Table 3.
Anti-ERBB combinations
| Combination | Mechanism(s) of action | Relevant clinical trials |
|---|---|---|
| Trastuzumab + lapatinib (or neratinib, afatinib) | ADCC, partial disruption of HER2-HER3 dimers, inhibition of HER2 and EGFR tyrosine kinases | (Baselga et al., 2012a; Blackwell et al., 2010) |
| Trastuzumab + pertuzumab (only approved combination) | More complete inhibition of ligand-induced and ligand-independent HER2-containing heterodimers, ADCC, downregulation of HER2 from cell surface | (Baselga et al., 2012b; Gianni et al., 2012; Schneeweiss et al., 2013) |
| T-DM1 + pertuzumab | Same as above plus inhibition of polymerization of microtubules with DM1 | MARIANNE (NCT01120184) |
| Trastuzumab + everolimus | ADCC, disruption of ligand-independent HER2-HER3 dimers, inhibition of TORC1 | BOLERO-3 (NCT01007942) |
| Trastuzumab + pertuzumab + PI3K inhibitor | Inhibition of ligand-induced and ligand-independent HER2-containing heterodimers, ADCC, ATP-competitive inhibition of catalytic activity of p110 | Pending |
| Trastuzumab + HER3 neutralizing antibody | ADCC, partial disruption of HER2-HER3 dimers, inhibition of heregulin binding, downregulation of HER3 and/or HER3 dimerization | Pending |
| Trastuzumab + HER3 antibody + PI3K inhibitor | Same as above plus direct inhibition of p110 | Pending |
| T-DM1 + PI3K inhibitor | ADCC, partial disruption of HER2-HER3 dimers, inhibition of polymerization of microtubules, direct inhibition of p110 | Pending |
| Afatinib + cetuximab | Combined targeting of EGFR T790M to compensate for complete inhibition of target by either approach alone. Afatinib may also target resistance due to HER2 activation | Pending |
| EGFR + PI3K inhibitor | Block resistance due to re-activation of PI3K signaling | Pending |
| Erlotinib + MET inhibitor | Block MET dependent resistance to EGFR inhibitors | MetLung Trial and others |
| EGFR inhibitor + IGF-IR antibody | Block IGF-IR dependent resistance to EGFR inhibitors | Pending |
| Erlotinib + Hydroxychloroquine | Effort to block the survival of “drug tolerant” cells following treatment with EGFR TKIs (Sharma et al, Cell, 2010) | (Goldberg et al., 2012) |
| Irreversible EGFR inhibitor + MET inhibitor | Overcome both T790M and MET mediated resistance | Pending |