Lingzhi Hong, Alessandro Di Federico, Bolun Liu, Alissa J Cooper, Joao V Alessi, Phoebe Clark, Waree Rinsurongkawong, Chingyi Young, Hui Li, Kang Qin, Muhammad Aminu, Yasir Elamin, Boris Sepesi, Jeff Lewis, Don L Gibbons, Ara A Vaporciyan, J Jack Lee, Xiuning Le, Jia Wu, Sinchita Roy-Chowdhuri, Mark J Routbort, P Andrew Futreal, John V Heymach, Mark M Awad, Adam J Schoenfeld, Jianjun Zhang, Biagio Ricciuti, Lei Deng, Natalie I Vokes
{"title":"Distinct Clinicogenomic Features and Immunotherapy Associations in Pulmonary Sarcomatoid Carcinoma: A Multi-Center Retrospective Study.","authors":"Lingzhi Hong, Alessandro Di Federico, Bolun Liu, Alissa J Cooper, Joao V Alessi, Phoebe Clark, Waree Rinsurongkawong, Chingyi Young, Hui Li, Kang Qin, Muhammad Aminu, Yasir Elamin, Boris Sepesi, Jeff Lewis, Don L Gibbons, Ara A Vaporciyan, J Jack Lee, Xiuning Le, Jia Wu, Sinchita Roy-Chowdhuri, Mark J Routbort, P Andrew Futreal, John V Heymach, Mark M Awad, Adam J Schoenfeld, Jianjun Zhang, Biagio Ricciuti, Lei Deng, Natalie I Vokes","doi":"10.1016/j.jtho.2025.07.121","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Pulmonary sarcomatoid carcinoma (PSC) is a rare non-small cell lung cancer (NSCLC) subtype with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) and genomic features in PSC remain underexplored compared to other NSCLC subtypes.</p><p><strong>Patients and methods: </strong>Patients from three institutions and the National Cancer Database (NCDB) with metastatic NSCLC treated with ICI alone or with chemotherapy were identified. Clinicogenomics and treatment outcomes were compared across PSC, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC).</p><p><strong>Results: </strong>We analyzed 4,841 patients including 165 PSC cases treated with ICI-based therapy from three institutions, and 201 PSC from NCDB. In MDACC, 65 (4.3%) were PSC, 1,138 (75.1%) LUAD, and 312 (20.6%) LUSC. PSC patients were older and more likely to present with metastatic disease. In both the MDACC and NCDB cohorts, ICIs resulted in better outcomes for PSC patients compared with chemotherapy. In these patients, there was no difference in outcome between ICI-monotherapy and ICI-chemotherapy. Across the three institutional cohorts, 37%-43% of patients with PSC who received ICIs were responders, compared to 26%-29% in LUAD and 22%-46% in LUSC (P < 0.05). Improved ICI outcomes in PSC appeared driven by high PD-L1 (≥50% in 73%-77% cases). Among patients with high PD-L1, response rates were similar across histologic subtypes. Conversely, TMB was similar in PSC compared to LUAD/LUSC, and was not associated with ICI outcomes. Across cohorts, PSC tumors were enriched for TP53, NF1, NF2, and NRAS, with relative depletion of STK11 and KEAP1 compared to LUAD. Case observation showed relatively better outcomes to ICI than targeted therapies in PSC patients with MET exon 14 skipping or KRAS G12C.</p><p><strong>Conclusion: </strong>PSC exhibits improved outcomes to ICI relative to other therapies, potentially driven by high PD-L1 expression. Genomic analysis highlights a distinct genomic landscape of PSC when compared with LUAD.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":20.8000,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Thoracic Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jtho.2025.07.121","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare non-small cell lung cancer (NSCLC) subtype with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) and genomic features in PSC remain underexplored compared to other NSCLC subtypes.
Patients and methods: Patients from three institutions and the National Cancer Database (NCDB) with metastatic NSCLC treated with ICI alone or with chemotherapy were identified. Clinicogenomics and treatment outcomes were compared across PSC, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC).
Results: We analyzed 4,841 patients including 165 PSC cases treated with ICI-based therapy from three institutions, and 201 PSC from NCDB. In MDACC, 65 (4.3%) were PSC, 1,138 (75.1%) LUAD, and 312 (20.6%) LUSC. PSC patients were older and more likely to present with metastatic disease. In both the MDACC and NCDB cohorts, ICIs resulted in better outcomes for PSC patients compared with chemotherapy. In these patients, there was no difference in outcome between ICI-monotherapy and ICI-chemotherapy. Across the three institutional cohorts, 37%-43% of patients with PSC who received ICIs were responders, compared to 26%-29% in LUAD and 22%-46% in LUSC (P < 0.05). Improved ICI outcomes in PSC appeared driven by high PD-L1 (≥50% in 73%-77% cases). Among patients with high PD-L1, response rates were similar across histologic subtypes. Conversely, TMB was similar in PSC compared to LUAD/LUSC, and was not associated with ICI outcomes. Across cohorts, PSC tumors were enriched for TP53, NF1, NF2, and NRAS, with relative depletion of STK11 and KEAP1 compared to LUAD. Case observation showed relatively better outcomes to ICI than targeted therapies in PSC patients with MET exon 14 skipping or KRAS G12C.
Conclusion: PSC exhibits improved outcomes to ICI relative to other therapies, potentially driven by high PD-L1 expression. Genomic analysis highlights a distinct genomic landscape of PSC when compared with LUAD.
期刊介绍:
Journal of Thoracic Oncology (JTO), the official journal of the International Association for the Study of Lung Cancer,is the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies.The readship includes epidemiologists, medical oncologists, radiation oncologists, thoracic surgeons, pulmonologists, radiologists, pathologists, nuclear medicine physicians, and research scientists with a special interest in thoracic oncology.