Large Granular Lymphocytes in mNSCLC Treated With Nivolumab

Official title

Large Granular Lymphocytes as a Prognostic Factor in Metastatic Non-small Cell Lung Cancer Treated With Nivolumab

Overview

Large granular lymphocytes (LGLs), which constitute 10-15% of peripheral blood mononuclear cells, are large lymphocytes with a round nucleus, large cytoplasm, and azurophilic granules in the cytoplasm. Most normal LGLs in peripheral blood are natural killer (NK) cells, but some are T lymphocytes. These cells cannot be measured by a standard complete blood count (CBC) test. These cells, which can be detected by peripheral smear, are expressed numerically and as a percentage relative to other cells. The aim of this study is to determine the relationship between the percentage of LGLs at baseline and at three months and the response and clinical parameters in participants with metastatic non-small cell lung cancer treated with nivolumab in second-line therapy.

Detailed description

Non-small cell lung cancer ranks first worldwide in 2022 in terms of both incidence and mortality when both genders are considered . Historically, the 5-year survival rate for patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy was 5%. Effective treatment options for patients without targetable molecular alterations, especially those who progressed after first-line chemotherapy, were limited until recently. Immunotherapy checkpoint inhibitors, with clinically meaningful survival benefits, long-term responses, and favorable safety profiles compared to chemotherapy, have become the standard of care for patients who progress during or after platinum-based chemotherapy. Immune checkpoint inhibitors are also effective as first-line therapy and are recommended as standard treatment for untreated advanced NSCLC patients, either in combination with chemotherapy or without chemotherapy.

Nivolumab, a fully human, monoclonal, anti-programmed death-1 (PD-1) antibody, is the first PD-1 inhibitor to demonstrate clinically meaningful efficacy in NSCLC. Nivolumab is approved for second-line treatment of advanced NSCLC in patients with advanced squamous (CheckMate 017; NCT01642004) and non-squamous (CheckMate 057; NCT01673867) NSCLC, following platinum-based chemotherapy, compared to docetaxel, showing improved overall survival and a favorable safety profile. Pembrolizumab is a humanized IgG4 monoclonal antibody against programmed cell death protein 1 (PD-1). Phase 1 KEYNOTE-0018 and phase 2/3 KEYNOTE-0109 studies demonstrated a correlation between increased expression of the PD-1 ligand PD-L1 in patients with advanced non-small cell lung cancer and the benefit achieved with pembrolizumab treatment. KEYNOTE-024 is a study comparing pembrolizumab monotherapy as first-line treatment with platinum-based chemotherapy in 305 patients with metastatic non-small cell lung cancer and a PD-L1 tumor proportion score (TPS) of 50% or higher. Both progression-free survival and overall survival were significantly longer in the pembrolizumab group compared to the standard chemotherapy group (median 10.3 months and 6.0 months vs. 30.0 months and 14.2 months).

Large granular lymphocytes (LGLs) are large lymphocytes with a round or kidney-shaped nucleus, a large cytoplasm, and azurophilic granules in the cytoplasm. They constitute 10-15% of peripheral blood mononuclear cells. Most normal LGLs in peripheral blood are natural killer (NK) cells, but some are T lymphocytes. These cells cannot be measured by a normal hemogram test. These cells, which can be detected by peripheral smear, are expressed both numerically and as a percentage relative to other cells. It has been shown that an absolute decrease in lymphocyte count reduces the response to immunotherapy. However, there are no studies in the literature showing the relationship between LGL and immunotherapy response.

In this prospectively planned study, the investigators aim to investigate the relationship between LGL (large granular lymphocyte) levels at the start of treatment and at 3 months in participants with non-small cell lung cancer treated with anti-PD-1 (programmed cell death-1) and survival and clinical parameters.

Primary outcome measures

• Objective response rate according to RECIST 1.1 Evaluation of target lesions [Time frame: From enrollment to the end of treatment at 12 weeks]

Secondary outcome measures (2)

• Progression-free survival [Time frame: From July 2025 to July 2027]
• Overall survival [Time frame: From July 2025 to July 2027]

Eligibility criteria

Inclusion criteria

• Histological and staging diagnosis of metastatic non-small cell lung cancer
• ECOG performance score between 0 and 2
• No contraindications for nivolumab

Exclusion criteria

• Patients diagnosed with mNSCLC who received nivolumab as adjuvant or perioperative therapy
• Those with a second primary malignancy undergoing active treatment
• Those who have not signed the informed consent form
• Those with additional hematological malignancies such as leukemia, lymphoma, or myelodysplastic syndrome
• Those who have undergone palliative or curative radiotherapy within the last three months
• Those with active viral/bacterial infections before nivolumab treatment
• Patients who have used steroids in the last three months

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Turkey (Türkiye) · 1 center

• Necmettin Erbakan University Faculty of Medicine, Department of Medical Oncology — Konya

Publications

• Conroy MR, O'Sullivan H, Collins DC, Bambury RM, Power D, Grossman S, O'Reilly S. Exploring the prognostic impact of absolute lymphocyte count in patients treated with immune-checkpoint inhibitors. BJC Rep. 2024 Apr 18;2(1):31. doi: 10.1038/s44276-024-00058-6. PMID 39516713
• Oshimi K. Clinical Features, Pathogenesis, and Treatment of Large Granular Lymphocyte Leukemias. Intern Med. 2017;56(14):1759-1769. doi: 10.2169/internalmedicine.56.8881. Epub 2017 Jul 15. PMID 28717070
• Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lan PMID 30955977
• Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J, Pluzanski A, Arrieta O, Frontera OA, Chiari R, Butts C, Wojcik-Tomaszewska J, Coudert B, Garassino MC, Ready N, Felip E, Garcia MA, Waterhouse D, Domine M, Barlesi F, Antonia S, Wohlleber M, Gerber DE, Czyzewicz G, Spigel DR, Crino L, Eberhardt WEE, Li A, Marimuthu S, Brahmer J. Five-Year Outcomes From the Randomized, Pha PMID 33449799
• Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. doi: 10.1056/NEJMoa1606774. Epub 2016 Oct 8. PMID 27718847
• Assi HI, Kamphorst AO, Moukalled NM, Ramalingam SS. Immune checkpoint inhibitors in advanced non-small cell lung cancer. Cancer. 2018 Jan 15;124(2):248-261. doi: 10.1002/cncr.31105. Epub 2017 Dec 6. PMID 29211297
• Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263. doi: 10.3322/caac.21834. Epub 2024 Apr 4. PMID 38572751

Identifiers

NCT: NCT07363811 · 26105/2025/5927

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