Comparative safety analysis of immunotherapy combined with chemotherapy versus monotherapy in solid tumors: a meta-analysis of randomized clinical trials

Background: Combination treatment (chemotherapy plus immune checkpoint blockade [ICB]) has shown promising activity in terms of efficacy, but it has been suggested that its toxicity profile is less favorable compared to monotherapy. Methods: We conducted a meta-analysis of published randomized clinical trials comparing combination treatment to monotherapy (chemotherapy or ICB) in patients with metastatic solid tumors. Differences in rates of safety issues (all-grade adverse events, grade 3/4 adverse events, treatment-related deaths, treatment discontinuations) between groups were estimated. Subgroup analyses for the control group (chemotherapy or ICB as monotherapy) and immune checkpoint inhibitor (anti-CTLA-4 or anti-PD-1/PD-L1 antibodies) were performed. Results: A total of 4379 patients (ten studies) were included (monotherapy: 2026 patients; combination treatment: 2353 patients). Combination treatment presented more grade 3/4 adverse events (RR 1.32, 95% CI 1.12-1.55) and discontinuations (RR 2.31, 95% CI 1.28-4.16). There were no differences in the mortality rate between groups. Subgroup analyses showed a potentially more toxic profile with anti-CTLA-4 agents. Conclusions: Combination treatment is associated with an increase in grade 3/4 adverse events and treatment discontinuations compared to monotherapy, but not increased mortality. The toxicity profile of combination therapy should be considered with regard to the overlapping safety profiles.