Table 1 Clinical development of RAF kinase inhibitors in patients with advanced melanoma
RAF inhibitor | Chemical class | Target | Additional target | Status | n | Clinical outcome | Toxicity profile grade ⩾2 |
|---|---|---|---|---|---|---|---|
Non-selective RAF inhibitors | |||||||
Sorafenib | Diphenyl urea | CRAF, BRAFwt, BRAFV599E | VEGFR-2&3, PDGFR-β, FGFR-1, Flt-3, c-Kit | Phase-II | 37 | SD 19% | Diarhea, HFS |
+ Temsirolimus | Phase-I/II | 69 | Diarrhea, rash Hyperlipidemia | ||||
+/− Dacarbazine | Phase-II | 101 | Improved PFS=NS, OS=NS | Haemtox, nausea, hypertension, bleeding lipase | |||
+/ Carboplatin/paclitaxel | Phase-III (first-line) | 270 | PFS=NS | Haemtox, nausea, neuropathy, rash, HFS | |||
+/− Carboplatin/paclitaxel | Phase-III (second-line) | 823 | OS=NS | Haemtox, nausea, neuropathy, rash, HFS | |||
RAF265 | Benzazole | CRAF, BRAFwt, BRAFV600E | VEGFR-2 | Phase-I/II (ST) | 211 | Recruiting | |
Selective RAF inhibitors | |||||||
PLX4032 | Pyrrolo, pyridine | BRAFV600E, BRAFwt, CRAF | Phase-I (ST) | RR 58%a (PFS 9 monthsa) | Fatigue, rash, arthralgia, SCC | ||
Phase-II | 100 | Results awaited | |||||
Phase-III | 680 | Recruiting | |||||
GSK 2118436 | Thiazole | BRAFV600E,K,D CRAF BRAFwt | Phase-I/II (ST) | 100 | RR 63%a | Nausea, Fatigue Headache Fever Rash SCC | |
Phase-III | Planned | ||||||
+ GSK 1120212 (MEK-I) | Phase-I | 93 | Recruiting | ||||
XL281 | CRAF, BRAF wt, BRAFV600E | Phase-I (ST) | 180 | Results awaited | Fatigue, N/V Diarrhea | ||
