Original StudyImmune-Checkpoint Inhibitors in Advanced Non-Small Cell Lung Cancer With Uncommon Histology
Introduction
The introduction of immune checkpoint inhibitors (ICIs) has recently changed the landscape of treatment for patients (pts) with advanced squamous (Sq) and non-squamous (Nsq) non-small cell lung cancer (NSCLC).1, 2, 3, 4, 5, 6, 7, 8 However, uncommon lung histologies were generally excluded from clinical trials of ICIs or deeply underrepresented. Therefore, despite intense efforts to study the safety and efficacy of ICIs in patients with advanced NSCLC (aNSCLC), data regarding the use of these programmed death-(ligand)1 (PD-(L)1) inhibitors in patients with uncommon histotypes (UH) are lacking.
Uncommon lung cancer subtypes include a wide spectrum of different histologies such as sarcomatoid carcinoma (SC), large cell neuroendocrine carcinoma (LCNEC), salivary gland-type tumors, some variants of adenocarcinoma (ADC) (enteric-type, colloid, mucinous and fetal ADC) and mixed histologies.9,10 Standard cytotoxic treatments are usually less effective in these subsets of patients and the prognosis remains poor compared to the general NSCLC population.11 Importantly, emerging data indicate that ICIs might represent an attractive therapeutic option for patients with UH. Lung SC (<1% of all NSCLCs) has been reported to have high PD-L1 expression levels and high tumor mutational burden (TMB) 12, 13, 14 and also a more frequent association with MET exon-14 skipping mutations has been described. Consistently, case reports and small retrospective series showed promising activity of ICIs in patients with SC,15, 16, 17, 18, 19, 20, 21, 22, 23, 24 while preliminary data suggested a lower efficacy of ICIs in a subgroup of lung cancer patients harboring MET exon 14-alterations.25 Likewise, neuroendocrine neoplasms (NEN) of the lung are a very heterogenous disease with different prognosis and limited therapeutic options, including large-cell neuroendocrine carcinomas (LCNEC) and carcinoids subtypes. Treatments available for these disease are frequently extrapolated from other NENs, such as small cell lung cancer (SCLC) and gastroenteric NENs 26 due to their low incidence. However, recent studies evaluated the role of PD-L1 expression in LCNEC 27, 28, 29, 30 reporting a positive correlation between PD-L1 expression in these tumors and improved overall survival (OS).27, 28 Some data suggest that molecular characteristics of these uncommon lung NENs 31 may promote a good response to ICIs, especially in high-grade tumors, where a higher TMB and PD-L1 expression was reported compared to well-differentiated NeuroEndocrine Tumours (NETs).32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49. Moreover, among other uncommon histologies, even adenosquamous (ADS) lung cancer may represent a challenge to be treated, due to its worse prognosis compared to the ADC and Sq subtypes with standard regimens.50 However, PD-L1 expression rate seems to be similar to the ADC and Sq ones,51, 52 suggesting a potential role for ICIs in ADS disease.53 Similarly, enteric ADC has been reported to have higher TMB and mismatch repair (MMR) genes mutation compared to the common ADC, which provide a rational for the use of PD-(L)1 blockade in this subset of patients.54 Jointly, these data indicate that ICIs might be effective in patients with UH. However, the efficacy of ICIs in patients with SC and enteric-like ADC is still in need of further investigation. In addition, there is no evidence regarding the efficacy of ICIs in patients with other NSCLC uncommon variants, such as mucinous, salivary gland-type tumor and mixed tumors, which represent another proportion of patients with NSCLC.
In order to explore the efficacy of ICIs in a real world population of advanced NSCLC with UH we conducted a single center retrospective study.
Section snippets
Materials and Methods
This retrospective study was conducted at the Thoracic Oncology Unit of the “Fondazione IRCCS Istituto Nazionale Tumori” of Milan, Italy. The study protocol was approved by the Internal Review Boards (IRB) and the Local Ethics Committees. Patient data were collected in accordance with the Declaration of Helsinki, Good Clinical Practice and local ethical rules (Apollo: INT 22/15). All patients have signed informed consent for the use of their clinical data for research purposes at some time of
Patients' Characteristics
Of 375 aNSCLC patients treated with anti-PD-(L)-1 in first or further-lines, 79 pts (21.1%) had UH. The uncommon histotypes were distributed as follow: 19 (24.1%) SC, 15 (19.0%) mucinous ADC, 10 (12.6%) pulmonary enteric ADC, 8 (10.1%) ADC not otherwise specified (NOS), 7 (8.9%) LCNEC, 6 (7.6%) mixed histology other than adenosquamous (ADS), 5 (6.3%) ADS carcinoma, 9 (11.4%) other UH (signet ring cells carcinoma, salivary gland type tumor, colloid ADC) (Figure 1). Patients’ characteristics are
Discussion
In the last decade ICIs radically changed the clinical practice of aNSCLC. Many studies led to the approval of several anti-PD(L)1 both in the first and in further lines of therapy. However, NSCLCs include a large variety of uncommon histotype and histologies in which the benefit of immunotherapy is still unclear due to their exclusion or underrepresentation into the main clinical trials. Moreover, some of these tumor types usually show lower responsiveness to chemotherapy and a worse prognosis
Conclusions
In this paper no significant difference was found between the UH and CH group treated with ICIs. However, preliminary data suggest a less important role of PD-L1 status and immunotherapy line setting on ICIs efficacy in these patients. Given the retrospective nature of this study further prospective studies with a larger population are needed to better clarify the ICIs role in UH aNSCLC patients.
