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. 2025 Jun;26(4):288-298.e8.
doi: 10.1016/j.cllc.2025.01.014. Epub 2025 Feb 4.

Tumor Immunophenotypic Correlates in Patients Aged 80 Years or Older With Non-Small Cell Lung Cancer and Outcomes to First-Line Pembrolizumab in PD-L1 High (≥50%) Patients

Adriana P C Barrichello  1 , Arielle Elkrief  2 , Biagio Ricciuti  3 , Teja Ganta  4 , Thomas U Marron  4 , Xinan Wang  5 , William Lotter  6 , James Lindsay  6 , Valentina Santo  1 , Alessio Cortellini  7 , Bijaya Sharma  8 , Kristen Felt  8 , Kathleen Pfaff  9 , Giuseppe Lamberti  1 , Federica Pecci  1 , Alessandro Di Federico  1 , Maisam Makarem  1 , Malini M Gandhi  1 , Tom Nguyen  1 , Danielle Haradon  1 , Victor R Vaz  1 , Bruce E Johnson  1 , Neha Debnath  4 , Yinghong Wang  10 , Andrew G Kuang  11 , Anwaar Saeed  12 , Maluki Radford  12 , Christine M Lovly  13 , Caroline A Nebhan  13 , David J Pinato  7 , Scott J Rodig  14 , Adam J Schoenfeld  2 , Mark M Awad  1 , Joao V Alessi  1 , Abdul Rafeh Naqash  15
Affiliations

Tumor Immunophenotypic Correlates in Patients Aged 80 Years or Older With Non-Small Cell Lung Cancer and Outcomes to First-Line Pembrolizumab in PD-L1 High (≥50%) Patients

Adriana P C Barrichello et al. Clin Lung Cancer. 2025 Jun.

Abstract

Background: Non-small cell lung cancer (NSCLC) patients aged ≥80 years [y] are underrepresented in clinical trials. We evaluated whether age correlates with a distinct immunophenotype or impacts outcomes to first-line pembrolizumab in patients with advanced NSCLC, PD-L1 Tumor Proportion Score (TPS) of ≥50%, and aged ≥80y.

Methods: Three NSCLC cohorts were retrospectively analyzed to assess the impact of age (<80y versus ≥80y) on pembrolizumab efficacy and the tumor microenvironment (TME). Cohort A encompassed patients receiving first-line pembrolizumab for advanced NSCLC with PD-L1 ≥50%. Cohort B comprised patients with tumor profiling using multiplexed immunofluorescence (ImmunoPROFILE). Cohort C included The Cancer Genome Atlas (TCGA) and Stand Up to Cancer (SU2C) databases for gene expression analysis.

Results: In Cohort A (N = 669), patients ≥80y (N = 111) showed no significant differences in objective response rate or median progression-free survival compared to younger patients (N = 558), but had shorter median overall survival and were less likely to receive second-line therapy after progression on pembrolizumab. In Cohort B (N = 567), tumors from patients ≥80y (N = 45) exhibited higher intratumoral FOXP3+ T cells and closer vicinity of PD-1+ immune cells to tumor cells compared to <80y (N = 522). Cohort C revealed a distinct immunophenotype in samples from patients ≥ 80y, with elevated specific immune cell subsets and up-regulated immune checkpoint proteins.

Conclusion: Patients ≥80y with PD-L1-high NSCLC displayed a distinct immunophenotype in the TME but achieved similar ORR and mPFS with first-line pembrolizumab compared to younger patients. OS was shorter in older patients, who were less likely to receive second-line therapy.

Keywords: Immune cells; Immunotherapy; Older adults; Thoracic tumors; Tumor microenvironment.

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Conflict of interest statement

Disclosure A.P.C.B. has previously served as a speaker engagement and educational session for the following pharmaceutical companies: Merck, Sharp & Dohme, Roche, and AstraZeneca. APCB received complimentary registrations and travel compensations from Lilly and Bristol-Myers Squibb. A.E. is supported by the Canadian Institutes of Health Research, the Royal College of Physicians and Surgeons of Canada Detweiler Travelling Fellowship, and the Cedar's Cancer Center Henry R. Shibata Fellowship. T.U.M. has previously served on Advisory and/or Data Safety Monitoring Boards for Rockefeller University, Regeneron, AbbVie, Merck, Bristol-Meyers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, DrenBio, Glenmark, Simcere, Surface, G1 Therapeutics, NGMbio, DBV Technologies, Arcus, and Astellas, and has research grants from Regeneron, Bristol-Myers Squibb, Merck, and Boehringer Ingelheim. B.E.J. reports support from the Taylor Family-Lung Cancer Research Fund and the Anthony F. Sola Fund for Lung Cancer Research. BEJ reports he is a paid consultant to Novartis, Checkpoint Therapeutics, Astra Zeneca, Daichi Sankyo, GSK, Hummingbird Diagnostics, Genentech, Bluedot Bio, G1 Therapeutics, Jazz Pharmaceuticals, Merus, Abdera, Redona, and Simcere Pharmaceutical, and unpaid Member of Steering Committee for Pfizer. Y.W. Consulting service for Sorriso, MabQuest, Sanarentero, AzurRx, IOTA Ilyapharma, and Janssen. Research grants from Gateway, Adopt A Scientist, Moonshot, HESI, and Sabin Fellowship. C.M.L. has served as a consultant for Amgen, AnHeart, Arrivent, Astra Zeneca, Blueprints Medicine, Boehringer Ingelheim, Cepheid, D2G, Daiichi Sankyo, EMD Serono, Foundation Medicine, Genentech, Gilead, Indupro, Janssen, Medscape, Novartis, Pfizer, Roche, Takeda, Tempus. S.J.R. receives research support from Bristol-Myers Squibb and KITE/Gilead. SR is on the SAB of Immunitas Therapeutics. A.J.S. has had a consulting or advisory role for Johnson & Johnson, Bristol Myers Squibb, Merck, Enara Bio, KSQ therapeutics, Lyell Immunopharma, Iovance Biotherapeutics, Perceptive Advisors, and Heat Biologics; research funding from GlaxoSmithKline, PACT Pharma, Inc, Iovance Biotherapeutics, Achilles Therapeutics, Merck, Amgen, Bristol Myers Squibb, and Harpoon Therapeutics. M.M.A. serves as a consultant to Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Nektar, Maverick, Blueprint Medicine, Syndax, Abbvie, Gritstone, ArcherDX, Mirati, NextCure, and EMD Serono. Research Funding: Bristol-Myers Squibb, Lilly, Genentech and AstraZeneca. A.R.N. is supported in part by the SWOG Hope Foundation Impact Award and the FDA Broad Agency Announcement Contract Grant. ARN also reports funding to Institution for Trials he is PI on: Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals. ARN receives consultant Editor Compensation for JCO Precision Oncology and Travel Compensations: SITC/ AACR/ Conquer Cancer Foundation. All other authors state that they have no conflicts of interest.

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