum-based first-line therapy in this study ( Figure 2 ) are comparable to the results of other prospective and retrospective LCNEC series analyzing platinum regimens, which have observed median PFS intervals of 4–6 and median OS intervals of 8–12 months (10, 34–37).

Of particular interest are the more favorable characteristics and course of LCNEC patients with secondary metastatic disease ( Figure 4 ). This finding extends the observations of some older studies, which had observed a longer OS for chemotherapy-treated patients with secondary stage IV NSCLC of the usual histological subtypes (38–40). Special features of secondary metastatic lung cancer in the current and previous studies are a lower number of initial metastatic sites and a better baseline ECOG PS (38, 39) ( Figure 4 ), parameters which are linked to a better OS of LCNEC patients ( Table 2 ) and could explain the improved prognosis compared to de novo cases. These differences are likely caused by the fact that secondary metastatic disease is diagnosed earlier, during the routine follow-up after definitive treatment of the preceding early-stage tumors, which can detect subsequent relapse or progression already while this is still asymptomatic. Consistent with this notion, a more recent study analyzing tyrosine kinase inhibitor (TKI)-treated patients with EGFR-mutated NSCLC found very similar molecular profiles between de novo and secondary tumors, despite clinical differences similar to those observed between de novo and secondary stage IV LCNEC (41). Of note, the proportion of secondary metastatic LCNEC, namely 36/191 or 19% in this study, is not a biologic feature either, but depends on the efficacy of lung cancer detection strategies. For example, the upcoming adoption of CT-based lung cancer screening is expected to increase this ratio, since many tumors currently detected as de novo metastatic LCNEC will then be diagnosed already in earlier stages, and also proportionally contribute more to the pool of “secondary” cases after relapse (42).

The observed patient attrition rate between lines of systemic treatment observed in this study was approximately 50% ( Figure 5 ), which is very similar to the rate reported for chemotherapy-treated NSCLC of the usual histological subtypes (43–45). Lack of subsequent treatment was significantly associated with more aggressive disease, evident as a higher baseline serum LDH ( Figure 6A ), and with a worse patient condition, as captured by a worse ECOG PS at diagnosis ( Figure 6B ), but did not differ according to the type of treatment (platinum-based or not, Figure 5 ). The lower rate of attrition reported for EGFR- and ALK-mutated NSCLC, i.e. approximately 30% in the real-world setting ( (46) and data of the authors about ALK⁺ NSCLC currently under review for publication), is probably attributable to the higher efficacy of targeted therapies and the lower biologic aggressiveness of these tumors (47, 48), as also suggested by the more frequent occurrence of oligoprogression in these tumors compared to non-oncogene-dependent NSCLC (49).

The clinical utility of TKI is very limited in LCNEC currently, because routinely actionable genetic alterations are exceedingly rare, <2% in the literature (7, 50) as well as our cohort ( Table 1 ), and “blind” administration of targeted drugs without reliable predictive biomarkers is unlikely to have a significant impact (51). This underlines the importance of immunotherapy, for which a survival benefit of several months has recently been demonstrated in several retrospective series of LCNEC patients (15–18). In our study, the gain was also considerable, with a median OS from the start of palliative systemic treatment exceeding 2 years ( Figure 2A ). This result is well in line with the higher tumor mutational burden (TMB) of LCNEC compared to other lung cancers (52) and with the importance of PD-L1 expression on LCNEC cells and their microenvironment for patient outcome (53). Of special interest in this regard is also the exquisite immune reactivity of LCNEC, with readily detectable T-cell receptor (TCR) repertoire alterations in the peripheral blood, which could be exploited for guidance of immunotherapeutic interventions and improved disease monitoring (54).

Main limitation of our study is its retrospective design, which cannot guarantee absence of some confounding. In addition, delineating the diagnosis of LCNEC from the small biopsies routinely used in case of metastatic disease is challenging and cannot exclude presence of another NSCLC component outside the sampled area (3). Nevertheless, this might not have major clinical consequences, as mixed LCNEC tumors appear to have a similar aggressiveness and prognosis as their “pure” counterparts (4).

Also, while the number of immunotherapy-treated patients in our study was not large, our results add to the observations of previous studies which similarly demonstrated a significant benefit from immune checkpoint inhibitors in metastatic LCNEC (15–18). Beyond this, our work describes one of the largest published LCNEC cohorts, with homogenous decision-making in the same institution and deep clinical annotation, which make it a valuable source of insights into the contemporary clinical reality of this rare entity. The delineation of treatment patterns, elucidation of the complex interplay between clinicolaboratory parameters and the disease course, as well as the identification of factors with key importance for patient survival presented here, could support daily clinical practice and provide a benchmark for assessing the real-world impact of future therapeutic developments.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by ethics committee of Heidelberg University S-145/2017. Written informed consent for participation was not required for this retrospective study in accordance with the national legislation and the institutional requirements.

DF: conceptualization, methodology, investigation, data curation, formal analysis, visualization, writing - original draft. FB: investigation, data curation, validation, writing - review & editing. DK: investigation, data curation, validation, writing – original draft. JK: investigation, data curation, validation, writing - review & editing. LK: investigation, data curation, validation, writing - review & editing. RS: investigation, data curation, validation, writing - review & editing. FE: investigation, data curation, validation, writing - review & editing. MK: investigation, data curation, writing - review & editing. MS: investigation, data curation, validation, supervision, writing - review & editing. TM: investigation, data curation, validation, supervision, writing - review & editing. AS: validation, supervision, project administration, writing - review & editing. HB: methodology, validation, writing - review & editing. PC: conceptualization, methodology, investigation, data curation, formal analysis, visualization, supervision, project administration, writing - original draft, writing - review & editing. All authors contributed to the article and approved the submitted version.

This study was funded by the German Center for Lung Research (DZL). The funding source did not have any influence on the design, conduction, and report of the results for this study.

FB reports research funding from BMS and travel grants from BMS and MSD. DK reports advisory board and speaker’s honoraria from AstraZeneca, BMS, Pfizer. JK reports research funding from AstraZeneca and Celgene. RS reports research funding from BMS and speaker’s honoraria from Roche. TM reports research funding from Roche and patents with Roche. AS reports advisory board honoraria from BMS, AstraZeneca, ThermoFisher, Novartis, speaker’s honoraria from BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche, and research funding from Chugai. PC reports research funding from AstraZeneca, Novartis, Roche, Takeda, and advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, Chugai, Novartis, Pfizer, Roche, Takeda.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.