title: Targeting immune checkpoints in unresectable metastatic cutaneous melanoma: a systematic review and meta-analysis of anti-CTLA-4 and anti-PD-1 agents trials.
abstract: Anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) inhibitors have been shown to significantly improve survival in patients with metastatic cutaneous melanoma. However, there was some heterogeneity as well as some variation in the degree of benefit across studies. We reviewed randomized trials and performed a meta-analysis to determine the efficacy and safety of immune checkpoint inhibitors in comparison with conventional regimens. Eligible studies were limited to randomized controlled trials comparing anti-CTLA-4 or anti-PD-1 inhibitors to chemotherapy or vaccination treatment in adult patients with unresectable cutaneous metastatic melanoma. Progression-free survival (PFS) rate at 6 months was 28.5% versus 17.7% (RR: 0.84, 95% CI: 0.76-0.93), overall survival (OS) rate at 1 year was 51.2% versus 38.8% (RR: 0.72, 95% CI: 0.59-0.88), and overall response rate (ORR) at 6 months was 29.6% versus 17.7% (RR: 0.85, 95% CI: 0.76-0.95) favoring immune check point inhibitors over chemotherapies or vaccination. Immune check point inhibitors were associated with more frequent immune-related adverse events at 13.7% versus 2.4% of treated patients (RR: 6.74, 95% CI: 4.65-9.75). Subgroup analyses demonstrated significant PFS (RR: 0.92 vs. 0.74, P < 0.00001) and ORR (RR: 0.95 vs. 0.76, P = 0.0004) improvement with anti-PD-1 treatment compared to anti-CTLA-4 when each of them was compared to control treatments. Collectively, these results demonstrate that immune checkpoint inhibitors have superior outcomes compared to conventional chemotherapies or vaccination, and support the results of recent randomized trials that showed superior outcomes with anti-PD-1 agents over ipilimumab in unresectable metastatic cutaneous melanoma patients.
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona, 85721.|Hematology and Oncology, University of Arizona, Tucson, Arizona, 85721.
authors.forename: Seongseok
authors.identifier: 0000-0001-7343-1635
authors.initials: S
authors.lastname: Yun
authors.affiliation: Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, 55905.
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Vincelette
authors.affiliation: Hematology and Oncology, University of Arizona, Tucson, Arizona, 85721.
authors.forename: Myke R
authors.initials: MR
authors.lastname: Green
authors.affiliation: Medical Oncology, Mayo Clinic, Rochester, Minnesota, 55905.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Wahner Hendrickson
authors.affiliation: Center for Health Outcomes and PharmacoEconomic Research, University of Arizona, Tucson, Arizona, 85721.|Arizona Cancer Center, University of Arizona, Tucson, Arizona, 85721.
authors.forename: Ivo
authors.initials: I
authors.lastname: Abraham
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D002986:Clinical Trials as Topic; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016017:Odds Ratio; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D017594:Publication Bias; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology*; D016896:Treatment Outcome; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor
keywords: CTLA-4; Ipilimumab; Lambrolizumab; PD-1; metastatic melanoma; nivolumab; pembrolizumab; tremelimumab