RO5068760

Female nude mice subcutaneously implanted with human cancer cells (LOX and HT-29 (both B-Raf V600E mutant), MIA PaCa-2 (KRAS G12C mutation) and H460 (KRAS Q61H mutation))^[1]

6.25, 12.5, 25, 50, 100, 200 and 500 mg/kg

p.o., b.i.d. or q.d. or weekly for approximately 3 to 4 weeks

Showed significant tumor growth inhibition (TGI > 65%) in all models when administered once or twice daily.
Exhibited partial (PR) or complete regression (CR) at doses as low as 12.5 mg/kg (b.i.d.) in the LOX melanoma model harboring B-RafV600E mutation.
Resulted in PR or CR in four of four tumor models tested at a dose of 100 mg/kg twice daily.
Exhibited antitumor activity in the LOX melanoma model even at 500 mg/kg once weekly with three PRs and five CRs compared with vehicle controls.
In K-Ras mutant tumors, twice-daily dosing yielded better efficacy than once-daily or weekly regimens at equivalent total doses.
Showed superior in vivo efficacy in B-RafV600E xenografts (LOX and HT-29) compared with K-Ras mutant xenografts (H460 and MIA PaCa-2).
In the MIA PaCa-2 and H460 xenograft models, C_max levels in plasma reached or exceeded the EC₉₀ of p-ERK suppression, whereas in the LOX and HT-29 models, maximal plasma levels required for a similar degree of efficacy were significantly lower.