Disclosures
DS declares personal fees from AstraZeneca, MSD, Boehringer Ingelheim and BMS, outside the submitted work. GLR declares personal fees from Eli Lilly, BMS, Roche, Italfarmaco, Novartis and AstraZeneca, outside the submitted work. CP declares personal fees from BMS and MSD, outside the submitted work. FdB: provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom received honoraria or education grants: Amgen, AstraZeneca,
Acknowledgments
The authors would like to thank nurse assistant Anna Maria Leone for her support. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki, and all patients signed informed consent for scientific research purposes. The protocol was submitted to the Ethics Committee of the Coordinating Center, Fondazione IRCCS Istituto Nazionale Tumori.
Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data are contained within the article.
CRediT authorship contribution statement
Sara Manglaviti: Investigation, Data curation, Writing – original draft, Visualization. Marta Brambilla: Investigation, Data curation, Writing – original draft, Visualization. Diego Signorelli: Conceptualization, Methodology, Validation. Roberto Ferrara: Investigation, Validation, Supervision. Giuseppe Lo Russo: Formal analysis, Writing – review & editing, Supervision. Claudia Proto: Writing – review & editing, Validation. Giulia Galli: Writing – review & editing, Project administration.
References (60)
- et al.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
Lancet
(2016) - et al.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open label, multicentre randomised controlled trial
Lancet
(2017) - et al.
WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart
J Thorac Oncol
(2015) - et al.
Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1)
J Thorac Oncol
(2013) - et al.
Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD-L1) and strong immune-cell infiltration by TCD3 cells and macrophages
Lung Cancer
(2016) - et al.
Pulmonary sarcomatoid carcinomas commonly harbor either potentially targetable genomic alterations or high tumor mutational burden as observed by comprehensive genomic profiling
J Thorac Oncol
(2017) - et al.
Efficacy of immunotherapy in sarcomatoid lung cancer, a case report and literature review
Respir Med Case Reports
(2019) - et al.
Efficacy of immune checkpoint inhibitors in lung sarcomatoid carcinoma
J Thorac Oncol
(2020) - et al.
PD-L1 expression, tumor mutational burden and response to immunotherapy n patients with MET exon 14 altered lung cancers
Ann Oncol
(2018) - et al.
PD-L1 expression in neuroendocrine tumors of the lung
Lung Cancer
(2017)
Prevalence and prognostic value of PD-L1 expression in molecular subtypes of metastatic large cell neuroendocrine carcinoma (LCNEC)
Lung Cancer
New insights into the molecular characteristics of pulmonary carcinoids and large cell neuroendocrine carcinomas, and the impact on their clinical management
J Thorac Oncol
Complete tumor response of a locally advanced lung large-cell neuroendocrine carcinoma after palliative thoracic radiotherapy and immunotherapy with nivolumab
Lung Cancer
Efficacy of immune checkpoint inhibitors in large cell neuroendocrine lung cancer: results from a French retrospective cohort
P1.07-012, J Thorac Oncol
Distinctive features of immunostaining and mutational load in primary pulmonary enteric adenocarcinoma: implications for differential diagnosis and immunotherapy
J Transl Med
Pembrolizumab vs. Chemotherapy for PD-L1–positive non–small-cell lung cancer
N Engl J Med
Pembrolizumab plus Chemotherapy for Squamous non–small-cell lung cancer
N Engl J Med
Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer
N Engl J Med
Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer
N Engl J Med
Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer
N Engl J Med
Uncommon types of lung carcinoma with mixed histology
Arch Pathol Lab
Efficacy of first-line chemotherapy in patients with advanced lung sarcomatoid carcinoma
J Thorac Oncol
Relashionship between programmed death receptor-ligand 1 expression and response to checkpoint inhibitor immunotherapy in pulmondary sarcomatoid carcinoma: a pooled analysis
Clin Lung Cancer
Case series of pleomorphic carcinomas of the lung treated with nivolumab
Thorac Cancer
Rapid and Long-term response of pulmonary pleomorphic carcinoma to nivolumab
Intern Med
Successful treatment of pulmonary pleomorphic carcinoma with nivolumab: a case report
Case Rep Oncol
Pulmonary pleomorphic carcinoma with few PD-1-positive immune cells and regulatory T cells that showed a complete response to nivolumab
Thorac Cancer
Dramatic response to nivolumab after local radiotherapy in pulmonary pleomorphic carcinoma with rapid progressive post-surgical recurrence
Thorac Cancer
The successful treatment of pulmonary pleomorphic carcinoma with pembrolizumab: a case report
Case Rep Oncol
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These authors contributed equally to this work.