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.

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.

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

Patients diagnosed with metastatic non-small cell lung cancer who were followed up at the Medical Oncology Clinic of Necmettin Erbakan University Hospital and treated with nivolumab as second-line therapy.