Table 2. Hypotheses justifying combination trials.

Target	Tumor type	Examples
Target multiple mechanisms of action	Gastric, colorectal, NSCLC	Addition of HER-2 (22), EGFR (23) or VEGF (46-48, 60) pathway inhibitors broadened anticancer activity of standard chemotherapy while minimizing cross-resistance.
Optimize the inhibition of a specific target or pathway	Melanoma	Combination of CTLA-4 and PD-1 receptor inhibitors resulted in tumor regression beyond that expected from monotherapy (61).
Target a potential resistance mechanism (bypass pathway)	Breast, melanoma, NSCLC	Addition of an mTOR inhibitor to antiestrogens (62), a MEK inhibitor to a BRAF kinase inhibitor (34), or an EGFR inhibitor to a MET inhibitor (49, 63) results in restoration of sensitivity and decreased proliferation in cell lines and, for NSCLC patients, to increased progression free survival.

NSCLC = non-small cell lung cancer; HER-2 = human epidermal growth factor receptor 2; EGFR = epidermal growth factor receptor; VEGF = vascular endothelial growth factor; CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4; PD-1 = programmed death 1; mTOR= mammalian target of rapamycin; MEK = mitogen-activated protein/extracellular signal-regulated kinase kinase.