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. 2025 Jul 25:S1556-0864(25)00967-0.
doi: 10.1016/j.jtho.2025.07.121. Online ahead of print.

Distinct Clinicogenomic Features and Immunotherapy Associations in Pulmonary Sarcomatoid Carcinoma: A Multicenter Retrospective Study

Lingzhi Hong  1 , Alessandro Di Federico  2 , Bolun Liu  3 , Alissa J Cooper  4 , Joao V Alessi  2 , Phoebe Clark  4 , Waree Rinsurongkawong  1 , Chingyi Young  5 , Hui Li  1 , Kang Qin  1 , Muhammad Aminu  6 , Valentina Santo  2 , Yasir Elamin  1 , Boris Sepesi  7 , Jeff Lewis  8 , Don L Gibbons  1 , Ara A Vaporciyan  7 , J Jack Lee  8 , Xiuning Le  1 , Jia Wu  6 , Sinchita Roy-Chowdhuri  9 , Mark J Routbort  9 , P Andrew Futreal  10 , John V Heymach  1 , Mark M Awad  4 , Adam J Schoenfeld  4 , Jianjun Zhang  11 , Biagio Ricciuti  2 , Lei Deng  12 , Natalie I Vokes  13
Affiliations

Distinct Clinicogenomic Features and Immunotherapy Associations in Pulmonary Sarcomatoid Carcinoma: A Multicenter Retrospective Study

Lingzhi Hong et al. J Thorac Oncol. .

Abstract

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare NSCLC subtype with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) and genomic features in PSC remain underexplored compared with other NSCLC subtypes.

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 4841 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, 1138 (75.1%) LUAD, and 312 (20.6%) LUSC. Patients with PSC were older and more likely to present with metastatic disease. In both the MDACC and NCDB cohorts, ICIs resulted in better outcomes for patients with PSC compared with chemotherapy. In these patients, there was no difference in outcome between ICI-monotherapy and ICI-chemotherapy. Across the three institutional cohorts, 37% to 43% of patients with PSC who received ICIs were responders, compared with 26% to 29% in LUAD and 22% to 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 with LUAD or 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 with LUAD. Case observation revealed relatively better outcomes to ICI than targeted therapies in patients with PSC 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.

Keywords: Genomics; Immunotherapy; KRAS inhibitors; MET inhibitors; Non–small cell lung cancer; Pulmonary sarcomatoid carcinoma.

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Conflict of interest statement

