Efficacy and Safety of Immune Checkpoint Inhibitors for Advanced Malignant Melanoma: A Meta-Analysis on Monotherapy Vs Combination Therapy

Abstract

Background: Immune checkpoint inhibitors (ICIs) are approved as cancer immunotherapeutic agents for advanced malignant melanoma (MM) in recent years, and nivolumab and ipilimumab are the most widely used ICIs either alone or in combination. However, their efficacy and safety between single and combined ICIs are not clear. This meta-analysis (MA) is aimed to update the efficacy and safety of ICIs by comparing monotherapy and combination therapy in the treatment of advanced MM. Method: We searched PubMed, Embase, EbscoHost and ClinicalTrials.gov for the eligible randomized controlled trials (RCTs) which compared the efficacy and safety of ICIs between a single ICI and combined ICIs. The outcomes analyzed included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on the study heterogeneity. Results: A total of nine RCTs were included in this MA. Regarding the efficacy, combined nivolumab and ipilimumab therapy showed statistically significant prolonged OS and PFS with HR 0.65, 95% CI [0.53, 0.79], p <0.0001 and HR 0.48, 95% CI [0.38, 0.60], p<0.0001 respectively. Combination therapy with nivolumab and ipilimumab also showed statistically significant longer ORR than monotherapy; with RR 2.15, 95% CI [1.63, 2.84], p <0.00001. In terms of safety, the incidence of all AEs which include any AEs, high-grade, haematological, gastrointestinal, dermatological, pulmonary, liver and endocrine AEs were significantly lower with monotherapy (either nivolumab or ipilimumab) of ICI compared to combination ICI therapy with a p-value <0.00001 to 0.03. Conclusion: Efficacy of the combined nivolumab and ipilimumab was better than a single ICI, especially in the treatment of advanced MM. Although combination therapy showed better efficacy than monotherapy, monotherapy (either nivolumab or ipilimumab) was safer than combination therapy as it tended to decrease the incidence of most of the treatment-related AEs.

Keywords: Immune checkpoint inhibitors; advanced malignant melanoma; combination therapy.; meta-analysis; monotherapy; systematic review.

Figure 1

PRISMA flowchart indicating study selection .

Figure 2A

Assessment of risk of bias (Risk of Bias Graph).

Figure 2B

Assessment of risk of bias (Risk of Bias summary).

Figure 3

A: Forest plot for overall survival (OS); B: Forest plot for progression free survival (PFS).

Figure 4

Forest plot for objective response rate (ORR).

Figure 5

A: Forest plot for adverse effects of any grade; B: Forest plot for high grade adverse effects.