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Immune Checkpoint Inhibitors: efficacy, safety, and biomarkers - a systematic review
Hebatalla Ismail1, Anees Hassan2
1Medical Oncology, St. Vincent's University Hospital, UCD Cancer Centre, Dublin, Ireland.
Abstract:
Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors and cytotoxic Lymphocyte-associated protein 4 (CTLA-4) inhibitors are the core classes of immune checkpoint inhibitors (ICIs) widely used in cancer treatment. These agents, including PD-1, PD-L1, and CTLA4 inhibitors, have demonstrated efficacy across multiple cancer types, enhancing progression free survival (PFS) and overall survival (OS). However, their use is associated with immune related adverse events (irAEs) that can manifest as skin rashes, hepatitis, diarrhea, colitis, hypopituitarism, and pneumonitis, among other conditions. In this systematic review, we discuss the safety and efficacy of ICIs based on 15 randomized controlled trials and cohort studies that met our eligibility criteria. All selected studies focused on analysing primary clinical outcomes including OS, PFS, objective response rate (ORR), and irAEs. These findings demonstrate that ICIs offer durable antitumor activity with favourable outcomes observed in patients with high tumour mutational burden (TMB) and PD-L1 expression. However, toxicity remains a significant concern, as some reports show substantial adverse events requiring immunosuppressive management. While PD-L1 expression and TMB are established biomarkers for predicting ICI response, their role in predicting immune-related adverse events remains investigational and is not supported by robust evidence. This review further examines combination strategies, including dual checkpoint blockade and ICI combined with chemotherapy, which have demonstrated superior clinical outcomes compared with monotherapy but are associated with increased toxicity. Future research should focus on refining patient selection criteria, optimizing toxicity management protocols, and identifying novel predictive biomarkers for ICI therapy. Understanding these aspects will facilitate the development of more effective ICI-based treatments with improved benefit-to-risk ratios, ultimately enhancing patient outcomes in oncology.
Insights
Immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 and CTLA-4 inhibitors improve cancer survival but cause immune-related adverse events. High tumor mutational burden and PD-L1 expression predict response, but not toxicity.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 and CTLA-4 inhibitors, are crucial in cancer therapy.
- These agents enhance progression-free survival (PFS) and overall survival (OS) across various cancers.
- However, ICIs are linked to immune-related adverse events (irAEs) affecting multiple organ systems.
Purpose of the Study:
- To systematically review the safety and efficacy of ICIs.
- To analyze clinical outcomes such as OS, PFS, objective response rate (ORR), and irAEs.
- To evaluate combination strategies involving ICIs.
Main Methods:
- Systematic review of 15 randomized controlled trials and cohort studies.
- Analysis focused on primary clinical outcomes: OS, PFS, ORR, and irAEs.
- Assessment of biomarkers (PD-L1 expression, tumor mutational burden) for predicting response and toxicity.
Main Results:
- ICIs demonstrate durable antitumor activity, particularly in patients with high tumor mutational burden (TMB) and PD-L1 expression.
- Significant toxicities associated with ICIs necessitate immunosuppressive management in some cases.
- Combination therapies (dual blockade, ICI plus chemotherapy) show improved outcomes but increased toxicity compared to monotherapy.
Conclusions:
- While ICIs offer significant survival benefits, managing irAEs remains a challenge.
- PD-L1 expression and TMB are predictive of ICI response but not consistently of irAEs.
- Future research should prioritize refining patient selection, optimizing toxicity management, and discovering novel predictive biomarkers for enhanced ICI therapy benefit-risk ratios.
