Efficacy and safety of anticancer drug combinations: a meta-analysis of randomized trials with a focus on immunotherapeutics and gene-targeted compounds

Abstract

Hundreds of trials are being conducted to evaluate combination of newer targeted drugs as well as immunotherapy. Our aim was to compare efficacy and safety of combination versus single non-cytotoxic anticancer agents. We searched PubMed (01/01/2001 to 03/06/2018) (and, for immunotherapy, ASCO and ESMO abstracts (2016 through March 2018)) for randomized clinical trials that compared a single non-cytotoxic agent (targeted, hormonal, or immunotherapy) versus a combination with another non-cytotoxic partner. Efficacy and safety endpoints were evaluated in a meta-analysis using a linear mixed-effects model (guidelines per PRISMA Report).We included 95 randomized comparisons (single vs. combination non-cytotoxic therapies) (59.4%, phase II; 41.6%, phase III trials) (29,175 patients (solid tumors)). Combinations most frequently included a hormonal agent and a targeted small molecule (23%). Compared to single non-cytotoxic agents, adding another non-cytotoxic drug increased response rate (odds ratio [OR]=1.61, 95%CI 1.40-1.84)and prolonged progression-free survival (hazard ratio [HR]=0.75, 95%CI 0.69-0.81)and overall survival (HR=0.87, 95%CI 0.81-0.94) (all p<0.001), which was most pronounced for the association between immunotherapy combinations and longer survival. Combinations also significantlyincreased the risk of high-grade toxicities (OR=2.42, 95%CI 1.98-2.97) (most notably for immunotherapy and small molecule inhibitors) and mortality at least possibly therapy related (OR: 1.33, 95%CI 1.15-1.53) (both p<0.001) (absolute mortality = 0.90% (single agent) versus 1.31% (combinations)) compared to single agents. In conclusion, combinations of non-cytotoxic drugs versus monotherapy in randomized cancer clinical trials attenuated safety, but increased efficacy, with the balance tilting in favor of combination therapy, based on the prolongation in survival.

Keywords: Combination therapy; hormonal therapy; immunotherapy; solid tumors; targeted therapy.

Figure 1.

Forest plot representing the odds ratio for response rate (A) and hazard ratios for PFS (B) and OS (C) for experimental arms with combination of therapies compared to experimental arms with single-agent non-cytotoxic therapies. Studies are labeled by first author’s last name and year of publication and numbers in brackets are labeled according to supplementary references. Panel A shows odds ratio (95% confidence interval) for response rate for each randomized trial comparing combinations to single agents. The plot shows an overall increase in response rate for combinations: OR (95% CI) = 1.61 (1.40−1.84) (p < .001). Panel B shows hazard ratio (95% confidence interval) for PFS for each randomized trial comparing combinations to single agents. The plot shows an overall increase in PFS for combinations: HR (95% CI) = 0.75 (0.69–0.81) (p < .001). Panel C shows hazard ratio (95% confidence interval) for OS for each randomized trial comparing combinations to single agents. The plot shows an overall increase in OS for combinations: HR (95% CI) = 0.87 (0.81–0.94) (p < .001). Abbreviations: CI: confidence interval; NR: non-responders; OS: overall survival; PFS: progression-free survival; R: responders: RE model: random-effects model.

Figure 1.

(continued).

Figure 1.

(continued).

Figure 2.

Forest plot representing the odds ratio for high-grade toxicities (A), and for treatment-related mortality (B) for experimental arms with combination of therapies compared to experimental arms with single-agent non-cytotoxic therapies. Studies are labeled by first author’s last name and year of publication and numbers in brackets are labeled according to supplementary references. Panel A shows odds ratio (95% confidence interval) for high-grade toxicities for each randomized trial comparing combinations to single agents. The plot shows an overall increase in high-grade toxicities for combinations: OR (95% CI) = 2.42 (1.98−2.97) (p < .001). Panel B shows odds ratio (95% confidence interval) for treatment-related mortality for each randomized trial comparing combinations to single agents. The plot shows an overall increase in treatment-related mortality for combinations: OR (95% CI) = 1.33 (1.15–1.53) (p < .001). Abbreviations: CI: confidence interval; Non-Tox: number of patients without high-grade toxicities; OR: odds ratio; Tox: number of patients with high-grade toxicities: RE model: random-effects model.

Figure 2.

(continued).