The Role of Immune Checkpoint Inhibitors in Cancer Treatment: A Comprehensive Systematic Review

Abstract

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have transformed oncology by unleashing T-cell-mediated antitumor immunity, yielding durable responses across multiple malignancies where conventional therapies often fail. This systematic review synthesized evidence from 10 high-quality phase II/III randomized controlled trials involving over 8,000 patients with advanced melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), small-cell lung cancer (SCLC), and colorectal cancer (CRC), selected after rigorous screening of 2,580 records. Pooled analyses demonstrated consistent survival benefits: ICIs improved overall survival (OS) with hazard ratios (HRs) ranging from 0.48 to 0.72 versus chemotherapy or targeted therapy, progression-free survival (PFS) HRs of 0.34–0.67, and objective response rates (ORR) up to 58% in combination regimens such as nivolumab plus ipilimumab or pembrolizumab plus chemotherapy. Notable subgroup advantages emerged in PD-L1-high tumors (≥50% expression), microsatellite instability-high (MSI-H) CRC, and treatment-naïve settings, with landmark 5-year OS rates reaching 31–58% in responsive cohorts. Dual blockade (PD-1/CTLA-4) consistently outperformed monotherapy in melanoma and NSCLC but at the cost of higher grade ≥3 immune-related adverse events (irAEs) (32–59% versus 9–36%), primarily colitis, hepatitis, and endocrinopathies that were manageable with corticosteroids in most cases. Safety profiles remained favorable compared with chemotherapy-induced toxicities, with treatment-related deaths below 2% across trials. Limitations included heterogeneity in PD-L1 cutoffs, crossover effects, and underrepresentation of certain ethnic groups. Overall, ICIs establish a new standard of care, offering long-term remission potential while underscoring the need for biomarker-driven patient selection and irAE monitoring to optimize therapeutic indices in diverse cancer populations.