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

Figures & data

Table 1. Characteristics of randomized clinical trials analyzed.^a

Characteristics	N (%)
Total randomized trials	92
Number of patients -Single agent arm -Combination arm	28,704 13,381 (46.6) 15,323 (53.4)
Total randomized comparisons^b -Phase 2 trial -Phase 3 trial	95 (100) 57 (60) 38 (40)
Types of Randomized Comparisons -Targeted small molecule ± targeted small molecule -Targeted small molecule ± targeted mABs -Targeted small molecule ± immunotherapy -Targeted small molecule ± hormonal -Targeted small molecule ± other -Targeted mABs ± targeted small molecule -Targeted mABs ± targeted mABs -Targeted mABs ± immunotherapy -Immunotherapy ± immunotherapy -Immunotherapy ± not classified -Hormonal agent ± targeted small molecule -Hormonal agent ± targeted mABs -Hormonal agent ± hormonal agent -Hormonal agent ± not classified -Not classified^c ± targeted small molecule -Not classified^c ± targeted mABs -Not classified^c ± hormonal agent	95 19 (20) 11 (11) 2 (2) 1 (1) 1 (1) 9 (9) 3 (3) 2 (2) 7 (7) 3 (3) 22 (23) 5 (5) 5 (5) 2 (2) 1 (1) 1 (1) 1 (1)
Biomarker-based rational for the combination -Yes -No	9 (9) 86 (91)
Tumor Types -Breast -Colorectal -Endometrial -GIST -Head and Neck -Hepatocellular carcinoma -Malignant Mesothelioma -Melanoma -Neuroendocrine -NSCLC -Prostate -Renal cell -Sarcoma -SCLC	95 28 (29) 6 (6) 1 (1) 2 (2) 3 (3) 3 (3) 1 (1) 3 (3) 1 (1) 22 (23) 9 (9) 13 (14) 1 (1) 1 (1)

^aSee Methods for selection criteria.

^bThree trials included to more than one randomized comparison.

^cNot Classified included: prednisone, lenalidomide, cimetidine, retinoic acid, simvastatin, zoledronic acid, alendronate, sargramostim. For a full list of classification of agents see Table 1.

Abbreviations: GIST: gastrointestinal stromal tumor; mAB: monoclonal antibody; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer.

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)

Table 2. Meta-analysis for the effects of combination therapies versus single agents on outcome in randomized trials (multivariate)^a.

	Response rate		PFS		OS
	N	OR (95% CI)	N	HR (95% CI)	N	HR (95% CI)
Overall P-value	88	1.61 (1.40–1.84) <0.001	71	0.75 (0.69–0.81) <0.001	48	0.87 (0.81–0.94) <0.001
Class of backbone drug Targeted small molecule inhibitors Targeted monoclonal antibodies Immunotherapy Hormonal Not classified^b	33 12 9 31 3	1.31 (1.07–1.61) p = .01 2.17 (1.55–3.02) p < .001 2.13 (1.38–3.28) p < .001 1.54 (1.27–1.87) p < .001 4.71 (1.90–11.67) p = .001	29 12 3 25 2	0.90 (0,59–1.36)p = .60 0.87 (0.53–1.44) p = .59 0.64 (0.36–1.12) p = .11 0.69 (0.61–0.78) p < .001 1.32 (0.82–2.14) p = .25	24 8 3 11 2	0.82 (0.57–1.17) p = .26 0.57 (0.38–0.85) p = .007 0.49 (0.33–0.74) p = .001 0.95 (0.78–1.17) p = .65 1.61 (0.97–2.65) p = .06
Tumor Type Breast Cancer Colorectal Cancer NSCLC Prostate Cancer RCC Others	28 5 21 6 12 16	NS NS NS NS NS NS	24 4 20 5 10 8	0.90 (0.59–1.36) p = .60 0.83 (0.56–1.24) p = .36 0.83 (0.73–0.94) 0.005 0.50 (0.29–0.86) p = .01 0.82 (0.64–1.05) p = .11 0.92 (0.72–1.18) p = .50	9 4 18 6 7 4	0.82 (0.57–1.17) p = .26 1.55 (0.94–2.56) p = .08 1.32 (1.01–1.71) p = .04 0.54 (0.38–0.77) p = .001 1.27 (1.02–1.59) 0.035 0.98 (0.83–1.14) p = .75
Median Number Prior Regimens^c 0 1 2 3 or more	35 35 11 5	NS NS NS NS	33 27 9 2	NS NS NS NS	19 19 8 2	0.82 (0.57–1.17) p = .26 0.59 (0.40–0.87) p = .008 0.70 (0.45–1.07) p = .09 0.76 (0.58–0.99) p = .04

^aSingle agents are the reference point for all statistics. The final model included the following variables in each category: RR (Backbone drug class and linear start of enrollment year); OS (backbone drug class, tumor indication, and median prior regimens); PFS (backbone drug class and tumor indication).

^bNot Classified included: prednisone, lenalidomide, cimetidine, retinoic acid, simvastatin, zoledronic acid, alendronate, sargramostim. For a full list of classification of agents see Supplemental Table 1.

^cTwo trials included in response rate analysis did not reported number of prior regimens.

Abbreviations: HR, hazard ratio; mAB: monoclonal antibody; N, number of randomized comparisons included; NS: not significant in (and therefore not included in) multivariate model; NSCLC: non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; OR, odds ratio; RCC: renal cell carcinoma.

Table 3. Meta-analysis for the effects of combination therapies versus single agents^a upon high-grade toxicities and treatment-related mortality (multivariate^b)

	High-grade toxicity		Treatment-related mortality
	N	OR (95% CI) P value	N	OR (95% CI) P value
Overall P-value	76	2.42 (1.98–2.97) <0.001	87	1.33 (1.15–1.53) <0.001
Class of experimental drug added^c Targeted small molecule inhibitor Targeted monoclonal antibody Immunotherapy Hormonal Not classified	41 19 8 5 3	3.14 (2.49–3.97) p < .001 1.81 (1.24–2.64) p = .002 3.04 (1.76–5.28) p < .001 1.62 (0.85–3.08) p = .14 1.08 (0.43–2.72) p = .86	47 18 10 6 6	1.49 (1.19–1.87) p < .001 1.81 (1.33–2.46) p < .001 1.67 (1.13–2.45) p = .01 2.18 (1.43–3.32) p < .001 0.53 (0.26–1.08) p = .08
Phase of the Study Phase II Phase III	46 30	2.45 (1.82–3.31) p < .0001 2.40 (1.80–3.19) p < .0001	52 35	1.25 (0.93–1.67) p = .13 1.72 (1.31–2.25) p = .003

^aSingle agents are the reference point for all statistics. The final model included the following variables: High-Grade Toxicity (experimental drug class and linear toxicity rate in single arm); Treatment-related mortality (experimental drug class and linear treatment mortality rate in single arm);

^bEstimated ORs in each model are valid after accounting for a linear dependence on the appropriate rate in the single arm. Model chosen using forward selection with entry p-value 0.10

^cClass of experimental drug added to the backbone drug.

Abbreviations: N, number of randomized comparisons included; OR, odds ratio.

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)