Table 1.
Selected clinical trials of synthetic small molecule inhibitors in metastatic melanoma
| Inhibitor (code and common name) | Target(s) | Mechanism of action | Phase of clinical trial | Treatment effect or trial status | Mutations selected in patient population | Reference or NCT trial number (if not completed) |
|---|---|---|---|---|---|---|
| Tipifarnib (R115777) | RAS | Inhibition of posttranslation farnesylation of RAS | Phase II | No evidence of clinical activity | None selected | 24 |
| Sorafenib (BAY 43-9006; Nexavar) | BRAF CRAF VEGF PFGF |
Multikinase inhibitor | Phase III | No significant improvement in PFS, OS or RR | None selected | 45 |
| Vermurafenib (PLX4032; Zelboraf) | BRAFV600E BRAFV600K |
Selective BRAF kinase inhibitor | Phase III | Significant improvement in PFS and OS | BRAFV600E BRAFV600K |
52 |
| Dabrafenib (GSK 2118436) | BRAFV600E BRAFV600K |
Selective BRAF kinase inhibitor | Phase III | Significant improvement in PFS | BRAFV600E BRAFV600K |
55 |
| Encorafenib (LGX818) | BRAFV600 | Selective BRAF kinase inhibitor | Phase I | In progress | BRAFV600 | NCT01436656 |
| RAF265 (CHIR-265) | BRAFV600E VEGFR2 |
Multikinase inhibitor | Phase II | Completed results pending | None selected | NCT00304525 |
| Cobimetinib (GDC-0973; XL518) | MEK1/2 | MEK1/2 inhibitor | Phase I | In progress | None selected | NCT01271803 |
| Selumetinib (ARRY-142886; AZD6244) | MEK1/2 | MEK1/2 inhibitor | Phase II | Significantly improved PFS when combined with dacarbazine but no significant improvement in OS | BRAFV600 | 78 |
| Trametinib (GSK1120212; JTP-74057; Mekinist) | MEK1/2 | MEK1/2 inhibitor | Phase III | Significantly improved PFS and OS | BRAFV600E BRAFV600K |
82 |
| MEK162 (ARRY-438162; PD0325901) | MEK1/2 | MEK1/2 inhibitor | Phase II | Partial responses observed | NRAS BRAFV600 |
34 |
| Phase III | In progress | NRAS | NCT01763164 | |||
| Pimasertib (AS703026; MSC1936369B) | MEK1/2 | MEK1/2 inhibitor | Phase II | In progress | NRAS | NCT01693068 |
| Temsirolimus (CCI-779; Torisel) | mTOR | Rapamycin analog, inhibitor of mTORC1 | Phase II | No significant improvement in OS or PFS | None selected | 118 |
| Phase II | In progress | mTOR | NCT01960829 | |||
| Imatinib (CGP 57148; CGP57148B; STI-571; Gleevec) | c-kit | Tyrosine kinase inhibitor | Phase II | Objective responses observed | c-kit | 148, 149 |
| Phase II | In progress | c-kit | NCT00470470 | |||
| Dasatinib (BMS-354825; Sprycel) | c-kit | Tyrosine kinase inhibitor | Phase II | No significant improvement in PFS or RR | None selected | 151 |
| Phase II | In progress | c-kit | NCT00700882 | |||
| Nilotinib AMN 107; Tasigna) | c-kit | Tyrosine kinase inhibitor | Phase II | Preliminary results showed objectives responses | c-kit | 152, NCT01099514 |
| Phase II | In progress | c-kit | NCT01028222 |
OS – Overall survival, PFS – Progression free survival, RR – Response Rate