Comprehensive Evaluation of Anti-PD-1, Anti-PD-L1, Anti-CTLA-4 and Their Combined Immunotherapy in Clinical Trials: A Systematic Review and Meta-analysis

Abstract

Immunotherapy with immune checkpoint inhibitor (ICI) drugs is gradually becoming a hot topic in cancer treatment. To comprehensively evaluate the safety and efficacy of ICI drugs, we employed the Bayesian model and conducted a network meta-analysis in terms of progression-free survival (PFS), overall survival (OS) and severe adverse events (AEs). Our study found that treatment with ipilimumab was significantly worse than standard therapies in terms of PFS, whereas treatment with cemiplimab significantly improved PFS. The results also indicated that cemiplimab was the best choice for PFS. Treatment with nivolumab, pembrolizumab and nivolumab plus ipilimumab significantly improved OS compared to standard therapies. In terms of OS, cemiplimab was found to be the best choice, whereas avelumab was the worst. In terms of severe AEs, atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab all significantly reduced the risk of grade 3 or higher AEs compared to standard therapy. The least likely to be associated with severe AEs were as follows: cemiplimab, avelumab, nivolumab, atezolizumab, and camrelizumab, with nivolumab plus ipilimumab to be the worst. Therefore, different ICI drug therapies may pose different risks in terms of PFS, OS and severe AEs. Our study may provide new insights and strategies for the clinical practice of ICI drugs.

Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States

“…It is extremely important to determine whether the assessment of ICI toxicity is needed to predict the occurrence of irAEs or provide early treatment that can modulate the immune system to obtain lasting antitumor effects [26][27][28][29]. As a new class of targeted anticancer drugs, ICIs target the immune tolerance pathways of tumor cells, such as PD-1, PD-L1 and CTLA-4, to kill tumor cells [30]. Chemokines and their receptors exert essential functions in all aspects of immune processes involved in physiology (hematopoiesis, immune defense and tissue health) and pathophysiology (chronic inflammation, allergy, and cancer), suggesting that irAEs may limit the use of chemokine-based reagents including ICIs in cancer treatment [3].…”

Characterization of TCF‐1 and its relationship between CD8+ TIL densities and immune checkpoints and their joint influences on prognoses of lung adenocarcinoma patients

“…The past decade has witnessed the rapid development of immunotherapy for the treatment of cancer 24 . Among these immunotherapies, use of coinhibitory immune ICIs, including PD‐1, PD‐L1, and CTLA‐4 monoclonal antibodies (mAbs), have become the most promising clinical treatments 25 . The next generation of ICIs such as for LAG‐3, TIM‐3, TIGIT, VISTA, B7 homolog 3 protein, and B and T cell lymphocyte attenuators are now in preclinical trials.…”

“…24 Among these immunotherapies, use of coinhibitory immune ICIs, including PD-1, PD-L1, and CTLA-4 monoclonal antibodies (mAbs), have become the most promising clinical treatments. 25 The next generation of ICIs such as for LAG-3, TIM-3, TIGIT, VISTA, B7 homolog 3 protein, and B and T cell lymphocyte attenuators are now in preclinical trials. However, the responses of anti-PD-1/PD-L1mAb or anti-CTLA-4 mAb is still far from satisfactory.…”

Frontiers and future of immunotherapy for pancreatic cancer: from molecular mechanisms to clinical application

“…In this context, the FDA approved another PD-1 inhibitor, namely, cemiplimab-rwlc (Libtayo), on February 22, 2021 for the first-line treatment of advanced non-small cell lung cancer ( 65 ) with high PD-L1 expression (tumor proportion score ≥ 50%); it was approved for either metastatic or locally advanced cases without EGFR , ALK , or ROS1 mutations. However, a few clinical trials have evaluated the use of cemiplimab for the treatment of pancreatic cancer ( 66 ). There is a need for further in-depth research in this area.…”