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

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.