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Int J Cancer. 2017 Dec 15;141(12):2562-2570. doi: 10.1002/ijc.31012. Epub 2017 Aug 30.

The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta-analysis of efficacy and safety.

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Medical School of Nantong University, Jiangsu, China.
Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
Laboratory Animal Center of Nantong University, Chongchuan District, Nantong, Jiangsu, China.
Department of Medical Informatics, Medical School of Nantong University, Jiangsu, China.


The use of immune checkpoint inhibitors (ICIs) in combination therapy is an emerging trend in tumor immunology. However, the value of combination immunotherapy remains controversial, because of the toxic effects induced by combination. The added benefit of each additional drug has not been assessed against the added toxicity. We searched for clinical trials that evaluated ICI monotherapies and combination therapies in lung cancer and melanoma patients. The overall response rate (ORR), grade 3/4 treatment-related adverse event rate, overall survival (OS), and progression-free survival (PFS) were extracted from the most recently published studies to determine the relative risk (RR), hazard ratios (HRs), and 95% confidence intervals (CIs). Seven randomized controlled trials and one open-label study were identified (n = 3,097). Treatments included combinations of several ICIs, a combination of an ICI and dacarbazine, two combinations of an ICI, paclitaxel and carboplatin, and a combination of an ICI and gp100 vaccine. Higher ORR (RR: 1.51, 95% CI: 1.03-2.20, p = 0.034), OS (HR: 0.86, 95% CI: 0.78-0.95, p = 0.000), and PFS (HR: 0.93, 95% CI: 0.72-1.14, p = 0.000) values were observed in combination therapy than in monotherapy. In addition, the toxicity of combination ICI immunotherapy was higher (RR: 1.50, 95% CI: 1.03-2.19, p = 0.036) than that of monotherapy. This meta-analysis showed that the addition of nivolumab to ipilimumab better benefits PFS and ORR. Adding sargramostim was associated with better OS and safety. The efficacy and safety of a nivolumab-ipilimumab-sargramostim combination should be investigated further.


CTLA-4; combination immunotherapy; immune checkpoint inhibitor; ipilimumab; meta-analysis

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