PD-1 and CTLA-4 inhibitors in combination vs. alone for the treatment of advanced melanoma: A systematic review and meta-analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials and cohort studies
PubMed 36254050 · doi:10.1097/MD.0000000000030561
What was done
A systematic review and meta-analysis of EMBASE, PubMed, Scopus, Cochrane Central, and Web of Science was conducted to evaluate combined PD-1 and CTLA-4 inhibitors versus monotherapy in advanced melanoma. Out of 3,092 citations, 5 studies were included (3 randomized controlled trials and 2 retrospective cohort studies). Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using the Mantel-Haenszel method.
What was found
Combination therapy significantly improved overall response (OR 2.144, 95% CI 1.650–2.786; I² = 80.38%, P = .000) and complete response (CR; OR 2.117, 95% CI 1.578–2.841; I² = 70.17%, P = .000) compared to monotherapy. - Versus nivolumab monotherapy, combination therapy showed improved overall response (OR 1.766, 95% CI 1.324–2.355; I² = 0.0%, P = .000), but CR was not statistically significant (OR 1.284, 95% CI 0.889–1.855; I² = 0.0%, P = .182). - Versus ipilimumab monotherapy, combination therapy showed higher overall response (OR 5.440, 95% CI 2.896–10.220; I² = 70.89%, P = .001) and CR (OR 5.169, 95% CI 3.163–8.446; I² = 0.0%, P = .000). - Treatment-related adverse events were higher with combination therapy than with nivolumab alone (OR 4.044, 95% CI 1.740–9.403; I² = 91.64%, P = .001) and ipilimumab alone (OR 2.465, 95% CI 0.839–7.236; I² = 93.02%, P = .101).
Why it matters
This review quantifies the efficacy advantage of combining nivolumab and ipilimumab over single-agent regimens in advanced melanoma while highlighting the substantial increase in toxicity risk.
Limits
The total number of included studies was small (5 studies), mixing 3 RCTs with 2 retrospective observational cohorts. The abstract does not report total patient counts, survival endpoints (progression-free or overall survival), or adverse event severity grading. Several pooled analyses exhibited extreme statistical heterogeneity (I² > 70–93%).