Twenty-two RCTS (n=5,473) were included in the review: 7 phase II trials and 15 phase III trials.
The methodological quality of the included studies was good: all studies were considered to have a Jadad score of 3 or higher.
GEM combination therapy significantly improved overall survival at 6 months (22 trials; RD 0.04, 95% CI: 0.01, 0.06, p=0.008) compared with GEM monotherapy. There was no evidence of statistically significant heterogeneity (p=0.19). At 1 year, GEM combination therapy continued to significantly improve survival (21 trials; RD 0.03, 95% CI: 0.01, 0.05, p=0.01) compared with GEM monotherapy.
GEM combination therapy showed a statistically significant improvement in both the objective remission rate (21 trials; RD 0.04, 95% CI: 0.01, 0.07, p=0.02), where statistical heterogeneity was significant (p<0.0001), and the clinical benefit rate (6 trials; RD 0.10, 95% CI: 0.02, 0.17, p=0.01), where statistical heterogeneity was of borderline significance.
GEM combination therapy significantly improved the time to progress/progress-free survival rate at 6 months (13 trials; RD 0.07, 95% CI: 0.04, 0.10, p<0.00001) compared with GEM monotherapy. Statistical heterogeneity was not evident (p=0.20).
Grade 3-4 toxicity was significantly higher in GEM combination patients for neutropenia (21 trials; RD 0.05, 95% CI: 0.01, 0.10, p=0.02), thrombocytopenia (21 trials; RD 0.05, 95% CI: 0.02, 0.08, p=0.002) and vomiting/nausea (21 trials; RD 0.03, 95% CI: 0.00, 0.05, p=0.02).
A post-hoc subgroup analysis that stratified trials by type of combination therapy revealed that only the GEM plus targeted drug (marimastat, tipifarnib or erlotinib) combination versus GEM monotherapy yielded a significantly improved survival rate at 6 months (3 trials; RD 0.06, 95% CI: 0.01, 0.11, p=0.02).
Funnel plots for overall survival at 6 months and 1 year did not suggest the presence of publication bias.