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
• targeted therapy
• immunotherapy
• hormonal therapy
• solid tumors

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Authors’ contributions

DLJ, DMG and RK conceived and designed the work; DLJ and DMG participate in data acquisition; DAB analyzed the data; DLJ, MN, and RK proceeded with interpretation of data; DLF, DMG, MN, DAB, and RK have drafted the work. All authors approved the submitted version.

Conflict of interests

Dr. Jardim receives speaker fees from Roche, Janssen, Astellas, MSD, Bristol-Myers Squibb and Libbs, as well as consultant fees from Janssen, Bristol-Myers Squibb and Libbs. Dr. Gagliato receives speaker fees from Roche, Astra Zeneca, United and Libbs, as well as consultant fees from Libbs. Dr. Kurzrock has research funding from Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, and Konica Minolta, as well as consultant fees from LOXO, X-Biotech, Actuate Therapeutics, Genentech and NeoMed. She receives speaker fees from Roche and has an ownership interest in IDbyDNA and Curematch, Inc.

Data Availability

All data reported in this manuscript are found in the literature as referenced in the text.

Ethical approval and consent to participate

Not applicable to this study

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

Funded in part by National Cancer Institute [grant P30 CA023100] and the Joan and Irwin Jacobs Fund philanthropic fund. The funding source had no role in any aspect of the study.