Disclosure Dr. Federico reports serving on the scientific advisory of Hanson-Wade, Novartis, and IQVIA; receiving honoraria from society for immunotherapy of cancer (SITC) and travel support from Johnson & Johnson and Pfizer, outside the current work. Dr. Cooper has received honoraria from MJH Life Sciences, Ideology Health, Intellisphere LLC, MedStar Health, and CancerGRACE; receiving consulting fees from Gilead Sciences, Inc., Daiichi and AstraZeneca, Novartis, and Regeneron; and receiving research funding to institution from Merck, Monte Rosa, AbbVie, Roche, Daiichi Sankyo, and Amgen, outside the current work. Dr. Alessi is on the advisory boards of AstraZeneca and Bristol Myers Squibb and has served as a consultant for Merck Sharp & Dohme and Janssen, outside the current work. Dr. Elamin reports receiving grants from Takeda, AstraZeneca, Eli Lilly, Xcovery, Turning Point Therapeutics, BluPrint, and Elevation Oncology; receiving consulting fees from AstraZeneca, Eli Lilly, Takeda, Spectrum, Bristol Myers Squibb, and Turning Point; and receiving travel support from Eli Lilly, outside the current work. Dr. Sepesi reports receiving consulting fees from AstraZeneca, Bristol Myers Squibb, and Medscape, outside the current work. Dr. Gibbons reports receiving honoraria for scientific advisory boards from AstraZeneca, Sanofi, Alethia Biotherapeutics, Menarini, Eli Lilly, 4D Pharma, and Onconova; and research support from Janssen, Takeda, Astellas, Ribon Therapeutics, NGM Biopharmaceuticals, Boehringer Ingelheim, Mirati Therapeutics, and AstraZeneca, outside the current work. Dr. Lee reports receiving partial support by CA016672 from the National Cancer Institute, outside the current work. Dr. Le reports receiving consulting and advisory fees from Eli Lilly, EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, ArriVent, Abion, BlossomHill, and AbbVie; receiving research funding to institution from Eli Lilly, EMD Serono, ArriVent, Dizal, Teligene, Regeneron, Janssen, Thermo Fisher, Takeda, and Boehringer Ingelheim, outside the current work. Dr. Wu reports receiving research funding from NIH and Siemens; travel, accommodations, and expenses from ESMO, DAVA Oncology, 3PSOLUTION, and International Summit on Lung Cancer, outside the current work. Dr. Heymach reports serving on the advisory committees of Genentech, Mirati Therapeutics, Eli Lilly & Co, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAlta, Sanofi, Spectrum Pharmaceuticals, GlaxoSmithKline, EMD Serono, BluePrint Medicine, and Chugai Pharmaceutical; receiving research support from AstraZeneca, Boehringer-Ingelheim, Spectrum, Mirati, Bristol Myers Squibb, and Takeda; and having licensing and royalties from Spectrum, outside the current work. Dr. Awad reports having consulting or advisory role for Merck, Pfizer, Bristol Myers Squibb, Foundation Medicine, Novartis, Gritstone Bio, Mirati Therapeutics, EMD Serono, AstraZeneca, Instil Bio, Regeneron, Janssen, and Affini-T Therapeutics; receiving research funding from Genentech and Roche (inst), Lilly (inst), AstraZeneca (inst), Bristol Myers Squibb (inst), and Amgen (inst); receiving travel, accommodations, and expenses from Bristol Myers Squibb Foundation; and having open payments link: https://openpaymentsdata.cms.gov/physician/1127368, outside the current work. Dr. Schoenfeld reports having consulting and advising role to J&J, Bayer, KSQ Therapeutics, Bristol Myers Squibb, Merck, AstraZeneca, Oxford Biotherapeutics, Roche, Synthekine, cTRL Therapeutics, Regeneron, Enara Bio, Perceptive Advisors, Oppenheimer and Co, Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Obsidian Therapeutics, Prelude Therapeutics, Immunocore, Lyell Immunopharma, Amgen, and Heat Biologics; receiving research funding from GlaxoSmithKline (inst), Obsidian (inst), Lilly (inst), PACT pharma (inst), Iovance Biotherapeutics (inst), Achilles Therapeutics (inst), Merck (inst), Synthekine (inst), Bristol Myers Squibb (inst), Harpoon Therapeutics (inst), AffiniT Therapeutics (inst), Legend Therapeutics (inst), Synthekine (inst), and Amgen (inst), outside the current work. Dr. Zhang reports receiving research funding from Helius, Johnson and Johnson, Merck, Novartis, and Summit, and personal fees from AstraZeneca, Catalyst, GenePlus, Helius, Hengrui, Innovent, Johnson and Johnson, Novartis, Oncohost, Takeda and Varian, outside the current work. Dr. Ricciuti is on the advisory boards of Regeneron, AstraZeneca, and AMGEN; has received travel support from Regeneron, Genentech, and Bristol Myers Squibb; received speaker fees from AstraZeneca; and received honoraria from Targeted Oncology, outside the current work. Dr. Deng reports consulting or advisory from Bristol Myers Squibb and Regeneron; receiving honoraria from MJH Life Science, PrecisCa, and DAVA Oncology; receiving travel support from Merck; and receiving institutional research funding from BridgeBio Oncology Therapeutics, Revolution Medicines, and Merck, outside the current work. Dr. Vokes consults for Sanofi, Oncocyte, Lilly, Regeneron, Amgen, Xencor, AstraZeneca, Tempus, Pfizer, Summit, and OncoHost; has received speaking fees from Guardant; received travel support from Regeneron; received research funding from Circulogene and Mirati; and received honoraria from Scienomics, Cancer GRACE, OncLive, and OMNIOncology, outside the current work. The remaining authors declare no conflict of interest.

References

    1. Yendamuri S, Caty L, Pine M et al. Outcomes of sarcomatoid carcinoma of the lung: a Surveillance, Epidemiology, and End Results Database analysis. Surgery 2012; 152 (3): 397–402. - PubMed
    1. Steuer CE, Behera M, Liu Y et al. Pulmonary Sarcomatoid Carcinoma: An Analysis of the National Cancer Data Base. Clin Lung Cancer 2017; 18 (3): 286–292. - PubMed
    1. Nicholson AG, Tsao MS, Beasley MB et al. The 2021 WHO Classification of Lung Tumors: Impact of Advances Since 2015. J Thorac Oncol 2022; 17 (3): 362–387. - PubMed
    1. Zheng Y, Fu Y, Zhong Q et al. The treatment of advanced pulmonary sarcomatoid carcinoma. Future Oncol 2022; 18 (6): 727–738. - PubMed
    1. Martin LW, Correa AM, Ordonez NG et al. Sarcomatoid carcinoma of the lung: a predictor of poor prognosis. Ann Thorac Surg 2007; 84 (3): 973–980. - PubMed

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